Search Results (563)

Obesity and type 2 diabetes mellitus are global public health issues. Although males show higher obesity and insulin resistance prevalence, current treatments often neglect sex-specific differences. White adipose tissue (WAT) is crucial in preventing lipotoxicity and inflammation and has become a key therapeutic target. Rosiglitazone (RSG), a potent PPARγ agonist, promotes healthy WAT growth and mitochondrial function through MitoNEET modulation. Recent RSG-based strategies specifically target white adipocytes, avoiding side effects. Our aim was to investigate whether sex-specific differences in the insulin-sensitizing effects of RSG exist on WAT during obesity and inflammation. We used Wistar rats of both sexes fed a high-fat diet (HFD, 22.5% fat content) for 16 weeks. Two weeks before sacrifice, a group of HFD-fed rats received RSG treatment (4 mg/kg of body weight per day) within the diet. HFD male rats showed greater insulin resistance, inflammation, mitochondrial dysfunction, and dyslipidemia than females. RSG had more pronounced effects in males, significantly improving insulin sensitivity, fat storage, mitochondrial function, and lipid handling in WAT while reducing ectopic fat deposition and enhancing adiponectin signaling in the liver. Our study suggests a significant sexual dimorphism in the anti-diabetic effects of RSG on WAT, correlating with the severity of metabolic dysfunction. Full article

Photoreceptors in the mammalian retina convert light signals into electrical and molecular signals through phototransduction and transfer the visual inputs to second-order neurons via specialized ribbon synapses. Two kinds of photoreceptors, rods and cones, possess distinct morphology and function. Currently, we have limited knowledge about rod versus (vs.) cone synapse development and the associated genes. The transcription factor neural retina leucine zipper (NRL) determines the rod vs. cone photoreceptor cell fate and is critical for rod differentiation. Nrl knockout mice fail to form rods, generating all cone or S-cone-like (SCL) photoreceptors in the retina, whereas ectopic expression of Nrl using a cone-rod homeobox (Crx) promoter (CrxpNrl) forms all rods. Here, we examined rod and cone pre-synapse development, including axonal elongation, terminal shaping, and synaptic lamination in the outer plexiform layer (OPL) in the presence or absence of Nrl. We show that NRL loss and knockdown result in delayed OPL maturation and plasticity with aberrant dendrites of bipolar neurons. The integrated analyses of the transcriptome in developing rods and SCLs with NRL CUT&RUN and synaptic gene ontology analyses identified G protein subunit beta (Gnb) 1 and p21 (RAC1) activated kinase 5 (Pak5 or Pak7) transcripts were upregulated in developing rods and down-regulated in developing SCLs. Notably, Gnb1 and Gnb5 are rod dominant, and Gnb3 is enriched in cones. NRL binds to the genes of Gnb1, Gnb3, and Gnb5. NRL also regulates pre-synapse ribbon genes, and their expression is altered in rods and SCLs. Our study of histological and gene analyses provides new insights into the morphogenesis of photoreceptor pre-synapse development and regulation of associated genes in the developing retina. Full article

Genetic variants in the zone of polarizing activity regulatory sequence (ZRS) that induce ectopic expression of the SHH gene have been associated with different ZRS-related phenotypes. We report the first patient with a de novo variant, c.423+4916 T>C, in ZRS (previously classified as a variant of uncertain significance) that causes tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome (THPTTS). A two-month-old male patient presented with bilateral preaxial polydactyly, triphalangeal thumb, and tibial agenesis and was heterozygous for the variant c.423+4916T>C (neither of his parents was a carrier). The findings obtained from the family study were sufficient to reclassify the variant from “uncertain significance” to “likely pathogenic” according to three criteria from the American College of Medical Genetics and Genomics guidelines, as follows: (1) absence of gnomAD, (2) confirmation of paternity and maternity, and (3) strong phenotype–genotype association. In ZRS-associated syndromes, a wide clinical spectrum has been observed, ranging from polydactyly to THPTTS; our patient has the most severe and rare phenotype. We did not perform functional assays. However, the c.423+4916T>C variant is flanked by three variants, which have been proven not only to cause the phenotype but also to increase the expression of SHH. Through all this data gathering, we consider the c.423+4916T>C variant to be causative of THPTTS. Full article

Adenomyosis is characterized by ectopic proliferation of endometrial tissue within the myometrium. Histologically, this condition is marked by the presence of islands of benign endometrial glands surrounded by stromal cells. The myometrium appears thinner, and cross-sectional analysis often reveals signs of recent or chronic hemorrhage. The ectopic endometrial tissue may respond to ovarian hormonal stimulation, exhibiting proliferative or secretory changes during the menstrual cycle, potentially leading to bleeding, uterine swelling, and pain. Adenomyosis can appear as either a diffuse or focal condition. It is crucial to understand that adenomyosis involves the infiltration of the endometrium into the myometrium, rather than its displacement. The surgical management of adenomyosis is contingent upon its anatomical extent. The high incidence of the disease and the myths that develop around it increase the need to study its characteristics and its association with pregnancy and potential obstetric complications. These complications often require quick decisions, appropriate diagnosis, and proper counseling. Therefore, knowing the possible risks associated with adenomyosis is key to decision making. Pregnancy has a positive effect on adenomyosis and its painful symptoms. This improvement is not only due to the inhibition of ovulation, which inhibits the bleeding of adenomyotic tissue, but also to the metabolic, hormonal, immunological, and angiogenic changes associated with pregnancy. Adenomyosis affects pregnancy through disturbances of the endocrine system and the body’s immune response at both local and systemic levels. It leads to bleeding from the adenomyotic tissue, molecular and functional abnormalities of the ectopic endometrium, abnormal placentation, and destruction of the adenomyotic tissue due to changes in the hormonal environment that characterizes pregnancy. Some of the obstetric complications that occur in women with adenomyosis in pregnancy include miscarriage, preterm delivery, placenta previa, low birth weight for gestational age, obstetric hemorrhage, and the need for cesarean section. These complications are an understudied field and remain unknown to the majority of obstetricians. These pathological conditions pose challenges to both the typical progression of pregnancy and the smooth conduct of labor in affected women. Further multicenter studies are imperative to validate the most suitable method for concluding labor following surgical intervention for adenomyosis. Full article

Strawberry fruit is highly appreciated worldwide for its organoleptic and healthy properties. However, this plant is attacked by many pathogenic fungi, which significantly affect fruit production and quality at pre- and post-harvest stages, making chemical applications the most effective but undesirable strategy to control diseases that has been found so far. Alternatively, genetic manipulation, employing plant key genes involved in defense, such as members of the NPR-like gene family, has been successful in many crops to improve resistance. The identification and use of the endogenous counterpart genes in the plant of interest (as it is the case of strawberry) is desirable as it would increase the favorable outcome and requires prior knowledge of their defense-related function. Using RNAi technology in strawberry, transient silencing of Fragaria ananassa NPR3 members in fruit significantly reduced tissue damage after Colletotrichum acutatum infection, whereas the ectopic expression of either FaNPR3.1 or FaNPR3.2 did not have an apparent effect. Furthermore, the ectopic expression of FaNPR3.2 in Arabidopsis thaliana double-mutant npr3npr4 reverted the disease resistance phenotype to Pseudomonas syringe to wild-type levels. Therefore, the results revealed that members of the strawberry FaNPR3 clade negatively regulate the defense response to pathogens, as do their Arabidopsis AtNPR3/AtNPR4 orthologs. Also, evidence was found showing that FaNPR3 members act in strawberry (F. ananassa) as positive regulators of WRKY genes, FaWRKY19 and FaWRKY24; additionally, in Arabidopsis, FaNPR3.2 negatively regulates its orthologous genes AtNPR3/AtNPR4. We report for the first time the functional characterization of FaNPR3 members in F. ananassa, which provides a relevant molecular basis for the improvement of resistance in this species through new breeding technologies. Full article

Chimeric antigen receptor (CAR) T cell therapy has achieved extraordinary success in eliminating B cell malignancies; however, so far, it has shown limited efficacy in the treatment of solid tumors, which is thought to be due to insufficient CAR T cell activation. We hypothesized that the transcription factor PU.1, a master regulator of innate cell functionality, may augment pro-inflammatory CAR T cell activation. T cells were engineered with a CEA-specific CAR together with the constitutive expression of PU.1. CAR-redirected T cell activation was recorded for canonical functionality in vitro under conditions of prolonged repetitive antigen exposure. Ectopic PU.1 expression in CAR T cells upregulated the costimulatory receptors CD40, CD80, CD86, and CD70, which, unexpectedly, did not augment effector functions but hampered the upregulation of 4-1BB, decreased IL-2 production, reduced CAR T cell proliferation, and impaired their cytotoxic capacities. Under “stress” conditions of repetitive engagement of cognate tumor cells, CAR T cells with ectopic PU.1 showed reduced persistence, and finally failed to control the growth of cancer cells. Mechanistically, PU.1 caused CAR T cells to secrete IFN-β, a cytokine known to promote CAR T cell attrition and apoptosis. Collectively, PU.1 can polarize the functional capacities of CAR T cells towards innate cells. Full article

Vitamin D plays an important pleiotropic role in maintaining global homeostasis of the human body. Its functions go far beyond skeletal health, playing a crucial role in a plethora of cellular functions, as well as in extraskeletal health, ensuring the proper functioning of multiple human organs, including the skin. Genes from the Grainyhead-like (GRHL) family code for transcription factors necessary for the development and maintenance of various epithelia. Even though they are involved in many processes regulated by vitamin D, a direct link between vitamin D-mediated cellular pathways and GRHL genes has never been described. We employed various bioinformatic methods, quantitative real-time PCR, chromatin immunoprecipitation, reporter gene assays, and calcitriol treatments to investigate this issue. We report that the vitamin D receptor (VDR) binds to a regulatory region of the Grainyhead-like 1 (GRHL1) gene and regulates its expression. Ectopic expression of VDR and treatment with calcitriol alters the expression of the GRHL1 gene. The evidence presented here indicates a role of VDR in the regulation of expression of GRHL1 and correspondingly a role of GRHL1 in mediating the actions of vitamin D. Full article

DNA strand breaks excessively accumulate in the brains of patients with Alzheimer’s disease (AD). While traditionally considered random, deleterious events, neuron activity itself induces DNA breaks, and these “adaptive” breaks help mediate synaptic plasticity and memory formation. Recent studies mapping the brain DNA break landscape reveal that despite a net increase in DNA breaks in ectopic genomic hotspots, adaptive DNA breaks around synaptic genes are lost in AD brains, and this is associated with transcriptomic dysregulation. Additionally, relationships exist between mitochondrial dysfunction, a hallmark of AD, and DNA damage, such that mitochondrial dysfunction may perturb adaptive DNA break formation, while DNA breaks may conversely impair mitochondrial function. A failure of DNA break physiology could, therefore, potentially contribute to AD pathogenesis. Full article

Eyespot foci on butterfly wings function as organizers of eyespot color patterns during development. Despite their importance, focal structures have not been examined in detail. Here, we microscopically examined scales, sockets, and the wing membrane in the butterfly eyespot foci of both expanded and unexpanded wings using the Blue Pansy butterfly Junonia orithya. Images from a high-resolution light microscope revealed that, although not always, eyespot foci had scales with disordered planar polarity. Scanning electron microscopy (SEM) images after scale removal revealed that the sockets were irregularly positioned and that the wing membrane was physically distorted as if the focal site were mechanically squeezed from the surroundings. Focal areas without eyespots also had socket array irregularities, but less frequently and less severely. Physical damage in the background area induced ectopic patterns with socket array irregularities and wing membrane distortions, similar to natural eyespot foci. These results suggest that either the process of determining an eyespot focus or the function of an eyespot organizer may be associated with wing-wide mechanics that physically disrupt socket cells, scale cells, and the wing membrane, supporting the physical distortion hypothesis of the induction model for color pattern determination in butterfly wings. Full article

Glypicans are closely associated with organ development and tumorigenesis in animals. Dally-like (Dlp), a membrane-bound glypican, plays pivotal roles in various biological processes in Drosophila. In this study, we observed that an excess of Dlp led to the malformation of legs, particularly affecting the distal part. Accordingly, the leg disc was shrunken and frequently exhibited aberrant morphology. In addition, elevated Dlp levels induced ectopic cell death with no apparent cell proliferation changes. Furthermore, Dlp overexpression in the posterior compartment significantly altered Wingless (Wg) distribution. We observed a marked expansion of Wg distribution within the posterior compartment, accompanied by a corresponding decrease in the anterior compartment. It appears that excess Dlp guides Wg to diffuse to cells with higher Dlp levels. In addition, the distal-less (dll) gene, which is crucial for leg patterning, was up-regulated significantly. Notably, dachshund (dac) and homothorax (hth) expression, also essential for leg patterning and development, only appeared to be negligibly affected. Based on these findings, we speculate that excess Dlp may contribute to malformations of the distal leg region of Drosophila, possibly through its influence on Wg distribution, dll expression and induced cell death. Our research advances the understanding of Dlp function in Drosophila leg development. Full article

Colorectal cancer (CRC) is the third most common cancer worldwide. The role of intestinal microbiota in carcinogenesis has also become an important research topic, and CRC is closely related to the intestinal microbiota. Selenium-containing compounds have attracted more attention as anticancer drugs as they can have minimal side effects. The purpose of this study was to determine and compare the effect of sodium selenite and selenomethionine on the microbial communities of nude mice with CRC. A CRC ectopic tumorigenesis model was established by subcutaneously injecting HCT116 cells into nude mice. The mice were then intraperitoneally injected with sodium selenite and selenomethionine for 24 days to regulate their intestinal microbiota. Compared with sodium selenite, selenomethionine resulted in a greater reduction in the richness and diversity of intestinal microbiota in nude mice with CRC, and the richness and diversity were closer to healthy levels. Selenomethionine also regulated a wider variety of flora. Additionally, sodium selenite and selenomethionine produced different microorganisms, changed function and metabolic pathways in the intestinal microbiota. Both sodium selenite and selenomethionine have certain effects on restoring the intestinal microbial diversity in nude mice with CRC, and the effect of selenomethionine is better than that of sodium selenite. Full article

Various human diseases are triggered by molecular alterations influencing the fine-tuned expression and activity of transcription factors, usually due to imbalances in targets including protein-coding genes and non-coding RNAs, such as microRNAs (miRNAs). The transcription factor EB (TFEB) modulates human cellular networks, overseeing lysosomal biogenesis and function, plasma–membrane trafficking, autophagic flux, and cell cycle progression. In endothelial cells (ECs), TFEB is essential for the maintenance of endothelial integrity and function, ensuring vascular health. However, the comprehensive regulatory network orchestrated by TFEB remains poorly understood. Here, we provide novel mechanistic insights into how TFEB regulates the transcriptional landscape in primary human umbilical vein ECs (HUVECs), using an integrated approach combining high-throughput experimental data with dedicated bioinformatics analysis. By analyzing HUVECs ectopically expressing TFEB using ChIP-seq and examining both polyadenylated mRNA and small RNA sequencing data from TFEB-silenced HUVECs, we have developed a bioinformatics pipeline mapping the different gene regulatory interactions driven by TFEB. We show that TFEB directly regulates multiple miRNAs, which in turn post-transcriptionally modulate a broad network of target genes, significantly expanding the repertoire of gene programs influenced by this transcription factor. These insights may have significant implications for vascular biology and the development of novel therapeutics for vascular disease. Full article

During infection, adenoviruses inhibit the cellular RNA interference (RNAi) machinery by saturating the RNA-induced silencing complex (RISC) of the host cells with large amounts of virus-derived microRNAs (mivaRNAs) that bind to the key component of the complex, Argonaute 2 (AGO2). In the present study, we investigated AGO2 as a prominent player at the intersection between human adenovirus 5 (HAdV-5) and host cells because of its ability to interfere with the HAdV-5 life cycle. First, the ectopic expression of AGO2 had a detrimental effect on the ability of the virus to replicate. In addition, in silico and in vitro analyses suggested that endogenous microRNAs (miRNAs), particularly hsa-miR-7-5p, have similar effects. This miRNA was found to be able to target the HAdV-5 DNA polymerase mRNA. The inhibitory effect became more pronounced upon overexpression of AGO2, likely due to elevated AGO2 levels, which abolished the competition between cellular miRNAs and mivaRNAs for RISC incorporation. Collectively, our data suggest that endogenous miRNAs would be capable of significantly inhibiting viral replication if adenoviruses had not developed a mechanism to counteract this function. Eventually, AGO2 overexpression-mediated relief of the RISC-saturating action of mivaRNAs strongly enhanced the effectiveness of artificial miRNAs (amiRNAs) directed against the HAdV-5 preterminal protein (pTP) mRNA, suggesting a substantial benefit of co-expressing amiRNAs and AGO2 in RNAi-based strategies for the therapeutic inhibition of adenoviruses. Full article

Takayasu’s arteritis (TAK) manifests as an insidiously progressive and debilitating form of granulomatous inflammation including the aorta and its major branches. The precise etiology of TAK remains elusive, with current understanding suggesting an autoimmune origin primarily driven by T cells. Notably, a growing body of evidence bears testimony to the widespread effects of B cells on disease pathogenesis and progression. Distinct alterations in peripheral B cell subsets have been described in individuals with TAK. Advancements in technology have facilitated the identification of novel autoantibodies in TAK. Moreover, emerging data suggest that dysregulated signaling cascades downstream of B cell receptor families, including interactions with innate pattern recognition receptors such as toll-like receptors, as well as co-stimulatory molecules like CD40, CD80 and CD86, may result in the selection and proliferation of autoreactive B cell clones in TAK. Additionally, ectopic lymphoid neogenesis within the aortic wall of TAK patients exhibits functional characteristics. In recent decades, therapeutic interventions targeting B cells, notably utilizing the anti-CD20 monoclonal antibody rituximab, have demonstrated efficacy in TAK. Despite the importance of the humoral immune response, a systematic understanding of how autoreactive B cells contribute to the pathogenic process is still lacking. This review provides a comprehensive overview of the biological significance of B cell-mediated autoimmunity in TAK pathogenesis, as well as insights into therapeutic strategies targeting the humoral response. Furthermore, it examines the roles of T-helper and T follicular helper cells in humoral immunity and their potential contributions to disease mechanisms. We believe that further identification of the pathogenic role of autoimmune B cells and the underlying regulation system will lead to deeper personalized management of TAK patients. We believe that further elucidation of the pathogenic role of autoimmune B cells and the underlying regulatory mechanisms holds promise for the development of personalized approaches to managing TAK patients. Full article

Background/Objectives: To assess the frequency, extent, localization and potential progression of optic disc drusen (ODD) and the correlation with the angioid streak (AS) length and retinal atrophy in patients with pseudoxanthoma elasticum (PXE). Methods: This retrospective study included patient data from a dedicated PXE clinic at the Department of Ophthalmology, University of Bonn, Germany (observation period from February 2008 to July 2023). Two readers evaluated the presence, localization, and the extent of the ODD on fundus autofluorescence (FAF) imaging at baseline and the follow-up assessments. Additionally, we measured the length of the longest AS visible at baseline and follow-up and the area of atrophy at baseline, both on FAF. Results: A total of 150 eyes of 75 PXE patients (median age at baseline 51.8 years, IRQ 46.3; 57.5 years, 49 female) underwent retrospective analysis. At baseline, 23 of 75 patients exhibited ODD in a minimum of one eye, resulting in an ODD prevalence of 30.7% in our cohort of PXE patients. Among these, 14 patients showed monocular and 9 binocular ODD that were localized predominantly nasally (46.9%). During the observational period (mean 97.5 ± 44.7 months), only one patient developed de novo ODD in one eye and one other patient showed a progression in the size of the existing ODD. The group of patients with ODD had significantly longer ASs (median 7020 µm, IQR 4604; 9183, vs. AS length without ODD: median 4404 µm, IQR 3512; 5965, p < 0.001). No association with the size of the atrophy was found at baseline (p = 0.27). Conclusions: This study demonstrates a prevalence of ODD of 30.7%. ODD presence is associated with longer ASs (an indicator of the severity and extent of ocular Bruch’s membrane calcification), suggesting that ODD formation is tightly related to ectopic calcification—possibly secondary to calcification of the lamina cribrosa. Prospective studies investigating the impact of ODD (in conjunction with intraocular pressure) on visual function in PXE warrant consideration. Full article