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Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cancer and is associated with poor prognosis. The present study identified a membrane-associated mucin, mucin 3A (MUC3A), a transmembrane glycoprotein, as a novel oncogenic factor in ccRCC. MUC3A was found to be highly expressed in ccRCC tissues and cell lines, with elevated levels associated with worse patient survival. Functional assays demonstrated that MUC3A knockdown significantly inhibited cell proliferation, migration, invasion, and promoted apoptosis. Mechanistically, MUC3A activated the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway, and activation of STAT3 reversed the effects of MUC3A knockdown. These findings suggest that MUC3A facilitates ccRCC progression via JAK/STAT signaling and may serve as a potential prognostic biomarker and therapeutic target.

Aims Neuroinflammation is widely acknowledged as a crucial pathogenic factor in neuropsychiatric systemic lupus erythematosus (NPSLE). However, specific clinical treatments to mitigate neuroinflammation associated with NPSLE are currently lacking. While ShenQi DiHuang decoction (SQDHD) has demonstrated significant anti‐inflammatory effects in lupus nephritis, its efficacy in NPSLE has yet to be investigated. This study aims to explore the neuroprotective effects of SQDHD in NPSLE and to elucidate the underlying mechanisms. Methods In vivo, the effects of SQDHD were studied in pristane‐induced lupus (PIL) mice using behavioral tests, intravital microscopy, blood–brain barrier (BBB) permeability assessment, cytokine quantification, and brain histopathological analysis. The active compounds and the underlying mechanism of SQDHD action against NPSLE were examined using ultra performance liquid chromatography–tandem mass spectrometry (UPLC‐MS/MS), network pharmacology, molecular docking, cellular thermal shift assays (CETSAs), and drug affinity responsive target stability (DARTS) assays. In vitro and in vivo experiments were performed to validate the proposed mechanism. Results SQDHD significantly ameliorated olfactory dysfunction, anxiety, and depression in PIL mice. Additionally, adhesion molecule upregulation, leukocyte recruitment, BBB leakage, and brain pathophysiological alterations, including cytokine overexpression, immunoglobulin G deposition, and lipofuscin accumulation were markedly reduced. By integrating UPLC‐MS/MS, network pharmacology, and molecular docking, we predicted the therapeutic mechanism of SQDHD against NPSLE to involve Janus kinase‐signal transducer and activator of transcription (JAK–STAT) signaling. Five primary active compounds of SQDHD, Alisol B acetate, Hederagenin, Ellagic acid, Wogonin, and Quercetin, exhibited strong binding affinities to JAK1 and other JAK–STAT pathway components, surpassing the binding affinities of Upadacitinib, a selective JAK1 inhibitor. CETSAs and DARTS assays confirmed the direct interactions between these compounds and JAK1. Alisol B acetate and Hederagenin inhibited the JAK1‐STAT3 pathway and its downstream effectors in cerebrovascular endothelial cells (CVECs). In vitro studies in lupus serum‐induced CVECs and in vivo studies in PIL mice further corroborated SQDHD downregulation of elevated levels of adhesion molecules, potentially through inhibition of JAK1‐STAT3 signaling. Conclusions SQDHD may exert neuroprotective effects in NPSLE by inhibiting the activation of CVECs through blocking the JAK1‐STAT3 signaling pathway, thereby suggesting its potential as a promising therapeutic strategy for NPSLE. SQDHD exerts neuroprotective effects and alleviates behavioral deficits in PIL mice, likely by inhibiting the JAK1‐STAT3 pathway in activated CVECs. These findings underscore the therapeutic potential of SQDHD and establish it as a promising candidate for the treatment of NPSLE.

Interferons (IFNs), which were discovered a half century ago, are a group of secreted proteins that play key roles in innate immunity against viral infection. The major signaling pathway activated by IFNs is the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, which leads to the expression of IFN-stimulated genes (ISGs), including many antiviral effectors. Viruses have evolved various strategies with which to antagonize the JAK/STAT pathway to influence viral virulence and pathogenesis. In recent years, notable progress has been made to better understand the JAK/STAT pathway activated by IFNs and antagonized by viruses. In this review, recent progress in research of the JAK/STAT pathway activated by type I IFNs, non-canonical STAT activation, viral antagonism of the JAK/STAT pathway, removing of the JAK/STAT antagonist from viral genome for attenuation, and the potential pathogenesis roles of tyrosine phosphorylation-independent non-canonical STATs activation during virus infection are discussed in detail. We expect that this review will provide new insight into the understanding the complexity of the interplay between JAK/STAT signaling and viral antagonism.

Background Long non-coding RNAs (lncRNAs) are tumor-associated biological molecules and have been found to be implicated in the progression of colorectal cancer (CRC). This study aims to examine the effects of lncRNA RP11-468E2.5 and its target genes (STAT5 and STAT6) on the biological activities of CRC cells via the Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling pathway. Methods We initially screened the GEO database for differentially expressed lncRNAs related to CRC and then made a prediction of the implicated target genes. Then we collected CRC tissues and adjacent normal tissues from 169 CRC patients. Human CRC HCT116 and SW480 cells were treated with small interference RNA (siRNA) against RP11-468E2.5, AG490 (an inhibitor of the JAK/STAT signaling pathway), or both in combination. Next, we measured the effects of RP11-468E2.5 treatment on cellular activities such as cell viability, cycle distribution and cell apoptosis, and studied interactions among RP11-468E2.5, STAT5/STAT6, and the JAK/STAT signaling pathway. Finally, an in vivo tumor formation assay was performed to observe the effect of RP11-468E2.5 on tumor growth. Results The CRC-related gene microarray data showed low expression of RP11-468E2.5 in CRC surgical specimens. However, RP11-468E2.5 was confirmed to target STAT5 and STAT6, which participate in the JAK/STAT signaling pathway. CRC tissues showed lower expression of RP11-468E2.5, higher expression of STAT5, STAT6 and of the cell cycle marker Cyclin D1 (CCND1), compared to the findings in adjacent normal tissues. The treatment of siRNA against RP11-468E2.5 increased expression of JAK2, STAT3, STAT5, STAT6, CCND1 and Bcl-2 along with the extent of STAT3, STAT5 and STAT6 phosphorylation, while lowering expression of P21 and P27. Treatment with AG490 exhibited approximately opposite effects, whereas siRNA against RP11-468E2.5 treatment stimulated CRC cell proliferation and reduced cell apoptosis, while promoting cell cycle entry; AG490 treatment reversed these results. Conclusions Altogether, we conclude that up-regulation of RP11-468E2.5 inhibits the JAK/STAT signaling pathway by targeting STAT5 and STAT6, thereby suppressing cell proliferation and promoting cell apoptosis in CRC.

Type I and III interferons (IFNs) are archetypally antiviral cytokines that are induced in response to recognition of foreign material by pattern recognition receptors (PRRs). Though their roles in anti-viral immunity are well established, recent evidence suggests that they are also crucial mediators of inflammatory processes during bacterial infections. Type I and III IFNs restrict bacterial infection in vitro and in some in vivo contexts. IFNs mainly function through the induction of hundreds of IFN-stimulated genes (ISGs). These include PRRs and regulators of antimicrobial signaling pathways. Other ISGs directly restrict bacterial invasion or multiplication within host cells. As they regulate a diverse range of anti-bacterial host responses, IFNs are an attractive virulence target for bacterial pathogens. This review will discuss the current understanding of the bacterial effectors that manipulate the different stages of the host IFN response: IFN induction, downstream signaling pathways, and target ISGs.

The present study investigated the association between the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway with tumor progression and prognosis of colon cancer. A total of 62 patients with colon cancer were selected as the colon cancer group, and 40 patients with colon lesions were selected as the benign colon lesion group. Immunohistochemistry was used to detect the expression levels of JAK-1 and STAT-3 proteins in colon tissues. The association of JAK-1 and STAT-3 proteins with the pathological parameters and prognosis of colon cancer were analyzed. The total positive rates of JAK-1 and STAT-3 proteins in lesions of patients in the colon cancer group were significantly higher compared with those in the benign colon lesion group (P<0.05). The positive expression of JAK-1 and STAT-3 proteins in patients with colon cancer were not significantly associated with sex, age, tumor differentiation degree and neurovascular invasion (P>0.05), but significantly associated with the clinical stage of colon cancer, tumor infiltration depth and lymph node metastasis (P<0.05). The survival time of patients with colon cancer with positively-expressed JAK-1 and STAT-3 proteins was significantly shorter compared with that of patients with negatively-expressed JAK-1 and STAT-3 proteins (P<0.05). tumor-node-metastasis (TNM) stage, lymph node metastasis and the expression of JAK-1 and STAT-3 proteins in the tumor were associated with the prognosis of patients with colon cancer (P<0.05). TNM stage and the expression levels of JAK-1 and STAT-3 proteins were independent risk factors influencing the prognosis of colon cancer (P<0.05). The JAK/STAT signal may be used as a novel tumor marker and prognostic factor for the diagnosis, assessment and prognosis of colon cancer.

ObjectivesTo investigate the mechanism of Liuwei Dihuang Pill (六味地黄丸, LDP) in treating postmenopausal osteoporosis (PMOP) with Shen (Kidney) yin deficiency.MethodsIn this study, 205 cases of PMOP were divided into the PMOP Shen-yin deficiency group (Group A), PMOP Shen-yang deficiency group (Group B), PMOP without Shen deficiency group (Group C), and control group (Group N). Real-time polymerase chain reaction (RT-PCR) and Western blot techniques were used to observe the effects of LDP treatment on the cardiotrophin-like cytokine factor 1 (CLCF1), ankyrin repeat and SOCS box containing 1 (ASB1), and prokineticin 2 (PROK2) genes and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway.ResultsThe mRNA (P<0.05) and protein (P<0.01) expression levels of the CLCF1 gene in Group A were significantly lower than the corresponding levels in Group N. After LDP treatment for 3 months, the mRNA expression levels of the CLCF1 gene were obviously up-regulated (P<0.01). After 6-month treatment, the expression levels of CLCF1 mRNA and protein were significantly up-regulated (both P<0.01), and the average bone density of the top femur had significantly increased (P<0.05). In vitro, CLCF1 overexpression resulted in a significant increase in the total protein and phosphorylated protein levels of JAK2 and STAT3.ConclusionsThe CLCF1 gene is an important gene associated with PMOP Shen-yin deficiency and the therapeutic effects of LDP may be mediated by up-regulation of CLCF1 gene expression and activation of the JAK/STAT signaling pathway.

Janus kinase 3 (JAK3) inhibitors have been used effectively in the treatment of several cases of alopecia universalis and its variants. Our study aims to evaluate whether the emulsion extract of brevilin A from Centipeda minima (CMX) stimulates hair regrowth in a clinical trial, as a JAK3 inhibitor, combined with network pharmacology-based analysis. CMX showed potent inhibition of JAK3 in a concentration-dependent manner. Significant differences in total hair count, terminal hair count, and anagen hair count from the baseline to 24 weeks were observed between the placebo and CMX subjects. The gene set enrichment analysis showed that the targets of CMX are mainly associated with the JAK-STAT signaling pathway, cytokine–cytokine receptor interactions, and the MAPK signaling pathway. This study suggests that the medicinal herbal extract CMX is useful in the treatment of mild to moderate vertex balding that contribute to the visible improvements in hair growth observed in treated patients.

The Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway is involved in cell immunity, division and death, as well as in tumor formation. The expression of key genes in the JAK-STAT signaling pathway in different types of cancer serves different roles. However, few reports are available on the prognostic value of the genes of the JAK-STAT signaling pathway in skin cutaneous melanoma (SKCM). The potential prognostic value of gene expression in the JAK-STAT signaling pathway in patients with SKCM was analyzed in the present study using data obtained from The Cancer Genome Atlas. To predict the potential functions and mechanisms of these genes in SKCM, gene set enrichment analysis (GSEA) and bioinformatics analysis were performed. A nomogram model including gene expression level and high risk factors was used to predict the risk level of prognostic. High expression levels of STAT1, STAT3, STAT4 and STAT5B, and low expression levels of STAT6 were associated with favorable prognosis [adjusted P<0.001; hazard ratio (HR), 0.595; 95% confidence interval (CI), 0.455-0.778; adjusted P=0.018; HR, 0.725; 95% CI, 0.555-0.947; adjusted P<0.001; HR, 0.590; 95% CI, 0.450-0.773; adjusted P=0.007; HR, 0.690; 95% CI, 0.526-0.940; and adjusted P=0.026; HR, 0.737, 95% CI, 0.563-0.964, respectively]. GSEA results demonstrated that these genes were involved in cell differentiation, invasion, adhesion, migration, cycle, colony formation and mitogen-activated protein kinase signaling. The combination of genes with favorable prognosis had a better effect on the overall survival (univariate survival analysis, P<0.05). The results of the present study suggest that STAT1, STAT3, STAT4, STAT5B and STAT6 gene expression may be used as a potential prognostic biomarker of SKCM, and the combined outcomes may exhibit a stronger interaction and higher survival time for SKCM.

The induction of apoptosis-resistant rheumatoid synovial tissue cells has been related to constitutively active Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling in rheumatoid arthritis (RA). The excessive proliferation and inherent resistance to apoptosis of fibroblast-like synoviocytes (FLS) is an important mechanism by which RA originates. However, the effects of matrine on FLS in RA is unclear. The present study aimed to investigate the mechanism of action of matrine in a rat model of collagen-induced arthritis (CIA). The CIA model was established using bovine type II collagen. FLS were isolated from control and CIA rats, cultured in vitro, and confirmed to harbor fibroblast-like characteristics. After treatment of FLS with varying concentrations of matrine, the JAK2 inhibitor AG490, or a combination of both drugs, cell proliferation, apoptosis rate, expression of apoptotic markers and the activation of the JAK/STAT pathway were assessed. Additionally, CIA rats were administered either matrine or methotrexate by oral gavage to examine the effects of therapeutic intervention on arthritis pathogenesis. The arthritis index (AI) was measured and ankle joint structure was analyzed histologically to determine the severity of CIA. Furthermore, expression levels of apoptotic markers and members of the JAK/STAT family were also examined in vivo. Compared with the CIA group, matrine reduced AI and improved ankle pathology. Matrine also inhibited FLS proliferation, induced G0/G1 cell cycle arrest, and increased the rate of apoptosis in vitro. The effects of matrine on apoptosis induction were further confirmed by observations that Bcl-2 levels were decreased, whereas Bax and caspase-3 levels were increased in the matrine-treated synovial tissues and FLS. Finally, matrine treatment also diminished the phosphorylation, and hence activation of JAK2, STAT1 and STAT3. Our results suggest that matrine induces the apop-tosis of FLS from rats with CIA by inhibiting activation of the JAK/STAT signaling pathway.