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Islr could rescue skeletal muscle atrophy. (a–a’) Levels of atrogin-1 and MuRF-1 at the mRNA and (b) protein level in siRNA transfected myoblasts or myotubes. (c–c’) Levels of atrogin-1, MuRF-1 mRNA, and protein (d). (e) Cells were treated with dexamethasone for 24 h and siRNA transfected for 48 h, followed by western blot analysis of atrogin-1 and Myog. (f) Dexamethasone-treated myoblasts were induced for 24 h and transfected with Islr-Flag or pcDNA3.1. Atrogin-1 and Myog expressions were assessed by western blot analysis. (g) qRT-PCR analysis of Islr expression after intramuscular lentivirus injection into the breast muscle. (h) Breast muscle weights (h), mean muscle fiber cross-sectional area (CSA) (i), and (j–j’) H-E staining of breast muscle fiber cross sections infected with the indicated lentiviruses. Scale bar = 100 μm. (k) qRT-PCR analysis of pWPXL-Islr expression. (l) Breast muscle weights, CSA (m), and (n–n’) H-E staining of breast muscle fiber cross sections. Scale bar = 100 μm. Data are the means ± SEM (n = 3). *p < 0.05; **p < 0.01
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Immunoglobulin superfamily containing leucine-rich repeat (Islr) contains an Ig-like domain, an LRR motif, and a transmembrane domain and is highly expressed in various chicken tissues. Although Islr has known roles in muscle regeneration, its role in the regulation of muscle atrophy has not been studied. In this study, we constructed Islr-silenced...
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... It is essential to note that in models of muscle atrophy, IGF-1 suppresses the transcription of MURF1 through the class O-type forkhead transcription factors (FOXOs) [14]. Furthermore, forkhead box protein O1 (FOXO1) can activate and induce the expression of MURF1, while inhibit-ing FOXO1 prevents the upregulation of MURF1 expression and offers protection against muscle atrophy [15]. The interplay of these mechanisms related to protein catabolism and muscle atrophy underscores the critical roles of the IGF-1-FOXO1-MURF1 pathway in skeletal muscle dysfunction. ...
... These processes are closely associated with amino acid synthesis and metabolism. The DEGs in the Coral1 module were significantly enriched in the FoxO and cGMP-PKG signaling pathways, which are associated with muscle development [50,51]. The Blue4 module was enriched in various metabolic processes, including primary metabolism, cellular metabolism, and metabolic pathways. ...
... Insulin resistance leads to increased lipolysis and consequent release of free fatty acids (FFAs) from adipose tissue to the liver, which is the main contributor to the increase of De novo lipogenesis (DNL) (63, 66). The mechanism of insulin-mediated decrease of muscle anabolic metabolism may be related to the activation of p38 mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR)/p70S6 kinase (74). Insulin resistance-induced hyperinsulinemia also increases myostatin levels, which further reduces skeletal muscle mass (48). ...
Nonalcoholic fatty liver disease (NAFLD) has become one of the most common chronic liver diseases in the world. The risk factor for NAFLD is often considered to be obesity, but it can also occur in people with lean type, which is defined as lean NAFLD. Lean NAFLD is commonly associated with sarcopenia, a progressive loss of muscle quantity and quality. The pathological features of lean NAFLD such as visceral obesity, insulin resistance, and metabolic inflammation are inducers of sarcopenia, whereas loss of muscle mass and function further exacerbates ectopic fat accumulation and lean NAFLD. Therefore, we discussed the association of sarcopenia and lean NAFLD, summarized the underlying pathological mechanisms, and proposed potential strategies to reduce the risks of lean NAFLD and sarcopenia in this review.
... SOD1 overexpression significantly attenuates transcription of several pro inflammatory cytokines like CCL2, IL6, TNFα, IL-8 [53]. ISLR is an immunoglobulin superfamily containing leucine rich repeats that stabilizes Wnt signalling and regulates muscle atrophy (skeletal muscles) via IGF1-PI3K/Akt-FOXO signalling pathway [54] PDHB plays role in metabolic processes TCA cycle, gluconeogenesis acetyl CoA synthesis and canonical pathways [55]. GLI-2 is a zinc finger protein which acts as transcriptional activator in hedgehog (hh) signalling. ...
... SOD1 overexpression significantly attenuates transcription of several pro inflammatory cytokines like CCL2, IL6, TNFα, IL-8 [53]. ISLR is an immunoglobulin superfamily containing leucine rich repeats that stabilizes Wnt signalling and regulates muscle atrophy (skeletal muscles) via IGF1-PI3K/Akt-FOXO signalling pathway [54] PDHB plays role in metabolic processes TCA cycle, gluconeogenesis acetyl CoA synthesis and canonical pathways [55]. GLI-2 is a zinc finger protein which acts as transcriptional activator in hedgehog (hh) signalling. ...
Salmonella enterica serovar typhimurium is the cause of significant morbidity and mortality worldwide that causes economic losses to poultry and is able to cause infection in humans. Indigenous chicken breeds are a potential source of animal protein and have the added advantage of being disease resistant. An indigenous chicken, Kashmir favorella and commercial broiler were selected for understanding the mechanism of disease resistance. Following infection in Kashmir favorella, three differentially expressed genes Nuclear Factor Kappa B (NF-κB1), Forkhead Box Protein O3 (FOXO3) and Paired box 5 (Pax5) were identified. FOXO3, a transcriptional activator, is the potential marker of host resistance in Salmonella infection. NF-κB1 is an inducible transcription factor which lays the foundation for studying gene network of the innate immune response of Salmonella infection in chicken. Pax5 is essential for differentiation of pre-B cells into mature B cell. The real time PCR analysis showed that in response to Salmonella Typhimurium infection a remarkable increase of NF-κB1 (P˂0.01), FOXO3 (P˂0.01) gene expression in liver and Pax5 (P˂0.01) gene expression in spleen of Kashmir favorella was observed. The protein–protein interaction (PPI) and protein-TF interaction network by STRINGDB analysis suggests that FOXO3 is a hub gene in the network and is closely related to Salmonella infection along with NF-κB1. All the three differentially expressed genes (NF-κB1, FOXO3 and PaX5) showed their influence on 12 interacting proteins and 16 TFs, where cyclic adenosine monophosphate Response Element Binding protein (CREBBP), erythroblast transformation-specific (ETSI), Tumour-protein 53(TP53I), IKKBK, lymphoid enhancer-binding factor-1 (LEF1), and interferon regulatory factor-4 (IRF4) play role in immune responses. This study shall pave the way for newer strategies for treatment and prevention of Salmonella infection and may help in increasing the innate disease resistance.
... It was previously suggested that ISLR may modulate glycolysis in human NSCLC cells by activating the IL-6/JAK/STAT3 signalling pathway 118 . It is involved in myoblast differentiation and can alleviate skeletal muscle atrophy and prevent muscle cell apoptosis via the IGF/ PI3K/AKT-FOXO signaling pathway 119 . Musashi RNA binding protein 2 (MSI2), a significant upstream in the 4P-PDOT treatment, plays essential roles in many cellular processes by activating the Wnt pathway 120 . ...
Melatonin is a known modulator of follicle development; it acts through several molecular cascades via binding to its two specific receptors MT1 and MT2. Even though it is believed that melatonin can modulate granulosa cell (GC) functions, there is still limited knowledge of how it can act in human GC through MT1 and MT2 and which one is more implicated in the effects of melatonin on the metabolic processes in the dominant follicle. To better characterize the roles of these receptors on the effects of melatonin on follicular development, human granulosa-like tumor cells (KGN) were treated with specific melatonin receptor agonists and antagonists, and gene expression was analyzed with RNA-seq technology. Following appropriate normalization and the application of a fold change cut-off of 1.5 (FC 1.5, p ≤ 0.05) for each treatment, lists of the principal differentially expressed genes (DEGs) are generated. Analysis of major upstream regulators suggested that the MT1 receptor may be involved in the melatonin antiproliferative effect by reprogramming the metabolism of human GC by activating the PKB signaling pathway. Our data suggest that melatonin may act complementary through both MT1 and MT2 receptors to modulate human GC steroidogenesis, proliferation, and differentiation. However, MT2 receptors may be the ones implicated in transducing the effects of melatonin on the prevention of GC luteinization and follicle atresia at the antral follicular stage through stimulating the PKA pathway.
... In nonsmall cell lung cancer (NSCLC), silencing ISLR increased the apoptotic rate of cells [24]. In chicken myoblasts, silencing ISLR similarly caused significantly higher expression of apoptosis-related proteins such as Caspase3, Caspase8, and Caspase9 [25]. These results suggested that inhibition of ISLR expression may be detrimental to cell proliferation, and we therefore speculate that ISLR2 may play a similar role as a paralogous homolog of ISLR. ...
Zearalenone (ZEN) is one of the mycotoxins that pose high risks for human and animal health, as well as food safety. However, the regulators involved in ZEN cellular toxicity remain largely unknown. Herein, we showed that cell viability of porcine intestinal epithelial cells (IPEC-J2) tended to decrease with increasing doses of ZEN by the cell counting kit-8 assay. Expression of the ISLR2 (immunoglobulin superfamily containing leucine-rich repeat 2) gene in IPEC-J2 cells was significantly downregulated upon ZEN exposure. Furthermore, we found the dose–effect of ZEN on ISLR2 expression. We then overexpressed the ISLR2 gene and observed that overexpression of ISLR2 obviously reduced the effects of ZEN on cell viability, apoptosis rate and oxidative stress level. In addition, ISLR2 overexpression significantly decreased the expression of TNF-α and IFN-α induced by ZEN. Our findings revealed the effects of ZEN on the ISLR2 gene expression and indicated the ISLR2 gene as a novel regulator of ZEN-induced cytotoxicity, which provides potential molecular targets against ZEN toxicity.
... The enriched signaling pathways of differentially expressed miRNAs in the KEGG results were highly overlapping, accounting for 46.27% and 38.75% in the IUGR and normal groups, respectively (Table S3). Commonly enriched signaling pathways include endocytosis [45], TNF signaling pathway [46], autophagy-animal [47], FoxO signaling pathway [48], and MAPK signaling pathway [49], which are closely related to skeletal muscle development. The FoxO signaling pathway and MAPK signaling pathway are related to skeletal muscle development in the IUGR [44,50]. ...
... According to functional enrichment analysis, the target genes of the miR-29 family were primarily involved in protein modification (protein methylation, protein alkylation, and histone methylation) and cell differentiation (regulation of cell differentiation and endodermal cell differentiation); these processes influence skeletal muscle formation and are closely related to muscle mass [6,9]. The KEGG results showed that among the miR-29 family-enriched signaling pathways, the PI3K-Akt signaling pathway was the core pathway regulating muscle atrophy [48]. Both the expression pattern of the miR-29 family and the enrichment analysis of target gene functions suggest that the miR-29 family might play an essential role in developing skeletal muscle in IUGR animals. ...
MicroRNAs (miRNAs) play an essential role in many biological processes. In this study, miRNAs in the skeletal muscle of normal and intrauterine growth retardation (IUGR) neonatal piglets were identified by sequencing, and canonical miRNAs were functionally validated in vitro. A total of 403 miRNAs were identified in neonatal piglet skeletal muscle, among them 30 and 46 miRNAs were upregulated and downregulated in IUGR pigs, respectively. Upregulated miRNAs were mainly enriched in propanoate metabolism, endocytosis, beta-Alanine metabolism, gap junction, and tumor necrosis factor signaling pathway. Down-regulated miRNAs were mainly enriched in chemical carcinogenesis—receptor activation, endocytosis, MAPK signaling pathway, insulin resistance, and EGFR tyrosine kinase inhibitor resistance. Co-expression network analysis of umbilical cord blood and skeletal muscle miRNAs showed that the miR-29 family is an essential regulator of IUGR pigs. The dual-luciferase reporter system showed that IGF1 and CCND1 were target genes of the miR-29 family. Transfection of IUGR pig umbilical cord blood exosomes and miR-29a mimic significantly inhibited cell proliferation and promoted the expression of cellular protein degradation marker genes Fbxo32 and Trim63. In summary, these results enrich the regulatory network of miRNAs involved in skeletal muscle development in IUGR animals.
... The involvement of Meflin in the regeneration of skeletal tissues and myoblast differentiation has also been evaluated in other studies but it was not covered in this review. 44,45 As described earlier, the function of the Meflin protein and that of Meflin + cells should be determined separately to better understand their specific roles in disease progression. It is also important to assess whether diverse fibroblasts are derived from different lineages or represent different faces of the same fibroblasts with plasticity. ...
Cancer and fibrotic diseases are characterized by continuous inflammation, tissue wounds, and injuries. Cancer is a "wound that does not heal," and the uncontrolled proliferation of cancer cells disrupts normal tissue integrity and induces stromal fibroinflammatory reactions. Fibroblasts proliferate extensively in the stroma, playing a major role in the development of these diseases. There has been considerable evidence that fibroblasts contribute to fibrosis and tissue stiffening and promote disease progression via multiple mechanisms. However, recent emerging findings, mainly derived from single-cell transcriptomic analysis, indicated that fibroblasts are functionally heterogeneous, leading to the hypothesis that both disease-promoting and -restraining fibroblasts exist. We recently showed that a fibroblast population, defined by the expression of the glycosylphosphatidylinositol-anchored membrane protein Meflin may suppress but not promote fibrotic response and disease progression in cancer and fibrotic diseases. Although currently hypothetical, the primary function of Meflin-positive fibroblasts may be tissue repair after injury and cancer initiation occurred. This observation has led to the proposal of a potential therapy that converts the phenotype of fibroblasts from pro-tumor to anti-tumor. In this short review, we summarize our recent findings on the function of Meflin in the context of cancer and fibrotic diseases and discuss how we can utilize this knowledge on fibroblasts in translational medicine. We also discuss several aspects of the interpretation of survival analysis data, such as Kaplan-Meier analysis, to address the function of specific genes expressed in fibroblasts.
... ISLR is detected in muscle tissues and satellite cells, and regulates the muscle regeneration and muscle atrophy [34,35]. Cui et al. have reported that ISLR plays a significant role in the differentiation of myoblasts, alleviating skeletal muscle atrophy and preventing myocyte apoptosis through IGF/PI3K/AKT-FOXO signaling pathway [34]. ...
... ISLR is detected in muscle tissues and satellite cells, and regulates the muscle regeneration and muscle atrophy [34,35]. Cui et al. have reported that ISLR plays a significant role in the differentiation of myoblasts, alleviating skeletal muscle atrophy and preventing myocyte apoptosis through IGF/PI3K/AKT-FOXO signaling pathway [34]. Xu et al. and Kobayashi et al. have verified that ISLR is crucial for regulating the growth of epithelial cells during intestinal tumourigenesis, particularly in colorectal carcinoma [36,37]. ...
This study aims to investigate the immunoglobulin superfamily containing leucine-rich repeat (ISLR) expression in gastric cancer (GC) and ISLR’s underlying mechanisms regulation of GC progression. Through The Cancer Genome Atlas (TCGA) cohort datasets, we analyzed the ISLR expression in GC tumor tissues and normal tissues. ISLR expression in GC tissues and cells was determined using quantitative real-time polymerase chain reaction. Cell viability, proliferation, migration, and invasion assays were performed in GC cells transfected with sh-ISLR, ISLR plasmids, or controls. TCGA results showed that ISLR expression was higher in GC tumor tissues compared to normal tissues, and its expression levels were related to lymph node metastasis, tumor size, and clinical stage. ISLR was highly expressed in tumor cells. ISLR knockdown suppressed cell viability, proliferation, migration, and invasion in HGC-27 cells, whereas ISLR overexpression led to opposite effects in AGS cells. Gene Set Enrichment Analysis showed that ISLR could activate the epithelial–mesenchymal transition (EMT) signaling pathway. Silencing of ISLR suppressed EMT in HGC-27 cells and overexpression of ISLR promoted EMT in AGS cells. ISLR was overexpressed in both GC cell lines and tumor tissues, and our study first showed that silencing of ISLR inhibited GC cell growth and metastasis by reversing EMT.
