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Volume 16
Issue 12
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Int. J. Mol. Sci., Volume 16, Issue 12 (December 2015) – 163 articles

Cover Story: Blood vessels are ubiquitous and one of the most important organs of all vertebrate animals, since they are essential for the supply of oxygen and nutrition for the whole body through the networks. During the network formation of vascular endothelial cells, a concentration gradient of the vascular endothelial growth factor (VEGF) is considered to have a dominant effect on the morphologies of networks. On the other hand, we found that chain-like clusters are formed in absence of VEGF, and in vitro experiments revealed these clusters act as primary networks. The numerical simulations show these chain-like clusters are stabilized by the surface charges of cells, and the concentration of ions surrounding them may also be involved in this process. Image provided by Shunto Arai. View this article
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4039 KiB  
Review
Epigenetics of Aging and Alzheimer’s Disease: Implications for Pharmacogenomics and Drug Response
by Ramón Cacabelos and Clara Torrellas
Int. J. Mol. Sci. 2015, 16(12), 30483-30543; https://doi.org/10.3390/ijms161226236 - 21 Dec 2015
Cited by 92 | Viewed by 12617
Abstract
Epigenetic variability (DNA methylation/demethylation, histone modifications, microRNA regulation) is common in physiological and pathological conditions. Epigenetic alterations are present in different tissues along the aging process and in neurodegenerative disorders, such as Alzheimer’s disease (AD). Epigenetics affect life span and longevity. AD-related genes [...] Read more.
Epigenetic variability (DNA methylation/demethylation, histone modifications, microRNA regulation) is common in physiological and pathological conditions. Epigenetic alterations are present in different tissues along the aging process and in neurodegenerative disorders, such as Alzheimer’s disease (AD). Epigenetics affect life span and longevity. AD-related genes exhibit epigenetic changes, indicating that epigenetics might exert a pathogenic role in dementia. Epigenetic modifications are reversible and can potentially be targeted by pharmacological intervention. Epigenetic drugs may be useful for the treatment of major problems of health (e.g., cancer, cardiovascular disorders, brain disorders). The efficacy and safety of these and other medications depend upon the efficiency of the pharmacogenetic process in which different clusters of genes (pathogenic, mechanistic, metabolic, transporter, pleiotropic) are involved. Most of these genes are also under the influence of the epigenetic machinery. The information available on the pharmacoepigenomics of most drugs is very limited; however, growing evidence indicates that epigenetic changes are determinant in the pathogenesis of many medical conditions and in drug response and drug resistance. Consequently, pharmacoepigenetic studies should be incorporated in drug development and personalized treatments. Full article
(This article belongs to the Special Issue Pharmacogenetics and Personalized Medicine)
2011 KiB  
Case Report
Brain Recovery after a Plane Crash: Treatment with Growth Hormone (GH) and Neurorehabilitation: A Case Report
by Jesús Devesa, Gustavo Díaz-Getino, Pablo Rey, José García-Cancela, Iria Loures, Sonia Nogueiras, Alba Hurtado de Mendoza, Lucía Salgado, Mónica González, Tamara Pablos and Pablo Devesa
Int. J. Mol. Sci. 2015, 16(12), 30470-30482; https://doi.org/10.3390/ijms161226244 - 21 Dec 2015
Cited by 30 | Viewed by 8129
Abstract
The aim of this study is to describe the results obtained after growth hormone (GH) treatment and neurorehabilitation in a young man that suffered a very grave traumatic brain injury (TBI) after a plane crash. Methods: Fifteen months after the accident, the patient [...] Read more.
The aim of this study is to describe the results obtained after growth hormone (GH) treatment and neurorehabilitation in a young man that suffered a very grave traumatic brain injury (TBI) after a plane crash. Methods: Fifteen months after the accident, the patient was treated with GH, 1 mg/day, at three-month intervals, followed by one-month resting, together with daily neurorehabilitation. Blood analysis at admission showed that no pituitary deficits existed. At admission, the patient presented: spastic tetraplegia, dysarthria, dysphagia, very severe cognitive deficits and joint deformities. Computerized tomography scanners (CT-Scans) revealed the practical loss of the right brain hemisphere and important injuries in the left one. Clinical and blood analysis assessments were performed every three months for three years. Feet surgery was needed because of irreducible equinovarus. Results: Clinical and kinesitherapy assessments revealed a prompt improvement in cognitive functions, dysarthria and dysphagia disappeared and three years later the patient was able to live a practically normal life, walking alone and coming back to his studies. No adverse effects were observed during and after GH administration. Conclusions: These results, together with previous results from our group, indicate that GH treatment is safe and effective for helping neurorehabilitation in TBI patients, once the acute phase is resolved, regardless of whether or not they have GH-deficiency (GHD). Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2015)
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Figure 1

Figure 1
<p>Immediate consequences of the TBI: (<b>A</b>) Brain CT-Scan performed four hours after the accident showing the fractures produced in the facial skeleton; (<b>B</b>,<b>C</b>) brain cerebral images from the same CT-Scan radiologically informed as normal; (<b>D</b>,<b>E</b>) images from a brain CT-Scan performed two months after the accident, observe the important destruction in the right hemisphere; and (<b>F</b>) corresponding image to the previous CT-Scan in (<b>D</b>,<b>E</b>) after administration of iodinated contrast. Notice the great lack of perfusion in the right hemisphere, while perfusion in the left one was informed as normal. CT- Scans: A = Anterior; P = Posterior; R = Right; L = Left.</p> Full article ">Figure 2
<p>Irreductible equinovarus feet produced by the strong spasticity that the patient developed after suffering brain trauma.</p> Full article ">Figure 3
<p>Feet surgery: (<b>Upper images</b>) Equinovarus feet before the surgery; (<b>Middle</b>) Left, surgery consisted in legs tendons transpositions; and right, the surgeon is testing the correction of equinovarus after the surgery; (<b>Down</b>) Equinovarus has been corrected in both feet.</p> Full article ">Figure 4
<p>Working and walking after the feet surgery: (<b>Left</b>) the patient beginning to walk in parallel bars with the help of a physiotherapist and (<b>Right</b>) the patient beginning to walk alone on the street. Observe the movement of his left foot and leg.</p> Full article ">Figure 5
<p>The changes: (<b>Left</b>) The patient two months after admission. Notice the weak control of head and trunk, the patient sitting on a wheel chair, the right and left arms flex and the irreducible carpal flex of the left wrist; (<b>Right</b>) The patient three and a half years later. Observe the patient sitting on a normal chair, the normal position of head, trunk and both arms, the corrected flex of both arms and the almost corrected flex of the left hand.</p> Full article ">Figure 6
<p>Two years of treatment. Despite the clinical improvements, a new CT-Scan revealed that the brain injury was higher than that observed in the first days after the accident and in the CT-Scan carried out two months later. Injuries in the right hemisphere were increased and new injuries appeared on the left one. Scale bar: 12 cm. F: Front. R: Right: P: Posterior.</p> Full article ">Figure 7
<p>Deep coma occurred as a consequence of the axonal diffuse injury. (<b>Upper</b>) Few days after the accident occurred, the strong spasticity, more prominent in the left hemibody, led to the apparition of dorsal-lumbar scoliosis. Notice the gastric tube for feeding and the tracheostomy; (<b>Lower</b>) Remarkable parietal bones collapse.</p> Full article ">
861 KiB  
Review
Understanding Melanocyte Stem Cells for Disease Modeling and Regenerative Medicine Applications
by Amber N. Mull, Ashwini Zolekar and Yu-Chieh Wang
Int. J. Mol. Sci. 2015, 16(12), 30458-30469; https://doi.org/10.3390/ijms161226207 - 21 Dec 2015
Cited by 29 | Viewed by 13444
Abstract
Melanocytes in the skin play an indispensable role in the pigmentation of skin and its appendages. It is well known that the embryonic origin of melanocytes is neural crest cells. In adult skin, functional melanocytes are continuously repopulated by the differentiation of melanocyte [...] Read more.
Melanocytes in the skin play an indispensable role in the pigmentation of skin and its appendages. It is well known that the embryonic origin of melanocytes is neural crest cells. In adult skin, functional melanocytes are continuously repopulated by the differentiation of melanocyte stem cells (McSCs) residing in the epidermis of the skin. Many preceding studies have led to significant discoveries regarding the cellular and molecular characteristics of this unique stem cell population. The alteration of McSCs has been also implicated in several skin abnormalities and disease conditions. To date, our knowledge of McSCs largely comes from studying the stem cell niche of mouse hair follicles. Suggested by several anatomical differences between mouse and human skin, there could be distinct features associated with mouse and human McSCs as well as their niches in the skin. Recent advances in human pluripotent stem cell (hPSC) research have provided us with useful tools to potentially acquire a substantial amount of human McSCs and functional melanocytes for research and regenerative medicine applications. This review highlights recent studies and progress involved in understanding the development of cutaneous melanocytes and the regulation of McSCs. Full article
(This article belongs to the Special Issue Molecular Research of Epidermal Stem Cells 2015)
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Graphical abstract

Graphical abstract
Full article ">Figure 1
<p>A schematic illustration of the migratory paths of neural crest cells and melanocyte development in a developing mammalian embryo. Cells that migrate from the trunk neural crest through the developing embryo may take a dorsolateral or ventrolateral path. Melanocytic differentiation from trunk neural crest cells begins with the specification of neural crest cells into melanoblast-glial progenitor cells which express SRY (sex determining region Y)-box 10 (SOX10). These progenitor cells are then committed into melanoblasts with the expression of dopachrome tautomerase (DCT), tyrosine protein kinase KIT (KIT) and microphthalmia-associated transcription factor (MITF). The melanoblast progenitor cells typically migrate along the dorsolateral path between the epidermis and dermomyotome. During embryogenesis, melanoblasts can move into embryonic hair follicles where some melanoblasts continue to differentiate into functional melanocytes that produce melanin and participate in the initial hair cycle. Subsets of melanoblasts become melanocyte stem cells (McSCs), which have the capacity of self-renewal. McSCs remain quiescent until activated in the next hair cycle, resulting in transient amplifying cells and their subsequent differentiation into functional melanocytes. <span class="html-italic">NT:</span> neural tube, <span class="html-italic">N:</span> notochord, <span class="html-italic">DM:</span> dermomyotome, <span class="html-italic">SC:</span> sclerotome.</p> Full article ">Figure 2
<p>The anatomical structure of a hair follicle in mammalian skin. Normal skin is composed of the epidermis and dermis. In the epidermis, several skin appendages such as hair follicles and sebaceous glands can be found. The bulge region of hair follicles is a well-known niche for stem cells in the skin. Hair follicle stem cells (HFSCs) and melanocyte stem cells (McSCs) reside in this niche. Usually, HFSCs and McSCs migrate toward the base of hair follicles and differentiate into keratinocytes and melanocytes to assemble pigmented hairs during the anagen of a hair cycle. In certain conditions, the niched McSCs in hair follicles may migrate upward and differentiate into melanocytes at the basal layer of the epidermis. This bi-directional migratory path of McSCs in hair follicles is indicated by the blue arrows.</p> Full article ">
7359 KiB  
Article
Cloning of the Lycopene β-cyclase Gene in Nicotiana tabacum and Its Overexpression Confers Salt and Drought Tolerance
by Yanmei Shi, Jinggong Guo, Wei Zhang, Lifeng Jin, Pingping Liu, Xia Chen, Feng Li, Pan Wei, Zefeng Li, Wenzheng Li, Chunyang Wei, Qingxia Zheng, Qiansi Chen, Jianfeng Zhang, Fucheng Lin, Lingbo Qu, John Hugh Snyder and Ran Wang
Int. J. Mol. Sci. 2015, 16(12), 30438-30457; https://doi.org/10.3390/ijms161226243 - 21 Dec 2015
Cited by 38 | Viewed by 7184
Abstract
Carotenoids are important pigments in plants that play crucial roles in plant growth and in plant responses to environmental stress. Lycopene β cyclase (β-LCY) functions at the branch point of the carotenoid biosynthesis pathway, catalyzing the cyclization of lycopene. Here, a β-LCY gene [...] Read more.
Carotenoids are important pigments in plants that play crucial roles in plant growth and in plant responses to environmental stress. Lycopene β cyclase (β-LCY) functions at the branch point of the carotenoid biosynthesis pathway, catalyzing the cyclization of lycopene. Here, a β-LCY gene from Nicotiana tabacum, designated as Ntβ-LCY1, was cloned and functionally characterized. Robust expression of Ntβ-LCY1 was found in leaves, and Ntβ-LCY1 expression was obviously induced by salt, drought, and exogenous abscisic acid treatments. Strong accumulation of carotenoids and expression of carotenoid biosynthesis genes resulted from Ntβ-LCY1 overexpression. Additionally, compared to wild-type plants, transgenic plants with overexpression showed enhanced tolerance to salt and drought stress with higher abscisic acid levels and lower levels of malondialdehyde and reactive oxygen species. Conversely, transgenic RNA interference plants had a clear albino phenotype in leaves, and some plants did not survive beyond the early developmental stages. The suppression of Ntβ-LCY1 expression led to lower expression levels of genes in the carotenoid biosynthesis pathway and to reduced accumulation of carotenoids, chlorophyll, and abscisic acid. These results indicate that Ntβ-LCY1 is not only a likely cyclization enzyme involved in carotenoid accumulation but also confers salt and drought stress tolerance in Nicotiana tabacum. Full article
(This article belongs to the Special Issue Plant Molecular Biology)
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Graphical abstract

Graphical abstract
Full article ">Figure 1
<p>Comparison of β-LCY amino acid sequences by Genedoc software from <span class="html-italic">Nicotiana tabacum</span> (1: Ntβ-LCY1; 2: Ntβ-LCY2; this work), <span class="html-italic">Nicotiana tomentosiformis</span> (3: Ntomε-LCY, XM_009618113.1), <span class="html-italic">Nicotiana sylvestris</span> (4: Nsyε-LCY, XM_009795141.1), <span class="html-italic">Solanum tuberosum</span> (5: Stε-LCY, XM_006351204.1), <span class="html-italic">Solanum lycopersicum</span> (6: Slε-LCY, XM_010313794.1), <span class="html-italic">Capsicum annuum</span> (7: Caβ-LCY, GU085267.1), and <span class="html-italic">Arabidopsis</span> <span class="html-italic">thaliana</span> (8: Atε-LCY, AF117256.1). Blank back ground, completely conserved region; Grey back ground, partly conserved region; White back ground, non-conserved region.</p> Full article ">Figure 2
<p>Phylogenetic analysis of the <span class="html-italic">β-LCY</span> genes in higher plants based on an alignment of the nucleotide sequences using MEGA5 software by the neighbor joining method. The bootstrap values were each estimated using 1000 replications.</p> Full article ">Figure 3
<p><span class="html-italic">Ntβ-LCY</span> expression. (<b>A</b>) Spatiotemporal expression of <span class="html-italic">Ntβ-LCY</span> in tobacco leaf, stem, root, and flower; (<b>B</b>,<b>C</b>) Relative expression levels of <span class="html-italic">Ntβ-LCY</span> following salt and drought stress, as compared with untreated control plants (control); (<b>D</b>) Relative expression level of <span class="html-italic">Ntβ-LCY</span> following ABA treatment. Error bars represent standard deviation (<span class="html-italic">n</span> = 3). The data presented here are representative of three independent experiments.</p> Full article ">Figure 4
<p>Identification and characterization of expression of the transgenic <span class="html-italic">Ntβ-LCY1</span> overexpression (OE) and RNAi plants by PCR and qRT-PCR. (<b>A</b>) Phenotypes of WT and <span class="html-italic">Ntβ-LCY1</span> OE transgenic tobacco; (<b>B</b>) Confirmation of the presence of the <span class="html-italic">Ntβ-LCY1</span> transgene construct in the OE transgenic plants based on PCR screening using primers flanking the <span class="html-italic">Ntβ-LCY1</span> gene. Lane 1: Marker DL2000; Lane 2: positive control; Lane 3: negative control. Lanes 4–9 are six independently <span class="html-italic">Ntβ-LCY1</span> OE transgenic lines; (<b>C</b>) Relative expression levels of <span class="html-italic">Ntβ-LCY1</span> in OE transgenic plants; (<b>D</b>) Phenotypes of WT and <span class="html-italic">Ntβ-LCY1</span> RNAi transgenic tobaccos; (<b>E</b>) Confirmation of the presence of the <span class="html-italic">Ntβ-LCY1</span> transgene construct in the RNAi transgenic lines based on PCR screening using primers of the kanamycin gene, Lane 1: Marker DL2000; Lane 2: positive control; Lane 3: negative control; Lanes 4–9: six independently <span class="html-italic">Ntβ-LCY1</span> RNAi transgenic lines; (<b>F</b>) Relative expression levels of <span class="html-italic">Ntβ-LCY1</span> in RNAi transgenic tobaccos. M, Marker DL2000; P, positive control (using plasmid as the PCR template); WT, negative control (DNA from WT lines used as the PCR template); L1–L6, DNA from L1–L6 transgenic lines used as the PCR template. Error bars represent standard deviation (<span class="html-italic">n</span> = 3). The data presented here are representative of three independent experiments.</p> Full article ">Figure 5
<p>Carotenoid and chlorophyll content in WT and <span class="html-italic">Ntβ-LCY1</span> OE transgenic plants. Error bars represent standard deviation (<span class="html-italic">n</span> = 6). The data presented here are representative of three independent experiments.</p> Full article ">Figure 6
<p>Carotenoid and chlorophyll content in control and <span class="html-italic">Ntβ-LCY1</span> RNAi transgenic plants. Error bars represent standard deviation (<span class="html-italic">n</span> = 6). The data presented here are representative of three independent experiments.</p> Full article ">Figure 7
<p>Effects of salt treatment on the T<sub>1</sub> generation of <span class="html-italic">Ntβ-LCY1</span> OE transgenic plants. (<b>A</b>) Phenotypes of WT and <span class="html-italic">Ntβ-LCY1</span> OE plants after three weeks of treatment with 300 mM NaCl; (<b>B</b>) Relative water content in leaves of WT and OE plants after salt stress treatment; (<b>C</b>,<b>D</b>) 3,3,-diaminobenzidine (DAB) (<b>C</b>) and nitro blue tetrazolium (NBT) staining; (<b>D</b>) for evaluation the accumulation of H<sub>2</sub>O<sub>2</sub> and O<sub>2</sub><sup>−</sup> in WT and OE plants after salt stress treatment; (<b>E</b>,<b>F</b>) Malondialdehyde (MDA) and abscisic acid (ABA) content in the leaves of WT and OE plants, with or without salt stress treatment; (<b>G</b>) Carotenoid and chlorophyll content in WT and <span class="html-italic">Ntβ-LCY1</span> OE transgenic lines after three weeks of salt stress treatment. L1–L3, three lines of <span class="html-italic">Ntβ-LCY1</span> OE transgenic plants. Error bars represent standard deviation (<span class="html-italic">n</span> = 6). The data presented here are representative of three independent experiments.</p> Full article ">Figure 8
<p>Effects of salt stress on <span class="html-italic">Ntβ-LCY1</span> RNAi transgenic plants. (<b>A</b>) Phenotypes of WT and <span class="html-italic">Ntβ-LCY1</span> RNAi plants under salt stress for eight days; (<b>B</b>) Relative water content in WT and RNAi plant leaves after salt stress for two weeks; (<b>C</b>,<b>D</b>) Malondialdehyde (MDA) and abscisic acid (ABA) content in leaves of WT and RNAi plants with or without salt stress; (<b>E</b>) Carotenoid and chlorophyll content in WT and <span class="html-italic">Ntβ-LCY1</span> RNAi transgenic plants after two weeks of salt treatment. Error bars represent standard deviation (<span class="html-italic">n</span> = 6). The data presented here are representative of three independent experiments.</p> Full article ">Figure 9
<p>Effects of drought treatment on T<sub>1</sub> generation <span class="html-italic">Ntβ-LCY1</span> OE transgenic plants. (<b>A</b>) Phenotypes of WT and <span class="html-italic">Ntβ-LCY1</span> OE plants after three weeks of drought stress; (<b>B</b>) Relative water content in leaves of WT and OE plants after drought stress; (<b>C</b>,<b>D</b>) 3,3,-diaminobenzidine (DAB) (<b>C</b>) and nitro blue tetrazolium (NBT) (<b>D</b>) staining for evaluation the accumulation of H<sub>2</sub>O<sub>2</sub> and O<sub>2</sub><sup>−</sup> in WT and OE plants after drought stress; (<b>E</b>,<b>F</b>) Malondialdehyde (MDA) and abscisic acid (ABA) content in leaves of WT and OE plants treated with or without drought stress; (<b>G</b>) Carotenoid and chlorophyll content in WT and <span class="html-italic">Ntβ-LCY1</span> OE transgenic plants after three weeks of drought treatment. L4–L6, three lines of <span class="html-italic">Ntβ-LCY1</span> OE transgenic plants. Error bars represent standard deviation (<span class="html-italic">n</span> = 6). The data presented here are representative of three independent experiments.</p> Full article ">Figure 10
<p>Effects of drought stress on <span class="html-italic">Ntβ-LCY1</span> RNAi transgenic plants. (<b>A</b>) Phenotypes of WT and <span class="html-italic">Ntβ-LCY1</span> RNAi plants under drought stress for eight days; (<b>B</b>) Relative water content in WT and RNAi plant leaves after drought treatment for two weeks; (<b>C</b>,<b>D</b>) Malondialdehyde (MDA) and abscisic acid (ABA) content in leaves of WT and RNAi plants with or without drought stress; (<b>E</b>) Carotenoids and chlorophyll content in WT and <span class="html-italic">Ntβ-LCY1</span> RNAi transgenic plants after two weeks of drought treatment. Error bars represent standard deviation (<span class="html-italic">n</span> = 6). The data presented here are representative of three independent experiments.</p> Full article ">
1413 KiB  
Article
Effects of Ethanol on the Expression Level of Various BDNF mRNA Isoforms and Their Encoded Protein in the Hippocampus of Adult and Embryonic Rats
by Shahla Shojaei, Saeid Ghavami, Mohammad Reza Panjehshahin and Ali Akbar Owji
Int. J. Mol. Sci. 2015, 16(12), 30422-30437; https://doi.org/10.3390/ijms161226242 - 21 Dec 2015
Cited by 12 | Viewed by 5504
Abstract
We aimed to compare the effects of oral ethanol (Eth) alone or combined with the phytoestrogen resveratrol (Rsv) on the expression of various brain-derived neurotrophic factor (BDNF) transcripts and the encoded protein pro-BDNF in the hippocampus of pregnant and embryonic rats. A low [...] Read more.
We aimed to compare the effects of oral ethanol (Eth) alone or combined with the phytoestrogen resveratrol (Rsv) on the expression of various brain-derived neurotrophic factor (BDNF) transcripts and the encoded protein pro-BDNF in the hippocampus of pregnant and embryonic rats. A low (0.25 g/kg body weight (BW)/day) dose of Eth produced an increase in the expression of BDNF exons I, III and IV and a decrease in that of the exon IX in embryos, but failed to affect BDNF transcript and pro-BDNF protein expression in adults. However, co-administration of Eth 0.25 g/kg·BW/day and Rsv led to increased expression of BDNF exons I, III and IV and to a small but significant increase in the level of pro-BDNF protein in maternal rats. A high (2.5 g/kg·BW/day) dose of Eth increased the expression of BDNF exons III and IV in embryos, but it decreased the expression of exon IX containing BDNF mRNAs in the maternal rats. While the high dose of Eth alone reduced the level of pro-BDNF in adults, it failed to change the levels of pro-BDNF in embryos. Eth differentially affects the expression pattern of BDNF transcripts and levels of pro-BDNF in the hippocampus of both adult and embryonic rats. Full article
(This article belongs to the Special Issue Mechanisms of Neurodegeneration)
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Figure 1

Figure 1
<p>Eth and Rsv affect brain-derived neurotrophic factor (BDNF) exon expression in the hippocampus of pregnant rats differently. Eth had no significant effect on expression of any of the BDNF exons except at a dose of 2.5 g/kg·BW/day, which caused a decreased in the expression of BDNF exon IX (<span class="html-italic">p</span> &lt; 0.05). Higher doses of Rsv in combination with Eth (0.25 g/kg·BW/day) significantly increased the expression of the BDNF exons I and III compared to the normal saline group and also increased expression of the BDNF exon IV compared to the Eth group (<span class="html-italic">p</span> &lt; 0.05). Rsv in combination with Eth (0.63 g/kg·BW/day) significantly increased expression of BDNF exon III compared to the Eth (0.63 g/kg·BW/day) group (<span class="html-italic">p</span> &lt; 0.05). Rsv in combination with Eth (2.5 g/kg·BW/day) reversed the significant decrease in the expression of BDNF exon IX at higher doses (<span class="html-italic">p</span> &lt; 0.05), while it had no effect on the expression of other BDNF exons. qRT-PCR analysis was performed to evaluate expression of BDNF transcripts containing exons I, III, IV and IX in the hippocampi of pregnant rats. Rats were treated by either Eth alone or in combination with RSV using oral gavage for 20 days, from day 1 to 20 of gestation, and another group was treated with normal saline as a control group (<a href="#ijms-16-26242-t001" class="html-table">Table 1</a>). The right hippocampi from four pregnant rats were pooled to make one sample (three samples in each group, for a total of 12 hippocampi). Expression of β-actin was analyzed to normalize gene expression in each sample to eliminate differences in RNA quality and amplification efficacy. Data are presented as the fold increase in the expression in treatment groups compared to the control group, and are presented as the mean ± standard error of the mean (SEM). * <span class="html-italic">p</span> &lt; 0.05</p> Full article ">Figure 2
<p>Differential effects of Eth and Rsv on the expression of BDNF exons in the hippocampus of embryonic rats. Eth (0.25 g/kg·BW/day) significantly increased expression of BDNF exons I, III and IV (<span class="html-italic">p</span> &lt; 0.05 for exon I and III and <span class="html-italic">p</span> &lt; 0.01 for exon IV) but decreased expression of BDNF exon IX compared to controls (<span class="html-italic">p</span> &lt; 0.05). Eth (0.63 g/kg·BW/day) had no significant effect on the expression of these exons. Eth (2.5 g/kg·BW/day) increased expression of all BDNF exons but this increase was significant only for BDNF exons III and IV (<span class="html-italic">p</span> &lt; 0.01 and <span class="html-italic">p</span> &lt; 0.05, respectively). The combination of Eth (0.25 g/kg·BW/day) and Rsv (60 or 120 mg/kg·BW/day) had no significant effect on the expression of BDNF exon I, III and IV, but it reversed the decreased expression of BDNF exon IX induced by Eth (0.25 g/kg·BW/day). The combination of Rsv with Eth (0.63 g/kg·BW/day) caused increased expression of BDNF exons I, III and IV compared to the control group (<span class="html-italic">p</span> &lt; 0.05 for exon I and <span class="html-italic">p</span> &lt; 0.01 for exon III and IV), and for exon III, this increase was significant compared to the Eth group. This combination significantly decreased the expression of BDNF exon IX compared to the control group (<span class="html-italic">p</span> &lt; 0.01). Combination of Rsv with Eth (2.5 g/kg·BW/day) significantly increased expression of BDNF exon I (<span class="html-italic">p</span> &lt; 0.01) with no effect on the expression of other exons compared to the control group. The expression of BDNF transcripts containing exons I, III, IV and IX in the hippocampi of embryonic rats was tested using qRT-PCR. Pregnant rats were treated via oral gavage using either Eth alone or in combination with Rsv for 20 days, from day 1 to 20 of gestation. Another group received the same treatment except that they received normal saline only by gavage to serve as the control group (<a href="#ijms-16-26242-t001" class="html-table">Table 1</a>). Half of the hippocampi from each embryo of the four pregnant rats were pooled to make one sample (three samples in each group). β-actin expression was used to normalize gene expression in each sample to eliminate differences in RNA quality and amplification efficacy. Data are presented as the fold increase in expression in treatment groups compared to the control group, and are presented as the mean ± SEM. * <span class="html-italic">p</span> &lt; 0.05; ** <span class="html-italic">p</span> &lt; 0.01.</p> Full article ">Figure 3
<p>Eth alone or in combination with Rsv affects the pro-BDNF protein level in pregnant rats but not in the embryos. (<b>A</b>) Higher doses of Eth decreased pro-BDNF protein levels in the hippocampus of pregnant rats. Rsv in combination with the lower doses of Eth increased pro-BDNF protein levels in these tissues; (<b>B</b>) In the tissue extracts from embryos, Eth alone or in combination with Rsv had no effect on the pro-BDNF protein level. Immunoblots were arranged to identify pre-mature (pro-) BDNF in tissue extracts from hippocampi of pregnant and embryonic rats. β-actin was used as a loading control. Each blot is representative of three replicates. Antibodies against BDNF and β-actin detected proteins bands of approximately 38 and 42 kDa for pro-BDNF and β-actin, respectively.</p> Full article ">
2943 KiB  
Article
Combination Treatment with Sublethal Ionizing Radiation and the Proteasome Inhibitor, Bortezomib, Enhances Death-Receptor Mediated Apoptosis and Anti-Tumor Immune Attack
by Ercan Cacan, Alexander M. Spring, Anita Kumari, Susanna F. Greer and Charlie Garnett-Benson
Int. J. Mol. Sci. 2015, 16(12), 30405-30421; https://doi.org/10.3390/ijms161226238 - 21 Dec 2015
Cited by 19 | Viewed by 5718
Abstract
Sub-lethal doses of radiation can modulate gene expression, making tumor cells more susceptible to T-cell-mediated immune attack. Proteasome inhibitors demonstrate broad anti-tumor activity in clinical and pre-clinical cancer models. Here, we use a combination treatment of proteasome inhibition and irradiation to further induce [...] Read more.
Sub-lethal doses of radiation can modulate gene expression, making tumor cells more susceptible to T-cell-mediated immune attack. Proteasome inhibitors demonstrate broad anti-tumor activity in clinical and pre-clinical cancer models. Here, we use a combination treatment of proteasome inhibition and irradiation to further induce immunomodulation of tumor cells that could enhance tumor-specific immune responses. We investigate the effects of the 26S proteasome inhibitor, bortezomib, alone or in combination with radiotherapy, on the expression of immunogenic genes in normal colon and colorectal cancer cell lines. We examined cells for changes in the expression of several death receptors (DR4, DR5 and Fas) commonly used by T cells for killing of target cells. Our results indicate that the combination treatment resulted in increased cell surface expression of death receptors by increasing their transcript levels. The combination treatment further increases the sensitivity of carcinoma cells to apoptosis through FAS and TRAIL receptors but does not change the sensitivity of normal non-malignant epithelial cells. Furthermore, the combination treatment significantly enhances tumor cell killing by tumor specific CD8+ T cells. This study suggests that combining radiotherapy and proteasome inhibition may simultaneously enhance tumor immunogenicity and the induction of antitumor immunity by enhancing tumor-specific T-cell activity. Full article
(This article belongs to the Collection Radiation Toxicity in Cells)
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<p>Tumor cells remain viable after a combination treatment of proteasome inhibitor and sub-lethal irradiation. Tumor cells were mock-irradiated (0 Gy) or irradiated with 5 Gy and cultured for 24 h. Following incubation, mock-irradiated or irradiated cells were treated with 10 nM bortezomib and incubated for an additional 24 h. An Annexin V-PE Apoptosis Detection Kit I (BD PharMingen, San Diego, CA, USA) was used for staining; results were quantified by Flow cytometry analysis and were analyzed using FlowJo software (FlowJo LLC, Ashland, OR, USA). Experiment was repeated three times with similar results. The relative increase of dead tumor cells in (<b>A</b>) SW620 (<b>B</b>) and HTC116 colorectal cancer cells.</p> Full article ">Figure 2
<p>Initial DNA damage response is not inhibited by 26S proteasome inhibition. (<b>A</b>) SW620 cells were untreated or treated with 10 nM bortezomib, incubated for 24 h, mock-irradiated (0 Gy) or irradiated with 10 Gy, and either immediately placed on ice and prepared for comet assays or incubated for 20 min at room temperature followed by 10 min on ice and prepared for comet assays; (<b>B</b>) Olive tail moments for non-irradiated, irradiated with 10 Gy with no incubation, and irradiated with 10 Gy with incubation were compared for untreated (black) and bortezomib treated (gray) cells. Data for irradiated cells are the average of two independent experiments with error bars denoting standard deviation.</p> Full article ">Figure 3
<p>Inhibition of the 26S proteasome enhances transcript expression of death receptors with combination of radiation in tumor cells. Following the treatments, adherent cells were harvested, RNA was extracted and cDNA was generated. Data was quantified using qRT-PCR with primers and probes specific for DR4, DR5 or Fas coding regions and the obtained data were normalized to housekeeping gene HPRT1 expression. Graphed data shows the average of three independent experiments, with error bars denoting SEM. * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.005. Relative mRNA expression of DR4, DR5 and Fas in (<b>A</b>) CCD-18Co, (<b>B</b>) SW620 (<b>C</b>) and HTC116 cells.</p> Full article ">Figure 4
<p>A combination treatment of sub-lethal dose of radiation and proteasome inhibition increases cell surface expression of death receptors. Following the treatments, cells were harvested and stained with PE-labeled antibody to human DR4, Fas or APC-labeled DR5. Cell surface protein expression was evaluated by flow cytometry. Isotype control stained cells were set to 5% positive. Graph represent average of three independent experiments, with error bars denoting SEM * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.005. Cells surface expression of DR4, DR5 and Fas in (<b>A</b>) CCD-18Co, (<b>B</b>) SW620 (<b>C</b>) and HTC116 cells. Representative cumulative distribution function (CDF) plots of DR4, DR5 and Fas expression in (<b>D</b>) CCD18Co, (<b>E</b>) SW620 and (<b>F</b>) HCT116 cells.</p> Full article ">Figure 5
<p>Combination of sub-lethal irradiation and bortezomib or irradiation alone enhances the killing of CRC mediated by CTLs. (<b>A</b>) SW620 cells were treated with 5 Gy, bortezomib or combination of radiation and bortezomib. Cells were harvested and co-incubated with human CEA specific CTLs (E:T ratio 10:1) for 3.5 h at 37 °C in a 96 well plate. The frequency of tumor cells expressing active caspase-3 was determined by flow cytometry and data was analyzed by flowjo software; (<b>B</b>) As a negative control, SW620 cells were treated and incubated under similar condition as described above in the absence of CTLs; (<b>C</b>,<b>D</b>) Bar graph showing the average of two additional replicate experiments. Error bars represent the SEM. * indicates <span class="html-italic">p</span> value &lt;0.05. ** indicate <span class="html-italic">p</span> value &lt;0.005. CEA = Carcinoembryonic antigen and E:T, effector cell to target cell ratio.</p> Full article ">Figure 5 Cont.
<p>Combination of sub-lethal irradiation and bortezomib or irradiation alone enhances the killing of CRC mediated by CTLs. (<b>A</b>) SW620 cells were treated with 5 Gy, bortezomib or combination of radiation and bortezomib. Cells were harvested and co-incubated with human CEA specific CTLs (E:T ratio 10:1) for 3.5 h at 37 °C in a 96 well plate. The frequency of tumor cells expressing active caspase-3 was determined by flow cytometry and data was analyzed by flowjo software; (<b>B</b>) As a negative control, SW620 cells were treated and incubated under similar condition as described above in the absence of CTLs; (<b>C</b>,<b>D</b>) Bar graph showing the average of two additional replicate experiments. Error bars represent the SEM. * indicates <span class="html-italic">p</span> value &lt;0.05. ** indicate <span class="html-italic">p</span> value &lt;0.005. CEA = Carcinoembryonic antigen and E:T, effector cell to target cell ratio.</p> Full article ">Figure 6
<p>Inhibition of the 26S proteasome and sub-lethal irradiation can enhance sensitivity to killing through FAS and TRAIL receptors in colorectal carcinoma cells, but not in CCD-18Co cells. Tumor cells were mock-irradiated (0 Gy) or irradiated with 5 Gy and cultured for 24 h. Following incubation, mock-irradiated or irradiated cells were treated with 10 nM bortezomib and incubated for an additional 24 h. The tumor cells were then incubated for 3 h with agonistic anti-Fas antibody (FASL) or recombinant TRAIL protein. Control cells were incubated with IgM isotype control antibody. Cells were subsequently fixed and permeabilized before being stained for intracellular active caspase-3 with a PE-labeled monoclonal antibody. The level of activated caspase-3 was evaluated by flow cytometry. Isotype control stained cells were analyzed for each treatment group individually and set to 5% positive. Graph shows average of three independent experiments, with error bars denoting SEM * <span class="html-italic">p</span> &lt; 0.05, *** <span class="html-italic">p</span> &lt; 0.0005. Percentage of active caspase-3 in (<b>A</b>) CCD-18Co, (<b>B</b>) SW620, (<b>C</b>) and HTC116 cells inhibition sensitizes tumor cells to Fas or TRAIL mediated killing possibly through enhancing cell surface expression of death receptors, which sensitizes tumor cells to killing by their ligands.</p> Full article ">
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Article
Effects of Heat Stress on Metabolite Accumulation and Composition, and Nutritional Properties of Durum Wheat Grain
by Anna Maria De Leonardis, Mariagiovanna Fragasso, Romina Beleggia, Donatella Bianca Maria Ficco, Pasquale De Vita and Anna Maria Mastrangelo
Int. J. Mol. Sci. 2015, 16(12), 30382-30404; https://doi.org/10.3390/ijms161226241 - 19 Dec 2015
Cited by 49 | Viewed by 7749
Abstract
Durum wheat (Triticum turgidum (L.) subsp. turgidum (L.) convar. durum (Desf.)) is momentous for human nutrition, and environmental stresses can strongly limit the expression of yield potential and affect the qualitative characteristics of the grain. The aim of this study was to [...] Read more.
Durum wheat (Triticum turgidum (L.) subsp. turgidum (L.) convar. durum (Desf.)) is momentous for human nutrition, and environmental stresses can strongly limit the expression of yield potential and affect the qualitative characteristics of the grain. The aim of this study was to determine how heat stress (five days at 37 °C) applied five days after flowering affects the nutritional composition, antioxidant capacity and metabolic profile of the grain of two durum wheat genotypes: “Primadur”, an elite cultivar with high yellow index, and “T1303”, an anthocyanin-rich purple cultivar. Qualitative traits and metabolite evaluation (by gas chromatography linked to mass spectrometry) were carried out on immature (14 days after flowering) and mature seeds. The effects of heat stress were genotype-dependent. Although some metabolites (e.g., sucrose, glycerol) increased in response to heat stress in both genotypes, clear differences were observed. Following the heat stress, there was a general increase in most of the analyzed metabolites in “Primadur”, with a general decrease in “T1303”. Heat shock applied early during seed development produced changes that were observed in immature seeds and also long-term effects that changed the qualitative and quantitative parameters of the mature grain. Therefore, short heat-stress treatments can affect the nutritional value of grain of different genotypes of durum wheat in different ways. Full article
(This article belongs to the Special Issue Metabolomics in the Plant Sciences)
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<p>Analysis of the relative variance for each class of metabolite.</p> Full article ">Figure 2
<p>Changes in the metabolite profiles for the “Primadur” seeds, for the control compared to the heat-stressed conditions, for the immature (14 DAF) and mature (MS) stages of seed development. Changes in the metabolite levels were calculated as the ratios between the levels for the heat stress and the control. Anthocyanins were not detected. To visualize the changes, significant increases and decreases are indicated in red and blue, respectively, within a metabolic scheme (<span class="html-italic">p</span> &lt; 0.05; Student’s <span class="html-italic">t</span> tests). b-alanine, β-Alanine; GABA, γ-4-aminobutyric acids. Solid line arrows: single step reactions; dash line arrows: pathways composed of more than one reaction; light gray shape: compounds which are not significantly different in seeds from heat stressed plants and control; red shape: compounds whose level is higher in seeds from heat stressed plants compared to control; blue shape: compounds whose level is lower in seeds from heat stressed plants compared to control; black shape: compounds not evaluated in the present study. The metabolic scheme is modified from [<a href="#B71-ijms-16-26241" class="html-bibr">71</a>].</p> Full article ">Figure 3
<p>Changes in metabolite profiles for the “T1303” seeds, for the control compared with the heat-stressed conditions, for the immature (14 DAF) and mature (MS) stages of seed development. Changes in the metabolite levels were calculated as the ratios between the levels for the heat stress and the control. To visualize the changes, significant increases and decreases are indicated in red and blue, respectively, within a metabolic scheme (<span class="html-italic">p</span> &lt; 0.05; Student’s <span class="html-italic">t</span> tests). b-alanine, β-Alanine; GABA, γ-4-aminobutyric acids. Solid line arrows: single step reactions; dash line arrows: pathways composed of more than one reaction; light gray shape: compounds which are not significantly different in seeds from heat stressed plants and control; red shape: compounds whose level is higher in seeds from heat stressed plants compared to control; blue shape: compounds whose level is lower in seeds from heat stressed plants compared to control; black shape: compounds not evaluated in the present study. The metabolic scheme is modified from [<a href="#B71-ijms-16-26241" class="html-bibr">71</a>].</p> Full article ">
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Review
Tissue Regeneration in the Chronically Inflamed Tumor Environment: Implications for Cell Fusion Driven Tumor Progression and Therapy Resistant Tumor Hybrid Cells
by Thomas Dittmar and Kurt S. Zänker
Int. J. Mol. Sci. 2015, 16(12), 30362-30381; https://doi.org/10.3390/ijms161226240 - 19 Dec 2015
Cited by 29 | Viewed by 8884
Abstract
The biological phenomenon of cell fusion in a cancer context is still a matter of controversial debates. Even though a plethora of in vitro and in vivo data have been published in the past decades the ultimate proof that tumor hybrid cells could [...] Read more.
The biological phenomenon of cell fusion in a cancer context is still a matter of controversial debates. Even though a plethora of in vitro and in vivo data have been published in the past decades the ultimate proof that tumor hybrid cells could originate in (human) cancers and could contribute to the progression of the disease is still missing, suggesting that the cell fusion hypothesis is rather fiction than fact. However, is the lack of this ultimate proof a valid argument against this hypothesis, particularly if one has to consider that appropriate markers do not (yet) exist, thus making it virtually impossible to identify a human tumor cell clearly as a tumor hybrid cell. In the present review, we will summarize the evidence supporting the cell fusion in cancer concept. Moreover, we will refine the cell fusion hypothesis by providing evidence that cell fusion is a potent inducer of aneuploidy, genomic instability and, most likely, even chromothripsis, suggesting that cell fusion, like mutations and aneuploidy, might be an inducer of a mutator phenotype. Finally, we will show that “accidental” tissue repair processes during cancer therapy could lead to the origin of therapy resistant cancer hybrid stem cells. Full article
(This article belongs to the Special Issue Stem Cell Activation in Adult Organism)
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<p>Induction of genomic instability by cell fusion. Fusion of two cells first result in heterokaryon being a hybrid cell with at least two distinct nuclei. The heterokaryon-to-synkaryon transition, representing the fusion of two parental nuclei to one hybrid nucleus, is a potent inducer of genomic instability in cells and is associated with a re-sorting, loss of chromosomes and putatively chromothripsis resulting in unique hybrid cells exhibiting an aneuploid karyotype and multiple mutations (indicated by small dots). However, most of the heterokaryons will die due to activation of tumor suppressor genes.</p> Full article ">Figure 2
<p>Induction of a mutator phenotype in cancer cells by cell fusion, mutation or aneuploidy. Cell fusion first result in heterokaryon formation (<b>A</b>); Such cells either remain in the heterokaryon state or could undergo ploidy reduction resulting in two daughter cells (<b>B</b>); However, in some cells cytogenesis might be defective causing the merging of the parental chromosomes (so-called heterokaryon-to-synkaryon transition) (<b>C</b>); Most of these hybrids will die because of activation of tumor suppressor genes, but a few cells will be able to survive and proliferate. Cell fusion, like mutations (<b>D</b>) and aneuploidy (<b>E</b>); is a potent inducer of genomic instability and could initiate a mutator phenotype in cancer cells (<b>F</b>) ultimately giving rise to phenotypically different genomic unstable cancer cells. Further cell fusion events could occur during tumor progression, whereby tumor cells and tumor cells (<b>G</b>) as well as tumor cells and other cells could fuse (<b>H</b>), thereby promoting the heterogeneity of the tumor tissue.</p> Full article ">Figure 3
<p>Model for tumor evolution and tumor tissue heterogeneity. In accordance with <a href="#ijms-16-26240-f003" class="html-fig">Figure 3</a>, and to the interactive interplay of cell fusion, mutation and aneuploidy in causing a mutator phenotype the events were synonymously displayed as stars. Blue stars indicate mutator events, red stars indicate driver events and green stars indicate passenger events. The heterogeneity of the tumor tissue concomitant with the event increases in dependence of time and tumor progression, which also accounts for the number of mutator, driver and passenger events. Adapted from [<a href="#B64-ijms-16-26240" class="html-bibr">64</a>]. Cell fusion, mutation and aneuploidy are interacting with each other and are the real co-conspirators for induction of a mutator phenotype in cancer cells.</p> Full article ">Figure 4
<p>The interrelationship between mutations, aneuploidy and cell fusion as inducers of genomic instability and a mutator phenotype in cancer.</p> Full article ">Figure 5
<p>The causative correlation between cancer therapy and cell fusion events. Cancer therapy, e.g., chemotherapy and/or radiation therapy, will eliminate rapidly proliferating cancer cells. The accumulating tumor cell debris will initiate a local inflammation concomitant with induction of a macrophage driven wound healing/tissue regeneration response including cell fusion events. Repeating cycles and/or fractions of chemotherapy/radiation therapy could lead to the evolution and selection of cell fusion-derived recurrence cancer stem cells exhibiting a more malignant phenotype.</p> Full article ">
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Article
Protein Sub-Nuclear Localization Based on Effective Fusion Representations and Dimension Reduction Algorithm LDA
by Shunfang Wang and Shuhui Liu
Int. J. Mol. Sci. 2015, 16(12), 30343-30361; https://doi.org/10.3390/ijms161226237 - 19 Dec 2015
Cited by 37 | Viewed by 5054
Abstract
An effective representation of a protein sequence plays a crucial role in protein sub-nuclear localization. The existing representations, such as dipeptide composition (DipC), pseudo-amino acid composition (PseAAC) and position specific scoring matrix (PSSM), are insufficient to represent protein sequence due to their single [...] Read more.
An effective representation of a protein sequence plays a crucial role in protein sub-nuclear localization. The existing representations, such as dipeptide composition (DipC), pseudo-amino acid composition (PseAAC) and position specific scoring matrix (PSSM), are insufficient to represent protein sequence due to their single perspectives. Thus, this paper proposes two fusion feature representations of DipPSSM and PseAAPSSM to integrate PSSM with DipC and PseAAC, respectively. When constructing each fusion representation, we introduce the balance factors to value the importance of its components. The optimal values of the balance factors are sought by genetic algorithm. Due to the high dimensionality of the proposed representations, linear discriminant analysis (LDA) is used to find its important low dimensional structure, which is essential for classification and location prediction. The numerical experiments on two public datasets with KNN classifier and cross-validation tests showed that in terms of the common indexes of sensitivity, specificity, accuracy and MCC, the proposed fusing representations outperform the traditional representations in protein sub-nuclear localization, and the representation treated by LDA outperforms the untreated one. Full article
(This article belongs to the Section Biochemistry)
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<p>A flowchart of the prediction process.</p> Full article ">Figure 2
<p>Success rate comparison for different <span class="html-italic">r<sub>i</sub></span> with our representations on Dataset 1, where each subplot, from (<b>a</b>) to (<b>i</b>), respectively represents each sub-nuclear location.</p> Full article ">Figure 3
<p>Success rate comparison for different <span class="html-italic">r<sub>i</sub></span> with our representations on Dataset 2, where each subplot, from (<b>a</b>) to (<b>j</b>), respectively represents each sub-nuclear location.</p> Full article ">Figure 4
<p>3D scatter on Dataset 1 with X-, Y- and Z-axes representing the first three components of LDA, respectively: (<b>a</b>) DipPSSM; (<b>b</b>) PseAAPSSM and (<b>c</b>) the patch of high resolution for the indicated region in (<b>b</b>).</p> Full article ">Figure 4 Cont.
<p>3D scatter on Dataset 1 with X-, Y- and Z-axes representing the first three components of LDA, respectively: (<b>a</b>) DipPSSM; (<b>b</b>) PseAAPSSM and (<b>c</b>) the patch of high resolution for the indicated region in (<b>b</b>).</p> Full article ">Figure 5
<p>3D scatter on Dataset 2 with X-, Y- and Z-axes representing the first three components of LDA, respectively: (<b>a</b>) DipPSSM; (<b>b</b>) PseAAPSSM and (<b>c</b>) the patch of high resolution for the indicated region in (<b>b</b>).</p> Full article ">Figure 6
<p>The overall success rates at different dimensions, reduced by LDA, from DipPSSM and PseAAPSSM, respectively: (<b>a</b>) Dataset 1 and (<b>b</b>) Dataset 2.</p> Full article ">Figure 7
<p>Comparison of success rates among different <span class="html-italic">k</span> values by DipPSSM, PseAAPSSM, DipPSSM with LDA and PseAAPSSM with LDA, respectively: (<b>a</b>) Dataset 1 and (<b>b</b>) Dataset 2.</p> Full article ">Figure 8
<p>Comparison of MCC performance on Dataset 1 among our proposed methods with Nuc-PLoc.</p> Full article ">Figure 9
<p>Comparison of our proposed methods with SubNucPred on Dataset 2: (<b>a</b>) Sensitivity (SE); (<b>b</b>) Specificity (SP); (<b>c</b>) Accuracy (ACC) and (<b>d</b>) Mathew’s Correlation Coeffcient (MCC).</p> Full article ">
0 pages, 147 KiB  
Retraction
RETRACTED: Ma et al. Hybrid Endovascular Repair in Aortic Arch Pathologies: A Retrospective Study. Int. J. Mol. Sci. 2010, 11, 4687–4696
by Mark L. Richter and International Journal of Molecular Sciences Editorial Office
Int. J. Mol. Sci. 2015, 16(12), 30342; https://doi.org/10.3390/ijms161226233 - 18 Dec 2015
Viewed by 4032
Abstract
We have been made aware that the figures and experimental data reported in the title paper [...] Full article
1713 KiB  
Review
FLIP the Switch: Regulation of Apoptosis and Necroptosis by cFLIP
by Yuichi Tsuchiya, Osamu Nakabayashi and Hiroyasu Nakano
Int. J. Mol. Sci. 2015, 16(12), 30321-30341; https://doi.org/10.3390/ijms161226232 - 18 Dec 2015
Cited by 112 | Viewed by 14543
Abstract
cFLIP (cellular FLICE-like inhibitory protein) is structurally related to caspase-8 but lacks proteolytic activity due to multiple amino acid substitutions of catalytically important residues. cFLIP protein is evolutionarily conserved and expressed as three functionally different isoforms in humans (cFLIPL, cFLIPS [...] Read more.
cFLIP (cellular FLICE-like inhibitory protein) is structurally related to caspase-8 but lacks proteolytic activity due to multiple amino acid substitutions of catalytically important residues. cFLIP protein is evolutionarily conserved and expressed as three functionally different isoforms in humans (cFLIPL, cFLIPS, and cFLIPR). cFLIP controls not only the classical death receptor-mediated extrinsic apoptosis pathway, but also the non-conventional pattern recognition receptor-dependent apoptotic pathway. In addition, cFLIP regulates the formation of the death receptor-independent apoptotic platform named the ripoptosome. Moreover, recent studies have revealed that cFLIP is also involved in a non-apoptotic cell death pathway known as programmed necrosis or necroptosis. These functions of cFLIP are strictly controlled in an isoform-, concentration- and tissue-specific manner, and the ubiquitin-proteasome system plays an important role in regulating the stability of cFLIP. In this review, we summarize the current scientific findings from biochemical analyses, cell biological studies, mathematical modeling, and gene-manipulated mice models to illustrate the critical role of cFLIP as a switch to determine the destiny of cells among survival, apoptosis, and necroptosis. Full article
(This article belongs to the Collection Programmed Cell Death and Apoptosis)
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<p>The structures of gene and proteins for human cFLIP. For gene structure, the red arrow (<span class="html-italic">CFLAR</span> gene) and black arrows (the nearby genes) indicate the positions and directions of genes present on human chromosome 2q33-34. For protein structures, light magenta and light yellow boxes indicate DEDs and caspase-8-like domains, respectively. The numbers below the boxes indicate amino acid residues, and arrows above the boxes indicate the caspase-8-mediated cleavage sites.</p> Full article ">Figure 2
<p>Functional role of cFLIP during classical death receptor-mediated extrinsic apoptosis pathway. Upon stimulation by death ligand (gray), death receptor (white) forms trimer and activated. Adaptor protein FADD (green) then binds to activated death receptor via DD-DD interaction. Subsequently, DED-containing proteins including procaspase-8 (blue), cFLIP<sub>L</sub> (red), and cFLIP<sub>S</sub> (orange) are recruited to death receptor-bound FADD via DED-DED interaction, thereby forming DISC. Fully processed active caspase-8, generated by procaspase-8 homodimerization, activates effector caspases and induces apoptosis. Procaspase-8-cFLIP<sub>L</sub> heterodimerization results in the production of p43-FLIP and p22-FLIP but does not process procaspase-8, leading to cellular survival. In contrast, procaspase-8-cFLIP<sub>S</sub> heterodimerization inhibits the activation of procaspase-8 and prevents apoptosis.</p> Full article ">Figure 3
<p>Functional role of cFLIP during ripoptosome formation. RIPK1 (brown) is composed of catalytic kinase domain, RIP homotypic interaction motif (RHIM), and DD. Upon RIPK1 activation by genotoxic stress, DD of RIPK1 is exposed and binds to DD of FADD (green). Subsequently, DED-containing proteins including procaspase-8 (blue), cFLIP<sub>L</sub> (red), and cFLIP<sub>S</sub> (orange) are recruited to RIPK1-bound FADD via DED-DED interaction, thereby forming ripoptosome. Fully processed active caspase-8, generated by procaspase-8 homodimerization, activates effector caspases, cleaves RIPK1, disassembles ripoptosome, and induces apoptosis. Procaspase-8-cFLIP<sub>L</sub> heterodimer produces p43-FLIP and p22-FLIP, cleaves RIPK1, disassembles ripoptosome, but does not process procaspase-8, leading to cellular survival. In contrast, procaspase-8-cFLIP<sub>S</sub> heterodimer fails to cleave RIPK1. This leads to the assembly of necrosome composed of RIPK1-RIPK3-MLKL and the execution of necroptosis.</p> Full article ">
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Review
Human Anti-Oxidation Protein A1M—A Potential Kidney Protection Agent in Peptide Receptor Radionuclide Therapy
by Jonas Ahlstedt, Thuy A. Tran, Sven-Erik Strand, Magnus Gram and Bo Åkerström
Int. J. Mol. Sci. 2015, 16(12), 30309-30320; https://doi.org/10.3390/ijms161226234 - 18 Dec 2015
Cited by 11 | Viewed by 7109
Abstract
Peptide receptor radionuclide therapy (PRRT) has been in clinical use for 15 years to treat metastatic neuroendocrine tumors. PRRT is limited by reabsorption and retention of the administered radiolabeled somatostatin analogues in the proximal tubule. Consequently, it is essential to develop and employ [...] Read more.
Peptide receptor radionuclide therapy (PRRT) has been in clinical use for 15 years to treat metastatic neuroendocrine tumors. PRRT is limited by reabsorption and retention of the administered radiolabeled somatostatin analogues in the proximal tubule. Consequently, it is essential to develop and employ methods to protect the kidneys during PRRT. Today, infusion of positively charged amino acids is the standard method of kidney protection. Other methods, such as administration of amifostine, are still under evaluation and show promising results. α1-microglobulin (A1M) is a reductase and radical scavenging protein ubiquitously present in plasma and extravascular tissue. Human A1M has antioxidation properties and has been shown to prevent radiation-induced in vitro cell damage and protect non-irradiated surrounding cells. It has recently been shown in mice that exogenously infused A1M and the somatostatin analogue octreotide are co-localized in proximal tubules of the kidney after intravenous infusion. In this review we describe the current situation of kidney protection during PRRT, discuss the necessity and implications of more precise dosimetry and present A1M as a new, potential candidate for renal protection during PRRT and related targeted radionuclide therapies. Full article
(This article belongs to the Collection Radiation Toxicity in Cells)
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<p>Visualizing the distribution of <sup>125</sup>I-labelled A1M 20 minutes post-injection at different magnification using SPECT/CT (<b>A</b>) and digital autoradiography (<b>B</b>) at the organ-level and fluorescence imaging showing both A1M (<b>green</b>), octreotide (<b>red</b>) and cell nuclei (<b>blue</b>) (<b>C</b>,<b>D</b>) at cellular and sub-cellular levels. The arrow in (<b>D</b>) indicates one single cell. The figure is modified from reference 35 with permission from the publisher.</p> Full article ">Figure 2
<p>Three-dimensional rendering of A1M based on the published crystal structure [<a href="#B51-ijms-16-26234" class="html-bibr">51</a>]. The position of the C34 group (mutated to serine in the crystal structure) is highlighted in <b>red</b>. This is the critical site for the reductase, heme binding, and radical scavenging properties of A1M.</p> Full article ">
2540 KiB  
Review
Oxidative Stress and Inflammation in Hepatic Diseases: Therapeutic Possibilities of N-Acetylcysteine
by Kívia Queiroz De Andrade, Fabiana Andréa Moura, John Marques Dos Santos, Orlando Roberto Pimentel De Araújo, Juliana Célia De Farias Santos and Marília Oliveira Fonseca Goulart
Int. J. Mol. Sci. 2015, 16(12), 30269-30308; https://doi.org/10.3390/ijms161226225 - 18 Dec 2015
Cited by 180 | Viewed by 19797
Abstract
Liver disease is highly prevalent in the world. Oxidative stress (OS) and inflammation are the most important pathogenetic events in liver diseases, regardless the different etiology and natural course. N-acetyl-l-cysteine (the active form) (NAC) is being studied in diseases characterized [...] Read more.
Liver disease is highly prevalent in the world. Oxidative stress (OS) and inflammation are the most important pathogenetic events in liver diseases, regardless the different etiology and natural course. N-acetyl-l-cysteine (the active form) (NAC) is being studied in diseases characterized by increased OS or decreased glutathione (GSH) level. NAC acts mainly on the supply of cysteine for GSH synthesis. The objective of this review is to examine experimental and clinical studies that evaluate the antioxidant and anti-inflammatory roles of NAC in attenuating markers of inflammation and OS in hepatic damage. The results related to the supplementation of NAC in any form of administration and type of study are satisfactory in 85.5% (n = 59) of the cases evaluated (n = 69, 100%). Within this percentage, the dosage of NAC utilized in studies in vivo varied from 0.204 up to 2 g/kg/day. A standard experimental design of protection and treatment as well as the choice of the route of administration, with a broader evaluation of OS and inflammation markers in the serum or other biological matrixes, in animal models, are necessary. Clinical studies are urgently required, to have a clear view, so that, the professionals can be sure about the effectiveness and safety of NAC prescription. Full article
(This article belongs to the Special Issue Antioxidant 2.0——Redox Modulation by Food and Drugs)
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<p>Chemical structures of <span class="html-italic">N</span>-acetyl-<span class="html-small-caps">l</span>-cysteine, <span class="html-small-caps">l</span>-cysteine and glutathione.</p> Full article ">Figure 2
<p>Chemical structure of taurine.</p> Full article ">Figure 3
<p>Transport of <span class="html-italic">N</span>-acetyl-<span class="html-small-caps">l</span>-cysteine and pathways for the generation of oxidative stress and inflammation in hepatocyte. Legend: CAT: catalase; Cys: cysteine; Cys-Cys: cystine; Cit c: cytochrome c; De-Acase: deacetylases; GSH: reduced glutathione; GSSG: oxidized glutathione; GPx: glutathione peroxidase; GR: glutathione reductase; HNE: 4-hydroxynonenal; iNOS: inducible nitric oxide synthase; IKKβ: inhibitor of κB kinase; IκB: inhibitor of NF-κB; IL: interleukin; IL-1R: interleukin-1 receptor; MDA: malondialdehyde; NADP<sup>+</sup>: oxidized nicotinamide adenine dinucleotide phosphate; NADPH: reduced nicotinamide adenine dinucleotide phosphate; NIK: NF-κB-inducing kinase; NO·: nitric oxide; NAC: <span class="html-italic">N</span>-acetylcysteine; NF-κB: nuclear factor κ-light-chain enhancer of activated B cells; p65: nuclear factor NF-κB protein p65 subunit; p50: nuclear factor NF-κB protein p50 subunit; Rel A: v-rel avian reticuloendotheliosis viral oncogene homolog A; ROOH: organic hydroperoxide; ROH: alcohol; SOD: superoxide dismutase; TGFβ1: transforming growth factor β 1; TNF-α: tumor necrosis factor α; TNF-R1: TNF-α receptor 1; ΔΨ: mitochondrial membrane potential; 1: NADH-ubiquinone reductase; 2: succinate-ubiquinone reductase; 3: ubiquinol-cytochrome c reductase; 4: cytochrome c oxidase.</p> Full article ">Figure 4
<p>Possible molecular mechanisms of action of <span class="html-italic">N</span>-acetylcysteine (NAC) in attenuation of liver injury involving oxidative stress and inflammation. Adapted from Cohen-Naftaly; Scott L. Friedman, 2011. Legend: CAT: catalase; ECM: extracellular matrix; FFA: free fatty acids; GPx: glutathione peroxidase; HSCs: hepatic stellate cells; iNOS: inducible nitric oxide synthase; IL: interleukin; INFγ: interferon gamma; MCP-1: monocyte chemoattractant protein-1; MDA/HNE: malondialdehyde/4-hydroxynonenal; NF-κB: nuclear factor κappa-light-chain enhancer of activated B cells; PDGF: platelet-derived growth factor; ROS: reactive oxygen species; SOD: superoxide dismutase; TGFβ1: transforming growth factor β 1; TNF-α: tumor necrosis factor α; TNF-R: TNF-α receptor; VEGF: Vascular endothelial growth factor. <span class="html-fig-inline" id="ijms-16-26225-i001"> <img alt="Ijms 16 26225 i001" src="/ijms/ijms-16-26225/article_deploy/html/images/ijms-16-26225-i001.png"/></span> inhibition; <span class="html-fig-inline" id="ijms-16-26225-i002"> <img alt="Ijms 16 26225 i002" src="/ijms/ijms-16-26225/article_deploy/html/images/ijms-16-26225-i002.png"/></span> stimulation; ↑ increase.</p> Full article ">Figure 5
<p>Positive effects of <span class="html-italic">N</span>-acetylcysteine <span class="html-italic">in vivo</span> and <span class="html-italic">in vitro</span> tests evaluated in this review and its mains results.</p> Full article ">
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Article
Short- and Long-Term Effects of Prenatal Exposure to Iron Oxide Nanoparticles: Influence of Surface Charge and Dose on Developmental and Reproductive Toxicity
by Kristin R. Di Bona, Yaolin Xu, Marquita Gray, Douglas Fair, Hunter Hayles, Luckie Milad, Alex Montes, Jennifer Sherwood, Yuping Bao and Jane F. Rasco
Int. J. Mol. Sci. 2015, 16(12), 30251-30268; https://doi.org/10.3390/ijms161226231 - 18 Dec 2015
Cited by 42 | Viewed by 6411
Abstract
Iron oxide nanoparticles (NPs) are commonly utilized for biomedical, industrial, and commercial applications due to their unique properties and potential biocompatibility. However, little is known about how exposure to iron oxide NPs may affect susceptible populations such as pregnant women and developing fetuses. [...] Read more.
Iron oxide nanoparticles (NPs) are commonly utilized for biomedical, industrial, and commercial applications due to their unique properties and potential biocompatibility. However, little is known about how exposure to iron oxide NPs may affect susceptible populations such as pregnant women and developing fetuses. To examine the influence of NP surface-charge and dose on the developmental toxicity of iron oxide NPs, Crl:CD1(ICR) (CD-1) mice were exposed to a single, low (10 mg/kg) or high (100 mg/kg) dose of positively-charged polyethyleneimine-Fe2O3-NPs (PEI-NPs), or negatively-charged poly(acrylic acid)-Fe2O3-NPs (PAA-NPs) during critical windows of organogenesis (gestation day (GD) 8, 9, or 10). A low dose of NPs, regardless of charge, did not induce toxicity. However, a high exposure led to charge-dependent fetal loss as well as morphological alterations of the uteri (both charges) and testes (positive only) of surviving offspring. Positively-charged PEI-NPs given later in organogenesis resulted in a combination of short-term fetal loss (42%) and long-term alterations in reproduction, including increased fetal loss for second generation matings (mice exposed in utero). Alternatively, negatively-charged PAA-NPs induced fetal loss (22%) earlier in organogenesis to a lesser degree than PEI-NPs with only mild alterations in offspring uterine histology observed in the long-term. Full article
(This article belongs to the Special Issue Developmental and Reproductive Toxicity of Iron Oxide Nanoparticles)
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<p>Supernumerary rib observations from fetuses of mice treated with 10 mg/kg (<b>A</b>) or 100 mg/kg (<b>B</b>) of iron oxide NPs and the control, C, on various days of gestation (GD 8, 9, or 10). * Significant differences between treatment group and the control (<span class="html-italic">p</span> &lt; 0.05).</p> Full article ">Figure 2
<p>Growth charts of mice exposed to 10 mg/kg (<b>A</b>) or 100 mg/kg (<b>B</b>) of iron oxide NPs <span class="html-italic">in utero</span> on various days of gestation (GD 8, 9, or 10). Calculations include values from cesarean evaluations and dams that littered.</p> Full article ">Figure 3
<p>Representative picture of an observed typical uterus (<b>A</b>) or edematous uterus (EU) (<b>B</b>), as well as incidence of EU (<b>C</b>) observed for all treatment groups exposed to 100 mg/kg PEI-NPs or PAA-NPs <span class="html-italic">in utero</span>, and the control, C. * Significant difference between treatment group and the control (<span class="html-italic">p</span> &lt; 0.05). <sup>‡</sup> Trend between treatment and control at (<span class="html-italic">p</span> &lt; 0.1).</p> Full article ">Figure 4
<p>Hematoxylin and eosin stained uterine sections from adult control mice (<b>A</b>) or those exposed to 100 mg/kg of iron oxide NPs <span class="html-italic">in utero</span> (<b>B</b>) (magnification of <b>A</b>,<b>B</b>: 200×). Relative endometrial thicknesses (<b>C</b>) were measured for all treatment groups exposed to 100 mg/kg iron oxide NPs <span class="html-italic">in utero</span> and the control, C, with GD 8, 9, or 10 pooled for all analyses. ** Significant differences between treatment group and the control (<span class="html-italic">p</span> &lt; 0.01).</p> Full article ">Figure 5
<p>Hematoxylin and eosin stained testis sections from adult control mice (<b>A</b>) or those exposed to 100 mg/kg of iron oxide NPs <span class="html-italic">in utero</span> (<b>B</b>) (magnification of <b>A</b>,<b>B</b>: 200×). Relative germinal epithelial thicknesses of the seminiferous tubule (<b>C</b>) were measured for all treatment groups exposed to 100 mg/kg iron oxide NPs <span class="html-italic">in utero</span> and the control, C, with GD 8, 9, and 10 pooled for all analyses. ** Significant differences between treatment group and the control (<span class="html-italic">p</span> &lt; 0.01).</p> Full article ">Figure 6
<p>Litter size (<b>A</b>) and fetal loss (<b>B</b>) measured from matings of adult mice previously exposed to 100 mg/kg of iron oxide NPs <span class="html-italic">in utero</span>, and the control, C, on various days of gestation (GD 8, 9, or 10). * Significant difference between treatment group and the control (<span class="html-italic">p</span> &lt; 0.05). <sup>‡</sup> Trend between treatment and control at (<span class="html-italic">p</span> &lt; 0.1).</p> Full article ">
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Review
Applications of Micro-Fourier Transform Infrared Spectroscopy (FTIR) in the Geological Sciences—A Review
by Yanyan Chen, Caineng Zou, Maria Mastalerz, Suyun Hu, Carley Gasaway and Xiaowan Tao
Int. J. Mol. Sci. 2015, 16(12), 30223-30250; https://doi.org/10.3390/ijms161226227 - 18 Dec 2015
Cited by 276 | Viewed by 27670
Abstract
Fourier transform infrared spectroscopy (FTIR) can provide crucial information on the molecular structure of organic and inorganic components and has been used extensively for chemical characterization of geological samples in the past few decades. In this paper, recent applications of FTIR in the [...] Read more.
Fourier transform infrared spectroscopy (FTIR) can provide crucial information on the molecular structure of organic and inorganic components and has been used extensively for chemical characterization of geological samples in the past few decades. In this paper, recent applications of FTIR in the geological sciences are reviewed. Particularly, its use in the characterization of geochemistry and thermal maturation of organic matter in coal and shale is addressed. These investigations demonstrate that the employment of high-resolution micro-FTIR imaging enables visualization and mapping of the distributions of organic matter and minerals on a micrometer scale in geological samples, and promotes an advanced understanding of heterogeneity of organic rich coal and shale. Additionally, micro-FTIR is particularly suitable for in situ, non-destructive characterization of minute microfossils, small fluid and melt inclusions within crystals, and volatiles in glasses and minerals. This technique can also assist in the chemotaxonomic classification of macrofossils such as plant fossils. These features, barely accessible with other analytical techniques, may provide fundamental information on paleoclimate, depositional environment, and the evolution of geological (e.g., volcanic and magmatic) systems. Full article
(This article belongs to the Section Biochemistry)
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<p>Simplified schematics of common Fourier transform infrared spectroscopy (FTIR) analysis modes including: (<b>a</b>) transmission FTIR; (<b>b</b>) attenuated total reflectance (ATR)-FTIR. Note that the penetration depth is dependent on the physical characteristics of internal reflection element (IRE) material and the angle of incidence [<a href="#B7-ijms-16-26227" class="html-bibr">7</a>]; (<b>c</b>) diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy; (<b>d</b>) reflectance micro-FTIR. The penetration depth for reflectance micro-FTIR is usually less than 10 μm. Modified after figure 1 in Parikh and Chorover [<a href="#B8-ijms-16-26227" class="html-bibr">8</a>] with copyright permission from Taylor &amp; Francis.</p> Full article ">Figure 2
<p>Micro-FTIR spectra of liptinite, vitrinite, and inertinite. Liptinite shows the strongest aliphatic CH<sub>x</sub> stretching signal and the most intense oxygenated group stretching at ~1710 cm<sup>−1</sup>, but the lowest intensities for C=C ring stretching at ~1600 cm<sup>−1</sup>, aromatic CH<sub>x</sub> stretching, and out-of-plane deformation. Dashed lines represent the linear baselines applied during the FTIR analysis. Note integrated areas of oxygenated and aromatic peak can be obtained by Fourier self-deconvolution [<a href="#B51-ijms-16-26227" class="html-bibr">51</a>] or curve-fitting of peaks in the ~1560–1800 cm<sup>−1</sup> region [<a href="#B26-ijms-16-26227" class="html-bibr">26</a>]. Note υ—stretching vibration; δ—deformation vibration in plane; γ—deformation vibration out of plane; subscript al—aliphatic; subscript ar—aromatic. The spectra of liptinite and inertinite have been moved up the vertical axis to avoid overlaps. Modified after figure 6 in Chen <span class="html-italic">et al.</span> [<a href="#B26-ijms-16-26227" class="html-bibr">26</a>] with copyright permission from Elsevier.</p> Full article ">Figure 3
<p>Chemical mapping of vitrinite, resinite, funginite, and exsudatinite in coal samples. (<b>a</b>) Photomicrograph of the sample in reflected light showing the location of transect <b><span class="html-italic">A</span></b> indicated by yellow dots. The sampling points are evenly distributed along the transect. The sampling area at point <b><span class="html-italic">A1</span></b> contains pure resinite, and points <b><span class="html-italic">A2</span></b> and <b><span class="html-italic">A3</span></b> represent pure vitrinite (Vit). The sampling area at point <b><span class="html-italic">A4</span></b> covers half resinite and half vitrinite; (<b>b</b>) FTIR spectra of resinite, vitrinite, and a resinite-vitrinite mixture. The blue-filled areas show how the absorbance plotted in panel (<b>c</b>) are defined. (<b>c</b>) the integrated area of aliphatic CH<sub>x</sub> stretching at 3000–2800 cm<sup>−1</sup> as a function of distance from point <b><span class="html-italic">A1</span></b>. The aliphatic character is strongest in resinite (point <b><span class="html-italic">A1</span></b>), decreases toward vitrinite (points <b><span class="html-italic">A2</span></b> and <b><span class="html-italic">A3</span></b>) and increases in the approach to point <b><span class="html-italic">A4</span></b> that receives a mixed signal from both vitrinite and resinite; (<b>d</b>) Photomicrograph of the sample in reflected light showing the location of transect <b><span class="html-italic">B</span></b> (yellow dots) through a funginite (Fu) maceral; points <b><span class="html-italic">B</span></b>1 and <b><span class="html-italic">B</span></b>5 are in the adjacent vitrinite; points <b><span class="html-italic">B2</span></b> and <b><span class="html-italic">B4</span></b> are on the exterior funginite rim; point <b><span class="html-italic">B3</span></b> is on the exsudatinite (Ex) impregnation; (<b>e</b>) An alternative way of showing the variation in FTIR-spectral absorbance of aliphatic CH<sub>x</sub> stretching bands at 3000–2800 cm<sup>−1</sup> across transect <b><span class="html-italic">B</span></b> (shown in <b>d</b>) through funginite into adjacent vitrinite. Units in panels <b>c</b> and <b>e</b> are arbitrary absorbance units (AU). Modified after figures 4 and 8 in Chen <span class="html-italic">et al.</span> [<a href="#B38-ijms-16-26227" class="html-bibr">38</a>] with copyright permission from John Wiley and Sons.</p> Full article ">Figure 4
<p>Chemical maps of a microscopic field with distinct sporinite (Sp), funginite (Fu), and vitrinite (V). (<b>a</b>) Photomicrograph in reflected light showing mapping sequence, indicated by yellow dots; (<b>b</b>) Representative FTIR spectra of sporinite, vitrinite, and funginite. The blue-filled areas represent the absorbance values that are mapped in panel (<b>c</b>); the ratios of red- over blue-filled areas are mapped in panel (<b>d</b>); (<b>c</b>) Chemical mapping of integrated peak of aliphatic CH<sub>x</sub> groups (3000–2800 cm<sup>−1</sup> region); (<b>d</b>) Map of the ratio of the integrated areas between 3100–3000 cm<sup>−1</sup> and 3000–2800 cm<sup>−1</sup> (<span class="html-italic">i.e.</span>, a proxy of aromaticity); Units in panels <b>c</b> and <b>d</b> are arbitrary absorbance units. Modified after figure 8 in Chen <span class="html-italic">et al.</span> [<a href="#B26-ijms-16-26227" class="html-bibr">26</a>] with copyright permission from Elsevier.</p> Full article ">Figure 5
<p>Micro-FTIR spectra of vitrinite in coals of different ranks. Adjacent pie diagrams represent elemental composition of these macerals measured by an electron microprobe. The hydrogen content is calculated by difference [<a href="#B33-ijms-16-26227" class="html-bibr">33</a>]. Red dashed lines represent the linear baselines applied to the FTIR spectra. Modified after figure 2 in Chen <span class="html-italic">et al.</span> [<a href="#B26-ijms-16-26227" class="html-bibr">26</a>] with copyright permission from Elsevier and Mastalerz and Bustin [<a href="#B33-ijms-16-26227" class="html-bibr">33</a>] with copyright permission from Elsevier. The elemental analysis results for low-volatile coal sample are not available.</p> Full article ">Figure 6
<p>Comparison between the spectra of shale (red) and coal (green). Dashed lines are the linear baselines applied to the FTIR spectra. Note that the IR spectrum of shale contains strong absorbance of minerals occurring at 1500–400 cm<sup>−1</sup>, but low band intensity from organic matter at 3000–2800 cm<sup>−1</sup>.</p> Full article ">Figure 7
<p>(<b>a</b>) A representative FTIR spectrum of the studied shale samples. The blue-filled areas represent the absorbance values that are mapped in panels <b><span class="html-italic">b1</span></b>, <b><span class="html-italic">c1</span></b>, <b><span class="html-italic">d1</span></b> and <b><span class="html-italic">e1</span></b>. Micro-FTIR chemical maps of organic matter in (<b>b</b>) early mature shale MM4; <b><span class="html-italic">b0</span></b>:photomicrograph; <b><span class="html-italic">b1</span></b>:micro-FTIR chemistry map of integrated peak area of aliphatic CH<sub>x</sub> groups; (<b>c</b>) mature shale NA2; <b><span class="html-italic">c0</span></b>: photomicrograph; <b><span class="html-italic">c1</span></b>:micro-FTIR chemistry map of integrated peak area of aliphatic CH<sub>x</sub> groups; (<b>d</b>) late mature shale IL5; <b><span class="html-italic">d0</span></b>: photomicrograph; <b><span class="html-italic">d1</span></b>: micro-FTIR chemistry map of integrated peak area of aliphatic CH<sub>x</sub> groups; and (<b>e</b>) postmature shale IL1; <b><span class="html-italic">e0</span></b>: photomicrograph; <b><span class="html-italic">e1</span></b>: micro-FTIR chemistry map of integrated peak area of aliphatic CH<sub>x</sub> groups. Min, med, and max values stand for the minimum, median, and maximum values of integrated peak areas of aliphatic CH<sub>x</sub> groups in 3000–2800 cm<sup>−1</sup>. Modified after figure 4 in Chen <span class="html-italic">et al.</span> [<a href="#B40-ijms-16-26227" class="html-bibr">40</a>] with copyright permission from John Wiley and Sons.</p> Full article ">Figure 8
<p>Model of petroleum generation for Yeoman Formation (Saskatchewan, Canada) <span class="html-italic">G. prisca</span> alginite [<a href="#B77-ijms-16-26227" class="html-bibr">77</a>]. Thin-walled <span class="html-italic">G. prisca</span> disseminated A contribute to pre-catagenic petroleum products. In contrast, thick-walled disseminated B alginite and stromatolitic <span class="html-italic">G. prisca</span> undergo a structural transformation into a bitumen-like maceral with increasing thermal maturity. Adjacent photomicrographs are those of <span class="html-italic">G. prisca</span> disseminated A and stromatolitic <span class="html-italic">G. prisca</span> alginite. Modified after figure 10 in Stasiuk <span class="html-italic">et al.</span> [<a href="#B77-ijms-16-26227" class="html-bibr">77</a>] with copyright permission from Elsevier.</p> Full article ">Figure 9
<p><b>Left</b>: Micro-IR spectra of stilbite collected at different temperatures (300, 425, 475, 575 and 770 K) in the 4000–400 cm<sup>−1</sup> wavenumber range. Modified after figure 2 in Prasad <span class="html-italic">et al.</span> [<a href="#B134-ijms-16-26227" class="html-bibr">134</a>] with copyright permission from Mineralogical Society of America; <b>Right</b>: absorbance of H<sub>2</sub>O (represented by O–H bending, purple-filled area) with increasing temperature from 425 to 770 K normalized to that at 300 K. The normalized H<sub>2</sub>O absorbances were derived from corresponding FTIR spectra on the left and show dehydration with increasing temperature.</p> Full article ">Figure 10
<p><b>Left</b>: Micro-FTIR spectra of prasinophycean algae (<b>a</b>) <span class="html-italic">Tasmanites</span> sp. from the Silurian, Oklahoma (USA) and (<b>b</b>) <span class="html-italic">Leiosphaeridia</span> sp. from the Late Silurian, Hazro area (Turkey); (<b>c</b>) a megaspore <span class="html-italic">Zonalessporites</span> sp. from the Pennsylvanian, Saarland (Germany); (<b>d</b>) a plant cuticle from the Late Cretaceous-Early Paleocene (western Germany); and (<b>e</b>) zoomorph Chitinozoa from the Silurian, Gotland (Sweden). Dashed lines indicate the linear baselines applied to the spectra. <b>Right</b>: Photomicrography of corresponding microfossils. Modified after figures 1–5 in Dutta <span class="html-italic">et al.</span> [<a href="#B139-ijms-16-26227" class="html-bibr">139</a>] with copyright permission from Elsevier.</p> Full article ">Figure 11
<p>Relationship between R<sub>3/2</sub> (aliphatic CH<sub>3</sub>/CH<sub>2</sub> absorbance ratios) and ratio of CH<sub>3</sub>/CH<sub>2</sub> for <span class="html-italic">n</span>-alkane standard samples (<span class="html-italic">n</span>-C<sub>5</sub> to <span class="html-italic">n</span>-C<sub>40</sub>). The CH<sub>3</sub>/CH<sub>2</sub> ratio can be converted to carbon number of the <span class="html-italic">n</span>-alkane. Modified after figure 6 in Igisu <span class="html-italic">et al.</span> [<a href="#B142-ijms-16-26227" class="html-bibr">142</a>] with copyright permission from Elsevier. Using this equation, R<sub>3/2</sub> values of Eucarya, Bacterial and Archaeal lipids are estimated to be 0.19–0.22, 0.32–0.37, and 1.16, respectively [<a href="#B142-ijms-16-26227" class="html-bibr">142</a>]. The carbon number of Eucarya lipids (C<sub>25</sub>–C<sub>29</sub>) and bacterial lipids (C<sub>16</sub>–C<sub>18</sub>) are from Han and Calvin [<a href="#B143-ijms-16-26227" class="html-bibr">143</a>] and Ladygina <span class="html-italic">et al.</span> [<a href="#B144-ijms-16-26227" class="html-bibr">144</a>].</p> Full article ">
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Article
MicroRNA-Target Network Inference and Local Network Enrichment Analysis Identify Two microRNA Clusters with Distinct Functions in Head and Neck Squamous Cell Carcinoma
by Steffen Sass, Adriana Pitea, Kristian Unger, Julia Hess, Nikola S. Mueller and Fabian J. Theis
Int. J. Mol. Sci. 2015, 16(12), 30204-30222; https://doi.org/10.3390/ijms161226230 - 18 Dec 2015
Cited by 11 | Viewed by 8563
Abstract
MicroRNAs represent ~22 nt long endogenous small RNA molecules that have been experimentally shown to regulate gene expression post-transcriptionally. One main interest in miRNA research is the investigation of their functional roles, which can typically be accomplished by identification of mi-/mRNA interactions and [...] Read more.
MicroRNAs represent ~22 nt long endogenous small RNA molecules that have been experimentally shown to regulate gene expression post-transcriptionally. One main interest in miRNA research is the investigation of their functional roles, which can typically be accomplished by identification of mi-/mRNA interactions and functional annotation of target gene sets. We here present a novel method “miRlastic”, which infers miRNA-target interactions using transcriptomic data as well as prior knowledge and performs functional annotation of target genes by exploiting the local structure of the inferred network. For the network inference, we applied linear regression modeling with elastic net regularization on matched microRNA and messenger RNA expression profiling data to perform feature selection on prior knowledge from sequence-based target prediction resources. The novelty of miRlastic inference originates in predicting data-driven intra-transcriptome regulatory relationships through feature selection. With synthetic data, we showed that miRlastic outperformed commonly used methods and was suitable even for low sample sizes. To gain insight into the functional role of miRNAs and to determine joint functional properties of miRNA clusters, we introduced a local enrichment analysis procedure. The principle of this procedure lies in identifying regions of high functional similarity by evaluating the shortest paths between genes in the network. We can finally assign functional roles to the miRNAs by taking their regulatory relationships into account. We thoroughly evaluated miRlastic on a cohort of head and neck cancer (HNSCC) patients provided by The Cancer Genome Atlas. We inferred an mi-/mRNA regulatory network for human papilloma virus (HPV)-associated miRNAs in HNSCC. The resulting network best enriched for experimentally validated miRNA-target interaction, when compared to common methods. Finally, the local enrichment step identified two functional clusters of miRNAs that were predicted to mediate HPV-associated dysregulation in HNSCC. Our novel approach was able to characterize distinct pathway regulations from matched miRNA and mRNA data. An R package of miRlastic was made available through: http://icb.helmholtz-muenchen.de/mirlastic. Full article
(This article belongs to the Collection Regulation by Non-coding RNAs)
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<p>Functional characterization of miRNAs in a condition-specific manner by data-driven inference of mi-/mRNA networks and subsequent functional annotation in the networks. (<b>A</b>) MiRlastic uses a two-step approach integrating prior knowledge and mi-/mRNA expressions to infer mi-/mRNA network and miRNA functional annotation; (<b>B</b>) Schematic drawing of miRNAs co-expressed in clusters induced by an yet unknown regulatory layer. Only several of the putative miRNA regulators are collectively regulating the mRNA expression.</p> Full article ">Figure 2
<p>Collective effects of co-expressed miRNAs. (<b>A</b>) Pairwise correlation of putative, expressed miRNA regulators together with their target gene C9orf85 (obtained from the HNSCC dataset). The miRNAs are themselves clustered into several co-expressed groups; (<b>B</b>) The distribution of correlation strengths <math display="inline"> <mrow> <mi>c</mi> <mo stretchy="false">(</mo> <mi mathvariant="bold-italic">X</mi> <mo stretchy="false">)</mo> </mrow> </math> of miRNA sets, which are predicted to target a common gene, (red curve and histogram) is higher than for randomly re-sampled mi-/mRNA associations (blue, Wilcoxon rank sum test has <math display="inline"> <mrow> <mi>p</mi> <mo>&lt;</mo> <mn>1</mn> <mo>×</mo> <msup> <mn>10</mn> <mrow> <mo>-</mo> <mn>80</mn> </mrow> </msup> </mrow> </math>) in the HNSCC miRNA expression dataset.</p> Full article ">Figure 3
<p>Node scoring strategy of local enrichment analysis. (<b>A</b>) Example of a network in which the nodes are represented by miRNAs (green) and genes (grey) and the edges are represented by the mi-/mRNA interactions. The network is given as input for the functional annotation step. We assume that four genes are assigned to a certain functional group—A, I, J, P (diamond shape); (<b>B</b>) The transformed network after computing the shortest path distances between these four nodes and the two nodes M (blue) and B (purple). The edge labels denote the weights after the transformation. The edge weight indicates the strength of the mi-/mRNA negative regulation; (<b>C</b>) The distribution of shortest paths from node M to the nodes A, I, J and P is significantly shifted to lower values. No shift can be observed for node B. The <span class="html-italic">p</span>-values determined by left-tailed Wilcoxon rank-sum test are converted to the node scores; (<b>D</b>) Network visualization after annotating functional groups. The node scores are indicated by the color. The size of the miRNA nodes corresponds to the miR score.</p> Full article ">Figure 4
<p>Benchmark with synthetic data. (<b>A</b>) Heatmap illustrating a set of randomly generated synthetic miRNAs with 30 samples; (<b>B</b>) Heatmap of pairwise correlations between the generated miRNAs; (<b>C</b>) Success-rate (<math display="inline"> <msub> <mi>F</mi> <mn>1</mn> </msub> </math>) of all algorithms across varying sample numbers and noise levels to recover the true synthetic mi-/mRNA associations.</p> Full article ">Figure 5
<p>mi-/mRNA regulatory network inference in HNSCC samples. (<b>A</b>) 44 miRNA expression profiles show differential expression between HPV+ (blue) and HPV- (green) patients; (<b>B</b>) mi-/mRNA regulatory network generated by our inference algorithm. The network consists of 766 regulations between 44 miRNAs (light blue) and 16,617 genes (light yellow). The edges represent miRNA-target relationships in the context of the TCGA HNSCC cohort; (<b>C</b>) Performance evaluation of the mi-/mRNA associations inference module. The left bar plot indicates the number of mi-/mRNA interactions detected by our approach, lasso, Pearson and Spearman. The right bar plot shows the <math display="inline"> <mrow> <mo>-</mo> <mi>log</mi> <mn>10</mn> </mrow> </math>-transformed <span class="html-italic">p</span>-values when testing for enrichment of experimentally validated targets within the results of each method. We provide an interactive representation of this network at <a href="http://icb.helmholtz-muenchen.de/mirlastic/hnscc" target="_blank">http://icb.helmholtz-muenchen.de/mirlastic/hnscc</a> [<a href="#B71-ijms-16-26230" class="html-bibr">71</a>].</p> Full article ">Figure 6
<p>Functional characterization of the HNSCC mi-/mRNA network. Heatmap of miR scores <math display="inline"> <mrow> <msub> <mi>S</mi> <mrow> <mi>m</mi> <mi>i</mi> <mi>R</mi> </mrow> </msub> <mrow> <mo stretchy="false">(</mo> <mi>v</mi> <mo stretchy="false">)</mo> </mrow> </mrow> </math> for each miRNA <span class="html-italic">v</span> in the network indicating the functional role in the significantly locally enriched KEGG pathways.</p> Full article ">
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Article
Comparative Transcriptome Analysis of Genes Involved in GA-GID1-DELLA Regulatory Module in Symbiotic and Asymbiotic Seed Germination of Anoectochilus roxburghii (Wall.) Lindl. (Orchidaceae)
by Si-Si Liu, Juan Chen, Shu-Chao Li, Xu Zeng, Zhi-Xia Meng and Shun-Xing Guo
Int. J. Mol. Sci. 2015, 16(12), 30190-30203; https://doi.org/10.3390/ijms161226224 - 18 Dec 2015
Cited by 52 | Viewed by 9971
Abstract
Anoectochilus roxburghii (Wall.) Lindl. (Orchidaceae) is an endangered medicinal plant in China, also called “King Medicine”. Due to lacking of sufficient nutrients in dust-like seeds, orchid species depend on mycorrhizal fungi for seed germination in the wild. As part of a conservation plan [...] Read more.
Anoectochilus roxburghii (Wall.) Lindl. (Orchidaceae) is an endangered medicinal plant in China, also called “King Medicine”. Due to lacking of sufficient nutrients in dust-like seeds, orchid species depend on mycorrhizal fungi for seed germination in the wild. As part of a conservation plan for the species, research on seed germination is necessary. However, the molecular mechanism of seed germination and underlying orchid-fungus interactions during symbiotic germination are poorly understood. In this study, Illumina HiSeq 4000 transcriptome sequencing was performed to generate a substantial sequence dataset of germinating A. roxburghii seed. A mean of 44,214,845 clean reads were obtained from each sample. 173,781 unigenes with a mean length of 653 nt were obtained. A total of 51,514 (29.64%) sequences were annotated, among these, 49 unigenes encoding proteins involved in GA-GID1-DELLA regulatory module, including 31 unigenes involved in GA metabolism pathway, 5 unigenes encoding GID1, 11 unigenes for DELLA and 2 unigenes for GID2. A total of 11,881 genes showed significant differential expression in the symbiotic germinating seed sample compared with the asymbiotic germinating seed sample, of which six were involved in the GA-GID1-DELLA regulatory module, and suggested that they might be induced or suppressed by fungi. These results will help us understand better the molecular mechanism of orchid seed germination and orchid-fungus symbiosis. Full article
(This article belongs to the Special Issue Plant Molecular Biology)
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<p>Light micrographs of germinating seeds of <span class="html-italic">A. roxburghii</span>: (<b>a</b>) DS, dry seeds; (<b>b</b>) AGS, asymbiotic germinating seeds; (<b>c</b>) SGS, symbiotic germinating seeds; (<b>b</b>,<b>c</b>) the third-stage seeds, appearance of promeristem. Scale bars = 0.5 mm.</p> Full article ">Figure 2
<p>Length distribution of Unigene.</p> Full article ">Figure 3
<p>Characteristics of similarity search of unigenes against NR database: (<b>a</b>) <span class="html-italic">E</span>-value distribution of BLAST hits for each unigene with a cutoff <span class="html-italic">E</span>-value of 10<sup>−5</sup>; (<b>b</b>) Similarity distribution of the top BLAST hit for each unigene; (<b>c</b>) Species distribution of the top BLAST hit for each unigene in the NR database.</p> Full article ">Figure 4
<p>Venn diagram of differentially expressed genes in the germination <span class="html-italic">of A. roxburghii</span> seeds. “X <span class="html-italic">vs.</span> Y” means Y is control.</p> Full article ">Figure 5
<p>GO functional classification of differentially expressed genes. (<b>a</b>,<b>b</b>) Third-stage seeds from asymbiotic germination (AGS) or the same stage seeds from symbiotic germination (SGS), both compared with dry seeds (DS), respectively; Also, (<b>c</b>) SGS compared with AGS. BP, Biological Processes, CC, Cellular Components, and MF, Molecular Function.</p> Full article ">
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Article
Randomized Controlled Trial of Darbepoetin α Versus Continuous Erythropoietin Receptor Activator Injected Subcutaneously Once Every Four Weeks in Patients with Chronic Kidney Disease at the Pre-Dialysis Stage
by Tetsuya Furukawa, Kazuyoshi Okada, Masanori Abe, Ritsukou Tei, Osamu Oikawa, Noriaki Maruyama and Takashi Maruyama
Int. J. Mol. Sci. 2015, 16(12), 30181-30189; https://doi.org/10.3390/ijms161226229 - 18 Dec 2015
Cited by 9 | Viewed by 6664
Abstract
Continuous erythropoietin receptor activator (CERA) seems to maintain a stable hemoglobin (Hb) level because its half-life is longer than darbepoetin α (DA). Twenty chronic kidney disease (CKD) patients at the pre-dialysis stage who had been administered DA for over 24 weeks were randomly [...] Read more.
Continuous erythropoietin receptor activator (CERA) seems to maintain a stable hemoglobin (Hb) level because its half-life is longer than darbepoetin α (DA). Twenty chronic kidney disease (CKD) patients at the pre-dialysis stage who had been administered DA for over 24 weeks were randomly assigned to receive subcutaneous CERA or DA once every four weeks during 48 weeks. In both groups, the rate of achievement of target Hb level changed from 70% to 100% in weeks 0 to 48, with no significant difference between the groups. Compared with week 0, the Hb level was significantly increased from week 24 in the DA group and from week 8 in the CERA group. In addition, the reticulocyte count was significantly increased from week 4 in the CERA group compared with the DA group. There was no significant difference in the levels of estimated glomerular filtration rate and iron status between both groups. Because of the small number of patients in this study, only limited conclusions can be drawn. However, the results suggest that subcutaneous administration of DA or CERA once every four weeks to predialysis patients has similar effects on achievement of target Hb levels. Full article
(This article belongs to the Special Issue Advances in Chronic Kidney Disease)
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<p>Change in hemoglobin (Hb) concentration. Solid line, darbepoetin α continuation group; dotted line, continuous erythropoietin receptor activator. * <span class="html-italic">p</span> &lt; 0.05 <span class="html-italic">vs.</span> week 0 in each group.Change in hemoglobin (Hb) concentration. Solid line, darbepoetin α continuation group; dotted line, continuous erythropoietin receptor activator. * <span class="html-italic">p</span> &lt; 0.05 <span class="html-italic">vs.</span> week 0 in each group.Change in hemoglobin (Hb) concentration. Solid line, darbepoetin α continuation group; dotted line, continuous erythropoietin receptor activator. * <span class="html-italic">p</span> &lt; 0.05 <span class="html-italic">vs.</span> week 0 in each group.</p> Full article ">Figure 2
<p>Change in reticulocyte (Reti) concentration. Solid line, darbepoetin α continuation group; dotted line, continuous erythropoietin receptor activator.</p> Full article ">Figure 3
<p>Study protocol.</p> Full article ">
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Review
Plant Adaptation to Multiple Stresses during Submergence and Following Desubmergence
by Bishal Gole Tamang and Takeshi Fukao
Int. J. Mol. Sci. 2015, 16(12), 30164-30180; https://doi.org/10.3390/ijms161226226 - 17 Dec 2015
Cited by 102 | Viewed by 12560
Abstract
Plants require water for growth and development, but excessive water negatively affects their productivity and viability. Flash floods occasionally result in complete submergence of plants in agricultural and natural ecosystems. When immersed in water, plants encounter multiple stresses including low oxygen, low light, [...] Read more.
Plants require water for growth and development, but excessive water negatively affects their productivity and viability. Flash floods occasionally result in complete submergence of plants in agricultural and natural ecosystems. When immersed in water, plants encounter multiple stresses including low oxygen, low light, nutrient deficiency, and high risk of infection. As floodwaters subside, submerged plants are abruptly exposed to higher oxygen concentration and greater light intensity, which can induce post-submergence injury caused by oxidative stress, high light, and dehydration. Recent studies have emphasized the significance of multiple stress tolerance in the survival of submergence and prompt recovery following desubmergence. A mechanistic understanding of acclimation responses to submergence at molecular and physiological levels can contribute to the deciphering of the regulatory networks governing tolerance to other environmental stresses that occur simultaneously or sequentially in the natural progress of a flood event. Full article
(This article belongs to the Special Issue Plant Molecular Biology)
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<p>External and internal stresses induced during submergence and following desubmergence in plants. When immersed in water, plants encounter drastic changes in environmental parameters (external stresses), triggering a variety of internal stresses. When floodwaters recede, submerged plants are suddenly exposed to aerobic conditions, inducing additional external and internal challenges. To overcome submergence and post-submergence stresses, plants require tolerance to multiple stresses that occur simultaneously or sequentially over a flood event.</p> Full article ">Figure 2
<p>Model of the regulatory mechanisms underlying the quiescence and escape responses to submergence in rice. (<b>a</b>) Quiescence response: Under submergence, the level of endogenous ethylene quickly rises due to physical entrapment and increased biosynthesis, triggering mRNA accumulation of <span class="html-italic">SUB1A</span> [<a href="#B18-ijms-16-26226" class="html-bibr">18</a>]. <span class="html-italic">SUB1A</span> ultimately limits ethylene production, contributing to a reduction in ethylene-mediated GA biosynthesis. <span class="html-italic">SUB1A</span> also upregulates production of brassinosteroids (BR), promoting degradation of bioactive gibberellins (GA) and accumulation of SLR1, a negative regulator of GA signaling [<a href="#B21-ijms-16-26226" class="html-bibr">21</a>]. As a result, GA-mediated shoot elongation and carbohydrate consumption are suppressed in a <span class="html-italic">SUB1A</span>-dependent manner, enabling the avoidance of carbohydrate starvation and an energy crisis during submergence; (<b>b</b>) Escape response: Submergence-induced ethylene also increases the abundance of <span class="html-italic">SNORKEL</span> (<span class="html-italic">SK</span>) mRNAs [<a href="#B20-ijms-16-26226" class="html-bibr">20</a>]. It is anticipated that the regulatory role of BR in breakdown of bioactive GA and accumulation of SLR1 is conserved within <span class="html-italic">O. sativa</span> varieties. Based on the antithetical functions of <span class="html-italic">SUB1A</span> and <span class="html-italic">SKs</span>, upregulation of GA biosynthesis and responsiveness observed in deepwater rice [<a href="#B20-ijms-16-26226" class="html-bibr">20</a>,<a href="#B22-ijms-16-26226" class="html-bibr">22</a>,<a href="#B23-ijms-16-26226" class="html-bibr">23</a>] might be regulated via suppression of BR accumulation by <span class="html-italic">SKs</span>. This response allows deepwater rice to outgrow submergence water through GA-mediated internode elongation. Blue and red lines represent positive and negative regulation, respectively. A dashed line indicates a hypothetical relationship.</p> Full article ">Figure 3
<p>Oxygen-dependent stabilization and localization of ERF-VII proteins. Under oxygen-replete conditions (normoxia), ERF-VII proteins are degraded via the N-end rule pathway of proteolysis (NERP). All ERF-VII proteins contain methionine and cysteine (MC) at the N-terminal [<a href="#B25-ijms-16-26226" class="html-bibr">25</a>] and the first methionine (M) is constitutively cleaved by methionine aminopeptidase (MAP) [<a href="#B36-ijms-16-26226" class="html-bibr">36</a>]. The exposed cysteine (C) is converted to Cys-sulfinic or Cys-sulfonic acid (C*) by plant cysteine oxidase (PCO) [<a href="#B37-ijms-16-26226" class="html-bibr">37</a>,<a href="#B38-ijms-16-26226" class="html-bibr">38</a>]. An arginine residue (R) is added to the oxidized cysteine (C*) by arginyl t-RNA transferases (ATE1/2), which is recognized and ubiquitinated by an E3 ubiquitin ligase, PROTEOLYSIS6 (PRT6) [<a href="#B1-ijms-16-26226" class="html-bibr">1</a>,<a href="#B36-ijms-16-26226" class="html-bibr">36</a>]. The ubiquitinated ERF-VII proteins are targeted for proteasomal degradation. Under oxygen deprivation (hypoxia), oxidation of cysteine by PCO is inhibited, resulting in the escape of ERF-VII proteins from targeted proteolysis and activation of hypoxia-responsive genes. Alternatively, at least one ERF-VII protein, RAP2.12, physically interacts with plasma membrane-localized acyl-CoA-binding proteins (ACBPs) in an oxygen-dependent manner, limiting its turnover via NERP and participation in the transcriptional activation under normoxia [<a href="#B30-ijms-16-26226" class="html-bibr">30</a>]. Under hypoxia, RAP2.12 protein is relocated to the nucleus, activating gene expression [<a href="#B39-ijms-16-26226" class="html-bibr">39</a>].</p> Full article ">Figure 4
<p>Molecular regulation of germination and early seedling growth in rice under aerobic and anaerobic conditions. Rapid consumption of soluble carbohydrates at the early stage of germination and seedling growth leads to sugar starvation, which stimulates accumulation of an energy sensor protein, SnRK1A [<a href="#B54-ijms-16-26226" class="html-bibr">54</a>]. SnRK1A upregulates expression of a MYB transcription factor gene, <span class="html-italic">MYBS1</span>. MYBS1 protein directly binds to the promoter region of α-amylase genes, activating the conversion of starch into soluble carbohydrates. Under anaerobic conditions such as submergence, the SnRK1A-mediated signaling cascade is triggered by a calcineurin B-like protein-interacting protein kinase15 (CIPK15) [<a href="#B55-ijms-16-26226" class="html-bibr">55</a>]. Physical interaction between CIPK15 and SnRK1 proteins activates the downstream signaling components, promoting starch breakdown to support germination and stand establishment under submergence.</p> Full article ">
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Review
Alterations of Dopamine D2 Receptors and Related Receptor-Interacting Proteins in Schizophrenia: The Pivotal Position of Dopamine Supersensitivity Psychosis in Treatment-Resistant Schizophrenia
by Yasunori Oda, Nobuhisa Kanahara and Masaomi Iyo
Int. J. Mol. Sci. 2015, 16(12), 30144-30163; https://doi.org/10.3390/ijms161226228 - 17 Dec 2015
Cited by 45 | Viewed by 10829
Abstract
Although the dopamine D2 receptor (DRD2) has been a main target of antipsychotic pharmacotherapy for the treatment of schizophrenia, the standard treatment does not offer sufficient relief of symptoms to 20%–30% of patients suffering from this disorder. Moreover, over 80% of patients experience [...] Read more.
Although the dopamine D2 receptor (DRD2) has been a main target of antipsychotic pharmacotherapy for the treatment of schizophrenia, the standard treatment does not offer sufficient relief of symptoms to 20%–30% of patients suffering from this disorder. Moreover, over 80% of patients experience relapsed psychotic episodes within five years following treatment initiation. These data strongly suggest that the continuous blockade of DRD2 by antipsychotic(s) could eventually fail to control the psychosis in some point during long-term treatment, even if such treatment has successfully provided symptomatic improvement for the first-episode psychosis, or stability for the subsequent chronic stage. Dopamine supersensitivity psychosis (DSP) is historically known as a by-product of antipsychotic treatment in the manner of tardive dyskinesia or transient rebound psychosis. Numerous data in psychopharmacological studies suggest that the up-regulation of DRD2, caused by antipsychotic(s), is likely the mechanism underlying the development of the dopamine supersensitivity state. However, regardless of evolving notions of dopamine signaling, particularly dopamine release, signal transduction, and receptor recycling, most of this research has been conducted and discussed from the standpoint of disease etiology or action mechanism of the antipsychotic, not of DSP. Hence, the mechanism of the DRD2 up-regulation or mechanism evoking clinical DSP, both of which are caused by pharmacotherapy, remains unknown. Once patients experience a DSP episode, they become increasingly difficult to treat. Light was recently shed on a new aspect of DSP as a treatment-resistant factor. Clarification of the detailed mechanism of DSP is therefore crucial, and a preventive treatment strategy for DSP or treatment-resistant schizophrenia is urgently needed. Full article
(This article belongs to the Special Issue The Pathophysiology of Neuropsychiatric Disorders and New Therapeutic Targets)
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<p>Dopamine D2 receptor (DRD2) early signaling. The stimulation of DRD2 by agonists induces early and late signals. In the early phase, acute and evanescent G protein-mediated signaling occurs. This signaling is amplified at several stages of the cascade. As a result, the function of phosphorylation of protein kinase A (PKA) and DARPP-32 is suppressed, and PP1 is activated. The heavy up-pointing red arrows indicate functional facilitation, and the heavy down-pointing blue arrows indicate functional suppression. The thin red arrows indicate activation and the thin blue arrows indicate inactivation. The black arrows represent either activation or inhibition of each specific substrate. The yellow arrow with red frame border indicates DRD2 early signaling. The α, β and γ indicate each subunit of G proteins. The yellow α represents guanosine triphosphate (GTP) type, while the purple one represents guanosine diphosphate (GDP) type. Abbreviations: AC, adenylate cyclase; DA, dopamine; DARPP-32, dopamine- and cyclic adenosine monophosphate (cAMP)-regulated phosphoprotein of 32 kDa; DRD2, dopamine D2 receptor; PKA, protein kinase A; PP1, protein phosphatase 1.</p> Full article ">Figure 2
<p>Dopamine D2 receptor late signaling. In the late phase, GRK6 phosphorylates the stimulated DRD2, and then ARRB2 binds to the phosphorylated receptors and prevents further G protein activation. Subsequently, the DRD2 binding to the ARRB2 promote the formation of the ARRB2/PP2A/AKT complex, resulting in the deactivation of AKT and stimulation of GSK-3 signaling. This G protein-independent signal is more moderate and longer lasting than the early signal. On the other hand, DRD2 is internalized from the cell membrane and experiences CME. Finally, the internalized receptors recycle back to the cell surface or degrade. The straight black arrows indicate the process to form the AKT/PP2A/ARRB2 complex or internalization of DRD2. The arcate black arrow indicates recycling or degeneration of DRD2. The up-pointing red arrows indicate functional facilitation, and the down-pointing blue arrows indicate functional suppression. The blue T-arrows indicate inhibition and the dashed T-arrows indicate disinhibition. The short yellow arrow with red frame border and long one indicate early signal and late signal, respectively. Abbreviations: AKT, protein kinase v-akt murine thymoma viral oncogene homolog; AP2, adaptor protein; ARRB2, β-arrestin 2; CME, clathrin-mediated endocytosis; DA, dopamine; DRD2, Dopamine D2 receptor; GSK-3, glycogen synthase kinase-3; GRK6, G protein-coupled receptor kinase-6.</p> Full article ">Figure 3
<p>Effect of antipsychotic brain level on dopamine supersensitivity psychosis (DSP). If we set the condition that four DRD2 is the optimal number to maintain appropriate signaling, 80% occupancy of DRD2 in the up-regulated state is an adequate blockade. However, it could induce EPS in the standard state for excessive blockade. In the same way, 60% occupancy in up-regulated state could provoke psychosis relative to the adequate blockade in the standard state. Therefore, patients with DSP may be more affected by a reduction or elimination half-life of antipsychotics. The number of DRD2 in the area framed with the black box is optimal one and that with the red box is excessive available one which could induce psychotic symptom. The white circles indicate available DRD2 and the blue circles indicate DRD2 occupied by antipsychotics. Abbreviation, DRD2, dopamine D2 receptor; EPS, extrapyramidal symptom.</p> Full article ">Figure 4
<p>Hypothesis of DSP mechanism. Chronic excess blockade of DRD2 by antipsychotics induces vicarious increase in DRD2 densities. Following DRD2 up-regulation, G protein-mediated early signaling is enhanced. On the other hand, the alteration of the GRK6/ARRB2 system could induce tolerance to the antipsychotic effect. Moreover, GSK-3 also experiences compensatory up-regulation. Therefore, both early and late DRD2 signaling becomes strong, ultimately resulting in DSP. The red arrows indicate activation and the blue arrows indicate inactivation. The dashed T-arrows indicate disinhibition. The heavy yellow arrow with red frame border represents enhanced signal. The black arrow indicates the several processes to form the AKT/PP2A/ARRB2 complex. Abbreviations: AC, adenylate cyclase; AKT, protein kinase v-akt murine thymoma viral oncogene homolog; AP2, adaptor protein; ARRB2, β-arrestin 2; CME, clathrin-mediated endocytosis; DA, dopamine; DRD2, Dopamine D2 receptor; GSK-3, glycogen synthase kinase-3; GRK6, G protein-coupled receptor kinase-6.</p> Full article ">
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Article
Selective Analysis of Sulfur-Containing Species in a Heavy Crude Oil by Deuterium Labeling Reactions and Ultrahigh Resolution Mass Spectrometry
by Xuxiao Wang and Wolfgang Schrader
Int. J. Mol. Sci. 2015, 16(12), 30133-30143; https://doi.org/10.3390/ijms161226205 - 17 Dec 2015
Cited by 22 | Viewed by 6705
Abstract
A heavy crude oil has been treated with deuterated alkylating reagents (CD3I and C2D5I) and directly analyzed without any prior fractionation and chromatographic separation by high-field Orbitrap Fourier Transform Mass Spectrometry (FTMS) and Fourier Transform Ion Cyclotron [...] Read more.
A heavy crude oil has been treated with deuterated alkylating reagents (CD3I and C2D5I) and directly analyzed without any prior fractionation and chromatographic separation by high-field Orbitrap Fourier Transform Mass Spectrometry (FTMS) and Fourier Transform Ion Cyclotron Resonance Mass Spectrometry (FT-ICR MS) using electrospray ionization (ESI). The reaction of a polycyclic aromatic sulfur heterocycles (PASHs) dibenzothiophene (DBT), in the presence of silver tetrafluoroborate (AgBF4) with ethyl iodide (C2H5I) in anhydrous dichloroethane (DCE) was optimized as a sample reaction to study heavy crude oil mixtures, and the reaction yield was monitored and determined by proton nuclear magnetic resonance spectroscopy (1H-NMR). The obtained conditions were then applied to a mixture of standard aromatic CH-, N-, O- and S-containing compounds and then a heavy crude oil, and only sulfur-containing compounds were selectively alkylated. The deuterium labeled alkylating reagents, iodomethane-d3 (CD3I) and iodoethane-d5 (C2D5I), were employed to the alkylation of heavy crude oil to selectively differentiate the tagged sulfur species from the original crude oil. Full article
(This article belongs to the Special Issue Fourier Transform Mass Spectrometry in Molecular Sciences)
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<p><sup>1</sup>H-NMR spectra (<b>top</b>) and HRMS (electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry (ESI FT-ICR MS)) spectra (<b>bottom</b>) of 5-ethyldibenzo[<span class="html-italic">b</span>,<span class="html-italic">d</span>]thiophenium tetrafluoroborate.</p> Full article ">Figure 2
<p>ESI FT-ICR MS spectrum of a mixture of the ethylated standards (anthracene (ANTH), DBT, acridine (ACR) and dibenzofuran (DBF)).</p> Full article ">Figure 3
<p>ESI(+) Orbitrap FTMS mass spectrum of heavy crude oil (<b>left</b>) and deuterium labeling methylated heavy crude oil (<b>right</b>).</p> Full article ">Figure 4
<p>Class distribution for heavy crude oil from direct analysis (<b>left</b>) and heavy crude oil after deuterium labelled methylation (<b>right</b>).</p> Full article ">Figure 5
<p>Double bond equivalent (DBE) <span class="html-italic">versus</span> carbon number plots for the N<sub>1</sub>[H] and N<sub>1</sub>S<sub>1</sub>[H] classes from the protonated heavy crude oil (<b>left</b>) and for the D<sub>3</sub>S<sub>1</sub>[H] and D<sub>3</sub>S<sub>2</sub>[H] classes from the deuterated methylated heavy crude oil (<b>right</b>). Note that the [H] indicates a protonated molecule.</p> Full article ">Figure 6
<p>Heteroatom class distribution of heavy crude oil after deuterium labelled ethylation.</p> Full article ">Figure 7
<p>DBE <span class="html-italic">versus</span> carbon number plots for the D<sub>5</sub>S<sub>1</sub> and D<sub>5</sub>S<sub>2</sub> classes from the deuterated ethylated heavy crude oil.</p> Full article ">Figure 8
<p>Ethylation of dibenzothiphene (DBT), reaction carried out at room temperature (rt).</p> Full article ">
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Article
Exogenous Spermidine Alleviates Low Temperature Injury in Mung Bean (Vigna radiata L.) Seedlings by Modulating Ascorbate-Glutathione and Glyoxalase Pathway
by Kamrun Nahar, Mirza Hasanuzzaman, Md. Mahabub Alam and Masayuki Fujita
Int. J. Mol. Sci. 2015, 16(12), 30117-30132; https://doi.org/10.3390/ijms161226220 - 17 Dec 2015
Cited by 79 | Viewed by 7836
Abstract
The role of exogenous spermidine (Spd) in alleviating low temperature (LT) stress in mung bean (Vigna radiata L. cv. BARI Mung-3) seedlings has been investigated. Low temperature stress modulated the non-enzymatic and enzymatic components of ascorbate-glutathione (AsA-GSH) cycle, increased H2O [...] Read more.
The role of exogenous spermidine (Spd) in alleviating low temperature (LT) stress in mung bean (Vigna radiata L. cv. BARI Mung-3) seedlings has been investigated. Low temperature stress modulated the non-enzymatic and enzymatic components of ascorbate-glutathione (AsA-GSH) cycle, increased H2O2 content and lipid peroxidation, which indicate oxidative damage of seedlings. Low temperature reduced the leaf relative water content (RWC) and destroyed leaf chlorophyll, which inhibited seedlings growth. Exogenous pretreatment of Spd in LT-affected seedlings significantly increased the contents of non-enzymatic antioxidants of AsA-GSH cycle, which include AsA and GSH. Exogenous Spd decreased dehydroascorbate (DHA), increased AsA/DHA ratio, decreased glutathione disulfide (GSSG) and increased GSH/GSSG ratio under LT stress. Activities of AsA-GSH cycle enzymes such as ascorbate peroxidase (APX), monodehydroascorbate reductase (MDHAR), dehydroascorbate reductase (DHAR) and glutathione reductase (GR) increased after Spd pretreatment in LT affected seedlings. Thus, the oxidative stress was reduced. Protective effects of Spd are also reflected from reduction of methylglyoxal (MG) toxicity by improving glyoxalase cycle components, and by maintaining osmoregulation, water status and improved seedlings growth. The present study reveals the vital roles of AsA-GSH and glyoxalase cycle in alleviating LT injury. Full article
(This article belongs to the Special Issue Plant Molecular Biology)
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<p>Dry weight per seedling (<b>A</b>); leaf relative water content (RWC) (<b>B</b>); proline (Pro) content (<b>C</b>); and total chlorophyll, chl (<span class="html-italic">a</span> + <span class="html-italic">b</span>) content (<b>D</b>) in mung bean seedlings. Spd and LT indicate spermidine (0.25 mM) and low temperature (6 °C), respectively. Mean (±SD) was calculated from three replicates for each treatment. Bars with different letters are significantly different at <span class="html-italic">p</span> ≤ 0.05 applying Duncan’s multiple range test (DMRT).</p> Full article ">Figure 2
<p>Histochemical localization of H<sub>2</sub>O<sub>2</sub> (<b>A</b>); and O<sub>2</sub><sup>•−</sup> (<b>B</b>) in mung bean leaves. Spd and LT indicate spermidine (0.25 mM) and low temperature (6 °C), respectively.</p> Full article ">Figure 3
<p>MDA (malondialdehyde, a product of lipid peroxidation) (<b>A</b>) and H<sub>2</sub>O<sub>2</sub> (<b>B</b>) contents in mung bean seedlings. Spd and LT indicate spermidine (0.25 mM) and low temperature (6 °C), respectively. Mean (±SD) was calculated from three replicates for each treatment. Bars with different letters are significantly different at <span class="html-italic">p</span> ≤ 0.05 applying DMRT.</p> Full article ">Figure 4
<p>Ascorbate (AsA) (<b>A</b>) and dehydroascorbate (DHA) (<b>B</b>) contents; AsA/DHA ratio (<b>C</b>); glutathione (GSH) (<b>D</b>) and glutathione disulfide (GSSG) (<b>E</b>) contents; and GSH/GSSG ratio (<b>F</b>) in mung bean seedlings. Spd and LT indicate spermidine (0.25 mM) and low temperature (6 °C), respectively. Mean (±SD) was calculated from three replicates for each treatment. Bars with different letters are significantly different at <span class="html-italic">p</span> ≤ 0.05 applying DMRT.</p> Full article ">Figure 5
<p>Activities of ascorbate peroxidase (APX) (<b>A</b>); monodehydroascorbate reductase (MDHAR) (<b>B</b>); dehydroascorbate reductase (DHAR) (<b>C</b>) and glutathione reductase (GR) (<b>D</b>) in mung bean seedlings. Spd and LT indicate spermidine (0.25 mM) and low temperature (6 °C), respectively. Mean (±SD) was calculated from three replicates for each treatment. Bars with different letters are significantly different at <span class="html-italic">p</span> ≤ 0.05 applying DMRT.</p> Full article ">Figure 6
<p>Activities of catalase (CAT) (<b>A</b>) and glutathione peroxidase (GPX) (<b>B</b>) in mung bean seedlings. Spd and LT indicate spermidine (0.25 mM) and low temperature (6 °C), respectively. Mean (±SE) was calculated from three replicates for each treatment. Bars with different letters are significantly different at <span class="html-italic">p</span> ≤ 0.05 applying DMRT.</p> Full article ">Figure 7
<p>Activity of glyoxalase I (Gly I) (<b>A</b>) and glyoxalase II (Gly II) (<b>B</b>); and methylglyoxal (MG) content (<b>C</b>) in mung bean seedlings. Spd and LT indicate spermidine (0.25 mM) and low temperature (6 °C), respectively. Mean (±SD) was calculated from three replicates for each treatment. Bars with different letters are significantly different at <span class="html-italic">p</span> ≤ 0.05 applying DMRT.</p> Full article ">Figure 8
<p>Endogenous putrescine (Put) content (<b>A</b>); spermidine (Spd) content (<b>B</b>); spermine (Spm) content (<b>C</b>) and the ratio of (Spd + Spm)/Put (<b>D</b>) in mung bean seedlings. Spd and LT indicate exogenously applied spermidine (0.25 mM) and low temperature (6 °C), respectively. Mean (±SD) was calculated from three replicates for each treatment. Bars with different letters are significantly different at <span class="html-italic">p</span> ≤ 0.05 applying DMRT.</p> Full article ">
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Article
MicroRNA (miRNA) Signaling in the Human CNS in Sporadic Alzheimer’s Disease (AD)-Novel and Unique Pathological Features
by Yuhai Zhao, Aileen I. Pogue and Walter J. Lukiw
Int. J. Mol. Sci. 2015, 16(12), 30105-30116; https://doi.org/10.3390/ijms161226223 - 17 Dec 2015
Cited by 52 | Viewed by 8974
Abstract
Of the approximately ~2.65 × 103 mature microRNAs (miRNAs) so far identified in Homo sapiens, only a surprisingly small but select subset—about 35–40—are highly abundant in the human central nervous system (CNS). This fact alone underscores the extremely high selection pressure [...] Read more.
Of the approximately ~2.65 × 103 mature microRNAs (miRNAs) so far identified in Homo sapiens, only a surprisingly small but select subset—about 35–40—are highly abundant in the human central nervous system (CNS). This fact alone underscores the extremely high selection pressure for the human CNS to utilize only specific ribonucleotide sequences contained within these single-stranded non-coding RNAs (ncRNAs) for productive miRNA–mRNA interactions and the down-regulation of gene expression. In this article we will: (i) consolidate some of our still evolving ideas concerning the role of miRNAs in the CNS in normal aging and in health, and in sporadic Alzheimer’s disease (AD) and related forms of chronic neurodegeneration; and (ii) highlight certain aspects of the most current work in this research field, with particular emphasis on the findings from our lab of a small pathogenic family of six inducible, pro-inflammatory, NF-κB-regulated miRNAs including miRNA-7, miRNA-9, miRNA-34a, miRNA-125b, miRNA-146a and miRNA-155. This group of six CNS-abundant miRNAs significantly up-regulated in sporadic AD are emerging as what appear to be key mechanistic contributors to the sporadic AD process and can explain much of the neuropathology of this common, age-related inflammatory neurodegeneration of the human CNS. Full article
(This article belongs to the Special Issue MicroRNA Regulation)
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<p>Representative heat map (“color-coded cluster diagram”) of the relative signal strength for six inducible, NF-κB regulated, pro-inflammatory, CNS-enriched miRNAs in four control and four sporadic Alzheimer’s disease (AD) brains all having post-mortem intervals (PMIs) of ≤2.1 h; the most significantly up-regulated miRNAs exhibited relative signal strengths that were miRNA-146a &gt;&gt;&gt; miRNA-155 &gt;&gt; miRNA-125b &gt;&gt; miRNA-34a ≥ miRNA-9 ≥ miRNA-7; up-regulated miRNAs for this group ranged from 2.5-to-6-fold or more over age-matched non-AD controls; the control ncRNAs, including miRNA-183 and 5S RNA, were found not change significantly between age-matched controls and AD; in addition there were no significant differences in (<b>i</b>) age (control 71.5 ± 6.1 year; AD 72.2 ± 7.6 year); (<b>ii</b>) gender (all samples were from females); (<b>iii</b>) PMI (all samples &lt;2.1 h); (<b>iv</b>) RNA quality (all samples <b>A<sub>260/280</sub></b> ~2.1) and/or RNA integrity (RIN) values of &gt;8.5 or higher or (<b>v</b>) total RNA yield (all samples had a mean yield of 1.25 μg RNA/mg wet weight brain tissue) between the control and AD brain samples; these six up-regulated miRNAs have a significant number of sporadic-AD-relevant mRNA targets that can explain much of the discernible neuropathology of the AD brain; (see text; and <a href="#ijms-16-26223-f002" class="html-fig">Figure 2</a>); analogous miRNA profiles for the rarer forms of familial AD have not yet been analyzed to this extent.</p> Full article ">Figure 2
<p>Highly schematicized interactive miRNA-mRNA signaling map of up-regulated miRNAs (green ovals) targeting mRNA 3′-UTRs (black squares) and down-regulating gene expression from these sporadic Alzheimer’s disease (AD)-relevant targets; as has been previously shown one miRNA can target multiple mRNA 3′-UTRs (<span class="html-italic">i.e.</span>, miRNA-125b) and conversely, multiple miRNAs can target a single mRNA 3′-UTR (<span class="html-italic">i.e.</span>, miRNA-155, miRNA-155 and CFH); this scheme is also reiterated (with references) in <a href="#ijms-16-26223-t001" class="html-table">Table 1</a> (see above). Note that down-regulated regulatory mRNAs (such as the vitamin D receptor, VDR) may have ancillary effects on the transcriptional control of other RNA Pol II genes including 15-lipoxygenase (15-LOX; hatched line with arrow). Importantly this highly integrated gene expression signaling mechanism addresses the observed down-regulation in the expression of multiple mRNAs that are normally involved in physiological pathways that are known to be specifically targeted by the AD process; this miRNA-mRNA network is highly interactive and other miRNAs, mRNAs and miRNA-mRNA interactions may be involved. The inducible microRNAs miRNA-146a and miRNA-155 are typically found to be the most significantly increased miRNAs over age-matched controls (see <a href="#ijms-16-26223-f001" class="html-fig">Figure 1</a>). Inhibition of the pro-inflammatory transcription factor NF-κB or full or partial blocking of the pathogenic induction of these six miRNAs using AM approaches may provide effective therapeutic benefit. However, the design of practical NF-κB or miRNA inhibition protocols, or the individual or combinatorial use of one or more inhibitory strategies, still remain open to very active pharmacological investigation [<a href="#B22-ijms-16-26223" class="html-bibr">22</a>,<a href="#B37-ijms-16-26223" class="html-bibr">37</a>,<a href="#B38-ijms-16-26223" class="html-bibr">38</a>,<a href="#B39-ijms-16-26223" class="html-bibr">39</a>,<a href="#B57-ijms-16-26223" class="html-bibr">57</a>,<a href="#B58-ijms-16-26223" class="html-bibr">58</a>,<a href="#B59-ijms-16-26223" class="html-bibr">59</a>,<a href="#B60-ijms-16-26223" class="html-bibr">60</a>,<a href="#B61-ijms-16-26223" class="html-bibr">61</a>,<a href="#B62-ijms-16-26223" class="html-bibr">62</a>,<a href="#B63-ijms-16-26223" class="html-bibr">63</a>]. Recent data using stressed human brain cells in primary culture has suggested that single or combinatorial pharmacological approaches may useful in the neutralization of these inducible, pathogenic gene expression programs to enable brain cells to re-establish homeostasis, and be of ultimate benefit in the therapeutic management of the AD process [<a href="#B37-ijms-16-26223" class="html-bibr">37</a>,<a href="#B38-ijms-16-26223" class="html-bibr">38</a>,<a href="#B39-ijms-16-26223" class="html-bibr">39</a>,<a href="#B63-ijms-16-26223" class="html-bibr">63</a>,<a href="#B64-ijms-16-26223" class="html-bibr">64</a>,<a href="#B65-ijms-16-26223" class="html-bibr">65</a>,<a href="#B66-ijms-16-26223" class="html-bibr">66</a>,<a href="#B67-ijms-16-26223" class="html-bibr">67</a>,<a href="#B68-ijms-16-26223" class="html-bibr">68</a>,<a href="#B69-ijms-16-26223" class="html-bibr">69</a>,<a href="#B70-ijms-16-26223" class="html-bibr">70</a>]. A family of at least 6 up-regulated microRNAs down-regulate the expression of at least 10 sporadic AD-relevant mRNAs and their expression, and can explain much of the neuropathology observed in the AD brain.</p> Full article ">
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Correction
Correction: Xiong, Z., et al. Different Roles of GRP78 on Cell Proliferation and Apoptosis in Cartilage Development. Int. J. Mol. Sci. 2015, 16, 21153–21176
by Zhangyuan Xiong, Rong Jiang, Xiangzhu Li, Yanna Liu and Fengjin Guo
Int. J. Mol. Sci. 2015, 16(12), 30103-30104; https://doi.org/10.3390/ijms161226222 - 17 Dec 2015
Viewed by 3924
Abstract
The authors wish to replace Figure 4A on Page 21161 of their paper published in IJMS [1]. [...] Full article
(This article belongs to the Section Biochemistry)
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Figure 4

Figure 4
<p>Cellular proliferation analysis by FCM. (<b>A</b>) Flow cytometry images with propidium iodide staining and analysis on cell cycle distribution. Micromass culture of ATDC5 cells and C3H10T1/2 were treated with BMP2 (300 ng/mL) / BMP2 + Ad-GFP/BMP2 + Ad-siRFP / BMP2 + Ad-GRP78 / BMP2 + Ad-siGRP78. Flow cytometry analysis showed that the percentage of the BMP2 + Ad-GRP78 ATDC5 cells in S phase were increased significantly compared to those in BMP2 controls, whereas the percentage of the BMP2 + Ad-siGRP78 ATDC5 cells in S phase were dramatically decreased compared with BMP2 control. The result of C3H10T1/2 is the same. Experiments were repeated three times, and samples were analyzed by Student’s <span class="html-italic">t</span>-test and statistical significance with <span class="html-italic">p</span> &lt; 0.05. Representative images were shown; (<b>B</b>) Flow cytometry assay on the percentages of the ATDC5 and C3H10T1/2 cells in G2/M phase after treatment with BMP2 (300 ng/mL)/BMP2 + Ad-GFP / BMP2 + Ad-siRFP / BMP2 + Ad-GRP78 / BMP2 + Ad-siGRP78; (<b>C</b>) Flow cytometry analysis showed that the percentages of the ATDC5 and C3H10T1/2 Ad-GRP78 cells in S phase were increased significantly, whereas the percentages of the ATDC5 and C3H10T1/2 Ad-siGRP78 cells in S phase were decreased compared with those in their controls. * <span class="html-italic">p</span> &lt; 0.05 compared with control.</p> Full article ">
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Article
The Complete Mitochondrial Genome of Mindarus keteleerifoliae (Insecta: Hemiptera: Aphididae) and Comparison with Other Aphididae Insects
by Yuan Wang, Jing Chen, Li-Yun Jiang and Ge-Xia Qiao
Int. J. Mol. Sci. 2015, 16(12), 30091-30102; https://doi.org/10.3390/ijms161226219 - 17 Dec 2015
Cited by 13 | Viewed by 5713
Abstract
The mitogenome of Mindarus keteleerifoliae Zhang (Hemiptera: Aphididae) is a 15,199 bp circular molecule. The gene order and orientation of M. keteleerifoliae is similarly arranged to that of the ancestral insect of other aphid mitogenomes, and, a tRNA isomerism event maybe identified in [...] Read more.
The mitogenome of Mindarus keteleerifoliae Zhang (Hemiptera: Aphididae) is a 15,199 bp circular molecule. The gene order and orientation of M. keteleerifoliae is similarly arranged to that of the ancestral insect of other aphid mitogenomes, and, a tRNA isomerism event maybe identified in the mitogenome of M. keteleerifoliae. The tRNA-Trp gene is coded in the J-strand and the same sequence in the N-strand codes for the tRNA-Ser gene. A similar phenomenon was also found in the mitogenome of Eriosoma lanigerum. However, whether tRNA isomers in aphids exist requires further study. Phylogenetic analyses, using all available protein-coding genes, support Mindarinae as the basal position of Aphididae. Two tribes of Aphidinae were recovered with high statistical significance. Characteristics of the M. keteleerifoliae mitogenome revealed distinct mitogenome structures and provided abundant phylogenetic signals, thus advancing our understanding of insect mitogenomic architecture and evolution. But, because only eight complete aphid mitogenomes, including M. keteleerifoliae, were published, future studies with larger taxon sampling sizes are necessary. Full article
(This article belongs to the Section Biochemistry)
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<p>Circular map of the <span class="html-italic">Mindarus keteleerifoliae</span> mitogenome. Gene names not underlined indicate the direction of transcription in the major strand, and underlined names indicate the direction of transcription in the minor strand. The transfer RNAs (tRNAs) are denoted by the colored blocks and are labeled according to the single-letter amino acid codes.</p> Full article ">Figure 2
<p>The inferred secondary structure of the 22 transfer RNAs (tRNAs) in the <span class="html-italic">Mindarus keteleerifoliae</span> mitogenome. The tRNAs are labeled with the abbreviations of their corresponding amino acids. Dashed line (−) indicates Watson–Crick base pairing and (+) indicates G–U base pairing.</p> Full article ">Figure 3
<p>The tRNA isomer of <span class="html-italic">Mindarus keteleerifoliae</span>. The blue and red dots indicate Watson–Crick base pairing.</p> Full article ">Figure 4
<p>The tRNA isomer of <span class="html-italic">Eriosoma lanigerum</span>. The blue and red dots indicate Watson–Crick base pairing.</p> Full article ">Figure 5
<p>Control region organization in aphid mitogenomes. The lead region is in a yellow box; the green boxes with Roman numerals indicate the tandem repeat units; A+T represents a high A+T content region; red boxes refer to the poly-thymidine stretch; orange boxes indicate the stem-loop region.</p> Full article ">Figure 6
<p>ML and BI Phylogenetic tree inferred from aphid mitogenome sequences. The node support values are the bootstrap (BS) values and the Bayesian posterior probabilities (BPP).</p> Full article ">
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Review
Date (Phoenix dactylifera) Polyphenolics and Other Bioactive Compounds: A Traditional Islamic Remedy’s Potential in Prevention of Cell Damage, Cancer Therapeutics and Beyond
by Bibi R. Yasin, Hassan A. N. El-Fawal and Shaker A. Mousa
Int. J. Mol. Sci. 2015, 16(12), 30075-30090; https://doi.org/10.3390/ijms161226210 - 17 Dec 2015
Cited by 74 | Viewed by 10890
Abstract
This review analyzes current studies of the therapeutic effects of Phoenix dactylifera, or date palm fruit, on the physiologic system. Specifically, we sought to summarize the effects of its application in preventing cell damage, improving cancer therapeutics and reducing damage caused by [...] Read more.
This review analyzes current studies of the therapeutic effects of Phoenix dactylifera, or date palm fruit, on the physiologic system. Specifically, we sought to summarize the effects of its application in preventing cell damage, improving cancer therapeutics and reducing damage caused by conventional chemotherapy. Phoenix dactylifera exhibits potent anti-oxidative properties both in vitro and in vivo. This allows the fruit to prevent depletion of intrinsic protection from oxidative cell damage and assist these defense systems in reducing cell damage. Macroscopically, this mechanism may be relevant to the prevention of various adverse drug events common to chemotherapy including hepatotoxicity, nephrotoxicity, gastrotoxicity, and peripheral neuropathy. While such effects have only been studied in small animal systems, research suggests a potential application to more complex mammalian systems and perhaps a solution to some problems of chemotherapy in hepato-compromised and nephro-compromised patients. Full article
(This article belongs to the Special Issue Advances in Molecular Research of Functional and Nutraceutical Food)
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Article
Biochemical Characterization of An Arginine-Specific Alkaline Trypsin from Bacillus licheniformis
by Jin-Song Gong, Wei Li, Dan-Dan Zhang, Min-Feng Xie, Biao Yang, Rong-Xian Zhang, Heng Li, Zhen-Ming Lu, Zheng-Hong Xu and Jin-Song Shi
Int. J. Mol. Sci. 2015, 16(12), 30061-30074; https://doi.org/10.3390/ijms161226200 - 17 Dec 2015
Cited by 17 | Viewed by 11177
Abstract
In the present study, we isolated a trypsin-producing strain DMN6 from the leather waste and identified it as Bacillus licheniformis through a two-step screening strategy. The trypsin activity was increased up to 140 from 20 U/mL through culture optimization. The enzyme was purified [...] Read more.
In the present study, we isolated a trypsin-producing strain DMN6 from the leather waste and identified it as Bacillus licheniformis through a two-step screening strategy. The trypsin activity was increased up to 140 from 20 U/mL through culture optimization. The enzyme was purified to electrophoretic homogeneity with a molecular mass of 44 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and the specific activity of purified enzyme is 350 U/mg with Nα-Benzoyl-l-arginine ethylester as the substrate. The optimum temperature and pH for the trypsin are 65 °C and pH 9.0, respectively. Also, the enzyme can be significantly activated by Ba2+. This enzyme is relatively stable in alkaline environment and displays excellent activity at low temperatures. It could retain over 95% of enzyme activity after 180 min of incubation at 45 °C. The distinguished activity under low temperature and prominent stability enhance its catalytic potential. In the current work, the open reading frame was obtained with a length of 1371 nucleotides that encoded a protein of 456 amino acids. These data would warrant the B. licheniformis trypsin as a promising candidate for catalytic application in collagen preparation and leather bating through further protein engineering. Full article
(This article belongs to the Section Biochemistry)
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<p>Morphological characters of strain DMN6. (<b>a</b>) Growth on LB medium. The colony was cultivated at 37 °C for three days; (<b>b</b>) Microscopic image (×1000); (<b>c</b>) Transmission electron microscope (×15,000).</p> Full article ">Figure 2
<p>Phylogenetic analysis based on the 16S rRNA gene sequence of strain DMN6, constructed by the neighbor-joining method. Numbers in parentheses are accession numbers of published sequences in GenBank. Numbers at the nodes referred to the bootstrap values (%). Bootstrap values were based on 1000 replicates. The scale bar represented 0.01 substitutions per nucleotide position. <span class="html-italic">Lactobacillus paraplantarum</span> was used as the outgroup.</p> Full article ">Figure 3
<p>The fermentation experiments. (<b>a</b>) The fermentation curve of cell growth and enzyme activity, OD means optical density; (<b>b</b>) Effect of initial pH values on trypsin activity; (<b>c</b>) Effect of culture temperatures on trypsin activity; (<b>d</b>) Effect of carbon sources on trypsin activity and cell growth; (<b>e</b>) Effect of nitrogen sources on trypsin activity and cell growth; (<b>f</b>) Effect of metal ions on trypsin activity and cell growth.</p> Full article ">Figure 3 Cont.
<p>The fermentation experiments. (<b>a</b>) The fermentation curve of cell growth and enzyme activity, OD means optical density; (<b>b</b>) Effect of initial pH values on trypsin activity; (<b>c</b>) Effect of culture temperatures on trypsin activity; (<b>d</b>) Effect of carbon sources on trypsin activity and cell growth; (<b>e</b>) Effect of nitrogen sources on trypsin activity and cell growth; (<b>f</b>) Effect of metal ions on trypsin activity and cell growth.</p> Full article ">Figure 4
<p>SDS-PAGE analysis of the purified trypsin. Lane 1: Crude enzyme; Lane 2: DEAE collected fluid; Lane 3: G75 collected fluid; M: Standard protein marker.</p> Full article ">Figure 5
<p>Effect of temperature on activity (<b>a</b>) and stability (<b>b</b>).</p> Full article ">Figure 6
<p>Effect of pH on activity (<b>a</b>) and stability (<b>b</b>).</p> Full article ">Figure 7
<p>Amino acid sequence alignment of trypsin from different origins. BLDMN6, the trypsin from <span class="html-italic">B. licheniformis</span> DMN6; BAC, the putative serine protease from <span class="html-italic">Bacillus</span> genus (WP_003185101.1); BASO, the putative serine protease from <span class="html-italic">B. sonorensis</span> (WP_029418466.1); BAAM, the putative serine protease from <span class="html-italic">B. amyloliquefaciens</span> (WP_044803775.1); SAAI, the putative serine protease from <span class="html-italic">Salinibacillus aidingensis</span> (WP_044159062.1); STPN, the serine protease HtrA from <span class="html-italic">Streptococcus pneumoniae</span> (CON63954.1). The different colors represent the different sequence identities. The black color represents the highest identity, the second is pink color and the last is light blue color.</p> Full article ">Figure 7 Cont.
<p>Amino acid sequence alignment of trypsin from different origins. BLDMN6, the trypsin from <span class="html-italic">B. licheniformis</span> DMN6; BAC, the putative serine protease from <span class="html-italic">Bacillus</span> genus (WP_003185101.1); BASO, the putative serine protease from <span class="html-italic">B. sonorensis</span> (WP_029418466.1); BAAM, the putative serine protease from <span class="html-italic">B. amyloliquefaciens</span> (WP_044803775.1); SAAI, the putative serine protease from <span class="html-italic">Salinibacillus aidingensis</span> (WP_044159062.1); STPN, the serine protease HtrA from <span class="html-italic">Streptococcus pneumoniae</span> (CON63954.1). The different colors represent the different sequence identities. The black color represents the highest identity, the second is pink color and the last is light blue color.</p> Full article ">
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Article
Biosynthesis of Essential Polyunsaturated Fatty Acids in Wheat Triggered by Expression of Artificial Gene
by Daniel Mihálik, Lenka Klčová, Katarína Ondreičková, Martina Hudcovicová, Marcela Gubišová, Tatiana Klempová, Milan Čertík, János Pauk and Ján Kraic
Int. J. Mol. Sci. 2015, 16(12), 30046-30060; https://doi.org/10.3390/ijms161226137 - 16 Dec 2015
Cited by 11 | Viewed by 6606
Abstract
The artificial gene D6D encoding the enzyme ∆6desaturase was designed and synthesized using the sequence of the same gene from the fungus Thamnidium elegans. The original start codon was replaced by the signal sequence derived from the wheat gene for [...] Read more.
The artificial gene D6D encoding the enzyme ∆6desaturase was designed and synthesized using the sequence of the same gene from the fungus Thamnidium elegans. The original start codon was replaced by the signal sequence derived from the wheat gene for high-molecular-weight glutenin subunit and the codon usage was completely changed for optimal expression in wheat. Synthesized artificial D6D gene was delivered into plants of the spring wheat line CY-45 and the gene itself, as well as transcribed D6D mRNA were confirmed in plants of T0 and T1 generations. The desired product of the wheat genetic modification by artificial D6D gene was the γ-linolenic acid. Its presence was confirmed in mature grains of transgenic wheat plants in the amount 0.04%–0.32% (v/v) of the total amount of fatty acids. Both newly synthesized γ-linolenic acid and stearidonic acid have been detected also in leaves, stems, roots, awns, paleas, rachillas, and immature grains of the T1 generation as well as in immature and mature grains of the T2 generation. Contents of γ-linolenic acid and stearidonic acid varied in range 0%–1.40% (v/v) and 0%–1.53% (v/v) from the total amount of fatty acids, respectively. This approach has opened the pathway of desaturation of fatty acids and production of essential polyunsaturated fatty acids in wheat. Full article
(This article belongs to the Special Issue Metabolomics in the Plant Sciences)
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<p>Homology in DNA sequence between artificial and original gene <span class="html-italic">D6D</span> from <span class="html-italic">Thamnidium</span> <span class="html-italic">elegans</span> (different colors represent different nucleotides in DNA sequences of the artificial <span class="html-italic">D6D</span> gene and the <span class="html-italic">D6D</span> gene originated from <span class="html-italic">T. elegans</span>, the pink line presents conformity in DNA sequences between them).</p> Full article ">Figure 2
<p>Composition of amino acids of protein encoded by the synthetic <span class="html-italic">D6D</span> gene and original protein from <span class="html-italic">Thamnidium</span> <span class="html-italic">elegans</span> (Dx5 signal peptide—signal sequence originated from Dx5 HMW-GS, Cyt b5—cytochrome b5 heme-binding domain; His-box—histidine rich region, boxes and arrows indicate their positions in protein sequence, different colors represent different amino acids in sequence of the artificial D6D protein and the D6D protein originated from <span class="html-italic">T. elegans</span>, the pink line presents conformity in amino acid sequence between them).</p> Full article ">Figure 3
<p>(<b>A</b>) Scutella of immature wheat embryos prepared for biolistic transformation; (<b>B</b>) Plant regeneration on selection medium; (<b>C</b>) Rooting of PPT-resistant plantlet; (<b>D</b>) Plants transferred to soil and adapted to <span class="html-italic">ex vitro</span> conditions; (<b>E</b>) Reaction to application of PPT on leaves (non-transformed control—left, transformed—right, black lines differentiate leaf areas with and without application of the PPT); (<b>F</b>) Mature fertile wheat plants (non-transformed control—left, transformed—right).</p> Full article ">Figure 4
<p><span class="html-italic">D6D</span> transgene detection by PCR (<b>A</b>) and <span class="html-italic">D6D</span>-mRNA detection by reverse transcriptase PCR (<b>B</b>) in immature grains of T<sub>0</sub> transgenic wheat plants (M—100 bp DNA marker, NC—negative control (non-transformed plant), PC—positive control, 1–10—analyzed transgenic plants).</p> Full article ">Figure 5
<p>Semi-quantitative RT-PCR analysis of <span class="html-italic">D6D</span> transgene expression in leaves, stems, and roots of three different T<sub>1</sub> plants (4.1, 5.1, 5.2) and grains of T<sub>2</sub> generation. Relative amount of <span class="html-italic">D6D</span>-cDNA was expressed as the ratio between cDNAs of transgene and house-keeping gene (<span class="html-italic">GAPDH</span>). Control non-transformed plants had null values in all analyzed tissues (not shown).</p> Full article ">Figure 6
<p>Content of GLA (percentage from the total amount of fatty acids) in grains of T<sub>1</sub> generation originating from 6 transgenic plants of T<sub>0</sub> generation (No. 1–6). Control non-transformed plants had null content of GLA (not shown).</p> Full article ">Figure 7
<p>Contents of γ-linolenic acid (GLA)and stearidonic acid (SDA) in different plant tissues and grains of three transgenic plants (4.1, 5.1, 5.2) of T<sub>1</sub> and T<sub>2</sub> generations, respectively. Control non-transgenic plants did not synthesize both the GLA and SDA in their tissues (not included in the graph).</p> Full article ">Figure 8
<p>The GC-FID analysis of fatty acids composition in awns of T<sub>1</sub> generation (<b>A</b>) and immature grains of T<sub>2</sub> generation (<b>B</b>). The bottom most (pink colored) line represents control non-transgenic wheat plant; others (red, green, blue) lines represent transgenic wheat plants (4.1, 5.1, 5.2).</p> Full article ">
1469 KiB  
Article
A Combined Metabolomic and Proteomic Analysis of Gestational Diabetes Mellitus
by Joanna Hajduk, Agnieszka Klupczynska, Paweł Dereziński, Jan Matysiak, Piotr Kokot, Dorota M. Nowak, Marzena Gajęcka, Ewa Nowak-Markwitz and Zenon J. Kokot
Int. J. Mol. Sci. 2015, 16(12), 30034-30045; https://doi.org/10.3390/ijms161226133 - 16 Dec 2015
Cited by 23 | Viewed by 7737
Abstract
The aim of this pilot study was to apply a novel combined metabolomic and proteomic approach in analysis of gestational diabetes mellitus. The investigation was performed with plasma samples derived from pregnant women with diagnosed gestational diabetes mellitus (n = 18) and [...] Read more.
The aim of this pilot study was to apply a novel combined metabolomic and proteomic approach in analysis of gestational diabetes mellitus. The investigation was performed with plasma samples derived from pregnant women with diagnosed gestational diabetes mellitus (n = 18) and a matched control group (n = 13). The mass spectrometry-based analyses allowed to determine 42 free amino acids and low molecular-weight peptide profiles. Different expressions of several peptides and altered amino acid profiles were observed in the analyzed groups. The combination of proteomic and metabolomic data allowed obtaining the model with a high discriminatory power, where amino acids ethanolamine, l-citrulline, l-asparagine, and peptide ions with m/z 1488.59; 4111.89 and 2913.15 had the highest contribution to the model. The sensitivity (94.44%) and specificity (84.62%), as well as the total group membership classification value (90.32%) calculated from the post hoc classification matrix of a joint model were the highest when compared with a single analysis of either amino acid levels or peptide ion intensities. The obtained results indicated a high potential of integration of proteomic and metabolomics analysis regardless the sample size. This promising approach together with clinical evaluation of the subjects can also be used in the study of other diseases. Full article
(This article belongs to the Special Issue Advances in Proteomic Research)
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Full article ">Figure 1
<p>Score plots between first and second latent variable obtained in PLS-DA using plasma free amino acid concentrations (<b>A</b>) and peptide ion peak intensities; (<b>B</b>) Important variables; (<b>C</b>) plasma free amino acids; (<b>D</b>) peptide ions identified by PLS-DA.</p> Full article ">
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Review
Mesenchymal Stem Cell-Mediated Effects of Tumor Support or Suppression
by Ki-Jong Rhee, Jong In Lee and Young Woo Eom
Int. J. Mol. Sci. 2015, 16(12), 30015-30033; https://doi.org/10.3390/ijms161226215 - 16 Dec 2015
Cited by 164 | Viewed by 9968
Abstract
Mesenchymal stem cells (MSCs) can exhibit a marked tropism towards site of tumors. Many studies have reported that tumor progression and metastasis increase by MSCs. In contrast, other studies have shown that MSCs suppress growth of tumors. MSCs contribute to tumor growth promotion [...] Read more.
Mesenchymal stem cells (MSCs) can exhibit a marked tropism towards site of tumors. Many studies have reported that tumor progression and metastasis increase by MSCs. In contrast, other studies have shown that MSCs suppress growth of tumors. MSCs contribute to tumor growth promotion by several mechanisms: (1) transition to tumor-associated fibroblasts; (2) suppression of immune response; (3) promotion of angiogenesis; (4) stimulation of epithelial-mesenchymal transition (EMT); (5) contribution to the tumor microenvironment; (6) inhibition of tumor cell apoptosis; and (7) promotion of tumor metastasis. In contrast to the tumor-promoting properties, MSCs inhibit tumor growth by increasing inflammatory infiltration, inhibiting angiogenesis, suppressing Wnt signaling and AKT signaling, and inducing cell cycle arrest and apoptosis. In this review, we will discuss potential mechanisms by which MSC mediates tumor support or suppression and then the possible tumor-specific therapeutic strategies using MSCs as delivery vehicles, based on their homing potential to tumors. Full article
(This article belongs to the Special Issue Advances in Molecular Oncology)
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<p>Role of MSCs in tumor formation or suppression. MSCs can regulate transition to tumor-associated fibroblasts, immune response, angiogenesis, EMT, cancer stem cells, metastasis, and apoptosis. Alternatively, growing evidence shows that MSCs inhibit tumor cell function by inducing apoptosis, cell cycle arrest, and inflammatory infiltration and inhibiting the Wnt and AKT signaling pathways.</p> Full article ">
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