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Feature Papers in Cell Biology and Pathology
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Feature Papers in Cell Biology and Pathology

A topical collection in Biomedicines (ISSN 2227-9059). This collection belongs to the section "Cell Biology and Pathology".

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Editor

Prof. Dr. Paul Rösch

E-Mail Website
Collection Editor
Forschungszentrum für Bio-Makromoleküle (FZ BIOmac), University of Bayreuth, Bayreuth, Germany
Interests: NMR-spectroscopy; protein structures; viral proteins; bacterial proteins; transcription; translation; allergens; nuclear magnetic resonance; crystallography; electron microscopy; fluorescence spectroscopy
Special Issues, Collections and Topics in MDPI journals

Topical Collection Information

Dear Colleagues,

The special edition “Feature Papers in Cell Biology and Pathology” will comprise important contributions by scholars in the field of cell biology and the Editorial Board members of the section Cell Biology and Pathology in Biomedicines. Their broad expertise will result in a comprehensive array of the latest findings in this field, and thus we encourage submissions of high-quality research papers or review articles.

Contributions that explore the origin of diseases at the molecular level, such as structural, biochemical, and genetic studies of receptors, oncogenes, tumor suppressor and regulatory proteins, signal pathways, and RNA/DNA, as well as articles that propose new routes for curing and preventing diseases, are of particular interest. Cutting-edge diagnostic tools ranging from PCR to magnetic resonance as applied to the detection of cellular or organismic pathological dysfunctions on all levels are also appropriate topics for this special edition. We look forward to your submissions on the above-listed research areas of cell biology and pathology.

Prof. Dr. Paul Rösch
Collection Editor

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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the collection website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (14 papers)

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2024

Jump to: 2023, 2022

14 pages, 3475 KiB  
Article
Gallic Acid Induces HeLa Cell Lines Apoptosis via the P53/Bax Signaling Pathway
by Umut Sarı, Fuat Zaman, İlhan Özdemir, Şamil Öztürk and Mehmet Cudi Tuncer
Biomedicines 2024, 12(11), 2632; https://doi.org/10.3390/biomedicines12112632 - 18 Nov 2024
Viewed by 1130
Abstract
Background: Cervical cancer is a type of cancer that originates from the endometrium and is more common in developed countries and its incidence is increasing day by day in developing countries. The most commonly prescribed chemotherapeutic drugs limit their use due to serious [...] Read more.
Background: Cervical cancer is a type of cancer that originates from the endometrium and is more common in developed countries and its incidence is increasing day by day in developing countries. The most commonly prescribed chemotherapeutic drugs limit their use due to serious side effects and the development of drug resistance. For this reason, interest in new active ingredients obtained from natural products is increasing. This study aimed to reveal the apoptotic and antiproliferative effects of gallic acid and doxorubicin combination therapy against the HeLa cell line. Methods: We investigated the anti-cancer effects of doxorubicin and gallic acid in the human HeLa cervical cell line by using the MTT test, Nucblue staining for the identification of apoptotic cells due to nuclear condensation using fluorescent substance, and apoptotic markers P53 and Bax for the RT-PCR test. Results: The highest cytotoxic effect obtained in the study, the highest increase in apoptotic induction, and a significant difference in P53/Bax levels were seen in the gallic acid/doxorubicin combination. Additionally, it was determined that gallic acid exhibited an effective cytotoxic effect on HeLa and HaCat cells within 48 and 72 h of application. Conclusions: The obtained findings show that the gallic acid/doxorubicin combination applied to HeLa cells may be an alternative treatment against both the cytotoxic effect size and the side effects of the chemotherapy agent. Full article
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<p>The effect of DOX application on 9 different concentrations obtained by serial dilution in the concentration range of 10-1000 nM in HeLa cervix adenocarcinoma (<b>A</b>–<b>C</b>) and HaCaT human skin keratinocyte cell line (<b>D</b>–<b>F</b>) on compared to the vehicle group and the IC50 value of the chemotherapy agent (n = 6; data are mean ± standard deviation values, inhibition concentration (IC) values calculated by probit analysis). * Data are statistically significant compared to control, one-way ANOVA, Tukey HSD test, <span class="html-italic">p</span> ≤ 0.05.</p> Full article ">Figure 2
<p>Effect of GA application on 9 different concentrations obtained by serial dilution between 10-1000 µM concentration range in HeLa cervix adenocarcinoma (<b>A</b>–<b>C</b>) and HaCaT human skin keratinocyte cell line (<b>D</b>–<b>F</b>) cell lines for 24, 48 and 72 hours on cell viability compared to the vehicle group and the IC50 value of GA (n = 6; data are mean ± standard deviation values, inhibition concentration (IC) values calculated by probit analysis). * Data are statistically significant compared to control, one-way ANOVA, Tukey HSD test, <span class="html-italic">p</span> ≤ 0.05.</p> Full article ">Figure 3
<p>Cell morphology, nuclear structure, and apoptotic body formation (magnification: ×20) in HeLa cervical adenocarcinoma cell populations treated for 48 hours with vehicle control (<b>A</b>,<b>A1</b>), DOX IC50: 137.6 nM (<b>B</b>,<b>B1</b>), GA IC50: 239.2 μM (<b>C</b>,<b>C1</b>), and DOX IC50+GA IC50 (<b>D</b>,<b>D1</b>) (Arrow: apoptotic cell).</p> Full article ">Figure 4
<p>H-scores were derived from semi-quantitative assessments of both staining intensity (scale 0–3) and the percentage of positive cells (0–100%) and, when multiplied, generated a score ranging from 0 to 300.</p> Full article ">Figure 5
<p>Relative fold increases values of P53 and BAX gene expressions in HeLa cervical adenocarcinoma cell lines, DOX IC<sub>50</sub>: 137.6 nM, GA IC<sub>50</sub>: 239.2 μM, 48 h, after single and combined drug administration (data in multiple control with β-actin and GAPDH mRNA level). Method, n = 4 data mean ± SH), * means are statistically different, one-way ANOVA, Tukey HSD test, <span class="html-italic">p</span> values are given in the graph.</p> Full article ">Figure 6
<p>PPI and interaction between various genes of cervical cancer.</p> Full article ">Figure 7
<p>Enrichment analysis for the 530 common compound targets in cancer pathway.</p> Full article ">Figure 8
<p>Enrichment analysis for the 331 common compound targets in human papilloma virüs infection and cervical cancer.</p> Full article ">
15 pages, 592 KiB  
Review
Characterizing Fibroblast Heterogeneity in Diabetic Wounds Through Single-Cell RNA-Sequencing
by Helen H. Wang, Maria Korah, Serena L. Jing, Charlotte E. Berry, Michelle F. Griffin, Michael T. Longaker and Michael Januszyk
Biomedicines 2024, 12(11), 2538; https://doi.org/10.3390/biomedicines12112538 - 7 Nov 2024
Viewed by 1506
Abstract
Diabetes mellitus is an increasingly prevalent chronic metabolic disorder characterized by physiologic hyperglycemia that, when left uncontrolled, can lead to significant complications in multiple organs. Diabetic wounds are common in the general population, yet the underlying mechanism of impaired healing in such wounds [...] Read more.
Diabetes mellitus is an increasingly prevalent chronic metabolic disorder characterized by physiologic hyperglycemia that, when left uncontrolled, can lead to significant complications in multiple organs. Diabetic wounds are common in the general population, yet the underlying mechanism of impaired healing in such wounds remains unclear. Single-cell RNA-sequencing (scRNAseq) has recently emerged as a tool to study the gene expression of heterogeneous cell populations in skin wounds. Herein, we review the history of scRNAseq and its application to the study of diabetic wound healing, focusing on how innovations in single-cell sequencing have transformed strategies for fibroblast analysis. We summarize recent research on the role of fibroblasts in diabetic wound healing and describe the functional and cellular heterogeneity of skin fibroblasts. Moreover, we highlight future opportunities in diabetic wound fibroblast research, with a focus on characterizing distinct fibroblast subpopulations and their lineages. Leveraging single-cell technologies to explore fibroblast heterogeneity and the complex biology of diabetic wounds may reveal new therapeutic targets for improving wound healing and ultimately alleviate the clinical burden of chronic wounds. Full article
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Graphical abstract

Graphical abstract
Full article ">Figure 1
<p>Illustrated Workflow for scRNAseq of Diabetic Wounds. An example workflow for single-cell RNA-seq of diabetic skin wounds using a droplet-based method such as 10x Genomics Chromium, from specimen harvest to downstream analysis of sequencing data. Optional cell sorting and in silico cell type isolation steps are illustrated using forked arrows. Created in BioRender. Wang, H. (2024) <a href="http://BioRender.com/p83k591" target="_blank">BioRender.com/p83k591</a> (accessed on 11 October 2024).</p> Full article ">
19 pages, 24345 KiB  
Review
Remarks on Selected Morphological Aspects of Cancer Neuroscience: A Microscopic Photo Review
by Ewa Iżycka-Świeszewska, Jacek Gulczyński, Aleksandra Sejda, Joanna Kitlińska, Susana Galli, Wojciech Rogowski and Dawid Sigorski
Biomedicines 2024, 12(10), 2335; https://doi.org/10.3390/biomedicines12102335 - 14 Oct 2024
Viewed by 1268
Abstract
Background: This short review and pictorial essay presents a morphological insight into cancer neuroscience, which is a complex and dynamic area of the pathobiology of tumors. Methods: We discuss the different methods and issues connected with structural research on tumor innervation, interactions between [...] Read more.
Background: This short review and pictorial essay presents a morphological insight into cancer neuroscience, which is a complex and dynamic area of the pathobiology of tumors. Methods: We discuss the different methods and issues connected with structural research on tumor innervation, interactions between neoplastic cells and the nervous system, and dysregulated neural influence on cancer phenotypes. Results: Perineural invasion (PNI), the most-visible cancer–nerve relation, is briefly presented, focusing on its pathophysiology and structural diversity as well as its clinical significance. The morphological approach to cancer neurobiology further includes the analysis of neural density/axonogenesis, neural network topographic distribution, and composition of fiber types and size. Next, the diverse range of neurotransmitters and neuropeptides and the neuroendocrine differentiation of cancer cells are reviewed. Another morphological area of cancer neuroscience is spatial or quantitative neural-related marker expression analysis through different detection, description, and visualization methods, also on experimental animal or cellular models. Conclusions: Morphological studies with systematic methodologies provide a necessary insight into the structure and function of the multifaceted tumor neural microenvironment and in context of possible new therapeutic neural-based oncological solutions. Full article
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<p>(<b>A</b>) Poorly differentiated prostatic adenocarcinoma: only bigger nerves (arrows) embedded within the neoplastic tissue are visible, HE, 200×. (<b>B</b>) Well-differentiated prostatic adenocarcinoma: perineural invasion with glandular structures cuffing the ganglion (*) and nerve branches (arrow) at the periphery and extraprostatic tumor extension, HE, 100×. (<b>C</b>) Poorly differentiated prostatic adenocarcinoma: solid growth pattern with mild inflammatory infiltrate (upper-right corner); no nerve fibers are visible at all; HE, 200×.</p> Full article ">Figure 2
<p>(<b>A</b>) Normal intestinal wall with a regular, dense network of axons within the muscular layers of the colon (arrows) and Auerbach’s myenteric plexus (*), S100, 100×. (<b>B</b>) Normal intestinal mucosa and submucosa presenting a regular, small-fiber network and Meissner plexus (arrow), CD56, 200×. (<b>C</b>) Colon adenocarcinoma: disruption and paucity of the axonal framework inside the cancer infiltrate (*) with the preservation of condensed or pre-existing axons (arrow) at the stroma outside the infiltrate, S100, 200×. (<b>D</b>) Well-differentiated colon adenocarcinoma: interface between normal intestinal mucosa and carcinoma in a normal gut; regular innervation is seen (arrows); only single axons are present in cancer infiltrate (*); CD56, 200×.</p> Full article ">Figure 3
<p>(<b>A</b>) Prostatic adenocarcinoma: multiple small fibers intermixed with neoplastic cells forming new cancer–nerve interactions, PGP 9.5, 600×. (<b>B</b>) Prostatic adenocarcinoma: sheath nerve branches embedded within cancer infiltrate visualized with perineural marker GLUT1; intravascular red blood cells are also stained; GLUT1, 200×. (<b>C</b>) Hyperplastic prostate: dense, slightly irregular axonal network within the periglandular stroma in the periphery of cancer (TH, 400×). (<b>D</b>) Prostatic adenocarcinoma with many axons among the infiltrating neoplastic glands, PGP9.5, 200×.</p> Full article ">Figure 4
<p>(<b>A</b>) Pancreatic adenocarcinoma: small nerve branch (arrow) almost completely destroyed by cancer cells (*) at the tumor invasion front accompanied with marked lympho-plasmocytic infiltrate (X), TH, 600×. (<b>B</b>) Poorly differentiated pancreatic adenocarcinoma: axonal network among tumor cells at the invasion front, probably based on destroyed, dissected, pre-existent nerves, PGP 9.5, 600×. (<b>C</b>) Pancreatic adenocarcinoma: accumulation of axons at the front of neoplastic infiltrate, destructed ganglion can be seen, PGP 9.5, 600×. (<b>D</b>) Prostate adenocarcinoma (PCa): peri- and intraneural invasion and multiple single axons within the surroundings, PGP 9.5, 200×. (<b>E</b>) Axonal distribution in prostate cancer (*) at the invasion front; sprouting from pre-existing prostatic stroma into high-grade infiltrate PGP9.5, 200×.</p> Full article ">Figure 5
<p>(<b>A</b>) Breast ductal adenocarcinoma (arrow) with the intraneural invasion (*) accompanied by a chronic perineural and focally intraneural inflammatory lymphocytic infiltrate (X), HE, 200×. (<b>B</b>) Colorectal adenocarcinoma stage pT3-diffuse invasion of cancer glands with mucin deposits inside the nerve branch within the mesenteric adipose tissue, HE, 200×. (<b>C</b>) Appendiceal goblet cell carcinoma: mucin-producing neoplastic cells spreading along the Auerbach’s plexus, HE, 100×. (<b>D</b>) Appendiceal goblet cell carcinoma with individual neoplastic cells directly contacting ganglion cells inside the myenteric plexus (arrow): physical cancer–nerve crosstalk, HE, 400×.</p> Full article ">Figure 6
<p>(<b>A</b>) Pancreatic neuroendocrine tumor (NET G2): neoplastic infiltrate encompassing the nerves together with small lymphocytic aggregates at the perineurium (arrows), HE, 200×. (<b>B</b>) Pancreatic adenocarcinoma: cancer cell invasion (arrow) inside the nerve accompanied by an inflammatory reaction within the adipose tissue, HE, 600×. (<b>C</b>) Melanoma infiltration within and around the subcutaneous nerve at the surgical margin (dyed in black), HE, 400×. (<b>D</b>) Gastric adenocarcinoma mixed-type poorly cohesive mucocellular component destroying thick nerve (arrow) and better-differentiated cancer glands within the fibro-adipose tissue, HE, 400×. (<b>E</b>) Salivary gland adenoid cystic carcinoma: nerve splitting and disintegration by the neoplastic infiltrate, HE, 200×. (<b>F</b>) Retroperitoneal germinoma family tumor-primitive germ cells widely infiltrate the nerve (arrow) incorporated within the tumor, HE, 400×.</p> Full article ">Figure 7
<p>(<b>A</b>) Breast ductal adenocarcinoma cancer glands with an intense subperineurial invasion, GLUT1, 400×. (<b>B</b>) Squamous cell carcinoma of the lung: central preserved cluster of axons from the pre-existing nerve and dispersed axons inside the tumor infiltrate, PGP 9.5, 600×. (<b>C</b>) Retroperitoneal germinoma family tumor: primitive germ cells splitting and aggressively infiltrating the nerve, neurofilament protein, 400×.</p> Full article ">Figure 8
<p>(<b>A</b>) Gastric adenocarcinoma: myenteric plexus invasion with partial separation of the fibers, synaptophysin, 400×. (<b>B</b>) Colorectal adenocarcinoma: massive intraneural invasion with destruction of the nerve branches, PGP9.5, 200×. (<b>C</b>) Gastric adenocarcinoma with scattered GLUT1 immunopositive tumor cells dispersed inside the nerve and in the subperineurial area (arrow), GLUT1, 400×. (<b>D</b>) Appendiceal goblet cell carcinoma: myenteric plexus infiltration; axons crossing tumor cell groups; PGP 9.5, 600×.</p> Full article ">Figure 9
<p>(<b>A</b>) Perineural dissemination of Ewing sarcoma (ES) cells in an experimental metastatic ES model in mice: small-round-blue-cell tumor surrounding paravertebral ganglia (*) and entering the vertebral bone, HE, 200×. (<b>B</b>) ES neoplastic cells (arrows) encompassing paravertebral ganglia (*), HE, 600×.</p> Full article ">Figure 10
<p>(<b>A</b>) Poorly differentiated gastric adenocarcinoma: axons dispersed among tumor cells, with heterogenous neural density, PGP 9.5, 600×. (<b>B</b>) Poorly differentiated PCa: dispersed tiny axonal structures within the cancer infiltrate, visible as dots or threads, PGP 9.5, 400×. (<b>C</b>) Cross-sections and longitudinal sections of the axons within PCa; note the pre-existing blood vessel innervation (arrow), PGP9.5, 400×. (<b>D</b>) Salivary gland adenocarcinoma NOS with high neural density, PNI, and nerve branch hypertrophy, PGP9.5, 200×.</p> Full article ">Figure 11
<p>(<b>A</b>) Well-differentiated PCa-focal neuronal transdifferentiation showing tyrosine hydroxylase-positive tumor cells, TH, 200×. (<b>B</b>) PCa bone metastasis showing intense neuroendocrine differentiation, chromogranin, 200×. (<b>C</b>) PCa PNI showing groups of cells with strong chromogranin expression, whereas carcinoma within the nerve is immunonegative, chromogranin, 400×. (<b>D</b>) Squamous cell carcinoma of the base of the tongue: TH-positive tumor cells at the front of the invasion, surrounded with lympho-plasmocytic infiltrate, TH, 200×. (<b>E</b>) Squamous cell carcinoma of the base of the tongue: TH-positive tumor cells in the vicinity of encircled nerve fibers, TH, 600×. (<b>F</b>) Gastric diffuse carcinoma with single neuroendocrine cells, chromogranin, 400×.</p> Full article ">Figure 12
<p>(<b>A</b>) PCa: high NPY expression in cancer glands compared to pre-existent non-neoplastic glands, NPY, 200×. (<b>B</b>) PCa-NPY-positive tumor cells with immunoreactivity equal to that of the ganglion cells, NPY, 400×. (<b>C</b>) PCa-NPY-expressing cancer cells infiltrating periprostatic fat tissue and peptide-positive intraneural axons, NPY, 400×. (<b>D</b>) PCa-NPY expression zonation with increased expression in the invasion front, NPY, 200×.</p> Full article ">
18 pages, 2732 KiB  
Article
Increased Myocardial MAO-A, Atrogin-1, and IL-1β Expression in Transgenic Mice with Pancreatic Carcinoma—Benefit of MAO-A Inhibition for Cardiac Cachexia
by Kira Stelter, Annalena Alabssi, Gabriel Alejandro Bonaterra, Hans Schwarzbach, Volker Fendrich, Emily P. Slater, Ralf Kinscherf and Wulf Hildebrandt
Biomedicines 2024, 12(9), 2009; https://doi.org/10.3390/biomedicines12092009 - 3 Sep 2024
Viewed by 1146
Abstract
Cancer cachexia (CC) continues to challenge clinicians by massively impairing patients’ prognosis, mobility, and quality of life through skeletal muscle wasting. CC also includes cardiac cachexia as characterized by atrophy, compromised metabolism, innervation and function of the myocardium through factors awaiting clarification for [...] Read more.
Cancer cachexia (CC) continues to challenge clinicians by massively impairing patients’ prognosis, mobility, and quality of life through skeletal muscle wasting. CC also includes cardiac cachexia as characterized by atrophy, compromised metabolism, innervation and function of the myocardium through factors awaiting clarification for therapeutic targeting. Because monoamine oxidase-A (MAO-A) is a myocardial source of H2O2 and implicated in myofibrillar protein catabolism and heart failure, we presently studied myocardial MAO-A expression, inflammatory cells, and capillarization together with transcripts of pro-inflammatory, -angiogenic, -apoptotic, and -proteolytic signals (by qRT-PCR) in a 3x-transgenic (LSL-KrasG12D/+; LSL-TrP53R172H/+; Pdx1-Cre) mouse model of orthotopic pancreatic ductal adenoarcinoma (PDAC) compared to wild-type (WT) mice. Moreover, we evaluated the effect of MAO-A inhibition by application of harmine hydrochloride (HH, 8 weeks, i.p., no sham control) on PDAC-related myocardial alterations. Myocardial MAO-A protein content was significantly increased (1.69-fold) in PDAC compared to WT mice. PDAC was associated with an increased percentage of atrogin-1+ (p < 0.001), IL-1β+ (p < 0.01), COX2+ (p < 0.001), and CD68+ (p > 0.05) cells and enhanced transcripts of pro-inflammatory IL-1β (2.47-fold), COX2 (1.53-fold), TNF (1.87-fold), and SOCS3 (1.64-fold). Moreover, PDAC was associated with a reduction in capillary density (−17%, p < 0.05) and transcripts of KDR (0.46-fold) but not of VEGFA, Notch1, or Notch3. Importantly, HH treatment largely reversed the PDAC-related increases in atrogin-1+, IL-1β+, and TNF+ cell fraction as well as in COX2, IL-1β, TNF, and SOCS3 transcripts, whereas capillary density and KDR transcripts failed to improve. In mice with PDAC, increased myocardial pro-atrophic/-inflammatory signals are attributable to increased expression of MAO-A, because they are significantly improved with MAO-A inhibition as a potential novel therapeutic option. The PDAC-related loss in myocardial capillary density may be due to other mechanisms awaiting evaluation with consideration of cardiomyocyte size, cardiac function and physical activity. Full article
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<p>Relative MAO-A protein content in the ventricular left myocardium of untreated or HH-treated wild type (WT, WT-HH) and PDAC-bearing mice (CA, CA-HH). Data are given as mean ± SEM. Two-factorial ANOVA detected a significant increasing effect of factor CA (<span class="html-italic">p</span> = 0.02) but no impact of factor HH (<span class="html-italic">p</span> = 0.61) on MAO-A content; (<span class="html-italic">n</span> = 4 independent experiments); * for <span class="html-italic">p</span> &lt; 0.05 CA + CA-HH vs. WT + WT-HH. Representative Western blots for MAO-A and for tubulin (loading control) are given below with indications of the sample group assignments.</p> Full article ">Figure 2
<p>Atrogin-1+ cells in the ventricular left myocardium of WT (<span class="html-italic">n</span> = 7), WT-HH (<span class="html-italic">n</span> = 11), CA (<span class="html-italic">n</span> = 7), and CA-HH (<span class="html-italic">n</span> = 9) mice. (<b>a</b>) Percentage of atrogin-1+ cells. Data are given as mean ± SEM. Two-factorial ANOVA detected a significant opposing impact of factor CA (<span class="html-italic">p</span> &lt; 0.001) and factor HH treatment (<span class="html-italic">p</span> &lt; 0.05), with significant interaction (<span class="html-italic">p</span> &lt; 0.01) within the total study population. ** <span class="html-italic">p</span> &lt; 0.01, *** <span class="html-italic">p</span> &lt; 0.001 CA vs. WT or CA-HH vs. WT-HH; ## <span class="html-italic">p</span> &lt; 0.01, WT-HH vs. WT or CA-HH vs. CA; ++ <span class="html-italic">p</span> &lt; 0.01 CA-HH vs. WT. (<b>b</b>) Representative photos of left myocardial cross-sections of WT, WT-HH, CA, and CA-HH mice indicating five examples of atrogin-1+ (black arrows) and atrogin-1-negative cardiomyocytes (empty arrow heads).</p> Full article ">Figure 3
<p>ILβ+ cells in the left ventricular myocardium of WT, WT-HH, CA, and CA-HH mice. (<b>a</b>) Percentage of IL-1β+ cells. Data are given as mean ± SEM. Two-factorial ANOVA detected significant opposing impacts of factor CA (<span class="html-italic">p</span> &lt; 0.001) and factor HH treatment (<span class="html-italic">p</span> &lt; 0.001) without significant interaction within the total study population. * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01 CA vs. WT or CA-HH vs. WT-HH; ## <span class="html-italic">p</span> &lt; 0.01, WT-HH vs. WT or CA-HH vs. CA. (<b>b</b>) Representative photos of left myocardial cross-sections of WT, WT-HH, CA, and CA-HH mice showing IL-1β+ cells (arrows). (<b>c</b>) x-fold expression of IL-1β transcripts in the left myocardium of WT-HH, CA, and CA-HH mice relative to WT mice as assessed in pooled samples.</p> Full article ">Figure 4
<p>TNF+ cells in the ventricular left myocardium of WT, WT-HH, CA, and CA-HH mice. (<b>a</b>) Percentage TNF+ cells. Data are given as mean ± SEM. Two-factorial ANOVA applied to the total study population detected no significant impact of factor CA or factor HH treatment; however, revealed a significant interaction (<span class="html-italic">p</span> &lt; 0.05) between these factors, as reflected by a significant decrease in increased TNF+ cell density through HH in PDAC-bearing mice. # <span class="html-italic">p</span> &lt; 0.05 (posthoc) CA-HH vs. CA. (<b>b</b>) Representative photos of left myocardial cross-sections of WT, WT-HH, CA, and CA-HH mice showing TNF+ cells (arrows). (<b>c</b>) x-fold expression of TNF transcripts in the left myocardium of WT-HH, CA, and CA-HH relative to WT mice as assessed in pooled samples.</p> Full article ">Figure 5
<p>CD68+ cells in the left ventricular myocardium of WT, WT-HH, CA, and CA-HH mice. (<b>a</b>) Percentage CD68+ cells. Data are given as mean ± SEM. Two-factorial ANOVA detected no significant impact of factor CA or factor HH treatment; however, revealed a significant interaction (<span class="html-italic">p</span> ≤ 0.05) between these factors within the total study population. * <span class="html-italic">p</span> &lt; 0.05 CA vs. WT. # <span class="html-italic">p</span> &lt; 0.05 WT-HH vs. WT. (<b>b</b>) Representative photos of left myocardial cross-sections of WT, WT-HH, CA, and CA-HH mice showing CD68+ cells (arrows). (<b>c</b>) X-fold expression of CD68 transcripts in WT-HH, CA, and CA-HH relative to WT mice as assessed in pooled samples.</p> Full article ">Figure 6
<p>COX2+ cells in the left ventricular myocardium of WT, WT-HH, CA, and CA-HH mice. (<b>a</b>) Percentage of COX2+ cells. Data are given as mean ± SEM. Two-factorial ANOVA detected significant impacts of factor CA (<span class="html-italic">p</span> &lt; 0.001) and factor HH treatment (<span class="html-italic">p</span> &lt; 0.001) with significant interaction (<span class="html-italic">p</span> &lt; 0.05) within the total study population. * <span class="html-italic">p</span> &lt; 0.05, *** <span class="html-italic">p</span> &lt; 0.001 CA vs. WT or CA-HH vs. WT-HH; ### <span class="html-italic">p</span> &lt; 0.001 WT-HH vs. WT or CA-HH vs. CA. +++ <span class="html-italic">p</span> &lt; 0.001 CA-HH vs. WT. (<b>b</b>) Representative photos of left myocardial cross-sections of WT, WT-HH, CA, and CA-HH mice showing COX2+ cells (arrows). (<b>c</b>) X-fold expression of COX2 transcripts in the left myocardium of WT-HH, CA, and CA-HH mice relative to WT mice as assessed in pooled samples.</p> Full article ">Figure 7
<p>Capillary density in the ventricular left myocardium of WT, WT-HH, CA, and CA-HH mice. (<b>a</b>) Density of capillaries (n/mm<sup>2</sup>, diameter ≤ 7 µm, stained for α-lectin). Data are given as mean ± SEM. Two-factorial ANOVA detected a significant impact of factor PDAC (<span class="html-italic">p</span> &lt; 0.001). but not factor HH. * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01 CA vs. WT or CA-HH vs. WT-HH. (<b>b</b>) Representative photos of left myocardial cross-sections of WT, WT-HH, CA, and CA-HH mice showing α-lectin+ capillaries. (<b>c</b>) X-fold expression of KDR transcripts in the left myocardium of WT-HH, CA, and CA-HH relative to WT mice as assessed in pooled samples.</p> Full article ">
15 pages, 1515 KiB  
Review
Understanding Tendon Fibroblast Biology and Heterogeneity
by Sarah E. DiIorio, Bill Young, Jennifer B. Parker, Michelle F. Griffin and Michael T. Longaker
Biomedicines 2024, 12(4), 859; https://doi.org/10.3390/biomedicines12040859 - 12 Apr 2024
Cited by 6 | Viewed by 4384
Abstract
Tendon regeneration has emerged as an area of interest due to the challenging healing process of avascular tendon tissue. During tendon healing after injury, the formation of a fibrous scar can limit tendon strength and lead to subsequent complications. The specific biological mechanisms [...] Read more.
Tendon regeneration has emerged as an area of interest due to the challenging healing process of avascular tendon tissue. During tendon healing after injury, the formation of a fibrous scar can limit tendon strength and lead to subsequent complications. The specific biological mechanisms that cause fibrosis across different cellular subtypes within the tendon and across different tendons in the body continue to remain unknown. Herein, we review the current understanding of tendon healing, fibrosis mechanisms, and future directions for treatments. We summarize recent research on the role of fibroblasts throughout tendon healing and describe the functional and cellular heterogeneity of fibroblasts and tendons. The review notes gaps in tendon fibrosis research, with a focus on characterizing distinct fibroblast subpopulations in the tendon. We highlight new techniques in the field that can be used to enhance our understanding of complex tendon pathologies such as fibrosis. Finally, we explore bioengineering tools for tendon regeneration and discuss future areas for innovation. Exploring the heterogeneity of tendon fibroblasts on the cellular level can inform therapeutic strategies for addressing tendon fibrosis and ultimately reduce its clinical burden. Full article
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<p>Schematic of stages of tendon healing and fibrosis and the cells involved. A normal tendon is made up of multiple populations of tenocytes and a tendon stem and progenitor cells in a collagen matrix and is surrounded by the epitenon. Macrophages have also been documented to be present at baseline. After injury, tendon healing and fibrosis go through three overlapping phases: inflammatory, fibrotic/proliferative, and remodeling. In normal tendon healing, macrophages, neutrophils, and fibroblasts migrate into the site of the injury during the inflammatory phase. Then, intrinsic tenocytes and extrinsic fibroblasts begin laying down collagen III in the proliferative phase. In the remodeling phase, cellularity decreases, and collagen III is replaced with collagen I. All postnatal tendons heal with a scar, which has a compromised structure compared to normal tendons; however, some tendons go through a process of “over-healing” following the inflammatory phase (bottom row). In these fibrotic tendons, fibroblasts lay down an excess of disorganized collagen and other matrix proteins during the proliferative phase. During the remodeling phase, the increased scar is maintained by replacing collagen III with collagen I. Figure created using <a href="http://BioRender.com" target="_blank">BioRender.com</a> (accessed on 8 March 2024).</p> Full article ">Figure 2
<p>Representative image of tenocyte subpopulations from Kendal et al. [<a href="#B49-biomedicines-12-00859" class="html-bibr">49</a>]. (<b>A</b>) Uniform Manifold Approximation and Projection (UMAP) showing diseased, or tendinopathy, and healthy patient samples. Eight overall cell populations and five tenocyte populations were identified. All cell populations were present in both diseased and healthy tendon tissue. Tenocytes were defined as cells expressing <span class="html-italic">COL1A1</span> or <span class="html-italic">COL1A2</span>. (<b>B</b>) Split Violin plots displaying gene expression for diseased (black) versus healthy (blue) tenocytes in all five subpopulations. Every dot represents an individual cell’s gene expression level. Figure adapted from Kendal et al. [<a href="#B49-biomedicines-12-00859" class="html-bibr">49</a>], an open access publication.</p> Full article ">Figure 3
<p>Considerations for tendon tissue engineering. Tendon tissue engineering is dependent on multiple factors and combinations of these factors: biomaterials, engineering strategies, choice of stem cells or mature cells, growth factors, and drugs. Abbreviations. PGA: polyglycolic acids, PLA: polylactic acids, PCL: polycaprolactones, PLGA: poly(lactic-co-glycolic) acids, PLCL: poly (lactil-co-captolactone) acids, ESCs: embryonic stem cells, iPSCs: induced pluripotent stem cells, AECs: amniotic epithelial stem cells, AMCs: amniotic mesenchymal stem cells, AFCs: amniotic fluid stem cells, UB-MSCs: umbilical cord mesenchymal stem cells, BMSCs: bone marrow mesenchymal stem cells, ADSCs: adipose derived mesenchymal stem cells, TPSCs: tendon progenitors stem cells, TGFβ: transforming growth factor beta, BMPs: bone morphogenetic proteins, CTGF: connective tissue growth factor, FGFs: fibroblastic growth factors, IGF-1: insulin-like growth factor-1, VEGF: vascular endothelial growth factor, PDGFs: platelet-derived growth factor, NSAIDs: non-steroidal anti-inflammatory drugs. Figure adapted from Citeroni et al. [<a href="#B70-biomedicines-12-00859" class="html-bibr">70</a>], an open access publication. Adaptation created using <a href="http://BioRender.com" target="_blank">BioRender.com</a>.</p> Full article ">
16 pages, 2899 KiB  
Article
PD-L1 Expression in Neoplastic and Immune Cells of Thymic Epithelial Tumors: Correlations with Disease Characteristics and HDAC Expression
by Ioanna E. Stergiou, Kostas Palamaris, Georgia Levidou, Maria Tzimou, Stavros P. Papadakos, Georgios Mandrakis, Christos Masaoutis, Dimitra Rontogianni and Stamatios Theocharis
Biomedicines 2024, 12(4), 772; https://doi.org/10.3390/biomedicines12040772 - 31 Mar 2024
Cited by 1 | Viewed by 1738
Abstract
Background: Programmed death-ligand 1 (PD-L1) expression in neoplastic and immune cells of the tumor microenvironment determines the efficacy of antitumor immunity, while it can be regulated at the epigenetic level by various factors, including HDACs. In this study, we aim to evaluate the [...] Read more.
Background: Programmed death-ligand 1 (PD-L1) expression in neoplastic and immune cells of the tumor microenvironment determines the efficacy of antitumor immunity, while it can be regulated at the epigenetic level by various factors, including HDACs. In this study, we aim to evaluate the expression patterns of PD-L1 in thymic epithelial tumors (TETs), while we attempt the first correlation analysis between PD-L1 and histone deacetylases (HDACs) expression. Methods: Immunohistochemistry was used to evaluate the expression of PD-L1 in tumor and immune cells of 91 TETs with SP263 and SP142 antibody clones, as well as the expressions of HDCA1, -2, -3, -4, -5, and -6. Results: The PD-L1 tumor proportion score (TPS) was higher, while the immune cell score (IC-score) was lower in the more aggressive TET subtypes and in more advanced Masaoka–Koga stages. A positive correlation between PD-L1 and HDAC-3, -4, and -5 cytoplasmic expression was identified. Conclusions: Higher PD-L1 expression in neoplastic cells and lower PD-L1 expression in immune cells of TETs characterizes more aggressive and advanced neoplasms. Correlations between PD-L1 and HDAC expression unravel the impact of epigenetic regulation on the expression of immune checkpoint molecules in TETs, with possible future applications in combined therapeutic targeting. Full article
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<p>Immunohistochemical expression of PD-L1 with SP263 in different TET subtypes. (<b>A</b>) TET subtype A, (<b>B</b>) TET subtype B2, (<b>C</b>) TET subtype B3 (Magnification ×40).</p> Full article ">Figure 2
<p>Schematic representation of the association between PD-L1 (SP263) TPS and WHO TET subtypes (<b>left panel</b>), as well as Masaoka–Koga stage (<b>right panel</b>). Dots represent outliers. TC, thymic carcinoma; TETs, thymic epithelial tumors.</p> Full article ">Figure 3
<p>Schematic representation of the distributions of various PD-L1 (SP263) IC-score categories among WHO TET subtypes (<b>left panel</b>), as well as Masaoka–Koga stage (<b>right panel</b>). IC-score, immune cell score; TC, thymic carcinoma; TETs, thymic epithelial tumors.</p> Full article ">Figure 4
<p>Immunohistochemical expression of PD-L1 with SP142 in different TET subtypes. (<b>A</b>) TET subtype A, (<b>B</b>) TET subtype B2, (<b>C</b>) TET subtype B3 (Magnification ×40).</p> Full article ">Figure 5
<p>Schematic representation of the association between PD-L1 (SP142) TPS and WHO TET subtypes (<b>left panel</b>), as well as Masaoka–Koga stage (<b>right panel</b>). Dots represent outliers. TC, thymic carcinoma; TETs, thymic epithelial tumors.</p> Full article ">Figure 6
<p>Schematic representation of the distributions of various PD-L1 (SP142) IC-score categories among WHO TET subtypes (<b>left panel</b>), as well as Masaoka–Koga stage (<b>right panel</b>). IC-score, immune cell score; TC, thymic carcinoma; TETs, thymic epithelial tumors.</p> Full article ">
19 pages, 4655 KiB  
Article
The FLNC Ala1186Val Variant Linked to Cytoplasmic Body Myopathy and Cardiomyopathy Causes Protein Instability
by Marion Onnée, Audrey Bénézit, Sultan Bastu, Aleksandra Nadaj-Pakleza, Béatrice Lannes, Flavie Ader, Corinne Thèze, Pascal Cintas, Claude Cances, Robert-Yves Carlier, Corinne Metay, Mireille Cossée and Edoardo Malfatti
Biomedicines 2024, 12(2), 322; https://doi.org/10.3390/biomedicines12020322 - 30 Jan 2024
Cited by 2 | Viewed by 1827
Abstract
Filamin C-related disorders include myopathies and cardiomyopathies linked to variants in the FLNC gene. Filamin C belongs to a family of actin-binding proteins involved in sarcomere stability. This study investigates the pathogenic impact of the FLNC c.3557C > T (p.Ala1186Val) pathogenic variant associated [...] Read more.
Filamin C-related disorders include myopathies and cardiomyopathies linked to variants in the FLNC gene. Filamin C belongs to a family of actin-binding proteins involved in sarcomere stability. This study investigates the pathogenic impact of the FLNC c.3557C > T (p.Ala1186Val) pathogenic variant associated with an early-onset cytoplasmic body myopathy and cardiomyopathy in three unrelated patients. We performed clinical imaging and myopathologic and genetic characterization of three patients with an early-onset myopathy and cardiomyopathy. Bioinformatics analysis, variant interpretation, and protein structure analysis were performed to validate and assess the effects of the filamin C variant. All patients presented with a homogeneous clinical phenotype marked by a severe contractural myopathy, leading to loss of gait. There was prominent respiratory involvement and restrictive or hypertrophic cardiomyopathies. The Ala1186Val variant is located in the interstrand loop involved in intradomain stabilization and/or interdomain interactions with neighbor Ig-like domains. 3D modeling highlights local structural changes involving nearby residues and probably impacts the protein stability, causing protein aggregation in the form of cytoplasmic bodies. Myopathologic studies have disclosed the prominent aggregation and upregulation of the aggrephagy-associated proteins LC3B and p62. As a whole, the Ala1186Val variant in the FLNC gene provokes a severe myopathy with contractures, respiratory involvement, and cardiomyopathy due to protein aggregation in patients’ muscles. Full article
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<p>P1 MRI coronal views of the thoraco-lumbar spine before (<b>A</b>) and after (<b>B</b>–<b>D</b>) spine arthrodesis. Coronal and lateral radiographs of the spine in the patient in the sitting position (<b>B</b>,<b>C</b>). The right thoraco-lumbar inflexion is significantly reduced by the surgical fixation, but the rotation of the vertebral bodies is not totally corrected (<b>D</b>).</p> Full article ">Figure 2
<p>Selection of axial views performed from head to toes in a single multistacks MRI examination with a T2 Dixon sequence. All axial fat images (<b>A</b>–<b>L</b>) are comparable to T1-weighted images, and the water image (<b>F’</b>) is comparable to the T2-fat-saturated or STIR image. The examination showed that diffuse muscle atrophy was more pronounced in the paraspinal muscles, as well as in the abdominal belt and pelvic girdle areas. In the T2-fat-saturated image (water image, <b>F’</b>).</p> Full article ">Figure 3
<p>Selection of axial views performed from head to toes in a single multistacks MRI examination with a T2 Dixon sequence. All axial fat images (<b>A</b>–<b>K</b>) are comparable to T1-weighted images and performed at the same location as images A to L in <a href="#biomedicines-12-00322-f002" class="html-fig">Figure 2</a>. The examination showed a severe increase in the atrophy of all muscles, as well as an increase in the fat contents of the muscles.</p> Full article ">Figure 4
<p>P1 and P3 light microscopy morphological analysis. Myopathic changes observed in these two patients include internalized nuclei, cytoplasmic bodies (yellow arrowhead), rimmed vacuoles (black arrowhead), and inclusion bodies (white arrowhead) (<b>A</b>,<b>E</b>). Cytoplasmic bodies appear to be fuchsinophilic with Gömöri trichrome staining (<b>B</b>) and are easily recognizable at oxidative staining as they misplace the mitochondrial network (<b>C</b>,<b>F</b>). Desmin reactivity was evident at the periphery of and in the areas surrounding the cytoplasmic bodies (<b>G</b>). Pronounced fiber size variability with type 2 fibers’ atrophy and type 1 fibers’ predominance are also observed (<b>D</b>,<b>H</b>). Samples were derived from muscles of P1 (<b>A</b>–<b>D</b>) and P3 (<b>E</b>–<b>H</b>). (<b>A</b>): H&amp;E; (<b>B</b>): Gömöri trichrome; (<b>C</b>): COX; (<b>D</b>): Fast myosin immunohistochemistry; (<b>E</b>): H&amp;E; (<b>F</b>): NADH; (<b>G</b>): Desmin staining; (<b>H</b>): ATPase 9.4. Scale bars: 20 µm (<b>A</b>–<b>D</b>) and 50 µm (<b>E</b>–<b>H</b>).</p> Full article ">Figure 5
<p>P1 electron microscopy ultrastructural analysis. Cytoplasmic bodies are visible in (<b>A</b>,<b>B</b>). Massive disorganization of the sarcomeric structure associated with clusters of mitochondria (white arrowheads) (<b>C</b>,<b>D</b>). Lipofuscin residual bodies are also observed (black arrowhead) (<b>D</b>).</p> Full article ">Figure 6
<p>Two-dimensional and three-dimensional <span class="html-italic">FLNC</span> protein structures. (<b>A</b>) Schematic representation of human filamin C monomer with the actin-binding domain, different Ig domains forming Rods (ROD1, Ig1 to Ig15; ROD2, Ig16 to Ig23), and dimerization domain (Ig24). Hinges 1 and 2 are also indicated. Ig20 is bigger than other Ig domains because it presents an insertion of 83 amino acids compared to the other FLN proteins. The Ala1186 residue is located in Ig10 (shown by *). We note that hinge 1 of <span class="html-italic">FLNC</span> is spliced out during myogenesis. (<b>B</b>) The Ala1186Val missense variant is located in a conserved region among twelve different species. (<b>C</b>) Sequence alignment of the Ig10 domains of human FLNA, FLNB, and <span class="html-italic">FLNC</span>. The ESPript 3.0 server was used to output the alignment. The sequences’ and secondary structures’ depictions of our <span class="html-italic">FLNC</span>-Ig10 model and the FLNA-Ig10 (PDB: 3RGH) are also shown. The red box indicates a strict identity between all three FLN Ig10 protein sequences, while blue boxes indicate sequences presenting a similarity across at least two protein sequences. (<b>D</b>) Rainbow-colored 3D model of <span class="html-italic">FLNC</span>-Ig10 from N-terminus (blue) to the C-terminus (red). This model is based on the FLNA-Ig10 crystal structure (3RGH) using SWISS-MODEL. ꞵ-Strands are labeled from A to G, and interstrand loops are also labeled. The Ala1186 residue is shown in magenta, the side chain is represented as a ball and stick, and hydrogens atoms are represented as white balls. (<b>E</b>–<b>G</b>) Zoomed-in image of the Ala1186 residue and the mutated Val1186 residue, indicated in magenta. The residues at &lt;5 Å of the 1186 residue are shown in stick representation with colored atoms (H in white, O in red, and N in blue) and are labeled. Hydrophobic interactions are shown by black lines and within the circle (dotted lines for carbon–carbon interactions and black circle for non-polar interactions), and hydrogen bonds are shown in red lines (dotted lines for weak C–H⋯O interactions and solid lines for strong N–H⋯O interaction). (<b>E</b>) Zoomed-in image of the Ala1186 residue and its interactions with nearby residues. (<b>F</b>) Zoomed-in image of the mutated Val1186 residue, and clashes with nearby residues are shown in red while contacts are shown as cyan lines. (<b>G</b>) Zoomed-in version of the mutated Val1186 residue after the minor minimization of mutated and nearby residues.</p> Full article ">Figure 7
<p><span class="html-italic">FLNC</span> protein expression in muscle from P1 and control. (<b>A</b>) Immunofluorescence staining of nuclei (blue), laminin (red), and <span class="html-italic">FLNC</span> (green). Scale bar: 50 µm and 20 µm in zoomed-in images. (<b>B</b>) Soluble <span class="html-italic">FLNC</span> proteins in muscle homogenates from two controls and the patient. ꞵ-actin is used as the loading control. (<b>C</b>) Insoluble <span class="html-italic">FLNC</span> proteins representing <span class="html-italic">FLNC</span> aggregates in muscle biopsies from the patient and controls. Ponceau red is used as the loading control.</p> Full article ">Figure 8
<p>Immunofluorescence findings in muscle from P1 and the control. (<b>A</b>) Immunofluorescence analysis showing accumulations of <span class="html-italic">FLNC</span>, p62, and LC3B in myofibers from the patient’s muscle, which was not observed in the control. As shown by the histogram, we quantified the fluorescent signal of p62 and LC3B staining as the percentage of total area in the control’s and patient’s muscle biopsies. In the patient, LC3B colocalized with <span class="html-italic">FLNC</span> aggregates (<b>B</b>), whereas P62 accumulated inside the structure where <span class="html-italic">FLNC</span> accumulated but did not colocalize with <span class="html-italic">FLNC</span> (<b>C</b>). Colocalization analyses are presented as scatter plots with the Pearson coefficient (<b>B</b>,<b>C</b>). Scale bars: 50 µm and 25 µm in zoomed-in images (<b>B</b>,<b>C</b>).</p> Full article ">

2023

Jump to: 2024, 2022

12 pages, 806 KiB  
Review
Chemical Transdifferentiation of Somatic Cells: Unleashing the Power of Small Molecules
by Yu Zhang, Xuefeng Li, Jianyu Xing, Jinsong Zhou and Hai Li
Biomedicines 2023, 11(11), 2913; https://doi.org/10.3390/biomedicines11112913 - 27 Oct 2023
Cited by 4 | Viewed by 2568
Abstract
Chemical transdifferentiation is a technique that utilizes small molecules to directly convert one cell type into another without passing through an intermediate stem cell state. This technique offers several advantages over other methods of cell reprogramming, such as simplicity, standardization, versatility, no ethical [...] Read more.
Chemical transdifferentiation is a technique that utilizes small molecules to directly convert one cell type into another without passing through an intermediate stem cell state. This technique offers several advantages over other methods of cell reprogramming, such as simplicity, standardization, versatility, no ethical and safety concern and patient-specific therapies. Chemical transdifferentiation has been successfully applied to various cell types across different tissues and organs, and its potential applications are rapidly expanding as scientists continue to explore new combinations of small molecules and refine the mechanisms driving cell fate conversion. These applications have opened up new possibilities for regenerative medicine, disease modeling, drug discovery and tissue engineering. However, there are still challenges and limitations that need to be overcome before chemical transdifferentiation can be translated into clinical practice. These include low efficiency and reproducibility, incomplete understanding of the molecular mechanisms, long-term stability and functionality of the transdifferentiated cells, cell-type specificity and scalability. In this review, we compared the commonly used methods for cell transdifferentiation in recent years and discussed the current progress and future perspective of the chemical transdifferentiation of somatic cells and its potential impact on biomedicine. We believe that with ongoing research and technological advancements, the future holds tremendous promise for harnessing the power of small molecules to shape the cellular landscape and revolutionize the field of biomedicine. Full article
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<p>miRNAs regulate target mRNAs by disrupting their stability or inhibiting their translation.</p> Full article ">Figure 2
<p>Perspectives of chemical transdifferentiation in biomedicines.</p> Full article ">
16 pages, 2185 KiB  
Systematic Review
Prospect of Mesenchymal Stem-Cell-Conditioned Medium in the Treatment of Acute Pancreatitis: A Systematic Review
by Ke Pang, Fanyi Kong and Dong Wu
Biomedicines 2023, 11(9), 2343; https://doi.org/10.3390/biomedicines11092343 - 23 Aug 2023
Cited by 3 | Viewed by 2042
Abstract
Mesenchymal stem cells (MSCs) have demonstrated potential in both clinical and pre-clinical research for mitigating tissue damage and inflammation associated with acute pancreatitis (AP) via paracrine mechanisms. Hence, there has been a recent surge of interest among researchers in utilizing MSC cultured medium [...] Read more.
Mesenchymal stem cells (MSCs) have demonstrated potential in both clinical and pre-clinical research for mitigating tissue damage and inflammation associated with acute pancreatitis (AP) via paracrine mechanisms. Hence, there has been a recent surge of interest among researchers in utilizing MSC cultured medium (CM) and its components for the treatment of AP, which is recognized as the primary cause of hospitalization for gastrointestinal disorders globally. A systematic review was conducted by searching the MEDLINE, EMBASE, and Web of Science databases. Studies that involve the administration of MSC-CM, extracellular vesicles/microvesicles (EVs/MVs), or exosomes to AP animal models are included. A total of six research studies, including eight experiments, were identified as relevant. The findings of this study provide evidence in favor of a beneficial impact of MSC-CM on both clinical and immunological outcomes. Nevertheless, prior to clinical trials, large animal models should be used and prolonged observation periods conducted in pre-clinical research. Challenges arise due to the lack of standardization and consensus on isolation processes, quantifications, and purity testing, making it difficult to compare reports and conduct meta-analyses in MSC-CM-based therapies. Full article
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<p>A flow chart displaying the studies that qualify for the review.</p> Full article ">Figure 2
<p>Risk of bias assessment in individual studies [<a href="#B32-biomedicines-11-02343" class="html-bibr">32</a>,<a href="#B33-biomedicines-11-02343" class="html-bibr">33</a>,<a href="#B34-biomedicines-11-02343" class="html-bibr">34</a>,<a href="#B35-biomedicines-11-02343" class="html-bibr">35</a>,<a href="#B36-biomedicines-11-02343" class="html-bibr">36</a>,<a href="#B37-biomedicines-11-02343" class="html-bibr">37</a>].</p> Full article ">Figure 3
<p>The therapeutic roles of MSC-based therapy in inflammatory pancreatic diseases. Created with <a href="http://BioRender.com" target="_blank">BioRender.com</a>.</p> Full article ">Figure A1
<p>The summary for risk of bias of the included studies.</p> Full article ">
13 pages, 2529 KiB  
Article
Naturally Occurring N-Terminal Fragments of Bovine Milk Osteopontin Are Transported across Models of the Intestinal Barrier
by Brian Christensen, Nanna R. Nielsen, Marie R. Sørensen, Lotte N. Jacobsen, Marie S. Ostenfeld and Esben S. Sørensen
Biomedicines 2023, 11(3), 893; https://doi.org/10.3390/biomedicines11030893 - 14 Mar 2023
Cited by 8 | Viewed by 2212
Abstract
Osteopontin (OPN) is a bioactive integrin-binding protein found in high concentrations in milk, where it is present both as a full-length protein and as several N-terminally derived fragments. OPN resists gastric digestion, and via interaction with receptors in the gut or by crossing [...] Read more.
Osteopontin (OPN) is a bioactive integrin-binding protein found in high concentrations in milk, where it is present both as a full-length protein and as several N-terminally derived fragments. OPN resists gastric digestion, and via interaction with receptors in the gut or by crossing the intestinal barrier into circulation, ingested milk OPN may influence physiological processes. The aim of this study was to investigate OPN interaction with intestinal cells and its transport across models of the intestinal barrier. Immunodetection of OPN incubated with Caco-2 cells at 4 °C and 37 °C showed that OPN binds to the intestinal cells, but it is not internalised. Transepithelial transport was studied using mono- and co-cultures of Caco-2 cells and mucus-producing HT29-MTX cells in transwell membranes. OPN was shown to cross the barrier models in a time-, temperature-, and energy-dependent process inhibited by wortmannin, indicating that the transport takes place via the transcytosis pathway. Analyses of the naturally occurring milk mixture of full-length and N-terminal fragments showed that the N-terminal fragments of OPN bound intestinal cells most effectively and that the fragments were transported across the intestinal membrane models. This suggests that proteolytic processing of OPN increases its biological activity after ingestion. Full article
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<p>ELISA of intestinal Caco-2 cell lysates incubated with osteopontin (OPN). Caco-2 monolayers were incubated with serum-free medium (SFM) or OPN, washed extensively, and lysed. The OPN content in lysates was quantified by ELISA and normalised to the total protein concentration in the lysates. (<b>A</b>) Cells incubated with OPN at the indicated concentration for 2 h. (<b>B</b>) Cells incubated with 50 µg/mL OPN for the indicated times. (<b>C</b>) Cells incubated with SFM or OPN for 2 h at 4 °C or 37 °C. In (<b>A</b>–<b>C</b>), data are expressed as mean ± SD (n = 4) and the experiments were repeated two to three times. (<b>D</b>) Cytotoxicity of OPN was evaluated using an MTT assay. Cells were incubated with OPN (50, 100, or 200 μg/mL) or SFM for 2 h. Data are expressed as mean ± SD (n = 10) and are representative of three individual experiments. Statistical analysis: one-way ANOVA followed by Dunnett’s test (<b>A</b>,<b>D</b>), one-way ANOVA followed by Tukey’s test (<b>B</b>), or two-way ANOVA (<b>C</b>) followed by Bonferroni’s test. Different letters indicate significant differences, <span class="html-italic">p &lt;</span> 0.05.</p> Full article ">Figure 2
<p>Western blotting of Caco-2 cell lysates after incubation with osteopontin (OPN), full-length OPN, or N-terminal OPN fragments separated by gel filtration. Cell lysates were incubated with anti-OPN IgG-coupled Dynabeads before Western blotting, and OPN was detected using the biotinylated anti-OPN antibody MAB193p. (<b>A</b>) Lane 1, 100 ng OPN (positive control for purification); lane 2, cells incubated without OPN; lanes 3–5, cells incubated with OPN (lane 3, 100 μg/mL; lane 4, 50 μg/mL; lane 5, 10 μg/mL); lanes 6–8, cells incubated with full-length OPN (lane 6, 100 μg/mL; lane 7, 50 μg/mL; lane 8, 10 μg/mL); lanes 9–11, cells incubated with N-terminal OPN fragments (lane 9, 100 μg/mL; lane 10, 50 μg/mL; lane 11, 10 μg/mL). (<b>B</b>) Cell lysates incubated with PP3. PP3 was purified from lysates with anti-PP3 IgG-coupled Dynabeads before Western blotting. Lane 1, 100 ng PP3; lane 2; cells incubated without PP3; lanes 3–5, cells incubated with PP3 (lane 3, 100 μg/mL; lane 4, 50 μg/mL; lane 5, 10 μg/mL). Both blots are representative of three individual experiments.</p> Full article ">Figure 3
<p>Epithelial transport of osteopontin (OPN). Caco-2 cells were grown on transwell membranes and incubated with OPN in the apical compartment representing the intestinal luminal side. Samples from apical and basolateral compartments were collected separately after the indicated times, and OPN was detected in the medium by Western blotting using polyclonal anti-OPN antibodies. The Western blot of the apical sample is from medium collected after 2 h incubation with OPN, and it is representative of all incubation times. The blots are representative of three individual experiments.</p> Full article ">Figure 4
<p>Inhibition of epithelial transport of osteopontin (OPN). Caco-2 cells were grown on transwell membranes and incubated with OPN in the apical compartment representing the intestinal luminal side. The cells were pre-incubated with inhibitor solutions or incubated at 4 °C for 2 h before OPN was added, and then incubated for 2 h in the presence of inhibitors. OPN was detected in the basolateral medium by Western blotting using polyclonal anti-OPN antibodies. (<b>A</b>) Lane 1, cells incubated with OPN; lanes 2–5, cells incubated with OPN in the presence of inhibitors (lane 2, 10 mM Gly-Sar; lane 3, 0.5 μg/mL Cytochalasin D; lanes 4–5, 1 μM and 0.5 μM wortmannin. (<b>B</b>) Lanes 1–2, cells incubated with OPN at 37 °C; lanes 3–4; cells incubated with OPN at 37 °C in the presence of 10 mM NaN<sub>3</sub>; lanes 5–6, cells incubated with OPN at 4 °C. The blots are representative of three (<b>A</b>) or two (<b>B</b>) individual experiments.</p> Full article ">Figure 5
<p>Epithelial transport of osteopontin (OPN) across Caco-2/HT29-MTX monolayers after simulated gastrointestinal digestion. Cells were seeded at different Caco-2:HT29-MTX proportions on transwell membranes. Undigested OPN (U) and OPN after simulated gastric digestion (with pepsin (G)) or gastrointestinal digestion (with pepsin and subsequently trypsin, chymotrypsin, and elastase (G/I)) was added to the apical compartment of the monolayers. Cells only added serum-free medium (-) were used as control. After 2 h, apical and basolateral medium was analysed by Western blotting using polyclonal anti-OPN IgG. (<b>A</b>) Apical samples are representative for all Caco-2:HT29-MTX proportions. (<b>B</b>) Basolateral samples from the different cell cultures. The Caco-2:HT29-MTX seeding proportions are given above the gels. The blots are representative of two individual experiments.</p> Full article ">Figure 6
<p>Epithelial transport of PP3 across Caco-2/HT29-MTX monolayers. Cells were grown at different Caco-2:HT29-MTX proportions on transwell membranes. PP3 was added to the apical compartment of the monolayers, and after 2 h, apical and basolateral medium was analysed by Western blotting using polyclonal anti-PP3 IgG. The Western blot of the apical sample is representative of all Caco-2:HT29-MTX proportions. For basolateral samples, the Caco-2:HT29-MTX proportions are given above the gels. The blots are representative of two individual experiments.</p> Full article ">
13 pages, 1646 KiB  
Article
Smooth Muscle Cells of Dystrophic (mdx) Mice Are More Susceptible to Hypoxia; The Protective Effect of Reducing Ca2+ Influx
by Arkady Uryash, Alfredo Mijares, Eric Estève, Jose A. Adams and Jose R. Lopez
Biomedicines 2023, 11(2), 623; https://doi.org/10.3390/biomedicines11020623 - 19 Feb 2023
Cited by 1 | Viewed by 1857
Abstract
Duchenne muscular dystrophy (DMD) is an inherited muscular disorder caused by mutations in the dystrophin gene. DMD patients have hypoxemic events due to sleep-disordered breathing. We reported an anomalous regulation of resting intracellular Ca2+ ([Ca2+]i) in vascular smooth [...] Read more.
Duchenne muscular dystrophy (DMD) is an inherited muscular disorder caused by mutations in the dystrophin gene. DMD patients have hypoxemic events due to sleep-disordered breathing. We reported an anomalous regulation of resting intracellular Ca2+ ([Ca2+]i) in vascular smooth muscle cells (VSMCs) from a mouse (mdx) model of DMD. We investigated the effect of hypoxia on [Ca2+]i in isolated and quiescent VSMCs from C57BL/10SnJ (WT) and C57BL/10ScSn-Dmd (mdx) male mice. [Ca2+]i was measured using Ca2+-selective microelectrodes under normoxic conditions (95% air, 5% CO2) and after hypoxia (glucose-free solution aerated with 95% N2-5% CO2 for 30 min). [Ca2+]i in mdx VSMCs was significantly elevated compared to WT under normoxia. Hypoxia-induced [Ca2+]i overload, which was significantly greater in mdx than in WT VSMCs. A low Ca2+ solution caused a reduction in [Ca2+]i and prevented [Ca2+]i overload secondary to hypoxia. Nifedipine (10 µM), a Ca2+ channel blocker, did not modify resting [Ca2+]i in VSMCs but partially prevented the hypoxia-induced elevation of [Ca2+]i in both genotypes. SAR7334 (1 µM), an antagonist of TRPC3 and TRPC6, reduced the basal and [Ca2+]i overload caused by hypoxia. Cell viability, assessed by tetrazolium salt (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, was significantly reduced in mdx compared to WT VSMCs. Pretreatment with SAR7341 increases cell viability in normoxic mdx (p < 0.001) and during hypoxia in WT and mdx VSMCs. These results provide evidence that the lack of dystrophin makes VSMCs more susceptible to hypoxia-induced [Ca2+]i overload, which appears to be mediated by increased Ca2+ entry through L-type Ca2+ and TRPC channels. Full article
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<p><b><span class="html-italic">Effects of hypoxia on resting membrane potential and [Ca<sup>2+</sup>]<sub>i</sub> in WT and mdx VSMCs</span>.</b> (<b>A</b>) The average resting membrane potential in normoxic WT was −63 ± 2 mV, while in mdx it was 54 ± 3 mV (<span class="html-italic">p</span> &lt; 0.001 compared to WT). Acute hypoxia caused a significant depolarization in WT (52 ± 3 mV) and mdx (41 ± 3 mV). (<b>B</b>) [Ca<sup>2+</sup>]<sub>i</sub> in the WT VSMCs was (123 ± 3 nM) while in <span class="html-italic">mdx</span> it was significantly more elevated (285 ± 31 nM (<span class="html-italic">p</span> &lt; 0.001 compared to WT). Hypoxia caused in WT VSMCs an elevation of [Ca<sup>2+</sup>]<sub>i</sub> to 980 ± 119 nM and in mdx to 2962 ± 287 nM (<span class="html-italic">p</span> &lt; 0.001 compared to WT). <span class="html-italic">n</span><sub>mice</sub> = 5 WT and 7 mdx, <span class="html-italic">n</span><sub>cell</sub> = 17–23 for WT, and 11–20 for mdx. The values were expressed as means ± S.D; *** <span class="html-italic">p</span> &lt; 0.001.</p> Full article ">Figure 2
<p><b><span class="html-italic">The role of extracellular Ca<sup>2+</sup> in hypoxia-induced [Ca<sup>2+</sup>]<sub>i</sub> overload</span>.</b> Reduced [Ca<sup>2+</sup>]<sub>e</sub> caused a significant decrease in [Ca<sup>2+</sup>]<sub>i</sub> in WT from 122 ± 3 to 94 ± 5 nM (<span class="html-italic">p</span> &lt; 0.0001 compared to untreated) and <span class="html-italic">mdx</span> VSMC from 285 ± 31 nM to 128 ± 10 (<span class="html-italic">p</span> &lt; 0.0001 compared to untreated). Incubation in a low Ca<sup>2+</sup> solution consistently inhibited hypoxia-induced increases in [Ca<sup>2+</sup>]<sub>i</sub> in both genotypes. The insert shows the percentage of inhibition induced by lowering [Ca<sup>2+</sup>]<sub>e</sub> in acute hypoxia. <span class="html-italic">n</span><sub>mice</sub> = 3 per genotype, <span class="html-italic">n</span><sub>cell</sub> = 17–23 for WT and 17–20 for <span class="html-italic">mdx</span>. The values were expressed as means ± S.D; *** <span class="html-italic">p</span> &lt; 0.001.</p> Full article ">Figure 3
<p><b><span class="html-italic">Effects of nifedipine on</span><span class="html-italic">hypoxia-induced alteration of [Ca<sup>2+</sup>]<sub>i</sub></span><sub>.</sub></b> Nifedipine 10 µM did not modify resting [Ca<sup>2+</sup>]<sub>i</sub> in WT or <span class="html-italic">mdx</span> VSMC compared to untreated VSMCs. However, nifedipine partially prevented the magnitude of elevation of [Ca<sup>2+</sup>]<sub>i</sub> associated with hypoxia in both genotypes. In WT VSMCs pretreated with nifedipine [Ca<sup>2+</sup>]<sub>i</sub> was 760 ± 52 nM (<span class="html-italic">p</span> &lt; 0.0001 compared to untreated WT,) while the <span class="html-italic">mdx</span> VSMCs was 2013 ± 366 nM ( <span class="html-italic">p</span> &lt; 0.0001compared to untreated <span class="html-italic">mdx.</span> The insert shows the percentage of inhibition induced by nifedipine under acute hypoxia. <span class="html-italic">N</span><sub>mice</sub> = 4 per genotype, <span class="html-italic">n</span><sub>cell</sub> = 14–23 for WT and 14–20 for <span class="html-italic">mdx</span>. The values were expressed as means ± S.D; ns <span class="html-italic">p</span> &gt; 0.05, *** <span class="html-italic">p</span> &lt; 0.001.</p> Full article ">Figure 4
<p><b><span class="html-italic">SAR7334 blocked hypoxia-induced elevation of [Ca<sup>2+</sup>]<sub>i</sub></span>.</b> [Ca<sup>2+</sup>]<sub>i</sub> was measured in VSMCs isolated from WT and <span class="html-italic">mdx</span> mice before and after incubation in SAR7374 (1 µM), as well as during hypoxia. Preincubation in SAR7374 significantly reduced [Ca<sup>2+</sup>]<sub>i</sub> in WT VSMCs from 123 ± 3 nM to 100 ± 6 nM and in <span class="html-italic">mdx</span> VSMCs from 285 ± 31 nM to 154 ± 15 nM. In WT SAR7334 pretreated VSMCs hypoxia caused an elevation to 342 ± 38nM and in <span class="html-italic">mdx</span> VSMCs to 837 ± 95 nM. The insert shows the percentage of inhibition induced by SAR7341 during hypoxia. <span class="html-italic">N</span><sub>mice</sub> = 4 per genotype, <span class="html-italic">n</span><sub>cell</sub> = 15–23 for WT and 15–20 for <span class="html-italic">mdx</span>. The values were expressed as means ± S.D; ** <span class="html-italic">p</span> &lt; 0.01, *** <span class="html-italic">p</span> &lt; 0.001.</p> Full article ">Figure 5
<p><b><span class="html-italic">Effects of SAR7334 on cell viability</span></b>. The viability of <span class="html-italic">mdx</span> VSMC was significantly less than in WT VSMC under normoxic conditions and SAR7334 treatment increased the viability of <span class="html-italic">mdx</span> VSMC compared to untrtreated <span class="html-italic">mdx</span> VSMC (<span class="html-italic">p</span> &lt; 0.001). Hypoxia decreased cell viability in WT and <span class="html-italic">mdx</span> VSMCs and pretreatment with SAR7334 increased cell viability in both groups during hypoxia, compared to untreated WT and <span class="html-italic">mdx</span> VSMC (<span class="html-italic">p</span> &lt; 0.001, respectively). Cell viability data was obtained from <span class="html-italic">n</span><sub>mice</sub> = 3/group and <span class="html-italic">n</span><sub>cells</sub> = 10–15/group. All values were normalized to the control untreated VSMCs and expressed as mean ± S.D; *** <span class="html-italic">p</span> &lt; 0.001.</p> Full article ">

2022

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22 pages, 2630 KiB  
Review
The Role of Hsp27 in Chemotherapy Resistance
by Marios Lampros, Nikolaos Vlachos, Spyridon Voulgaris and George A. Alexiou
Biomedicines 2022, 10(4), 897; https://doi.org/10.3390/biomedicines10040897 - 14 Apr 2022
Cited by 29 | Viewed by 4669
Abstract
Heat shock protein (Hsp)-27 is a small-sized, ATP-independent, chaperone molecule that is overexpressed under conditions of cellular stress such as oxidative stress and heat shock, and protects proteins from unfolding, thus facilitating proteostasis and cellular survival. Despite its protective role in normal cell [...] Read more.
Heat shock protein (Hsp)-27 is a small-sized, ATP-independent, chaperone molecule that is overexpressed under conditions of cellular stress such as oxidative stress and heat shock, and protects proteins from unfolding, thus facilitating proteostasis and cellular survival. Despite its protective role in normal cell physiology, Hsp27 overexpression in various cancer cell lines is implicated in tumor initiation, progression, and metastasis through various mechanisms, including modulation of the SWH pathway, inhibition of apoptosis, promotion of EMT, adaptation of CSCs in the tumor microenvironment and induction of angiogenesis. Investigation of the role of Hsp27 in the resistance of various cancer cell types against doxorubicin, herceptin/trastuzumab, gemcitabine, 5-FU, temozolomide, and paclitaxel suggested that Hsp27 overexpression promotes cancer cell survival against the above-mentioned chemotherapeutic agents. Conversely, Hsp27 inhibition increased the efficacy of those chemotherapy drugs, both in vitro and in vivo. Although numerous signaling pathways and molecular mechanisms were implicated in that chemotherapy resistance, Hsp27 most commonly contributed to the upregulation of Akt/mTOR signaling cascade and inactivation of p53, thus inhibiting the chemotherapy-mediated induction of apoptosis. Blockage of Hsp27 could enhance the cytotoxic effect of well-established chemotherapeutic drugs, especially in difficult-to-treat cancer types, ultimately improving patients’ outcomes. Full article
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<p>Summary of Hsp27-mediated modulation of the Salvador-Warts-Hippo (SWH) pathway, eventually leading to tumorigenesis. Green indicates activation, Red indicates inhibition. Key: MST1, macrophage stimulating 1; LATS1, large tumor suppressor kinase 1; MOB1, MOB Kinase activator 1A; YAP, Yes-associated protein; TAZ, PDZ-binding motif.</p> Full article ">Figure 2
<p>Summary of the molecular mechanisms of Hsp27-mediated promotion of Epithelial-mesenchymal transition (EMT). Green indicates activation. Key: EMT, epithelial to mesenchymal transition; EGF, epidermal growth factor; STAT3, signal transducer and activator of transcription 3; NF-kb, nuclear factor kappa-light-chain-enhancer of activated B cells; IL-6, interleukin 6.</p> Full article ">Figure 3
<p>Summary of Hsp27-mediated molecular mechanisms which enable cancer stem cells to survive tumor microenvironment stresses. Green indicates activation. Key: CSC, cancer stem cells; PI3, phosphatidylinositol-3-kinase; mTOR, mammalian target of rapamycin.</p> Full article ">Figure 4
<p>Summary of Hsp27-mediated inhibition of apoptosis. Green indicates activation, Red indicates inhibition. Key: PI3, phosphatidylinositol-3-kinase.</p> Full article ">Figure 5
<p>Summary of the proposed mechanisms by which Hsp27 induces doxorubicin chemoresistance. Hsp27 overexpression or overactivation results in inhibition of p53, a key molecule involved in doxorubicin induced apoptosis and cell cycle arrest. Key: DOX, doxorubicin; ROS, reactive oxygen species; STAT3, signal transducer and activator of transcription 3; NF-kb, nuclear factor kappa-light-chain-enhancer of activated B cells; ATM, ataxia-telangiectasia mutated kinase.</p> Full article ">Figure 6
<p>Summary of the proposed mechanisms by which Hsp27 mediates gemcitabine chemoresistance. Hsp27 overexpression or phosphorylation, through different molecular pathways, results in inhibition of apoptosis, promotion of EMT and repair of gemcitabine-induced DNA damage. Key: SNAIL, zinc finger protein SNAI1; EMT, epithelial to mesenchymal transition; ERCC1, effects of excision repair cross-complementation group 1; mTOR, mammalian target of rapamycin; CHK1, checkpoint kinase 1; eIF4e, eukaryotic translation initiation factor 4E.</p> Full article ">Figure 7
<p>Summary of the molecular mechanisms of Hsp27-mediated resistance against 5-Fluorouracil (5-FU). Inhibition of both intrinsic and extrinsic apoptotic pathways play a key role in the 5-FU resistance. Key: NOTCH1, notch homolog 1; mTOR, mammalian target of rapamycin.</p> Full article ">
23 pages, 19124 KiB  
Review
Ion Channels and Transporters as Therapeutic Agents: From Biomolecules to Supramolecular Medicinal Chemistry
by Giacomo Picci, Silvia Marchesan and Claudia Caltagirone
Biomedicines 2022, 10(4), 885; https://doi.org/10.3390/biomedicines10040885 - 12 Apr 2022
Cited by 31 | Viewed by 9705
Abstract
Ion channels and transporters typically consist of biomolecules that play key roles in a large variety of physiological and pathological processes. Traditional therapies include many ion-channel blockers, and some activators, although the exact biochemical pathways and mechanisms that regulate ion homeostasis are yet [...] Read more.
Ion channels and transporters typically consist of biomolecules that play key roles in a large variety of physiological and pathological processes. Traditional therapies include many ion-channel blockers, and some activators, although the exact biochemical pathways and mechanisms that regulate ion homeostasis are yet to be fully elucidated. An emerging area of research with great innovative potential in biomedicine pertains the design and development of synthetic ion channels and transporters, which may provide unexplored therapeutic opportunities. However, most studies in this challenging and multidisciplinary area are still at a fundamental level. In this review, we discuss the progress that has been made over the last five years on ion channels and transporters, touching upon biomolecules and synthetic supramolecules that are relevant to biological use. We conclude with the identification of therapeutic opportunities for future exploration. Full article
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<p>(<b>a</b>) Ion channels and (<b>b</b>) ion transporters. Reproduced with permission from [<a href="#B26-biomedicines-10-00885" class="html-bibr">26</a>]. Copyright Elsevier 2022.</p> Full article ">Figure 2
<p>Cancer-associated defects of endoplasmic reticulum Ca<sup>2+</sup> homeostasis. Reproduced with permission from ref. [<a href="#B51-biomedicines-10-00885" class="html-bibr">51</a>]. Copyright Elsevier 2020.</p> Full article ">Figure 3
<p>Cystic fibrosis (CF) arises from defective anion channels on epithelial cells, due to <span class="html-italic">CFTR</span> mutations that are grouped into several classes, depending on the cellular process that results impaired. Reproduced with permission from [<a href="#B59-biomedicines-10-00885" class="html-bibr">59</a>]. Copyright Elsevier 2021.</p> Full article ">Figure 4
<p>Schematic representation of caspase-mediated apoptosis.</p> Full article ">Figure 5
<p>Fluorescence imaging in vivo after intravenous injection with SQU@PCN. Reproduced from ref. [<a href="#B143-biomedicines-10-00885" class="html-bibr">143</a>]. Copyright © 2019 American Chemical Society.</p> Full article ">Figure 6
<p>Examples of artificial ion (<b>a</b>) channels and (<b>b</b>) transporters for membrane insertion that derive from supramolecular-chemistry design.</p> Full article ">Scheme 1
<p>Chemical structures of artificial K<sup>+</sup> channels recently developed as AM agents [<a href="#B122-biomedicines-10-00885" class="html-bibr">122</a>,<a href="#B126-biomedicines-10-00885" class="html-bibr">126</a>].</p> Full article ">Scheme 2
<p>Chemical structures of <b>T15–T18</b> [<a href="#B145-biomedicines-10-00885" class="html-bibr">145</a>].</p> Full article ">
15 pages, 1303 KiB  
Review
Checkpoint Inhibitors and Induction of Celiac Disease-like Condition
by Aaron Lerner and Carina Benzvi
Biomedicines 2022, 10(3), 609; https://doi.org/10.3390/biomedicines10030609 - 4 Mar 2022
Cited by 4 | Viewed by 3718
Abstract
Immune checkpoint inhibitors herald a new era in oncological therapy-resistant cancer, thus bringing hope for better outcomes and quality of life for patients. However, as with other medications, they are not without serious side effects over time. Despite this, their advantages outweigh their [...] Read more.
Immune checkpoint inhibitors herald a new era in oncological therapy-resistant cancer, thus bringing hope for better outcomes and quality of life for patients. However, as with other medications, they are not without serious side effects over time. Despite this, their advantages outweigh their disadvantages. Understanding the adverse effects will help therapists locate, apprehend, treat, and perhaps diminish them. The major ones are termed immune-related adverse events (irAEs), representing their auto-immunogenic capacity. This narrative review concentrates on the immune checkpoint inhibitors induced celiac disease (CD), highlighting the importance of the costimulatory inhibitors in CD evolvement and suggesting several mechanisms for CD induction. Unraveling those cross-talks and pathways might reveal some new therapeutic strategies. Full article
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<p>T cell activation through checkpoint inhibitors. A schematic presentation of anti-PD-1/PD-L1 and anti-CTLA-4 agents in action. (<b>a</b>) APCs, such as dendritic cells, present processed peptides to T cells on MHC molecules. Upon activation, T cell gradually expresses on its membrane the CTLA-4. When it binds to B7-1/2, it initiates co-inhibition pathways that lead to T cell anergy. In peripheral tissues, activated T cell can be de-activated by the binding of PD-1 to PD-L1 or PD-L2. (<b>b</b>) The anti-CTLA-4 and anti-PD-1/PD-L1 monoclonal antibodies block those inhibitory pathways resulting in effective anti-tumor T lymphocyte responses.</p> Full article ">Figure 2
<p>Immune checkpoint inhibitors and celiac disease. (<b>A</b>) Gluten is ingested and digested, reaching the gut lumen as gliadin peptides. (<b>B</b>) Gliadins are rich in glutamine and proline, thus are a prime substrate for deamidation and cross-linking by luminal and mucosal transglutaminases, thus, turning those naïve molecules into immunogenic ones. Transglutaminase capacity to deamidate or transamidate, results in increased post-translation modified proteins (PTMP). Luminal digestive peptidases cannot further break down those bonds, hence, inducing gut inflammation, mucus disruption and intestinal epithelial damage. (<b>C</b>) Gluten increases intestinal permeability by binding to epithelial CXCR3 receptors, resulting in zonulin release. Gliadin-transglutaminase transformed peptides can potentially infiltrate through the open junctions or trans-enterocytically into the lamina propria. A breach in the epithelial barrier exposes the highly immunoreactive sub-epithelium to luminal foreign antigens, stimulating the local immune system. (<b>D</b>) In the lamina propria, gliadin-transglutaminase cross-linked complexes induce pro-inflammatory cytokines. Two types of DC are present, sub-epithelial DCs that send protrusions into the lumen and sense the gut microbiota, and the lamina propria DCs that migrate to lymph nodes, where they present antigens and activate T cells. Immune checkpoint inhibitors block co-inhibitory pathways unleashing effector T cells and depleting regulatory T cells. (<b>E</b>) Uncontrolled activation and proliferation of cytotoxic T lymphocytes (CTLs) further aggravate barrier perturbation, secreting IFNγ and TNFα cytokines, leading to severe intestinal damage.</p> Full article ">
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