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The Janus kinase (JAK) and signal transducer and activator of transcription (STAT) signaling pathways are essential for maintaining prompt immune responses to various cytokines. Both loss- and gain-of-function mutations in the JAK and STAT molecules result in different disease profiles in inborn errors of immunity. The discovery of gain-of-function mutations in STAT1 and STAT3 expanded immunological investigations aimed at understanding both signaling pathways and their associated disorders. Both defects are distinct from loss-of-function mutations that lead to alterations in immune regulation. In this context, we wanted to take a look at both diseases and focus on the mechanisms. [ABSTRACT FROM AUTHOR]

Pancreatic cancer remains a serious and deadly disease, impacting people globally. There remain prominent gaps in the current understanding of the disease, specifically regarding the role of the signal transducer and activator of transcription (STAT) family of proteins in pancreatic tumors. STAT proteins, particularly STAT3, play important roles in pancreatic cancer, especially pancreatic ductal adenocarcinoma (PDAC), which is the most prevalent histotype. The role of STAT3 across a continuum of molecular processes, such as PDAC tumorigenesis and progression, immune escape, drug resistance and stemness, and modulation of the tumor microenvironment (TME), are only a tip of the iceberg. In some ways, the role of STAT3 in PDAC may hold greater importance than that of oncogenic Kirsten rat sarcoma virus (KRAS). This makes STAT3 a highly attractive target for developing targeted therapies for the treatment of pancreatic cancer. In this review, the current knowledge of STAT3 in pancreatic cancer has been summarized, particularly relating to STAT3 activation in cancer cells, cells of the TME, and the state of targeting STAT3 in pre-clinical and clinical trials of PDAC.

Signal transducer and activator of transcription (STAT) proteins, pivotal regulators of signaling cascades, undergo activation in response to the stimulation of cytokines and growth factors, and participate in biological processes, including inflammation, immune responses, cell proliferation, and differentiation. During the process of pregnancy, STAT signaling is involved in regulating embryonic implantation, endometrial decidualization, and establishing and maintaining maternal-fetal immune tolerance. Increasing evidence suggests that aberrant STAT signaling contributes to the occurrence and development of pregnancy disorders, including repeated implantation failure (RIF), preeclampsia (PE), recurrent spontaneous abortion (RSA), preterm birth (PTB) and gestational diabetes mellitus (GDM). Elucidating the molecular mechanisms of the STAT signaling pathway holds promise for further understanding the establishment and maintenance of normal pregnancy, and thereby providing potent targets and strategic avenues for the prevention and management of ailments associated with pregnancy. In this review, we summarized the roles of the STAT signaling pathway and its related regulatory function in embryonic implantation, endometrial decidualization, and maternal-fetal immune tolerance. In conclusion, in-depth research on the mechanism of the STAT signaling pathway not only enhances our understanding of normal pregnancy processes but also offers STAT-based therapeutic approaches to protect women from the burden of pregnancy-related disorders [ABSTRACT FROM AUTHOR]

Mesangial proliferative glomerulonephritis (MsPGN), the most common pathological change in primary glomerulonephritis, is characterized by increased macrophage infiltration into glomeruli, which results in proinflammatory cytokine release. Macrophage infiltration and differentiation are induced by the Janus kinase 2 and signal transducer and activator of the transcription 1 (JAK2/STAT1) pathway. As a suppressor of cytokine signaling 1 (SOCS1) downregulates the immune response by inhibiting the JAK2/STAT1 pathway, we investigated whether a peptide mimicking the SOCS1 kinase inhibitor region, namely, SOCS1 peptidomimetic, protects against nephropathy. Glomerular JAK2/STAT1 pathway activation was synchronized with kidney injury in an MsPGN rat model. Rats treated with the SOCS1 peptidomimetic exhibited reduced pathological glomerular changes and lessened macrophage recruitment. Moreover, in vivo, the phosphorylation of the JAK2/STAT1 pathway was downregulated in infiltrated macrophages of glomeruli. In vitro, the SOCS1 peptidomimetic inhibited macrophage M1 polarization by suppressing JAK2/STAT1 activation. In conclusion, our study demonstrated that the SOCS1 peptidomimetic plays a protective role against pathologic glomerular changes in MsPGN by reducing macrophage infiltration and inhibiting macrophage polarizing to the M1 phenotype. SOCS1 peptidomimetic, therefore, presents a feasible therapeutic strategy to alleviate renal inflammation in MsPGN. [ABSTRACT FROM AUTHOR]

Background: The late detection of endometrial carcinoma (EC) at an advanced stage often results in a poor patient prognosis. It is hence important to identify reliable biomarkers to facilitate early detection of EC. Signal transducer and activator of transcription (STAT) family members play an important role in several tumors, however, their impact on EC development and progression remains unclear. Methods: Machine learning methods were used to investigate the importance of STAT5B in EC. Results: Hence, we explored the UALCAN data mining platform and found that while STAT1 and STAT2 were upregulated, STAT5A, STAT5B, and STAT6 were downregulated in EC. This high expression of STAT5B and STAT6 predicted favorable clinical outcomes, whereas the increased expression of STAT1 and STAT2 predicted poor clinical outcomes. Subsequent pathway enrichment analysis revealed that the STAT family was mainly involved in apoptosis pathway activation, cell cycle disruption, and epithelial--mesenchymal transition. Drug sensitivity analysis demonstrated that STAT5A/5B expression was negatively correlated with drug resistance in EC. Further, the expression of STAT5B mRNA and protein was correlated with several clinicopathological characteristics. Tumor Immune Estimation Resource (TIMER) analysis revealed that STAT5B expression was positively correlated with the abundance of infiltrating CD8+ T cells and neutrophils while its copy number variation was associated with the overall immune cell infiltration. The data on the correlations between STAT5B expression and related genes in uterine corpus endometrial carcinoma (UCEC) in cBio Cancer Portal showed the closest correlation of STAT5B expression with that of KIAA0753 (also known as moonraker and OFIP), followed by COL27A1 in EC. Pathway enrichment analysis further showed that STAT5B-related genes were involved in the mitogen-activated protein kinase (MAPK) and Ras signaling pathways. Conclusion: Collectively, our findings provided new insights into the role of the STAT family in EC. It also highlighted new targets for future research on diagnostic and prognostic markers and STAT5B as a novel marker for drug sensitivity screening. [ABSTRACT FROM AUTHOR]

Signal transducer and activator of transcription (STAT) proteins, pivotal regulators of signaling cascades, undergo activation in response to the stimulation of cytokines and growth factors, and participate in biological processes, including inflammation, immune responses, cell proliferation, and differentiation. During the process of pregnancy, STAT signaling is involved in regulating embryonic implantation, endometrial decidualization, and establishing and maintaining maternal-fetal immune tolerance. Increasing evidence suggests that aberrant STAT signaling contributes to the occurrence and development of pregnancy disorders, including repeated implantation failure (RIF), preeclampsia (PE), recurrent spontaneous abortion (RSA), preterm birth (PTB) and gestational diabetes mellitus (GDM). Elucidating the molecular mechanisms of the STAT signaling pathway holds promise for further understanding the establishment and maintenance of normal pregnancy, and thereby providing potent targets and strategic avenues for the prevention and management of ailments associated with pregnancy. In this review, we summarized the roles of the STAT signaling pathway and its related regulatory function in embryonic implantation, endometrial decidualization, and maternal-fetal immune tolerance. In conclusion, in-depth research on the mechanism of the STAT signaling pathway not only enhances our understanding of normal pregnancy processes but also offers STAT-based therapeutic approaches to protect women from the burden of pregnancy-related disorders.

Phosphatidic acid (PA) is a key bioactive glycerophospholipid that is implicated in the regulation of vital cell functions such as cell growth, differentiation, and migration, and is involved in a variety of pathologic processes. However, the molecular mechanisms by which PA exerts its pathophysiological actions are incompletely understood. In the present work, we demonstrate that PA stimulates the migration of the human non-small cell lung cancer (NSCLC) A549 adenocarcinoma cells, as determined by the transwell migration assay. PA induced the rapid phosphorylation of mitogen-activated protein kinases (MAPKs) ERK1-2, p38, and JNK, and the pretreatment of cells with selective inhibitors of these kinases blocked the PA-stimulated migration of cancer cells. In addition, the chemotactic effect of PA was inhibited by preincubating the cells with pertussis toxin (PTX), a Gi protein inhibitor, suggesting the implication of a Gi protein-coupled receptor in this action. Noteworthy, a blockade of LPA receptor 1 (LPA1) with the specific LPA1 antagonist AM966, or with the selective LPA1 inhibitors Ki1645 or VPC32193, abolished PA-stimulated cell migration. Moreover, PA stimulated the phosphorylation of the transcription factor STAT3 downstream of JAK2, and inhibitors of either JAK2 or STAT3 blocked PA-stimulated cell migration. It can be concluded that PA stimulates lung adenocarcinoma cell migration through an interaction with the LPA1 receptor and subsequent activation of the MAPKs ERK1-2, p38, and JNK, and that the JAK2/STAT3 pathway is also important in this process. These findings suggest that targeting PA formation and/or the LPA1 receptor may provide new strategies to reduce malignancy in lung cancer. [ABSTRACT FROM AUTHOR]

G-coupled protein receptors (GPCRs) comprise the largest class of druggable targets. Signaling by GPCRs is initiated from subcellular hot spots including the plasma membrane, signalosomes, and endosomes to contribute to vascular inflammation. GPCR-G protein signaling at the plasma membrane causes endothelial barrier disruption and also cross-talks with growth factor receptors to promote proinflammatory signaling. A second surge of GPCR signaling is initiated by cytoplasmic NFκB activation mediated by β-arrestins and CARMA-BCL10-MALT1 signalosomes. Once internalized, ubiquitinated GPCRs initiate signaling from endosomes via assembly of the transforming growth factor-β-activated kinase binding protein-1 (TAB1)-TAB2-p38 MAPK complex to promote vascular inflammation. Understanding the complexities of GPCR signaling is critical for development of new strategies to treat vascular inflammation such as that associated with COVID-19.

Tumor necrosis factor receptor (TNFR)-associated factors (TRAFs) are a family of intracellular signaling adaptors that associate with the cytoplasmic tails of a diverse range of lymphocyte receptors, including members of the TNFR superfamily, the Toll-like receptor (TLR)/interleukin-1 (IL-1) receptor superfamily, and the IL-6 receptor family that are major targets for therapeutic intervention for inflammatory diseases. TRAF5 is one of the seven family members of the TRAF family and is highly expressed by B- and T-lymphocytes. As compared to other family members, the biological and pathophysiological functions of TRAF5 have remained ambiguous since its discovery. TRAF5 promotes lymphocyte signaling for the TNFR family molecules such as glucocorticoid-induced TNFR family-related protein (GITR), CD27, and CD40. In contrast, TRAF5 limits the activity of the common signaling receptor subunit glycoprotein 130 kDa (gp130) in CD4+ T cells that requires signaling by IL-6 and IL-27. TRAF5 also restrains TLR signaling in B cells. Thus, TRAF5 regulates lymphocyte signaling in both positive and negative ways. This review will summarize the findings of recent studies of TRAF5 in terms of how TRAF5 regulates signaling in lymphocytes and other cell types and how TRAF5 expression contributes to inflammatory and autoimmune diseases in mice and humans.

The growth factor Neuregulin‐1 (NRG‐1) regulates myocardial growth and is currently under clinical investigation as a treatment for heart failure. Here, we demonstrate in several in vitro and in vivo models that STAT5b mediates NRG‐1/EBBB4‐stimulated cardiomyocyte growth. Genetic and chemical disruption of the NRG‐1/ERBB4 pathway reduces STAT5b activation and transcription of STAT5b target genes Igf1, Myc, and Cdkn1a in murine cardiomyocytes. Loss of Stat5b also ablates NRG‐1‐induced cardiomyocyte hypertrophy. Dynamin‐2 is shown to control the cell surface localization of ERBB4 and chemical inhibition of Dynamin‐2 downregulates STAT5b activation and cardiomyocyte hypertrophy. In zebrafish embryos, Stat5 is activated during NRG‐1‐induced hyperplastic myocardial growth, and chemical inhibition of the Nrg‐1/Erbb4 pathway or Dynamin‐2 leads to loss of myocardial growth and Stat5 activation. Moreover, CRISPR/Cas9‐mediated knockdown of stat5b results in reduced myocardial growth and cardiac function. Finally, the NRG‐1/ERBB4/STAT5b signaling pathway is differentially regulated at mRNA and protein levels in the myocardium of patients with pathological cardiac hypertrophy as compared to control human subjects, consistent with a role of the NRG‐1/ERBB4/STAT5b pathway in myocardial growth. Synopsis: STAT5b regulates hypertrophic and hyperplastic growth signaling via the NRG‐1/ERBB4 pathway in cardiomyocytes at adult and embryonic stages. Patients with pathological cardiac hypertrophy show perturbed STAT5b signaling.NRG‐1/ERBB4‐activated STAT5b induces hypertrophic growth in neonatal and adult cardiomyocytes.Loss of stat5b in embryonic zebrafish leads to reduced hyperplastic myocardial growth and cardiac function.Dynamin‐2 controls the cell surface localization of ERBB4, and its inhibition reduces cardiomyocyte hypertrophy.NRG‐1/ERBB4/STAT5b signaling is perturbed in the myocardium of hypertrophic cardiomyopathy patients. [ABSTRACT FROM AUTHOR]

Keloid tissues contain inflammatory cells and upregulated pro‐inflammatory cytokines. The Janus kinase (JAK)‐signal transducer and activator of transcription (STAT) pathway mediate cellular responses to these cytokines. We performed a systematic review on the role of the JAK–STAT pathway in keloid pathogenesis and the evidence for JAK–STAT inhibitors in keloid treatment. The search combined the terms (1) keloid and (2) JAK or TYK or STAT and included MeSH terms and synonyms. Two reviewers screened the articles and assessed the full texts on eligibility. Data were collected on the tested drugs and molecules, the type of cells and tissues used in the experiments, and study findings on the association between the JAK–STAT pathway and keloid cells and tissues. A total of twenty preclinical studies were included. Eleven preclinical studies proved that STAT3 expression and phosphorylation are enhanced in keloid tissue and keloid fibroblasts. Thirteen different JAK and/or STAT inhibitors were investigated. Tested drugs inhibited keloid progression as demonstrated by different processes, including reduced collagen production, cell proliferation and migration, increased cell cycle arrest and apoptosis, enhanced antioxidant responses, decreased (paracrine) signalling, and decreased profibrotic gene expression. No clinical studies have been published to date. Preclinical studies indicate a role for the JAK–STAT pathway in keloid pathogenesis and a potential role for JAK–STAT inhibitors in keloid treatment. The effect of these drugs should be further investigated on relevant biomarkers in a human keloid skin model, preferably including immune cells besides keloid fibroblasts and keratinocytes and in clinical studies. [ABSTRACT FROM AUTHOR]

Cholesterol‐25‐hydroxylase (CH25H) has been identified as an interferon‐stimulated gene (ISG) in mammals that exerts its antiviral effects by catalyzing the conversion of cholesterol to 25‐hydroxycholesterol (25HC). However, invertebrates lack an antiviral system homologous to vertebrate interferons (IFNs) because the genomes of invertebrates do not encode IFN‐like cytokines. Nevertheless, CH25H is present in insect genomes and it therefore deserves further study of whether and by which mechanism it could exert an antiviral effect in invertebrates. In this study, the Bombyx mori CH25H (BmCH25H) gene, of which the encoded protein has high homology with other lepidopteran species, was identified and located on chromosome 9. Interestingly, we found that the expression of BmCH25H was significantly upregulated in B. mori nucleopolyhedrovirus (BmNPV) ‐infected BmN cells and silkworm (B. mori) larvae at the early infection stage. The inhibitory effect of BmCH25H on BmNPV replication was further demonstrated to depend on its catalytic residues to convert cholesterol to 25HC. More importantly, we demonstrated that during BmNPV infection, BmCH25H expression was increased through the Janus kinase–signal transducer and activator of transcription (JAK–STAT) pathway, similar to the induction of ISGs following virus infection in vertebrates. This is the first report that CH25H has antiviral effects in insects; the study also elucidates the regulation of its expression and its mechanism of action. [ABSTRACT FROM AUTHOR]

Introduction: Hepatic inflammation is considered key driver of hepatic tissue impairment.We aimed to explore the interaction of Halamphora coffeaeformis (Amph.) with low dose ionizing γ radiation (γ R) exposure against D-galactosamine (D-GaIN)-induced chronic hepatitis in Albino rats. Methods: Chronic hepatitis was induced with single dose of D-GalN (400 mg/kg BW i.p.). Rats received 400 mg Amph /kg BW daily by gastric gavage concomitant with.25 Gy γ -R. Liver oxidative stress and inflammatory status were assessed. Gene expression levels of signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa B (NFKB) were estimated by q-PCR. D-Galactosamine injection significantly encouraged hepatic oxidative damage and inflammatory disturbance accompanied with improved intercellular adhesion molecule-1 level (ICAM-1). Results: messenger RNA gene expression levels of STAT3 and NF-kB were expressively higher in D-GaIN-treated animals. Histopathological examination supported results. Interestingly, Amph treatment with γ -radiation (γ -R) subjection displayed significant improvement of oxidative and inflammatory status along with controlled signaling molecular factors which was supported by amended histological structure of induced liver hepatitis. Conclusion: Results conclude the efficacious control of liver hepatitis progression by dual collaboration of Amph. with low dose γ -R via control of vital growth signaling factors linked with inflammation thru anti-inflammation, antioxidative and anti-proliferative activities. [ABSTRACT FROM AUTHOR]

STATa is a pivotal transcription factor for Dictyostelium development. dutA is the most abundant RNA transcribed by RNA polymerase II in Dictyostelium, and its functional interplay with STATa has been suggested. This study demonstrates that dutA RNA molecules are distributed as spot‐like structures in the cytoplasm, and that its cell type‐specific expression changes dramatically during development. dutA RNA was exclusively detectable in the prespore region of slugs and then predominantly localized in prestalk cells, including the organizer region, at the Mexican hat stage before most dutA transcripts, excluding those in prestalk O cells, disappeared as culmination proceeded. dutA RNA was not translated into small peptides from any potential open reading frame, which confirmed that it is a cytoplasmic lncRNA. Ectopic expression of dutA RNA in the organizer region of slugs caused a prolonged slug migration period. In addition, buffered suspension‐cultured cells of the strain displayed reduced STATa nuclear translocation and phosphorylation on Tyr702. Analysis of gene expression in various dutA mutants revealed changes in the levels of several STATa‐regulated genes, such as the transcription factors mybC and gtaG, which might affect the phenotype. dutA RNA may regulate several mRNA species, thereby playing an indirect role in STATa activation. [ABSTRACT FROM AUTHOR]

BackgroundSignal Transducer and Activator of Transcription 3 (STAT3) gain-of-function germline mutations are associated with diverse clinical manifestations, including autoimmune cytopenia, lymphadenopathy, immunodeficiency, endocrinopathy, and enteropathy. We describe a new feature: raised intracranial pressure with papilledema.Materials and methodsReport of two cases.ResultsThe first patient had a de novo heterozygous c.2144C>T (p.Pro715Leu) mutation in the STAT3 gene. At age 1 she had papilledema with marked sheathing of the proximal vessels on the optic discs. Follow-up 8 years later showed chronic papilledema, cystoid macular edema, and vision loss. The second patient had a de novo heterozygous c.2147C>T (p.Thr716Met) mutation. At age 12 he developed papilledema, which recurred despite treatment. In both patients, repeated sampling of the cerebrospinal fluid demonstrated a lymphocytic pleocytosis.ConclusionsPapilledema can occur as a manifestation of STAT3 gain-of-function mutation, sometimes accompanied by prominent vascular sheathing and cystoid macular edema. The mechanism may be chronic meningeal infiltration by white blood cells, impairing cerebrospinal fluid absorption.

Macrophages in the tumor microenvironment respond to complex cytokine signals. How these responses shape the phenotype of tumor-associated macrophages (TAMs) is incompletely understood. Here we explored how cytokines of the tumor milieu, interleukin (IL)-6 and IL-4, interact to influence target gene expression in primary human monocyte-derived macrophages (hMDMs). We show that dual stimulation with IL-4 and IL-6 synergistically modified gene expression. Among the synergistically induced genes are several targets with known pro-tumorigenic properties, such as CC-chemokine ligand 18 (CCL18), transforming growth factor alpha (TGFA) or CD274 (programmed cell death 1 ligand 1 (PD-L1)). We found that transcription factors of the signal transducer and activator of transcription (STAT) family, STAT3 and STAT6 bind regulatory regions of synergistically induced genes in close vicinity. STAT3 and STAT6 co-binding further induces the basic leucine zipper ATF-like transcription factor (BATF), which participates in synergistic induction of target gene expression. Functional analyses revealed increased MCF-7 and MDA-MB 231 tumor cell motility in response to conditioned media from co-treated hMDMs compared to cells incubated with media from single cytokine-treated hMDMs. Flow cytometric analysis of T cell populations upon co-culture with hMDMs polarized by different cytokines indicated that dual stimulation promoted immunosuppressive properties of hMDMs in a PD-L1-dependent manner. Analysis of clinical data revealed increased expression of BATF together with TAM markers in tumor stroma of breast cancer patients as compared to normal breast tissue stroma. Collectively, our findings suggest that IL-4 and IL-6 cooperate to alter the human macrophage transcriptome, endowing hMDMs with pro-tumorigenic properties.

Cadmium (Cd) is a common environmental pollutant that leads to severe cardiotoxic hazards. Several studies were carried out to protect the myocardium against Cd-induced cardiotoxicity. Up till now, no researches evaluated the protective effect of dapagliflozin (DAP) against Cd induced cardiotoxicity. Thus, we aimed to explore the role of DAP in such model with deep studying of the involved mechanisms. 40 male Wistar albino rats were included in current study. Cd (5 mg/kg/day) was administered orally for 7 days to induce cardiotoxicity with or without co-administration of DAP in three different doses (2.5, 5, 10 mg/kg/day) orally for 7 days. Our data revealed that Cd could induce cardiotoxicity with significant increase in serum cardiac enzymes, heart weight, tissue malondialdehyde (MDA), tumor necrosis factor alpha (TNFα), nuclear factor kappa B (NFκB), toll like receptor2 (TLR2), interleukin 6 (IL6) and caspase3 immunoexpression with abnormal histopathological changes. In addition, Cd significantly decreased the level of heme oxygenase1 (HO1), nuclear factor erythroid 2-related factor 2 (Nrf2), signal transducer and activator of transcription (STAT3), reduced glutathione (GSH), glutathione peroxidase (GPx), and total antioxidant capacity (TAC). Co-administration of DAP could ameliorate Cd cardiotoxicity with significant improvement of the biochemical and histopathological changes. We found that DAP had protective properties against Cd induced cardiotoxicity and this may be due to its anti-oxidant, anti-inflammatory, anti-apoptotic properties and modulation of IL6/STAT3 and TLR2/TNFα-signaling pathways. [ABSTRACT FROM AUTHOR]

The Janus kinase (JAK) family enzymes are non-receptor tyrosine kinases that phosphorylate cytokine receptors and signal transducer and activator of transcription (STAT) proteins in the JAK-STAT signaling pathway. Considering that JAK-STAT signal transduction is initiated by the binding of ligands, such as cytokines to their receptors, dysfunctional JAKs in the JAK-STAT pathway can lead to severe immune system-related diseases, including autoimmune disorders. Therefore, JAKs are attractive drug targets to develop therapies that block abnormal JAK-STAT signaling. To date, various JAK inhibitors have been developed to block cytokine-triggered signaling pathways. However, kinase inhibitors have intrinsic limitations to drug selectivity. Moreover, resistance to the developed JAK inhibitors constitutes a recently emerging issue owing to the occurrence of drug-resistant mutations. In this review, we discuss the role of JAKs in the JAK-STAT signaling pathway and analyze the structures of JAKs, along with their conformational changes for catalysis. In addition, the entire structure of the murine JAK1 elucidated recently provides information on an interaction mode for dimerization. Based on updated structural information on JAKs, we also discuss strategies for disrupting the dimerization of JAKs to develop novel JAK inhibitors.

Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease, which is characterized by inflammation of the axial skeleton and the peripheral arthritis. An increase in the number of Th17 cells in patients with AS has been reported. Although Th17 cells have been involved in the induction of inflammation, recent data suggest that not all Th17 cells are pathogenic, showing regulatory function of Th17 cell. Cells producing both interferon-gamma (IFN-γ) and interleukin (IL)-17 have been reported to be the main pathologic Th17 (pTh17) cells that induce inflammation at sites of joint. Emerging evidence demonstrated that IL-6 has a main role in regulating the balance between inflammatory and regulatory T cells. However, there is no direct study to assess pTh17 cell with IL-6 in AS. Therefore, we evaluated the effect of IL-6 on pTh17 cell activation, and it's mechanism, using ex vivo and mouse model of AS. As a result, we found that pTh17 cell is dependent on the cytokine milieu with IL-6. We confirmed pTh17 cells play a pathogenic role at sites of inflammation. As a mechanism, it was revealed that IL-6 induced STAT 3 phosphorylation contributes to the increased pTh17 responses in AS patients with peripheral arthritis. Though validation of our results is required, IL-6 inhibitor can be a promising treatment for inflammation in AS patients with peripheral arthritis. • Cells producing both (FN-γ and IL-17 is the main pathologic Th17 cells that induce inflammation at sites of joint. • Pathologic Th17 cell is dependent on the cytokine milieu with IL-6. • IL-6 induced -STAT-3 phosphorylation contributes to the increased pathologic Th17 responses in ankylosing spondylitis patients with peripheral arthritis. [ABSTRACT FROM AUTHOR]

Phosphatidic acid (PA) is a key bioactive glycerophospholipid that is implicated in the regulation of vital cell functions such as cell growth, differentiation, and migration, and is involved in a variety of pathologic processes. However, the molecular mechanisms by which PA exerts its pathophysiological actions are incompletely understood. In the present work, we demonstrate that PA stimulates the migration of the human non-small cell lung cancer (NSCLC) A549 adenocarcinoma cells, as determined by the transwell migration assay. PA induced the rapid phosphorylation of mitogen-activated protein kinases (MAPKs) ERK1-2, p38, and JNK, and the pretreatment of cells with selective inhibitors of these kinases blocked the PA-stimulated migration of cancer cells. In addition, the chemotactic effect of PA was inhibited by preincubating the cells with pertussis toxin (PTX), a Gi protein inhibitor, suggesting the implication of a Gi protein-coupled receptor in this action. Noteworthy, a blockade of LPA receptor 1 (LPA1) with the specific LPA1 antagonist AM966, or with the selective LPA1 inhibitors Ki1645 or VPC32193, abolished PA-stimulated cell migration. Moreover, PA stimulated the phosphorylation of the transcription factor STAT3 downstream of JAK2, and inhibitors of either JAK2 or STAT3 blocked PA-stimulated cell migration. It can be concluded that PA stimulates lung adenocarcinoma cell migration through an interaction with the LPA1 receptor and subsequent activation of the MAPKs ERK1-2, p38, and JNK, and that the JAK2/STAT3 pathway is also important in this process. These findings suggest that targeting PA formation and/or the LPA1 receptor may provide new strategies to reduce malignancy in lung cancer.

Objectives: This study aims to investigate the effectiveness of tofacitinib, a Janus kinase (JAK) 1/JAK3 inhibitor, in treating murine lupus, and also explore 12 related genes downstream of JAK-signal transducer and activator of transcription (STAT) signaling pathways to find the underlying mechanism. Materials and methods: This study was conducted between July 2017 and January 2020. Fifty-seven female BALB/c mice (aging 8 to 10 weeks old; weighing 18 to 20 g) were assigned to a saline control (SC) group and a pristane-induced lupus group. The latter included four groups, namely, pristane control (PC), tofacitinib (T), methylprednisolone (MP), and tofacitinib plus methylprednisolone (T+MP). Animal models of lupus were induced with pristane, whereas SC mice were treated with normal saline. From the 22nd week after induction, each group was given the aforementioned corresponding intervention for 11 weeks. The following variables were tested: serum concentrations of anti-double-stranded deoxyribonucleic acid (anti-dsDNA), interleukin 6 (IL-6), and interferon gamma (IFN-γ); number of regulatory T (Treg) cells; messenger ribonucleic acid levels of forkhead box P3 and 12 related genes downstream of JAK-STAT pathway; and renal impairment. Results: Red swollen joints and proteinuria were first observed in PC after the 12th week. After treatment, T, MP, and T+MP showed relieved red swollen joints and splenomegaly, as well as decreased urine protein, anti-dsDNA, IL-6, IFN-γ, Treg cells, pathological scores, and hyperplasia of mesangial matrix in glomeruli compared with PC. The IFN regulatory factor 7 level was higher in T+MP (p<0.01) and slightly higher in T (p>0.05) and MP (p>0.05) than in PC after treatment. The expression of suppressor of cytokine signaling (SOCS) 1 was lower in T (p>0.05), T+MP (p<0.01), and MP (p>0.05) than in PC. The SOCS3 level was higher in T (p>0.05) and T+MP (p<0.01) and lower in MP (p>0.05) than in PC. Conclusion: Tofacitinib can ameliorate glomerulonephritis and arthritis in a pristane-induced murine model of lupus. SOCS3 gene may be involved in the therapeutic mechanism of tofacitinib. [ABSTRACT FROM AUTHOR]

A subset of cytokines triggers the JAK‐STAT pathway to exert various functions such as the induction of inflammation and immune responses. The receptors for these cytokines are dimers/trimers of transmembrane proteins devoid of intracellular kinase activity. Instead, they rely on Janus kinases (JAKs) for signal transduction. Classical JAK‐STAT signalling involves phosphorylation of cytokine receptors' intracellular tyrosines, which subsequently serve as docking sites for the recruitment and activation of STATs. However, there is evidence to show that several cytokine receptors also use a noncanonical, receptor tyrosine‐independent path to induce activation of STAT proteins. We identified two main alternative modes of STAT activation. The first involves an association between a tyrosine‐free region of the cytokine receptor and STATs, while the second seems to depend on a direct interaction between JAK and STAT proteins. We were able to identify the use of noncanonical mechanisms by almost a dozen cytokine receptors, suggesting they have some importance. These alternative pathways and the receptors that employ them are discussed in this review. [ABSTRACT FROM AUTHOR]

• Agents targeting the JAK/STAT pathway are categorized into phytochemicals, synthetic drugs, and biomolecules, each of which plays a pivotal anti-cancer role. • Combining JAK/STAT inhibitors with other therapies provides new insights into cancer treatment and addresses the challenge of drug resistance. • Utilizing nanocarriers enhances the solubility and bioavailability of anticancer drugs and represents a new approach to cancer therapy. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, essential for cellular communication, orchestrates a myriad of physiological and pathological processes. Recently, the intricate association between the pathway's dysregulation and the progression of malignant tumors has garnered increasing attention. Nevertheless, there is no systematic summary detailing the anticancer effects of molecules targeting the JAK/STAT pathway in the context of tumor progression. This review offers a comprehensive overview of pharmaceutical agents targeting the JAK/STAT pathway, encompassing phytochemicals, synthetic drugs, and biomolecules. These agents can manifest their anticancer effects through various mechanisms, including inhibiting proliferation, inducing apoptosis, suppressing tumor metastasis, and angiogenesis. Notably, we emphasize the clinical challenges of drug resistance while spotlighting the potential of integrating JAK/STAT inhibitors with other therapies as a transformative approach in cancer treatment. Moreover, this review delves into the avant-garde strategy of employing nanocarriers to enhance the solubility and bioavailability of anticancer drugs, significantly amplifying their therapeutic prowess. Through this academic exploration of the multifaceted roles of the JAK/STAT pathway in the cancer milieu, we aim to sketch a visionary trajectory for future oncological interventions. [ABSTRACT FROM AUTHOR]

Background: Incidence of diabetes Mellitus (DM) is on the rise with each passing year in spite of available therapies in the management of DM. Metformin, a standard antidiabetic drug, and gallic acid (GA) are some of the compounds with established antidiabetic properties. However, there is dearth of information on their combination on JAK/STAT signaling pathway and glutathione metabolism in diabetic model. This study investigated the combined effect of metformin and GA on diabetic rats. Methods: Forty male wistar rats were divided into 5 groups viz: diabetic control, normal control, Metformin (100 mg/kg), GA (100 mg/kg) and GA (100 mg/kg) + Metformin (100 mg/kg). Diabetes was induced by administration of 10% fructose for 14 days followed by injection of streptozotocin (40 mg/kg). The therapy was administered for a total of 21 days. The pancreatic mRNA expression of antioxidant genes (glutamate cysteine ligase catalytic subunits (GCLC), glutamate cysteine ligase modifier subunits (GCLM) and Glutathione Synthetase (GSS), inflammatory genes (tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), interleukin 6 (IL-6) and proteins of the Janus Kinase/ Signal Transducer and Activator of Transcription pathway (Janus Kinase (JAK), Signal Transducer and Activator of Transcription (STAT), were quantified using reverse-transcriptase polymerase chain reaction (RT-PCR). Metformin and GA were also docked with Insulin, GSS, and Janus Kinase 2 (JAK2) to determine their binding affinity. Results: Rats treated with co-administration of GA and metformin significantly (p

Natural killer (NK) cells, key members of a distinct hematopoietic lineage, innate lymphoid cells, are not only critical effectors that mediate cytotoxicity toward tumor and virally infected cells but also regulate inflammation, antigen presentation, and the adaptive immune response. It has been shown that NK cells can regulate the development and activation of many other components of the immune response, such as dendritic cells, which in turn, modulate the function of NK cells in multiple synergistic feed back loops driven by cell-cell contact, and the secretion of cytokines and chemokines that control effector function and migration of cells to sites of immune activation. The signal transducer and activator of transcription (STAT)-3 is involved in driving almost all of the pathways that control NK cytolytic activity as well as the reciprocal regulatory interactions between NK cells and other components of the immune system. In the context of tumor immunology, NK cells are a first line of defense that eliminates pre-cancerous and transformed cells early in the process of carcinogenesis, through a mechanism of "immune surveillance." Even after tumors become established, NK cells are critical components of anticancer immunity: dysfunctional NK cells are often found in the peripheral blood of cancer patients, and the lack of NK cells in the tumor microenvironment often correlates to poor prognosis. The pathways and soluble factors activated in tumor-associated NK cells, cancer cells, and regulatory myeloid cells, which determine the outcome of cancer immunity, are all critically regulated by STAT3. Using the tumor microenvironment as a paradigm, we present here an overview of the research that has revealed fundamental mechanisms through which STAT3 regulates all aspects of NK cell biology, including NK development, activation, target cell killing, and fine tuning of the innate and adaptive immune responses.

• Low-dose doxorubicin or dopamine can be used as an immunomodulator to eliminate MDSC. • MDSC elimination is closely related to regulate the STAT pathways in MDSC. • MDSC elimination can delay TAM polarization, inhibit Tregs and proliferate T cells. • STAT1 pathway was activated while STAT3, STAT5 and STAT6 pathways were inactivated. • MDSC elimination alleviate immunosuppression and improve efficacy of neuroblastoma. Neuroblastoma (NB) has high morality rates and is the most common malignant tumor found in children. High aggregation of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment results in immunosuppression and affects therapeutic effectiveness. At present, doxorubicin (DOX) and dopamine (DA) are the specific drugs used to selectively remove or mature MDSCs. The aim of the present study was to explore the feasibility and underlying mechanism of targeting elimination of MDSCs via DOX or DA administration to alleviate tumor immunosuppression in NB. In the present study, a BALB/c tumor-bearing mouse model was established, and mice were grouped into the control, DOX2.5, DOX5 and DA50 mg/kg groups. DOX or DA were injected intravenously on days 7 and 12 after inoculation, following which the parameters related to the signal transducer and activator of transcription (STAT) pathway in MDSCs, the proportion of MDSCs, T cell infiltration, programmed death-1 (PD-1) on the surface of T cells, the number of regulatory T cells (Tregs), polarization of tumor-related macrophages (TAMs) and tumor growth were compared between the groups on days 14, 17 and 23 after inoculation. The results demonstrated that following DOX or DA administration, STAT1/phosphorylated (p)-STAT1 decreased, whereas STAT3/p-STAT3, STAT5/p-STAT5 and STAT6/p-STAT6 increased, which was accompanied by a decrease in the MDSC proportion in each experimental group. Simultaneously, T cell infiltration in tumors was increased, whereas expression of PD-1, the number of Tregs, TAM polarization and tumor growth were inhibited. The most significant findings were observed in the DOX2.5 mg/kg group. To conclude, low dose DOX or DA administration could effectively regulate the STAT pathway to eliminate MDSCs, alleviate immunosuppression and improve the immune response against NB tumor cells. [ABSTRACT FROM AUTHOR]

Janus kinases (JAKs) are a group of nonreceptor intracellular tyrosine kinases that could modify cytokine-mediated signals through the JAK-signal transducer and activator of transcription (STAT) pathway. The intracellular signaling pathway JAK/STAT has a principal role in sequential transfer of extracellular signals from cell membrane to the nucleus. This pathway is triggered by cytokines participating in inflammatory process, innate and adaptive immunological responses, as well as cell growth. Current researches suggest possible disruption in JAK/STAT pathway in different autoimmune and inflammatory skin diseases.

Janus kinases (JAKs) are a group of nonreceptor intracellular tyrosine kinases that could modify cytokine-mediated signals through the JAK-signal transducer and activator of transcription pathway. This pathway is triggered by cytokines participating in the inflammatory process, innate and adaptive immunological responses, as well as cell growth. Current researches suggest the possible disruption in JAK/signal transducer and activator of transcription pathway in different autoimmune and inflammatory skin diseases, such as psoriasis, vitiligo, atopic dermatitis, and alopecia areata. Various drugs that activate or block this pathway are under study for the assessment of their possible role in skin diseases.

Signal transducer and activator of transcription (STAT) family genes—of which there are seven members: STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B , and STAT6 —have been associated with the progression of multiple cancers. However, their prognostic values in glioma remain unclear. In this study, we systematically investigated the expression, the prognostic value, and the potential mechanism of the STAT family genes in glioma. The expression of STAT 1/2/3/5A/6 members were significantly higher and positively correlated with IDH mutations, while the expression of STAT5B was lower and negatively correlated with IDH mutations in glioma. Survival analysis indicated that the upregulation of STAT1/2/3/5A/6 and downregulation of STAT5B expression was associated with poorer overall survival in glioma. Joint effects analysis of STAT1/2/3/5A/5B/6 expression suggested that the prognostic value of the group was more significant than that of each individual gene. Thus, we constructed a risk score model to predict the prognosis of glioma. The receiver operating characteristic curve and calibration curves showed good performance as prognostic indicators in both TCGA (The Cancer Genome Atlas) and the CGGA (Chinese Glioma Genome Atlas) databases. Furthermore, we analyzed the correlation between STAT expression with immune infiltration in glioma. The Protein–protein interaction network and enrichment analysis showed that STAT members and co-expressed genes mainly participated in signal transduction activity, Hepatitis B, the Jak-STAT signaling pathway, transcription factor activity, sequence-specific DNA binding, and the cytokine-mediated signaling pathway in glioma. In summary, our study analyzed the expression, prognostic values, and biological roles of the STAT gene family members in glioma, based on which we developed a new risk score model to predict the prognosis of glioma more precisely. [ABSTRACT FROM AUTHOR]

Sleep disturbance and short sleep duration are associated with inflammation and related disorders including cardiovascular disease, arthritis, diabetes mellitus, and certain cancers. This study was undertaken to test the effects of experimental sleep loss on spontaneous cellular inflammation and activation of signal transducer and activator of transcription (STAT) family proteins, which together promote an inflammatory microenvironment. In 24 healthy adults (16 females; 8 males), spontaneous production of IL-6 and TNF-α in monocytes and spontaneous intranuclear expression of activated STAT1, STAT3, and STAT5 in peripheral blood mononuclear cells (PBMC), monocyte-, and lymphocyte populations were measured in the morning after uninterrupted baseline sleep, partial sleep deprivation (PSD, sleep period from 3a.m. to 7a.m.), and recovery sleep. Relative to baseline, spontaneous monocytic expression of IL-6 and TNF-α was significantly greater after PSD (P

Signal transducer and activator of transcription (STAT) family genes—of which there are seven members: STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6—have been associated with the progression of multiple cancers. However, their prognostic values in glioma remain unclear. In this study, we systematically investigated the expression, the prognostic value, and the potential mechanism of the STAT family genes in glioma. The expression of STAT1/2/3/5A/6 members were significantly higher and positively correlated with IDH mutations, while the expression of STAT5B was lower and negatively correlated with IDH mutations in glioma. Survival analysis indicated that the upregulation of STAT1/2/3/5A/6 and downregulation of STAT5B expression was associated with poorer overall survival in glioma. Joint effects analysis of STAT1/2/3/5A/5B/6 expression suggested that the prognostic value of the group was more significant than that of each individual gene. Thus, we constructed a risk score model to predict the prognosis of glioma. The receiver operating characteristic curve and calibration curves showed good performance as prognostic indicators in both TCGA (The Cancer Genome Atlas) and the CGGA (Chinese Glioma Genome Atlas) databases. Furthermore, we analyzed the correlation between STAT expression with immune infiltration in glioma. The Protein–protein interaction network and enrichment analysis showed that STAT members and co-expressed genes mainly participated in signal transduction activity, Hepatitis B, the Jak-STAT signaling pathway, transcription factor activity, sequence-specific DNA binding, and the cytokine-mediated signaling pathway in glioma. In summary, our study analyzed the expression, prognostic values, and biological roles of the STAT gene family members in glioma, based on which we developed a new risk score model to predict the prognosis of glioma more precisely.

Receptor interacting serine/threonine kinase 4 (RIPK4) is a member of the threonine/serine protein kinase family; it plays related functions in a variety of tumours, but its biological function has not been fully revealed. It has been reported that it is differentially expressed in hepatocellular carcinoma (HCC). Our research aimed to reveal the role of RIPK4 in the progression of HCC and to reveal the biological behaviour of RIPK4 in HCC. We analysed the differences in RIPK4 expression in HCC by using a publicly available data set. By using PCR, Western blotting and immunohistochemical staining methods, we detected the expression level of RIPK4 in HCC patient specimens and studied the relationship between the expression of RIPK4 and the clinicopathological features of HCC patients. The prognostic data were combined to analyse the relationship between RIPK4 and HCC patient survival and tumour recurrence. We found that the expression level of RIPK4 in nontumour tissues was significantly higher than that in tumour tissues, and the level of RIPK4 was significantly positively correlated with postoperative survival and recurrence in HCC patients. Further, our study found that RIPK4 inhibits the progression of HCC by influencing the invasion and metastasis of HCC and that overexpression of RIPK4 reduces the invasion and metastasis of HCC by inhibiting epithelial-mesenchymal transition (EMT) and the STAT3 pathway. In in vivo experiments, overexpression of RIPK4 stably inhibited HCC metastasis. To summarize, our research revealed the relationship between RIPK4 and the prognosis of patients with HCC. We discovered that RIPK4 affects the invasion and metastasis of HCC through the EMT and STAT3 pathways. Targeted inhibition of the RIPK4 gene and the STAT3 pathway may be potential therapeutic strategies for inhibiting the postoperative recurrence and metastasis of HCC.

Endothelins induce many biological responses, and they are composed of three peptides: ET-1, ET-2, and ET-3. Reports have indicated that ET-1 regulates cell proliferation, adipogenesis, and other cell responses and that ET-3 stimulates the growth of gastrointestinal epithelial cells and melanocytes. However, the signalling pathways of ET3 that mediate the growth of fat cells are still unclear. Using 3T3-L1 white preadipocytes, we found that ET-3 induced increases in both cell number and BrdU incorporation. Pretreatment with an ETAR antagonist (but not an ETBR antagonist) blocked the ET-3-induced increases in both cell number and BrdU incorporation. Additionally, BQ610 suppressed the ET-3-induced increases in phosphorylation of AMPK, c-JUN, and STAT3 proteins, and pretreatment with specific inhibitors of AMPK, JNK/c-JUN, or JAK/STAT3 prevented the ET-3-induced increases in phosphorylation of AMPK, c-JUN, and STAT3, respectively. Neither p38 MAPK inhibitor nor PKC inhibitor altered the effects of ET-3 on cell growth. These data suggest that ET-3 stimulates preadipocyte growth through the ETAR, AMPK, JNK/c-JUN, and STAT3 pathways. Moreover, ET-3 did not alter HIB1B brown preadipocyte and D12 beige preadipocyte growth, suggesting a preadipocyte type-dependent effect. The results of this study may help explain how endothelin mediates fat cell activity and fat cell-associated diseases.

Endothelins induce many biological responses, and they are composed of three peptides: ET-1, ET-2, and ET-3. Reports have indicated that ET-1 regulates cell proliferation, adipogenesis, and other cell responses and that ET-3 stimulates the growth of gastrointestinal epithelial cells and melanocytes. However, the signalling pathways of ET3 that mediate the growth of fat cells are still unclear. Using 3T3-L1 white preadipocytes, we found that ET-3 induced increases in both cell number and BrdU incorporation. Pretreatment with an ETAR antagonist (but not an ETBR antagonist) blocked the ET-3-induced increases in both cell number and BrdU incorporation. Additionally, BQ610 suppressed the ET-3-induced increases in phosphorylation of AMPK, c-JUN, and STAT3 proteins, and pretreatment with specific inhibitors of AMPK, JNK/c-JUN, or JAK/STAT3 prevented the ET-3-induced increases in phosphorylation of AMPK, c-JUN, and STAT3, respectively. Neither p38 MAPK inhibitor nor PKC inhibitor altered the effects of ET-3 on cell growth. These data suggest that ET-3 stimulates preadipocyte growth through the ETAR, AMPK, JNK/c-JUN, and STAT3 pathways. Moreover, ET-3 did not alter HIB1B brown preadipocyte and D12 beige preadipocyte growth, suggesting a preadipocyte type-dependent effect. The results of this study may help explain how endothelin mediates fat cell activity and fat cell-associated diseases. [ABSTRACT FROM AUTHOR]

Objectives: The Janus kinase/signal transducer and activator of transcription (JAK–STAT) pathway play a key role in immune modulation, especially in the polarization of T helper cells. JAK inhibitors reduce inflammation by inhibiting the phosphorylation of STAT. We investigated whether a JAK inhibitor, tofacitinib, can reduce inflammation in a mouse model of chronic rhinosinusitis with nasal polyps (CRSwNP). Methods: An eosinophilic CRSwNP model was induced using 4‐week‐old BALB/c mice. The therapeutic effects of topical tofacitinib were compared with the effects of triamcinolone acetonide (TAC). Polyp formation and eosinophilic infiltration were assessed by histology. Levels of phosphorylated STAT (pSTAT), eosinophil cationic protein, and eotaxin were measured by immunohistochemistry. Gene expression levels of GATA‐3 was measured using quantitative PCR. The production of cytokines in sinonasal tissues, including interleukin IL‐4, IL‐5, IL‐12, and interferon‐γ, were measured using enzyme‐linked immunosorbent assays (ELISA). Results: Topical tofacitinib administration significantly reduced the number of polyp‐like lesions and the degree of eosinophilic infiltration, with an efficacy comparable with that of systemic TAC administration. Similarly, the levels of pSTAT6, eosinophil cationic protein, and eotaxin decreased with tofacitinib treatment. Tofacitinib decreased the gene expression level of GATA‐3. Lastly, tofacitinib significantly decreased IL‐4 and IL‐5 production to a similar extent as that by systemic or topical TAC administration. Tofacitinib, but not TAC, significantly increased the production of interferon‐γ. Conclusion: Topical tofacitinib administration may be an effective treatment for eosinophilic CRSwNP by inhibiting phosphorylation of STATs. Level of Evidence: N/A. Laryngoscope, 131:E1400–E1407, 2021 [ABSTRACT FROM AUTHOR]

Pilocarpine-induced status epilepticus (SE), which results in temporal lobe epilepsy (TLE) in rodents, activates the JAK/STAT pathway. In the current study, we evaluate whether brief exposure to a selective inhibitor of the JAK/STAT pathway (WP1066) early after the onset of SE affects the severity of SE or reduces later spontaneous seizure frequency via inhibition of STAT3-regulated gene transcription. Rats that received systemic WP1066 or vehicle at the onset of SE were continuously video-EEG monitored during SE and for one month to assess seizure frequency over time. Protein and/or mRNA levels for pSTAT3, and STAT3-regulated genes including: ICER, Gabra1, c-myc, mcl-1, cyclin D1, and bcl-xl were evaluated in WP1066 and vehicle-treated rats during stages of epileptogenesis to determine the acute effects of WP1066 administration on SE and chronic epilepsy. WP1066 (two 50mg/kg doses) administered within the first hour after onset of SE results in transient inhibition of pSTAT3 and long-term reduction in spontaneous seizure frequency. WP1066 alters the severity of chronic epilepsy without affecting SE or cell death. Early WP1066 administration reduces known downstream targets of STAT3 transcription 24h after SE including cyclin D1 and mcl-1 levels, known for their roles in cell-cycle progression and cell survival, respectively. These findings uncover a potential effect of the JAK/STAT pathway after brain injury that is physiologically important and may provide a new therapeutic target that can be harnessed for the prevention of epilepsy development and/or progression.

Zhitao Dong1,*, Yi Chen2,*, Cheng Yang1,*, Meng Zhang2, Aixue Chen2, Jiamei Yang1, Yangqing Huang2 1Department of Special Treatment, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, 200438, People’s Republic of China; 2Department of Hepatobiliary Surgery, Shanghai Public Health Clinical Center, Fudan University, Shanghai 200083, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jiamei YangDepartment of Special Treatment, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, People’s Republic of ChinaEmail doc_yjm@126.comYangqing HuangDepartment of Hepatobiliary Surgery, Shanghai Public Health Clinical Center, Fudan University, Shanghai 200083, People’s Republic of ChinaEmail eric_huangyq@163.comBackground: Signal transducer and activator of transcription (STAT) proteins are well-known transcription factors that play an important role in the progression of cancer. However, the association between STAT family genes and hepatocellular carcinoma (HCC) remains unclear. This study investigates the expression level, the prognostic value and the potential mechanism of STAT family genes in HCC.Methods: Data from 365 HCC patients in The Cancer Genome Atlas (TCGA) database and 241 HCC patients in the Gene Expression Omnibus (GEO) database were used to investigate the diagnostic and prognostic values of STAT genes by survival analysis and nomogram. Gene set enrichment analysis (GSEA) was used to investigate the potential mechanism of the STAT genes in the development of HCC.Results: Our results showed that STAT4/5B mRNA expression levels in HCC tissues were lower than those in normal tissues. Importantly, our results indicated that high expression of STAT5A, STAT5B and STAT6 was associated with better overall survival in HCC patients. Joint effects analysis of STAT5A, STAT5B and STAT6 suggested that the prognosis difference for any combination of genes was more significant than that for any individual gene. Then, we developed a risk score model could predict HCC prognosis and the nomogram visualized gene expression and clinical factors of probability for HCC prognosis. The ROC and calibration curves showed good performance in survival prediction in both the TCGA and the GEO databases. GSEA suggested that high expression of STAT5A, STAT5B and STAT6 were involved in immune-related biological processes, drug metabolism cytochrome P450, JAK-STAT signalling pathway, and PPAR signalling pathways.Conclusion: Our data suggest that STAT5A, STAT5B and STAT6 expression may be potential prognostic markers of HCC and, in combination, have a better predictive value for HCC prognosis.Keywords: hepatocellular carcinoma, signal transducer and activator of transcription, prognosis, TCGA, GSEA

Context: Liuweibuqi (LWBQ) capsule has been reported to influence symptoms of patients with chronic obstructive pulmonary disease (COPD); however, specific function of LWBQ capsules in COPD with lung-qi deficiency syndrome remains elusive. Objective: This study investigates effect of LWBQ capsules on STAT4/STAT6 and MMP-9/TIMP-1 expression and pulmonary function in stable COPD with lung-qi deficiency syndrome. Materials and methods: Totally, 429 patients diagnosed with stable COPD and lung-qi deficiency syndrome were treated with starch capsules (each time for 9 capsules), or different doses: low (each dose for 8 capsules and 1 LWBQ capsules), medium (each time for 6 capsules and 3 LWBQ capsules), or high (each time for 9 LWBQ capsules) of LWBQ capsules for 30 days, 3 times a day. Forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC% and DLco%pred were evaluated by pulmonary function meter. STAT4/STAT6 and MMP-9/TIMP-1 expression was assessed by RT-qPCR and western blot analysis, and serum concentrations of IL-4, IFN-γ and IL-6 by ELISA. Results: Spearman rank correlation analysis and ROC curve showed that STAT4/STAT6 and MMP-9/TIMP-1 affected pulmonary functions and curative effect of stable COPD with lung-qi deficiency syndrome. After LWBQ capsule treatment, FEV1, FVC, FEV1/FVC% and DLco%pred elevated; STAT4/STAT6, MMP-9/TIMP-1, IFN-γ and IL-6 expression declined whereas IL-4 expression increased (p

T follicular helper (Tfh) cells participate in humoral immune by promoting inflammation and aiding B cells survival, proliferation, maturation, and generation autoantibodies. The plasticity of Tfh cells enables the immune system to adjust the direction of differentiation according to the degree of the immune response, regulate the germinal center (GC) response and maintain homeostasis. Tfh differentiation involves several signaling factors, including multiple cytokines, receptors, transcription factors and genes. The signal transducer and activator of transcription (STAT) family signaling pathways are crucial for Tfh formation. However, because of the multi-factorial and multi-stage features of Tfh differentiation, every STAT member plays a role in Tfh differentiation, but is not completely depended on. With the gradual recognition of different Tfh subsets (Tfh1, Tfh2, Tfh17), the process of Tfh differentiation can no longer be explained by straight-line derivation models. In this review, we summarize the roles of different STATs in mediating Tfh subsets, analyze the contributions of mutual restraint and cooperation among cytokine-STAT signals to terminal Tfh differentiation, and clarify the multi-source pathways of Tfh differentiation with a three-dimensional illustration.

Background: The Janus kinase–signal transducer and activator of transcription signaling pathway has been suggested as a promising therapeutic target in vitiligo. However, limited data is available on the cutaneous expression of JAK in vitiligo. Aim: This study is designed to analyze the cutaneous expression patterns of JAK1, 2, and 3 in vitiligo and investigate their relation to the disease clinical parameters. Methods: This case–control study recruited 24 patients having active vitiligo and 20 age, sex, and skin type-matched healthy volunteers. Skin biopsies were obtained from patients (lesional, perilesional and nonlesional) and controls for assessment of JAK1, 2, and 3 expression using RT-PCR. Results: JAK1 and JAK3 were overexpressed in patients' skin compared to control skin and showed a stepwise pattern of upregulation from control to nonlesional, perilesional and lesional skin. However, JAK3 showed much stronger expression. In contrast JAK2 expression showed no significant difference in any of lesional, perilesional or nonlesional skin compared to control skin. JAK1 and JAK3 expression levels showed no correlation with neither the disease activity nor severity. Conclusion: JAK1 and more prominently JAK3 are upregulated in vitiliginous skin and possibly contribute to the pathogenesis of the disease. Accordingly, selective JAK3/1 inhibition may provide a favorable therapeutic opportunity for vitiligo patients. This study is registered on the ClinicalTrials.gov Identifier: NCT03185312 [ABSTRACT FROM AUTHOR]

T follicular helper (Tfh) cells participate in humoral immune by promoting inflammation and aiding B cells survival, proliferation, maturation, and generation autoantibodies. The plasticity of Tfh cells enables the immune system to adjust the direction of differentiation according to the degree of the immune response, regulate the germinal center (GC) response and maintain homeostasis. Tfh differentiation involves several signaling factors, including multiple cytokines, receptors, transcription factors and genes. The signal transducer and activator of transcription (STAT) family signaling pathways are crucial for Tfh formation. However, because of the multi-factorial and multi-stage features of Tfh differentiation, every STAT member plays a role in Tfh differentiation, but is not completely depended on. With the gradual recognition of different Tfh subsets (Tfh1, Tfh2, Tfh17), the process of Tfh differentiation can no longer be explained by straight-line derivation models. In this review, we summarize the roles of different STATs in mediating Tfh subsets, analyze the contributions of mutual restraint and cooperation among cytokine-STAT signals to terminal Tfh differentiation, and clarify the multi-source pathways of Tfh differentiation with a three-dimensional illustration. [ABSTRACT FROM AUTHOR]