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Background: Recurrent metastasis after radical resection in patients of colorectal cancer (CRC) is a great challenge for the world, in which genomic alterations play a major role in tumorigenesis. MUC4 plays a significant role in recurrence and metastasis in tumor. This study is aimed at exploring the association between MUC4 variants and metastatic recurrence of CRC.Methods: Forty-seven patients relapsing with metastasis and 37 patients remaining disease‐free postoperatively were enrolled. Next-generation sequencing (NGS) detected mutations. Mutation and mRNA expression data were downloaded from TCGA and cBioPortal databases. We analyzed the relationship between MUC4 variants and clinical parameters, as well as possible molecular mechanisms.Results: MUC4 variants rs56359992 and rs781124621 were associated with survival in patients with CRC. Rs56359992 was more common in patients with metastatic recurrence. MAPK pathway, PI3K-Akt pathway, JAK-STAT pathway, cell cycle, WNT pathway and mTOR pathway were found to correlate with MUC4 mutation by GO/KEGG analysis, as well as resting and activated mast cell related to MUC4 mutation by CIBERSORT analysis.Conclusion: Genetic variants of MUC4 with CRC may constitute a molecular signature of metastatic recurrence. MUC4 may become a new target for the treatment of CRC recurrence. [ABSTRACT FROM AUTHOR]

Over the last decade, there has been an increase in the use of targeted therapy using small molecules such as Janus kinase (JAK) inhibitors. Since the introduction of ruxolitinib, the first non-selective JAK inhibitor approved for use in myelofibrosis, many other JAK inhibitors have been tried in a wide spectrum of immune-mediated disorders. Although various trials have shown the promising efficacy of JAK inhibitors in immune-mediated inflammatory disorders (IMIDs), there is a growing concern over the major cardiovascular events and malignancies associated with the use of these molecules in older adults, particularly those over 65 years of age. In this review, we aim to discuss the immunology of the JAK-STAT pathway, the scope of use of JAK inhibitors, and their safety in paediatric practice. Here, we discuss high-quality evidence favouring the use of JAK inhibitors in children with juvenile idiopathic arthritis (JIA) who are refractory to one or more conventional/biological disease-modifying drugs, demonstrated in two randomised controlled trials (RCTs). In addition to JIA, there are reports favouring the role of JAK inhibitors in other IMIDs such as systemic-onset JIA and interferonopathies. Thus far, the existing literature suggests an acceptable safety profile for JAK inhibitors in children. With the expanding scope of JAK inhibitors in a wide range of IMIDs in children, there is a significant need for long-term close vigilance for any potential harm. [ABSTRACT FROM AUTHOR]

Periodontitis is a chronic inflammatory disease that compromises the integrity of the supporting tissues of the teeth and leads to the loss of the alveolar bone. The Mir338 cluster has been proven to be a potential target for the treatment of osteoporosis and is also enriched in gingival tissues with periodontitis; however, its role in periodontitis remains unknown. Here, we aimed to use periodontitis as a model to expand our understanding of the Mir338 cluster in osteoimmunology and propose a new target to protect against bone loss during periodontitis progression. Significant enrichment of the Mir338 cluster was validated in gingival tissues from patients with chronic periodontitis and a ligature-induced periodontitis mouse model. In vivo, attenuation of alveolar bone loss after 7 d of ligature was observed in the Mir338 cluster knockout (KO) mice. Interestingly, immunofluorescence and RNA sequencing showed that ablation of the Mir338 cluster reduced osteoclast formation and elevated the inflammatory response, with enrichment of IFN-γ and JAK-STAT signaling pathways. Ablation of the Mir338 cluster also skewed macrophages toward the M1 phenotype and inhibited osteoclastogenesis via Stat1 in vitro and in vivo. Furthermore, the local administration of miR-338-3p antagomir prevented alveolar bone loss from periodontitis. In conclusion, the Mir338 cluster balanced M1 macrophage polarization and osteoclastogenesis and could serve as a novel therapeutic target against periodontitis-related alveolar bone loss. [ABSTRACT FROM AUTHOR]

Psoriasis (PsO) and atopic dermatitis (AD) are chronic skin disorders that may be associated with erectile dysfunction (ED). However, a Mendelian randomization study found that there was no significant genetic association between PsO and ED. On the other hand, the study showed that genetically predicted increase in AD was associated with a lower risk of ED. The study also identified specific genes and the JAK-STAT signaling pathway as potential factors linking AD and ED. Further research is needed to validate and expand upon these findings. [Extracted from the article]

This article discusses a case of a 23-year-old female with alopecia totalis and lichen planus hypertrophicus who responded well to treatment with oral tofacitinib, a Janus kinase (JAK) inhibitor. The patient had a history of itchy warty lesions on her legs and hair loss on her scalp. After unsuccessful treatment with cyclosporine, tofacitinib was initiated and resulted in significant improvement in both conditions. Tofacitinib is emerging as a promising therapy for severe cases of alopecia areata and has shown efficacy in lichen planus as well. The article highlights the potential of tofacitinib as an effective treatment option for patients with severe or treatment-resistant disease. [Extracted from the article]

This article reports on a case study of a 21-year-old man with refractory generalized pustular psoriasis and psoriatic arthritis. The patient had been treated with acitretin capsules but experienced recurring symptoms. After failed treatment with methotrexate, the patient was administered upadacitinib tablets, which resulted in a reduction of pustules and skin lesions. The use of upadacitinib for the treatment of generalized pustular psoriasis is not well-documented, and further research is needed to explore its effectiveness. [Extracted from the article]

Background. Cholesterol-rich low-density lipoprotein (LDL) particles have been demonstrated to regulate breast cancer cell proliferation and migration, but their biological function and relevant mechanisms in endometrial carcinoma (EC) remain unclear Methods. Serum and tissue samples were collected from EC patients (n = 50) and patients with benign endometrial hyperplasia (n = 50). Ishikawa and RL95-2 cells were stimulated with different concentrations of LDL, followed by treatment with a JAK2 inhibitor (SD-1029). LDL concentrations were determined by ELISA. The in vitro biological behavior of cells was examined using the CCK-8 assay, EdU staining, and Transwell assay. The tumorigenicity of LDL in vivo was examined using a xenograft mouse model. western blotting, immunofluorescence, and immunohistochemistry studies were performed to measure related protein expression. Results. The LDL concentrations and levels of p-JAK2 and p-STAT3 expression were elevated in the clinical samples. Similar trends in expression were detected in EC cells after LDL stimulation. LDL treatment significantly promoted EC cell proliferation, migration, and invasion, and also upregulated p-JAK2 and p-STAT3 expression in a dose-dependent manner. Moreover, SD-1029 dramatically blocked the LDL-mediated effects on EC cells. Intravenous injection of LDLs promoted tumor growth in the xenograft nude mice, and also increased p-JAK2, p-STAT3, and Ki-67 expression, and downregulated caspase-3 expression. Conclusions. These findings indicate that LDLs exert an oncogenic effect in EC cells by activating the JAK/STAT signaling pathway, and also suggest the JAK/STAT pathway as a possible therapeutic target for EC. [ABSTRACT FROM AUTHOR]

To explore the potential network markers and related signaling pathways of human B cells infected by COVID-19, we performed standardized integration and analysis of single-cell sequencing data to construct conditional cell-specific networks (CCSN) for each cell. Then the peripheral blood cells were clustered and annotated based on the conditional network degree matrix (CNDM) and gene expression matrix (GEM), respectively, and B cells were selected for further analysis. Besides, based on the CNDM of B cells, the hub genes and 'dark' genes (a gene has a significant difference between case and control samples not in a gene expression level but in a conditional network degree level) closely related to COVID-19 were revealed. Interestingly, some of the 'dark' genes and differential degree genes (DDGs) encoded key proteins in the JAK-STAT pathway, which had antiviral effects. The protein p21 encoded by the 'dark' gene CDKN1A was a key regulator for the COVID-19 infection-related signaling pathway. Elevated levels of proteins encoded by some DDGs were directly related to disease severity of patients with COVID-19. In short, the proteins encoded by 'dark' genes complement some missing links in COVID-19 and these signaling pathways played an important role in the growth and activation of B cells. [ABSTRACT FROM AUTHOR]

Background: Pulmonary rehabilitation training is of great significance for the prognosis of chronic obstructive pulmonary disease (COPD) patients. The purpose of this study was to investigate the therapeutic effect and pathway of a new sequential noninvasive positive pressure ventilation (NIPPV) + inspiratory muscle training (IMT) therapy. Methods: A total of 100 COPD patients were enrolled and randomly divided into oxygen therapy (OT), NIPPV, IMT and sequential (NIPPV + IMT) group. Lung function, exercise endurance, quality of life, and dyspnea symptoms were examined and recorded. Then, reactive oxygen species (ROS), malonaldehyde (MDA), superoxide dismutase (SOD) and glutathione (GSH) levels were detected by enzyme-linked immunoassay, and suppressor of cytokine signaling 5 (SOCS5)/janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway expression changes were detected by quantitative real time-polymerase chain reaction (qRT-PCR) and western blot. A mouse model of COPD was then established to further verify the effects of SOCS5/JAK2/STAT3 pathways on lung function and oxidative stress. Results: After 8 weeks of treatment, NIPPV, IMT or sequential (NIPPV + IMT) significantly improved exercise endurance, quality of life and dyspnea, reduced oxidative stress, promoted SOCS5 expression and inhibited the activation of JAK2/STAT3 pathway, and no significant effect was observed on lung function of COPD patients. Notably, sequential (NIPPV + IMT) showed better therapeutic outcomes than either IMT or NIPPV alone. Moreover, results at the animal level showed that overexpression of SOCS5 significantly reduced pulmonary inflammatory infiltration, pathological changes and oxidative stress levels in COPD mice, enhanced lung function, and inhibited the activation of JAK2/STAT3 pathway. Conclusion: Our results elucidated that sequential (NIPPV + IMT) significantly relieved COPD development by regulating SOCS5/JAK2/STAT3 signaling-mediated oxidative stress. [ABSTRACT FROM AUTHOR]

Background: Mycobacterium tuberculosis antigen (Mtb-Ag) is a polypeptide component with a molecular weight of 10-14 kDa that is obtained from the supernatant of the H37Ra strain after heat treatment. It stimulates the activation and proliferation of gdT cells in the blood to produce an immune response against tuberculosis. Mtb-Ag is therefore crucial for classifying and detecting the central genes and key pathways involved in TB initiation and progression. Methods: In this study, we performed high-throughput RNA sequencing of peripheral blood mononuclear cells (PBMC) from Mtb-Ag-stimulated and control samples to identify differentially expressed genes and used them for gene ontology (GO) and a Kyoto Encyclopedia of Genomes (KEGG) enrichment analysis. Meanwhile, we used PPI protein interaction network and Cytoscape analysis to identify key genes and qRT-PCR to verify differential gene expression. Single-gene enrichment analysis (GSEA) was used further to elucidate the potential biological functions of key genes. Analysis of immune cell infiltration and correlation of key genes with immune cells after Mtb-Ag-stimulated using R language. Results: We identified 597 differentially expressed genes in Mtb-Ag stimulated PBMCs. KEGG and GSEA enrichment analyzed the cellular pathways related to immune function, and DEGs were found to be primarily involved in the TNF signaling pathway, the IL-17 signaling pathway, the JAK-STAT signaling pathway, cytokine-cytokine receptor interactions, and the NF-kB signaling pathway. Wayne analysis using GSEA, KEGG, and the protein-protein interaction (PPI) network showed that 34 genes, including PTGS2, IL-1b, IL-6, TNF and IFN-g et al., were co-expressed in the five pathways and all were up-regulated by Mtb-Ag stimulation. Twenty-four DEGs were identified using qRT-PCR, including fourteen up-regulated genes (SERPINB7, IL20, IFNG, CSF2, PTGS2, TNF-a, IL36G, IL6, IL10, IL1A, CXCL1, CXCL8, IL4, and CXCL3) and ten down-regulated genes (RTN1, CSF1R CD14, C5AR1, CXCL16, PLXNB2, OLIG1, EEPD1, ENG, and CCR1). These findings were consistent with the RNA-Seq results. Conclusion: The transcriptomic features associated with Mtb-Ag provide the scientific basis for exploring the intracellular immune mechanisms against Mtb. However, more studies on these DEGs in pathways associated with Mtb-Ag stimulation are needed to elucidate the underlying pathologic mechanisms of Mtb-Ag during Mtb infection. [ABSTRACT FROM AUTHOR]

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Background: Previous studies have verified the dysfunction of mesenchymal stem cells (MSCs) for immunoregulation in acquired aplastic anemia (AA) patients. Exosomes derived from MSCs can partially substitute MSCs acting as immune regulator. Dysfunction of exosomes (Exos) derived from AA-MSC (AA-Exos) may play a key role in immunologic dissonance. Method: In this study, CD3 + T cells were collected and cocultured with AA-Exos and exosomes derived from HD-MSC (HD-Exos). The proliferation, differentiation and activation of CD3 + T cells were detected to compare the immunosuppressive effects between AA-Exos and HD-Exos. An immune-mediated murine model of AA was structured to compare the therapeutic effect of AA-Exos and HD-Exos. Furthermore, total RNA including miRNA from exosomes we purified and total RNA of CD3 + T cells were extracted for RNA-seq in order to construct the miRNA–mRNA network for interactions and functional analysis. Results: AA-Exos had impaired inhibition effects on CD3 + T cells in terms of cell proliferation, activation and differentiation compared with exosomes from HD-Exos. HD-Exos showed a more effective rescue of AA mice compared to AA-Exos. Importantly, we found some differentially expressed miRNA involved in immune response, such as miR-199, miR-128 and miR-486. The Gene Ontology analysis of differentially expressed genes (DEGs) revealed involvement of various cellular processes, such as lymphocyte chemotaxis, lymphocyte migration and response to interferon-gamma. The Kyoto Encyclopedia of Genes and Genomes analysis illustrated upregulation of critical pathways associated with T cell function after coculturing with AA-Exos compared with HD-Exos, such as graft-versus-host disease, Th17 cell differentiation and JAK-STAT signaling pathway. A miRNA–mRNA network was established to visualize the interaction between them. Conclusion: In summary, AA-Exos had impaired immunosuppressive effect on T cells, less ability to rescue AA mice and differently expressed miRNA profile, which might partly account for the pathogenesis of AA as well as provide a new target of AA treatment. [ABSTRACT FROM AUTHOR]

Background: The Janus kinase/signal transducers and activators of transcription (JAK-STAT) system regulates several biological processes by affecting transcription of genes as a response to cytokines and growth factors. In the present study, we have characterized the STAT genes in lumpfish (Cyclopterus lumpus L.), belonging to the order Perciformes, and investigated regulation of the JAK-STAT signaling pathway upon exposure to bacteria (Vibrio anguillarum) and poly(I:C), the latter mimicking antiviral responses. Methods: Characterization and evolutionary analyses of the STATs were performed by phylogeny, protein domain, homology similarity and synteny analyses. Antibacterial and antiviral responses were investigated by performing KEGG pathway analysis. Results: We observed that lumpfish have stat1a, 2, 3, 4, 5a, 5b, and 6. Transcriptome-wide analyses showed that most components of the JAK-STAT pathway were present in lumpfish. il-6, il-10, il-21, ikBa and stat3 were upregulated 6 hours post exposure (hpe) against bacteria while type I interferons (IFNs), irf1, irf3, irf10, stat1 and 2 were upregulated 24 hpe against poly(I:C). Conclusions: Our findings shed light on the diversity and evolution of the STATs and the data show that the STAT genes are highly conserved among fish, including lumpfish. The transcriptome-wide analyses lay the groundwork for future research into the functional significance of these genes in regulating critical biological processes and make an important basis for development of prophylactic measure such as vaccination, which is highly needed for lumpfish since it is vulnerable for both bacterial and viral diseases. [ABSTRACT FROM AUTHOR]

We identified STAT1 gain of function (GOF) in a 32-year-old female with pallor, weakness, cough, and dyspnea admitted to our Division of Medicine. She had severe oral ulcers (OU), type 1 diabetes (T1DM), and pancytopenia. Bone marrow (BM) biopsy showed the absence of erythroid precursors. Peripheral blood parameters such as neutrophils < 500/mL, reticulocytes < 2%, and BM hypo-cellularity allowed to diagnose severe aplastic anemia. A heterozygous variant (p.520T>C, p.Cys174Arg) of STAT1 was uncovered. Thus, p.Cys174Arg mutation was investigated as potentially responsible for the patient's inborn immunity error and aplastic anemia. Although STAT1 GOF is rare, aplastic anemia is a more common condition; therefore, we explored STAT1 functional role in the pathobiology of BM failure. Interestingly, in a cohort of six patients with idiopathic aplastic anemia, enhanced phospho-STAT1 levels were observed on BM immunostaining. Next, the most remarkable features associated with STAT1 signaling dysregulation were examined: in both pure red cell aplasia and aplastic anemia, CD8+ T cell genetic variants and mutations display enhanced signaling activities related to the JAK-STAT pathway. Inborn errors of immunity may represent a paradigmatic condition to unravel crucial pathobiological mechanisms shared by common pathological conditions. Findings from our case-based approach and the phenotype correspondence to idiopathic aplastic anemia cases prompt further statistically powered prospective studies aiming to elucidate the exact role and theragnostic window for JAK/STAT targeting in this clinical context. Nonetheless, we demonstrate how a comprehensive study of patients with primary immunodeficiencies can lead to pathophysiologic insights and potential therapeutic approaches within a broader spectrum of aplastic anemia cases. [ABSTRACT FROM AUTHOR]

Objective: Gastric cancer (GC) is one of the malignant tumors with the highest mortality worldwide. Our previous studies have revealed that LINC00691 is up-regulated in serum of GC patients as a novel potential biomarker for GC diagnosis and prognosis. However, the roles of serum exosomal LINC00691 in GC has not been clarified. This study aimed to find the expression pattern of serum exosomal LINC00691 in GC patients and the correlation between the level of serum exosomal LINC00691 and the pathology of gastric cancer patients. Methods: We collected the serum of 94 GC patients before surgery and extracted exosomes to detect the expression level of exosomal LINC00691, with 21 healthy volunteers and 17 patients with benign gastric diseases as controls. Surgical GC tissues and paired healthy tissues were collected to culture primary cancer-associated fibroblasts (CAFs) and normal fibroblasts (NFs). We then treated NFs with LINC00691-rich GC cell culture supernatant or exosomes and detected the activation markers and biological functions of the fibroblasts. Results: The results of real-time qPCR indicated that the serum exosomal LINC00691 of GC patients was significantly higher than that of healthy subjects and patients with benign gastric diseases, and was associated with the clinicopathology of GC patients. More interestingly, when the NFs were treated with GC exosomes, the level of LINC00691 was significantly increased, the cell proliferation and migration were noticeably enhanced, and the ability to accelerate GC cell proliferation and invasion was promoted, which means that the induced fibroblasts gained the properties of CAFs. In addition, we found that knockdown of LINC00691 and the use of the JAK2/STAT3 signaling pathway inhibitor ruxolitinib effectively deprived exosome-containing GC cell supernatants of the effects on NFs. Conclusion: Our study suggested that exosomal LINC00691 promoted NFs to gained the properties of CAFs depending on JAK2/STAT3 signaling pathway as a potential diagnostic biomarker for GC. [ABSTRACT FROM AUTHOR]

This study aims to investigate the relevant mechanism by which hydrazinocurcumin (HC) interferes with A431 cell autophagy by inhibiting the STAT3 signaling pathway. Different concentrations of HC are used to treat A431 cells to study the effects of HC on A431 cell proliferation and apoptosis. Real‐time fluorescent quantitative polymerase chain reaction (PCR) is used to further explore the relationship of HC with the JAK signaling pathway and autophagy. Double immunofluorescence staining is used to detect the fluorescence localization of LC3 and STAT3 after HC treatment. With increasing HC concentrations, A431 cell viability decreases in a dose‐dependent manner, and the apoptosis rate increases significantly. Laser confocal colocalization reveals that the fluorescence of labeled LC3 protein is significantly increased, and the fluorescence of labeled STAT3 is significantly reduced in this study. HC may induce autophagy in A431 cells and affect cell proliferation by downregulating the JAK/STAT3 signaling pathway. [ABSTRACT FROM AUTHOR]

Breast cancer remains the most frequently diagnosed cancer in women worldwide. Tumors that express hormone receptors account for 75% of all cases. Understanding alternative signaling cascades is important for finding new therapeutic targets for hormone receptor-positive breast cancer patients. JAK-STAT signaling is commonly activated in hormone receptor-positive breast tumors, inducing inflammation, proliferation, migration, and treatment resistance in cancer cells. In hormone receptor-positive breast cancer, the JAK-STAT cascade is stimulated by hormones and cytokines, such as prolactin and IL-6. In normal cells, JAK-STAT is inhibited by the action of the adaptor protein, LNK. However, the role of LNK in breast tumors is not fully understood. This review compiles published reports on the expression and activation of the JAK-STAT pathway by IL-6 and prolactin and potential inhibition of the cascade by LNK in hormone receptor-positive breast cancer. Additionally, it includes analyses of available datasets to determine the level of expression of LNK and various members of the JAK-STAT family for the purpose of establishing associations between expression and clinical outcomes. Together, experimental evidence and in silico studies provide a better understanding of the potential implications of the JAK-STAT-LNK loop in hormone receptor-positive breast cancer progression. [ABSTRACT FROM AUTHOR]

Objectives: Pancreatic cancer (PC) is a very lethal malignancy with a scarcity of treatment options. Although erlotinib- and gemcitabine-based treatments have been approved for PC, their effectiveness is limited. The present study is aimed at exploring the molecular and epigenetic mechanisms of anticancer activities of homoharringtonine (HHT) and its interaction with erlotinib to develop a potential therapeutic strategy for PC. Methods: The RT-qPCR, western blotting, immunofluorescence and expression-vectors and oligonucleotide transfection were employed to determine the expression characteristics of onco-factors. Anticancer activities were determined by MTT, colony forming, and flowcytometric analysis. Dual luciferase assay was conducted to confirm putative target of miR-130b-3p. In-vivo experiments were followed by immunohistochemical assay. Key findings: The EphB4/JAK2/STAT3 pathway drives the growth and proliferation of PC through induction of prosurvival factors and cell cycle mediators. HHT directly and epigenetically via miR-130b-3p targets EphB4, leading to downregulation of JAK2/STAT3 pathway. The inactivation of STAT3 results in diminution of antiapoptotic factors and cell cycle mediators. HHT also enhances the anticancer activity of erlotinib. Conclusions: HHT demonstrates potential anticancer activities in PC by downregulating EphB4/JAK2/STAT3 signalling. HHT also produces synergistic effects with erlotinib. [ABSTRACT FROM AUTHOR]

Previous studies revealed a link between inflammation and overactivation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling in syndromes associated with aging. Pseudoxanthoma elasticum (PXE), a rare autosomal-recessive disorder, arises from mutations in ATP-binding cassette subfamily C member 6 (ABCC6). On a molecular level, PXE shares similarities with Hutchinson–Gilford progeria syndrome, such as increased activity of senescence-associated- beta-galactosidase or high expression of inflammatory factors. Thus, this study's aim was the evaluation of activated STAT3 and the influence of JAK1/2-inhibitor baricitinib (BA) on inflammatory processes such as the complement system in PXE. Analysis of activation of STAT3 was performed by immunofluorescence and Western blot, while inflammatory processes and complement system factors were determined based on mRNA expression and protein level. Our results assume overactivation of JAK/STAT3 signaling, increased expression levels of several complement factors and high C3 protein concentration in the sera of PXE patients. Supplementation with BA reduces JAK/STAT3 activation and partly reduces inflammation as well as the gene expression of complement factors belonging to the C1 complex and C3 convertase in PXE fibroblasts. Our results indicate a link between JAK/STAT3 signaling and complement activation contributing to the proinflammatory phenotype in PXE fibroblasts. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Ulcerative lichen planus, a challenging variant of lichen planus, has limited response to traditional treatments. Tofacitinib, a JAK–STAT pathway inhibitor, shows promise in effectively treating these lesions. Lichen planus is a mucocutaneous disease that can cause various manifestations, such as itchy erythematous papules, cicatricial alopecia, erosion, and mucocutaneous ulcers. One uncommon manifestation of this disease is the occurrence of erosion and skin ulcers in the soles of the feet, which can cause many problems for patients. Tofacitinib, a Janus Kinase (JAK) inhibitor drug, has found a special place in the field of inflammatory diseases, especially inflammatory skin diseases. In this regard, studies on the effective role of this drug in the treatment of certain forms of lichen planus, including lichen planopilaris, and erosive lichen planus have been performed. In upcoming study, we introduce a 52‐year‐old woman with lichen planus who complained of ulcerative lesions on the sole of her foot, for whom a diagnosis of plantar ulcerative lichen planus was proposed. After the patient did not respond therapeutically to intralesional triamcinolone acetonide injection, as well as methotrexate and cyclosporine tablets, significant improvement was finally achieved with a 5 mg twice daily dose of tofacitinib. In the following, we will comprehensively review previous articles on the role of tofacitinib in the treatment of lichen planus lesions, as well as the proposed treatment options for erosive and ulcerative lichen planus lesions specifically located on the sole of the foot. Despite limited reports of the successful treatment of mucosal erosive lesions in the oral, esophageal, genital, and ocular mucosa areas with tofacitinib, no previous study has reported the successful treatment of ulcerative lichen planus lesions of the plantar area with tofacitinib. While reporting this case, we recommend considering tofacitinib as a treatment option for plantar ulcerative lichen planus. To confirm its effectiveness, it is necessary to conduct more extensive studies with a larger sample size. [ABSTRACT FROM AUTHOR]

Background: Clear cell renal cell carcinoma (ccRCC) has a high degree of malignancy and poor overall prognosis in advanced and metastatic patients. Therefore, it is of great significance to find new prognostic biomarkers and therapeutic targets for ccRCC. The expression of progestin and adipoQ receptor family member 5 (PAQR5) is significantly downregulated in ccRCC compared with normal tissues, but its specific mechanism and potential biological function in ccRCC remain unclear. Methods: The expression pattern of PAQR5 and the correlation between the PAQR5 expression and clinicopathological parameters and various survival periods in ccRCC patients were analyzed by using multiple public databases and ccRCC tissues chip. Its prognostic value was analyzed by univariate/multivariate Cox regression. In addition, MTT assay, EdU staining assay, flow cytometry, wound healing assay, transwell migration and invasion assay, colony formation assay, immunofluorescence assay, and a xenograft tumor model were conducted to assess the biological function of PAQR5 in ccRCC in vitro and in vivo. Results: Our results indicated that the downregulation of PAQR5 was demonstrated in ccRCC tumor tissues and associated with poorer OS, DSS, and PFI. Meanwhile, the univariate/multivariate Cox regression analysis confirmed that PAQR5 might serve as an independent prognostic factor for ccRCC, and its low expression was tightly correlated with tumor progression and distant metastasis. Mechanistically, a series of gain- and loss-of-function assay revealed that PAQR5 could suppress the ccRCC proliferation, invasion, metastasis, and tumorigenicity in vitro and in vivo by inhibiting the JAK/STAT3 signaling pathway. Conclusion: Our study revealed the tumor suppressor role of PAQR5 in ccRCC. PAQR5 is a valuable prognostic biomarker for ccRCC and may provide new strategies for clinical targeted therapy. [ABSTRACT FROM AUTHOR]

Butyrate (BU), a gut microbiota‐derived metabolite, has been reported to play a neuroprotective role in Parkinson's disease (PD). However, the specific molecular mechanism of BU has not been fully interpreted. This work aimed to verify the protective effects of BU against MPTP/MPP+‐induced neurotoxicity and explore the mechanisms involved. The results showed that BU protected against MPTP‐induced motor dysfunction and decreased tyrosine hydroxylase (TH) and dopamine transporter (DAT) levels. Additionally, BU pretreatment improved PC12 cell viability and reduced MPP+‐induced PC12 cell apoptosis. BU treatment also attenuated MPP+‐stimulated oxidative stress and inflammatory response in PC12 cells. Furthermore, BU inhibited MPTP/MPP+‐induced hyperactivation of the JAK2/STAT3 signaling in mice and PC12 cells. Besides, a JAK2 agonist, Coumermycin A1 (C‐A1), substantially reversed BU‐mediated inhibition on JAK2/STAT3 phosphorylation in MPP+‐challenged PC12 cells and abated BU‐induced repression on MPP+‐triggered apoptosis, oxidative stress, and inflammatory response in PC12 cells. To sum up, BU might exert neuroprotective effects against MPP+/MPTP‐induced neurotoxicity by inactivating the JAK2/STAT3 signaling. [ABSTRACT FROM AUTHOR]

The escalating prevalence of bladder cancer, particularly urothelial carcinoma, necessitates innovative approaches for prognosis and therapy. This study delves into the significance of genes related to epithelial–mesenchymal transition (EMT), a process inherently linked to carcinogenesis and comparatively better studied in other cancers. We examined 1184 EMT-related gene expression levels in bladder urothelial cancer cases through the TCGA dataset. Genes shown to be differentially expressed in relation to survival underwent further network and enrichment analysis to uncover how they might shape disease outcomes. Our in silico analysis revealed a subset of 32 genes, including those significantly represented in biological pathways such as VEGF signaling and bacterium response. In addition, these genes interact with genes involved in the JAK-STAT signaling pathway. Additionally, some of those 32 genes have been linked to immunomodulators such as chemokines CCL15 and CCL18, as well as to various immune cell infiltrates. Our findings highlight the prognostic utility of various EMT-related genes and identify possible modulators of their effect on survival, allowing for further targeted wet lab research and possible therapeutic intervention. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) implicates oxidative stress, apoptosis, and inflammation, all of which may contribute liver injury. Aerobic exercise is assured to positively regulate metabolism in the liver. This project was designed to investigate whether and how aerobic exercise improves DM-induced liver injury.Methods: Seven-week-old male db/db mice and age-matched m/m mice were randomly divided into a rest control group or a group that received 12 weeks of aerobic exercise by treadmill training (10 m/min). Haematoxylin and eosin (HE) staining, electron microscopy, Oil Red O staining and TUNEL assays were used to evaluate the histopathological changes in mouse liver. The serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TRIG), cholesterol (CHOL) were analyzed by serum biochemical analysis. Interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), and tissue levels of malondialdehyde (MDA) and superoxide dismutase (SOD) were analyzed via ELISA. Nuclear factor E2-associated factor-2 (Nrf2), nuclear factor κB (NF-κB) and JAK2/STAT3 pathway-related proteins were measured by immunofluorescence, Western blotting and q-PCR. F4/80 expression in liver tissues was assessed by immunohistochemistry.Results: In diabetic mice, exercise training significantly decreased the levels of serum TRIG, CHOL, IL-6, TNF-α, ALT and AST; prevented weight gain, hyperglycaemia, and impaired glucose and insulin tolerance. Morphologically, exercise mitigated the diabetes-induced increase in liver tissue microvesicles, inflammatory cells, F4/80 (macrophage marker) levels, and TUNEL-positive cells. In addition, exercise reduced the apoptosis index, which is consistent with the results for caspase-3 and Bax. Additionally, exercise significantly increased SOD activity, decreased MDA levels, activated Nrf2 and decreased the expression of NF-kB, phosphorylated JAK2 and STAT3 proteins in the livers of diabetic mice.Conclusion: This study demonstrated that aerobic exercise reversed liver dysfunction in db/db mice with T2DM by reducing oxidative stress, apoptosis and inflammation, possibly by enhancing Nrf2 expression and inhibiting the JAK2/STAT3 cascade response. [ABSTRACT FROM AUTHOR]

Background: Arylsulfatase D (ARSD) belongs to the sulfatase family and plays a crucial role in maintaining the proper structure of bone and cartilage matrix. Although several researches have revealed the functions of ARSD in tumor progression, the prognostic value of ARSD in glioma and the related mechanisms have not been fully investigated. Methods: We performed a pan-cancer analysis of ARSD, and investigated the relationship between expression of ARSD and overall survival (OS) in multiple glioma datasets. ROC curves and nomograms were created to investigate the predictive capacity of ARSD. Immune and analysis were conducted to investigate the mechanisms underlying the roles of ARSD in glioma. Glioma tissue samples were collected to verify the expression of ARSD in glioma, while the functions of ARSD were explored using cell experiment. M2 macrophage infiltration assay was used to determine the relation between ARSD and tumor immune microenvironment. Results: Survival analysis indicated that individuals with high ARSD expression in glioma had a shorter survival time. Cox analysis showed that ARSD had a good ability for predicting prognosis in glioma. Immune analysis suggested that ARSD could regulate immune cell infiltration and affect the Cancer-Immunity Cycle to create an immunosuppressive environment. Combined with cell experiment and bioinformatic analysis, we found that ARSD can promote glioma progression through regulation of JAK2/STAT3 pathway and M2 macrophage infiltration. Conclusion: Our study found that ARSD can promote glioma development by regulating immune microenvironment and JAK2/STAT3 signaling pathway, which provided a potential therapy target for glioma treatment. [ABSTRACT FROM AUTHOR]

Drosophila ovarian Follicle Stem Cells (FSCs) present a favorable paradigm for understanding how stem cell division and differentiation are balanced in communities where those activities are independent. FSCs also allow exploration of how this balance is integrated with spatial stem cell heterogeneity. Posterior FSCs become proliferative Follicle Cells (FCs), while anterior FSCs become quiescent Escort Cells (ECs) at about one fourth the frequency. A single stem cell can nevertheless produce both FCs and ECs because it can move between anterior and posterior locations. Studies based on EdU incorporation to approximate division rates suggested that posterior FSCs divide faster than anterior FSCs. However, direct measures of cell cycle times are required to ascertain whether FC output requires a net flow of FSCs from anterior to posterior. Here, by using live imaging and FUCCI cell-cycle reporters, we measured absolute division rates. We found that posterior FSCs cycle more than three times faster than anterior FSCs and produced sufficient new cells to match FC production. H2B-RFP dilution studies supported different cycling rates according to A/P location and facilitated live imaging, showing A/P exchange of FSCs in both directions, consistent with the dynamic equilibrium inferred from division rate measurements. Inversely graded Wnt and JAK-STAT pathway signals regulate FSC differentiation to ECs and FCs. JAK-STAT promotes both differentiation to FCs and FSC cycling, affording some coordination of these activities. When JAK-STAT signaling was manipulated to be spatially uniform, the ratio of posterior to anterior division rates was reduced but remained substantial, showing that graded JAK-STAT signaling only partly explains the graded cycling of FSCs. By using FUCCI markers, we found a prominent G2/M cycling restriction of posterior FSCs together with an A/P graded G1/S restriction, that JAK-STAT signaling promotes both G1/S and G2/M transitions, and that PI3 kinase signaling principally stimulates the G2/M transition. Author summary: Adult stem cells reside in various tissues in the body and replenish specialized cells throughout an organism's lifetime. Tissues control the rate of stem cell division to match differentiated cell loss by sending signals to the stem cells. We used Drosophila ovarian follicle stem cells as a model to measure stem cell division rates and how they are regulated. We accomplished this by imaging the stem cells in living and fixed tissue using genetically introduced fluorescent markers of progress through different phases of the cell cycle. The length of these phases (DNA replication, mitosis and the intervening preparation stages known as G1 and G2) were measured for stem cells in different locations and with genetic changes simulating changes in natural signals. The results showed large differences in division rates according to the precise location of stem cells, which are partly explained by a specific graded signal and its action at two phase transitions in the cell cycle. The measured division rates fit a model where the stem cells in two different locations produce different specialized cells at different rates but also exchange locations, with roughly equal flow in each direction, to produce a single dynamic stem cell community. [ABSTRACT FROM AUTHOR]

Background: T-cell Activation GTPase Activating Protein (TAGAP) plays a role in immune cell regulation. This study aimed to investigate TAGAP's expression and its potential impact on CD4+ T cell function and prognosis in lung adenocarcinoma (LUAD). Methods: We analyzed TAGAP expression and its correlation with immune infiltration and clinical data in LUAD patients using multiple datasets, including The Cancer Genome Atlas (TCGA-LUAD), Gene Expression Omnibus (GEO), and scRNA-seq datasets. In vitro and in vivo experiments were conducted to explore the role of TAGAP in CD4+ T cell function, chemotaxis, and cytotoxicity. Results: TAGAP expression was significantly lower in LUAD tissues compared to normal tissues, and high TAGAP expression correlated with better prognosis in LUAD patients. TAGAP was positively correlated with immune/stromal/ESTIMATE scores and immune cell infiltration in LUAD. Single-cell RNA sequencing revealed that TAGAP was primarily distributed in CD4+/CD8+ T cells. In vitro experiments showed that TAGAP overexpression enhanced CD4+ T cell cytotoxicity, proliferation, and chemotaxis. Gene Set Enrichment Analysis (GSEA) indicated that TAGAP was enriched in the JAK-STAT signaling pathway. In vivo experiments in a xenograft tumor model demonstrated that TAGAP overexpression suppressed tumor growth and promoted CD4+ T cell cytotoxicity. Conclusions: TAGAP influences CD4+ T cell differentiation and function in LUAD through the STAT pathway, promoting immune infiltration and cytotoxicity. This study provides a scientific basis for developing novel LUAD immunotherapy strategies and exploring new therapeutic targets. [ABSTRACT FROM AUTHOR]

Background Alpha kinase 1 (ALPK1) agonist has recently been reported to demonstrate anti–hepatitis B virus (HBV) efficacy via activating NF-κB signaling, which is crucial for maximizing interferon (IFN) responses. Here, we investigated the impact of ALPK1 on HBV replication and explored ALPK1 variants for predicting the response to pegylated IFN-α (PegIFN-α) treatment. Methods The potential anti-HBV effect of ALPK1 was evaluated in HBV-integrated and HBV-infected hepatoma cells. The potentially functional genetic variants of ALPK1 were screened out, and their correlations with PegIFN-α treatment response were assessed in 945 hepatitis B e antigen (HBeAg)–positive patients with chronic hepatitis B (CHB). Results We revealed that ALPK1 inhibited HBV replication in hepatocytes via activating the JAK-STAT pathway. ALPK1 overexpression improved the anti-HBV effect of IFN-α in cell models. A missense variant, rs35389530 (P660L), of ALPK1 was strongly associated with combined response (CR; namely, HBeAg seroconversion and HBV DNA level <3.3log10 IU/mL) to PegIFN-α treatment in patients with CHB (P = 2.12 × 10−6). Moreover, a polygenic score integrating ALPK1 _rs35389530 and 2 additional genetic variants was further significantly associated with CR (P trend = 9.28 × 10−7), hepatitis B surface antigen (HBsAg) level (P trend =.0002), and HBsAg loss (P trend =.025). Conclusions The anti-HBV effects of ALPK1 through activating JAK-STAT pathway provides a new perspective for CHB therapy. ALPK1 _rs35389530 and polygenic score are potential biomarkers to predict PegIFN-α treatment response and may be used for optimizing CHB treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: The intestinal epithelium is one of the tissues that renews the fastest in the body. This process is driven by intestinal stem cells and is greatly influenced by adenosine triphosphate supply. Glutamine is the preferred energy substrate for the intestinal epithelium, unlike most tissues in the body that prefer glucose. However, there needs to be more understanding of how glutamine affects gene expression in the intestinal epithelium. To address this gap, this study aimed to identify the essential genes and signals involved in glutamine-induced growth of intestinal epithelial cells by exploring gene expression profiles. The results showed that glutamine might upregulate deoxyribonucleic acid replication licensing factors, increasing proliferation-related signaling and suppressing inflammation-related pathways. Consequently, this mechanism leads to the proliferation of intestinal epithelial cells and the expansion of intestinal stem cells. Understanding these crucial targets provides new insight into regulating the homeostasis of the intestinal epithelium, particularly in porcine production. The intestinal epithelium is known for its rapid self-renewal, and glutamine is crucial in providing carbon and nitrogen for biosynthesis. However, understanding how glutamine affects gene expression in the intestinal epithelium is limited, and identifying the essential genes and signals involved in regulating intestinal epithelial cell growth is particularly challenging. In this study, glutamine supplementation exhibited a robust acceleration of intestinal epithelial cell proliferation and stem cell expansion. RNA sequencing indicated diverse transcriptome changes between the control and glutamine supplementation groups, identifying 925 up-regulated and 1152 down-regulated genes. The up-regulated DEGs were enriched in the KEGG pathway of cell cycle and GO terms of DNA replication initiation, regulation of phosphatidylinositol 3-kinase activity, DNA replication, minichromosome maintenance protein (MCM) complex, and ATP binding, whereas the down-regulated DEGs were enriched in the KEGG pathway of p53 signaling pathway, TNF signaling pathway, and JAK-STAT signaling pathway and GO terms of inflammatory response and intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress. Furthermore, GSEA analysis revealed a significant up-regulation of the cell cycle, DNA replication initiation, ATP-dependent RNA helicase activity, and down-regulation of the TNF signaling pathway. The protein–protein association network of the intersecting genes highlighted the significance of DNA replication licensing factors (MCM3, MCM6, and MCM10) in promoting intestinal epithelial growth in response to glutamine. Based on these findings, we propose that glutamine may upregulate DNA replication licensing factors, leading to increased PI3K/Akt signaling and the suppression of TNF, JAK-STAT, and p53 pathways. Consequently, this mechanism results in the proliferation of porcine intestinal epithelial cells and the expansion of intestinal stem cells. [ABSTRACT FROM AUTHOR]

Simple Summary: Midline2 (MID2) is widely involved in development, innate immunity, cancer, viral infections, and disease, but its role in pigs remains unexplored. In this study, we describe the structure and function of porcine MID2. Our results revealed that the gene of pMID2 is highly conserved with human and other vertebrate animals and its expression is started by NF-κB. pMID2 is distributed in cell membrane and cytoplasm and widely expressed in pig lung, spleen, and other organs. Moreover, pMID2 could enhance the activity of the ISRE promoter, and is mainly involved in the JAK-STAT signaling pathway. The above findings provide useful information for studying the function of pMID2 in pigs. Midline2 (MID2/TRIM1) is a member of the tripartite motif-containing (TRIM) family, which is involved in a wide range of cellular processes. However, fundamental studies on porcine MID2 (pMID2) are still lacking. In this study, we identified and characterized the full length MID2 gene of pig (Sus scrofa). The sequence alignment analysis results showed that pMID2 had an N-terminal RING zinc-finger domain, BBC domain, and C-terminal COS box, FN3 motif, and PRY-SPRY domain that were conserved and similar to those of other vertebrates. Furthermore, pMID2 had the highest expression levels in porcine lung and spleen. Serial deletion and site-directed mutagenesis showed that the putative nuclear factor-κB (NF-κB) binding site may be an essential transcription factor for regulating the transcription expression of pMID2. Furthermore, the immunofluorescence assay indicated that pMID2 presented in the cell membrane and cytoplasm. To further study the functions of pMID2, we identified and determined its potential ability to perceive poly (I:C) and IFN-α stimulation. Stimulation experiments showed pMID2 enhanced poly (I:C)-/IFN-α-induced JAK-STAT signaling pathway, indicating that pMID2 might participate in the immune responses. In conclusion, we systematically and comprehensively analyzed the characterizations and functions of pMID2, which provide valuable information to explore the pMID2 functions in innate immunity. Our findings not only enrich the current knowledge of MID2 in IFN signaling regulation but also offer the basis for future research of pig MID2 gene. [ABSTRACT FROM AUTHOR]

Background: IFN-λ has been shown to have a dual function in cancer, with its tumor-suppressive roles being well-established. However, the potential existence of a negative "tumor-promoting" effect of endogenous IFN-λ is still not fully understood. Methods: We conducted a comprehensive review and analysis of the perturbation of IFN-λ genes across various cancer types. Correlation coefficients were utilized to examine the relationship between endogenous IFN-λ expression and clinical factors, immune cell infiltration, tumor microenvironment, and response to immunotherapy. Genes working together with IFN-λ were obtained by constructing the correlation-based network related to IFN-λ and the gene interaction network in the KEGG pathway and IFN-λ-related genes obtained from the networks were integrated as candidate markers for the prognosis model. We then applied univariate and multivariate COX regression models to select cancer-specific independent prognostic markers associated with IFN-λ and to investigate risk factors for these genes by survival analysis. Additionally, computational methods were used to analyze the transcriptome, copy number variations, genetic mutations, and methylation of IFN-λ-related patient groups. Result: Endogenous expression of IFN-λ has been linked to poor prognosis in cancer patients, with the genes IFN-λ2 and IFN-λ3 serving as independent prognostic markers. IFN-λ acts in conjunction with related genes such as STAT1, STAT2, and STAT3 to affect the JAK-STAT signaling pathway, which promotes tumor progression. Abnormalities in IFN-λ genes are associated with changes in immune checkpoints and immune cell infiltration, which in turn affects cancer- and immune-related pathways. While there is increased immune cell infiltration in patients with IFN-λ expression, this does not improve survival prognosis, as T-cell dysfunction and an inflammatory environment are also present. The amplification of IFNL2 and IFNL3 copy number variants drives specific endogenous expression of IFN-λ in patients, and those with this specific expression have been found to have more mutations in the TP53 gene and lower levels of DNA methylation. Conclusion: Our study integrated multi-omics data to provide a comprehensive insight into the dark side of endogenous IFN-λ, providing a fundamental resource for further discovery and therapeutic exploration in cancer. [ABSTRACT FROM AUTHOR]

With an epidemic spread, metabolic syndrome represents an increasingly emerging risk for the population globally, and is currently recognized as a pathological entity. It is represented by a cluster of different conditions including increased blood pressure, high blood sugar, excess body fat around the waist and abnormal cholesterol or triglyceride levels. These conditions lead directly to several disorders, including obesity, dyslipidemia, hyperglycaemia, insulin resistance, impaired glucose tolerance and hypertension causing an increase in cardiovascular risk and in particular atherosclerotic disease. Despite efforts to promote healthier lifestyles through exercise, reduced caloric intake, and improved dietary choices, the incidence and prevalence of metabolic syndrome continue to rise worldwide. Recent research has highlighted the involvement of signaling pathways in chronic inflammatory conditions like obesity and type 2 diabetes mellitus, revealing the significance of the JAK/STAT pathway in atherosclerotic events. This pathway serves as a rapid membrane-to-nucleus signaling module that regulates the expression of critical mediators. Consequently, JAK inhibitors (JAKi) have emerged as potential therapeutic options for metabolic diseases, offering a promising avenue for intervention. The aim of this review is to shed light on the emerging indications of JAK inhibitors in metabolic syndrome, emphasizing their potential role in attenuating associated inflammatory processes, improving insulin sensitivity, and addressing cross-talk with the insulin pathway, with the intention of contributing to efforts in the field of inflammation pharmacology. [ABSTRACT FROM AUTHOR]

Multicellular organisms are constantly subjected to pathogens that might be harmful. Although insects lack an adaptive immune system, they possess highly effective anti-infective mechanisms. Bacterial phagocytosis and parasite encapsulation are some forms of cellular responses. Insects often defend themselves against infections through a humoral response. This phenomenon includes the secretion of antimicrobial peptides into the hemolymph. Specific receptors for detecting infection are required for the recognition of foreign pathogens such as the proteins that recognize glucans and peptidoglycans, together referred to as PGRPs and bGRPs. Activation of these receptors leads to the stimulation of signaling pathways which further activates the genes encoding for antimicrobial peptides. Some instances of such pathways are the JAK-STAT, Imd, and Toll. The host immune response that frequently accompanies infections has, however, been circumvented by diseases, which may have assisted insects evolve their own complicated immune systems. The role of ncRNAs in insect immunology has been discussed in several notable studies and reviews. This paper examines the most recent research on the immune regulatory function of ncRNAs during insect-pathogen crosstalk, including insect- and pathogenencoded miRNAs and lncRNAs, and provides an overview of the important insect signaling pathways and effector mechanisms activated by diverse pathogen invaders. [ABSTRACT FROM AUTHOR]

Daphnetin is a natural coumarin compound with anti‐inflammatory, anti‐oxidant, and anti‐apoptotic effects, which has been previously demonstrated to ameliorate DSS‐induced ulcerative colitis (UC). However, the molecular mechanism involved in the daphnetin‐mediated pathological process of UC remains unclarified. The current study used DSS‐induced mice and LPS‐challenged Caco‐2 cells as UC models. Bodyweight, disease activity index (DAI) score, and colon length were used to evaluate the severity of colitis. The histological changes in colon tissues were observed using H&E and PAS staining. Protein levels were detected by western blot. The malondialdehyde (MDA) and superoxide dismutase (SOD) activities were used to assess oxidative stress. Inflammatory responses were evaluated by detecting the levels of inflammatory cytokines (IFN‐r, IL‐1β, IL‐6, and TNF‐α) using flow cytometry. CCK‐8 and TUNEL assay were employed to determine cell growth and cell death, respectively. The results showed that daphnetin could ameliorate the severity of colitis and attenuate the damage to intestinal structure in DSS‐induced mice. Compared with the DSS group, the expression of ZO‐1, occludin, and anti‐apoptotic protein (BCL‐2) was increased while the level of pro‐apoptotic proteins (Bax and cleaved caspase 3) was decreased in DSS + daphnetin group. The activity of MDA and SOD, as well as the levels of inflammatory cytokines were substantially suppressed by daphnetin. In consistency, in vitro assays indicated that daphnetin protected Caco‐2 cells from LPS‐stimulated viability impairment, apoptosis, oxidative stress, and inflammation. Furthermore, daphnetin suppressed the activity of JAK2/STAT signaling in LPS‐induced Caco‐2 cells in a REG3A‐dependent manner. REG3A overexpression abated the ameliorative effects of daphnetin while JAK2/STAT signaling inhibition functioned synergically with daphnetin in LPS‐stimulated Caco‐2 cells. Collectively, this study deepened the understanding of the therapeutic effects of daphnetin on UC and uncovered for the first time that daphnetin functioned through REG3A‐activated JAK2/STAT3 signaling in UC, which may provide novel insights for the treatment of UC. [ABSTRACT FROM AUTHOR]

This study aims to explore the function of circRIMS in cerebral ischemia/reperfusion (CIR) and its regulatory mechanism. The expression of the circRIMS was examined in GEO chip data and validated by qRT-PCR analysis. A middle cerebral artery occlusion/repression (MCAO/R) model was developed using C57BL/6J mice. Starbase and circinteractome were employed to identify the target miRNA and mRNA. The result was confirmed by dual-luciferase reporter assay, and biotinylated RNA-pulldown assay. The cell viability and apoptosis were confirmed through CCK-8 and flow cytometry assay. This study revealed that circRIMS expression was upregulated in MCAO mice model and OGD/RX-simulated cell model. Knockdown circRIMS demonstrated the functional of circRIMS in increasing cell viability, reducing apoptosis, LDH activity and inflammatory factors secretion in OGD/RX-simulated CIR injury in vitro. Additionally, miR-96-5p was identified as a target of circRIMS, while the STAT1 gene is a downstream gene of miR-96-5p, and JAK was also considered to be a downstream gene of the JAK-STAT pathway. Furthermore, inhibition of miR-96-5p or overexpression of STAT1 promoted the progression of CIR injury by elevating apoptosis, reducing cell viability, and increasing the secretion of inflammatory cytokines. CircRIMS contributes to the progression of CIR injury via regulating miR-96-5p/JAK/STAT1 axis. [ABSTRACT FROM AUTHOR]

The objective of this study is to explore the clinical features and outcomes of pediatric patients with acute lymphoblastic leukemia (ALL) harboring JAK-STAT signaling pathway genetic abnormalities. This retrospective case series examined the clinical data of pediatric patients diagnosed with ALL harboring JAK-STAT pathway genetic abnormality at the Children's Hospital of the Capital Institute of Pediatrics between January 2016 and January 2022. Bone marrow next-generation sequencing was used to reveal the JAK pathway abnormalities. Descriptive statistics were used. From 432 children with ALL during the study period, eight had JAK-STAT pathway genetic abnormalities. Regarding immunotyping, there were four patients with common-B cell types and one with pre-B cell type. The three patients with T-ALL had early T-cell precursor(ETP) type, pre-T cell type, and T cell type. Gene mutations were more common than fusion genes. There was no central nervous system involvement in eight patients. All patients were considered at least at intermediate risk before treatments. Four patients underwent hematopoietic stem cell transplantation (HSCT). One child had a comprehensive relapse and died. The child had a severe infection and could not tolerate high-intensity chemotherapy. Another child relapsed 2 years after HSCT and died. Disease-free survival was achieved in six children. JAK-STAT pathway genetic abnormalities in pediatric Ph-like ALL are rare. Special attention should be paid to treatment-related complications, such as infection and combination therapy (chemotherapy, small molecule targeted drugs, immunotherapy, etc.) to reduce treatment-related death and improve long-term quality of life. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) of protozoan parasites have diverse biological functions that are essential for parasite survival and host–parasite interactions. In this study, we characterized the functional properties of EVs from Naegleria fowleri, a pathogenic amoeba that causes a fatal brain infection called primary amoebic meningoencephalitis (PAM). N. fowleri EVs (NfEVs) have been shown to be internalized by host cells such as C6 glial cells and BV-2 microglial cells without causing direct cell death, indicating their potential roles in modulating host cell functions. NfEVs induced increased expression of proinflammatory cytokines and chemokines such as TNF-α, IL-1α, IL-1β, IL-6, IL-17, IFN-γ, MIP-1α, and MIP-2 in BV-2 microglial cells; these increases were initiated via MyD88-dependent TLR-2/TLR-4. The production levels of proinflammatory cytokines and chemokines in NfEVs-stimulated BV-2 microglial cells were effectively downregulated by inhibitors of MAPK, NF-κB, or JAK-STAT. Phosphorylation levels of JNK, p38, ERK, p65, JAK-1, and STAT3 were increased in NfEVs-stimulated BV-2 microglial cells but were effectively suppressed by each corresponding inhibitor. These results suggest that NfEVs could induce proinflammatory immune responses in BV-2 microglial cells via the NF-κB-dependent MAPK and JAK-STAT signaling pathways. Taken together, these findings suggest that NfEVs are pathogenic factors involved in the contact-independent pathogenic mechanisms of N. fowleri by inducing proinflammatory immune responses in BV-2 microglial cells, further contributing to deleterious inflammation in infected foci by activating subsequent inflammation cascades in other brain cells. [ABSTRACT FROM AUTHOR]

Long non-coding RNAs (lncRNAs) are crucial players in the pathogenesis of non-small-cell lung cancer (NSCLC). A competing binding of lncRNAs and mRNAs with microRNAs (miRNAs) is one of the most common mechanisms of gene regulation by lncRNAs in NSCLC, which has been extensively researched in the last two decades. However, alternative mechanisms that do not depend on miRNAs have also been reported. Among them, the most intriguing mechanism is mediated by RNA-binding proteins (RBPs) such as IGF2BP1/2/3, YTHDF1, HuR, and FBL, which increase the stability of target mRNAs. IGF2BP2 and YTHDF1 may also be involved in m6A modification of lncRNAs or target mRNAs. Some lncRNAs, such as DLGAP1-AS2, MALAT1, MNX1-AS1, and SNHG12, are involved in several mechanisms depending on the target: lncRNA/miRNA/mRNA interactome and through RBP. The target protein sets selected here were then analyzed using the DAVID database to identify the pathways overrepresented by KEGG, Wikipathways, and the Reactome pathway. Using the STRING website, we assessed interactions between the target proteins and built networks. Our analysis revealed that the JAK-STAT and Hippo signaling pathways, cytokine pathways, the VEGFA-VEGFR2 pathway, mechanisms of cell cycle regulation, and neovascularization are the most relevant to the effect of lncRNA on NSCLC. [ABSTRACT FROM AUTHOR]

Acacetin is a natural flavonoid compound found in diverse plants, which has strong anti‐inflammatory and anti‐cancer activities. This work aimed at investigating how acacetin functions on esophageal squamous carcinoma cells. In this work, esophageal squamous carcinoma cell lines were subjected to increasing doses of acacetin, and the proliferative, migrative, invasive and apoptotic phenotypes were evaluated by a series of in vitro experiments. Genes related to acacetin and esophageal cancer were predicted by bioinformatics analysis. The levels of apoptosis‐relevant proteins and JAK2/STAT3 pathway‐relevant proteins in esophageal squamous carcinoma cells were probed by Western blot. It was revealed that acacetin could block the growth and aggressiveness of TE‐1 and TE‐10 cells and promote the apoptosis. Acacetin treatment induced bax's expression and repressed bcl‐2's expression. Notably, acacetin inhibits JAK2/STAT3 pathway in esophageal squamous carcinoma cells. In summary, acacetin inhibits the malignant progression of esophageal squamous carcinoma via restraining JAK2/STAT3 signaling. [ABSTRACT FROM AUTHOR]

[Objectives] To analyze the transcriptome of Calliptamus abbreviatus (Calliptaminae, Orthoptera), one of the main pests of grassland and semi-rural pastoral areas, in order to identify immune related signal pathways and genes in this pest. [Methods] Transcriptome data of female and male adults were sequenced on an Illumina high-throughput platform. Bioinformatics analysis of sequencing data, such as assembly and annotation, were implemented, and immune related pathways and genes were identified. [Results] A total of 36 804 unigenes were obtained, of which 21 137 were successfully annotated using the seven functional databases (Nr, Nt, GO, COG, KEGG, Swissprot and Interpro). 160 unigenes associated with innate immunity were identified in the Toll, IMD and JAK-STAT signaling pathways. 166 unigenes are associated with other immune related pathways (such as the MAPK and TLR signaling pathway), and 457 are associated with detoxification metabolism related pathways. In total 8 125 genes that are differentially expressed in males and females were identified, of which 6 326 were up-regulated and 1 799 down-regulated, respectively. Based on KEGG annotation, a total of 22 unigenes were annotated in the JAK-STAT signaling pathway, and six were annotated in the MAPK pathway. In addition, 6 227 SSRs were detected. [Conclusion] Transcriptome data on C. abbreviates was successfully obtained and immune related pathways and genes identified. These findings provide a molecular basis for gene function annotation, the identification of immune genes, and molecular marker development, in this species. [ABSTRACT FROM AUTHOR]

Simple Summary: This study presents the first comprehensive single-cell transcriptomic characterization at E16 in Ujumqin sheep and Hulunbuir short-tailed sheep (the day of mating was defined as day 0, and embryo samples were taken on the 16th day). TBXT mutations are related to tailless or short-tailed phenotypes in vertebrates. In our previous study, we detected the TBXT expression level at a different embryo stage in sheep and found that TBXT exhibited the highest expression at E16. We believe that TBXT plays an important role in E16; thus, we chose E16 as the focus of this study. This comprehensive single-cell map reveals previously unrecognized signaling pathways that will improve our understanding of the mechanism of short-tailed sheep formation. Cell types have been established during organogenesis based on early mouse embryos. However, our understanding of cell types and molecular mechanisms in the early embryo development of Mongolian sheep has been hampered. This study presents the first comprehensive single-cell transcriptomic characterization at E16 in Ujumqin sheep and Hulunbuir short-tailed sheep. Thirteen major cell types were identified at E16 in Ujumqin sheep, and eight major cell types were identified at E16 in Hulunbuir short-tailed sheep. Function enrichment analysis showed that several pathways were significantly enriched in the TGF-beta signaling pathway, the Hippo signaling pathway, the platelet activation pathway, the riboflavin metabolism pathway, the Wnt signaling pathway, regulation of the actin cytoskeleton, and the insulin signaling pathway in the notochord cluster. Glutathione metabolism, glyoxylate, and dicarboxylate metabolism, the citrate cycle, thyroid hormone synthesis, pyruvate metabolism, cysteine and methionine metabolism, thermogenesis, and the VEGF signaling pathway were significantly enriched in the spinal cord cluster. Steroid biosynthesis, riboflavin metabolism, the cell cycle, the Hippo signaling pathway, the Hedgehog signaling pathway, the FoxO signaling pathway, the JAK-STAT signaling pathway, and the Wnt signaling pathway were significantly enriched in the paraxial mesoderm cluster. The notochord cluster, spinal cord cluster, and paraxial mesoderm cluster were found to be highly associated with tail development. Pseudo-time analysis demonstrated that the mesenchyme can translate to the notochord in Ujumqin sheep. Molecular assays revealed that the Hippo signaling pathway was enriched in Ujumqin sheep. This comprehensive single-cell map revealed previously unrecognized signaling pathways that will further our understanding of the mechanism of short-tailed sheep formation. [ABSTRACT FROM AUTHOR]

Background: Ubiquitin‐conjugating enzyme E2S (UBE2S), an E2 enzyme, is associated with the development of various tumors and exerts oncogenic activities. UBE2S is overexpressed in tumors, including hepatocellular carcinoma (HCC). However, the key molecular mechanisms of UBE2S in HCC still need additional research. The aim of this study was to explore the role of UBE2S in HCC. Methods: The expression levels of UBE2S in HCC tissues and cells were detected by western blot analysis, quantitative real‐time polymerase chain reaction analysis (qRT–PCR), and immunohistochemistry (IHC). A 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl‐2H‐tetrazolium bromide (MTT) assay, wound healing assay, colony formation assay transwell assay, and animal models were used to detect the proliferation and migration ability of HCC cells. Western blot analysis, qRT–PCR, immunofluorescence, small‐interfering RNA (siRNA), and plasmid transfection and coimmunoprecipitation (Co‐IP) assays were performed to detect the interaction among UBE2S, von Hippel–Lindau (VHL), hypoxia‐inducible factor 1‐alpha (HIF‐1α), Janus kinase‐2 (JAK2), and signal transducer and activator of transcription 3 (STAT3). Results: In this study, we found that high UBE2S expression was associated with poor prognosis in HCC patients. In addition, UBE2S expression was upregulated in HCC tissues and cell lines. Knockdown of UBE2S inhibited the proliferation and migration of HCC cells in vitro and in vivo by directly interacting with VHL to downregulate the HIF‐1α and JAK2/STAT3 signaling pathways. Accordingly, overexpression of UBE2S significantly enhanced the proliferation and migration of HCC cells in vitro via VHL to upregulate HIF‐1α and JAK2/STAT3 signaling pathways. Furthermore, we found that downregulation of UBE2S expression enhanced the sensitivity of HCC cells to sorafenib in vivo and in vitro. Conclusion: UBE2S enhances malignant properties via the VHL/HIF‐1α and VHL/JAK2/STAT3 signaling pathways and reduces sensitivity to sorafenib in HCC. The findings of this study may open a new approach for HCC diagnosis and provide a potential option for the treatment of HCC. [ABSTRACT FROM AUTHOR]

For any biological response, transmission of extracellular signals to the nucleus is required for DNA transcription and gene expression. In that respect, cytokines/chemokines are well-known inflammatory agents which play a critical role in signalling pathways by activating the Janus kinase-signal transducers and activators of transcription (JAK-STAT) signalling proteins (Janus kinase-signal transducers and activators of transcription) which are a group of intracellular kinase molecules. Cytokines are a category of small proteins (∼5-25 kDa) that play a major role in cell signalling and are major drivers of an autoimmune response. Here we will discuss the role of Janus kinase-signal transducers and activators of transcription kinase cascades in the inflammatory-proliferative cascades of autoimmune disease and about the recent progress in the development of oral synthetic Janus kinase inhibitors (JAKi) and their therapeutic efficacies in dermatologic and systemic autoimmune diseases. Therapeutic efficacy of Janus kinase inhibitors is now well established in the treatment of array of autoimmune and inflammatory disease: spondylarthritis with a special focus on psoriatic arthritis (PsA) and its dermatologic manifestations (psoriasis) and ankylosing spondylitis (AS), atopic dermatitis (AD), alopecia areata (AA), rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). In addition to the first-generation Janus kinase inhibitors several new-generation Janus kinase inhibitors are currently being evaluated. It is expected that these Janus kinase inhibitors likely have higher potency and less adverse effects as compared to their predecessors. Here we have discussed: (1) the functional significance of the Janus kinase-signal transducers and activators of transcription kinase cascades in the inflammatory-proliferative processes of autoimmune diseases and its cellular/molecular mechanisms and (2) progress in the development of oral synthetic Janus kinase inhibitors and their therapeutic efficacies in several systemic and cutaneous autoimmune diseases. [ABSTRACT FROM AUTHOR]

Glaesserella parasuis (G. parasuis) can elicit meningitis in pigs; however, the pathogenic mechanisms of meningitis induced by G. parasuis remain unclear. Long non-coding RNAs (lncRNAs) have been proven to play key roles in a variety of physiological and pathological processes. However, whether lncRNAs are involved in meningitis triggered by G. parasuis has not been investigated. In this study, we performed an integrative analysis of lncRNAs expression profiles in the porcine brain infected with G. parasuis using RNA-seq. The results showed that lncRNA expressions in G. parasuis-induced meningitis were modified, and a total of 306 lncRNAs exhibited significant differential expression, in which 176 lncRNAs were up-regulated and 130 lncRNAs were down-regulated. KEGG enrichment analysis demonstrated that the differentially expressed target mRNAs of affected lncRNAs in G. parasuis-infected porcine brain were mainly involved in the cell adhesion molecules (CAMs), Jak-STAT signaling pathway, PI3k-Akt signaling pathway, and TNF signaling pathway. The expression relationship between the most affected differential lncRNAs and their differential target mRNAs was visualized by a co-expression network. A protein-protein interaction network consisting of 12 differential targets was constructed using STRING analysis. In addition, differential expressions of important lncRNAs were validated by qRT-PCR. lncRNA ALDBSSCT0000007362, ALDBSSCT0000001959, ALDBSSCT0000005529, MSTRG.2939.1, and MSTRG.32374.1 showed the same expression pattern with the lncRNA sequencing data. Our results demonstrated that G. parasuis could modify the lncRNA expression profiles in the porcine brain. To the best of our knowledge, this is the first report revealing the integrative analysis of lncRNA expression profiles in G. parasuis-induced meningitis, which could enhance important information to understand the inflammatory functions of lncRNAs involved in swine meningitis, and also provide a foundation for finding out novel strategies to prevent and treat meningitis in piglets triggered by G. parasuis. [ABSTRACT FROM AUTHOR]

Cyanotis arachnoidea C. B. Clarke is a traditional Chinese medicinal herb that has a limited clinical use in the treatment of diabetes mellitus (DM) in minority areas of Guizhou in China. However, few prior reports are available on the quality control of Cyanotis arachnoidea, and its quality markers and hypoglycemic mechanism are still unclear. The purpose of this study is to explore the quality markers (Q-markers) of Cyanotis arachnoidea and predict its hypoglycemic mechanism. In this study, ultrahigh-performance liquid chromatography (UHPLC) fingerprint combined with chemical pattern recognition were performed, and four differential components were screened out as quality markers, including 20-Hydroxyecdysone, 3-O-acetyl-20-hydroxyecdysone, Ajugasterone C, and 2-O-acetyl-20-hydroxyecdysone. Network pharmacology analysis revealed 107 therapeutic target genes of Cyanotis arachnoidea in DM treatment, and the key targets were Akt1, TNF, IL-6, MAPK3, and JUN. The hypoglycemic mode of action of Cyanotis arachnoidea may be mediated by tumor necrosis factor (TNF) signaling, cancer, insulin resistance, and JAK-STAT pathways. Molecular docking analysis disclosed that the foregoing quality markers effectively bound their key target genes. An in vitro experiment conducted on pancreatic islet ß-cells indicated that the forenamed active components of Cyanotis arachnoidea had hypoglycemic efficacy by promoting PI3K/Akt and inhibiting MAPK signaling. UHPLC also accurately quantified the quality markers. The identification and analysis of quality markers for Cyanotis arachnoidea is expected to provide references for the establishment of a quality control evaluation system and clarify the material basis and hypoglycemic mechanisms of this traditional Chinese medicine (TCM). [ABSTRACT FROM AUTHOR]

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Background: Pulmonary fibrosis is a progressive disease characterized by lung remodeling due to excessive deposition of extracellular matrix. Although the etiology remains unknown, aberrant angiogenesis and inflammation play an important role in the development of this pathology. In this context, recent scientific research has identified new molecules involved in angiogenesis and inflammation, such as the prolyl oligopeptidase (PREP), a proteolytic enzyme belonging to the serine protease family, linked to the pathology of many lung diseases such as pulmonary fibrosis. Therefore, the aim of this study was to investigate the effect of a selective inhibitor of PREP, known as KYP-2047, in an in vitro and in an in vivo model of pulmonary fibrosis. Methods: The in vitro model was performed using human alveolar A549 cells. Cells were exposed to lipopolysaccharide (LPS) 10 μg/ml and then, cells were treated with KYP-2047 at the concentrations of 1 μM, 10 μM and 50 μM. Cell viability was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) bromide colorimetric assay, while inflammatory protein expression was assessed by western blots analysis. The in vivo model was induced in mice by intra-tracheal administration of bleomycin (1 mg/kg) and then treated intraperitoneally with KYP-2047 at doses of 1, 2.5 and 5 mg/kg once daily for 12 days and then mice were sacrificed, and lung tissues were collected for analyses. Results: The in vitro results demonstrated that KYP-2047 preserved cell viability, reduced inflammatory process by decreasing IL-18 and TNF-α, and modulated lipid peroxidation as well as nitrosative stress. The in vivo pulmonary fibrosis has demonstrated that KYP-2047 was able to restore histological alterations reducing lung injury. Our data demonstrated that KYP-2047 significantly reduced angiogenesis process and the fibrotic damage modulating the expression of fibrotic markers. Furthermore, KYP-2047 treatment modulated the IκBα/NF-κB pathway and reduced the expression of related pro-inflammatory enzymes and cytokines. Moreover, KYP-2047 was able to modulate the JAK2/STAT3 pathway, highly involved in pulmonary fibrosis. Conclusion: In conclusion, this study demonstrated the involvement of PREP in the pathogenesis of pulmonary fibrosis and that its inhibition by KYP-2047 has a protective role in lung injury induced by BLM, suggesting PREP as a potential target therapy for pulmonary fibrosis. These results speculate the potential protective mechanism of KYP-2047 through the modulation of JAK2/STAT3 and NF-κB pathways. [ABSTRACT FROM AUTHOR]

EATL is an aggressive T-cell non-Hodgkin lymphoma with poor prognosis and is largely localized to the small intestine. EATL is closely associated with coeliac disease (CD) and is seen mostly in patients originating from Northern Europe. Various factors are associated with an increased risk of developing EATL, such as viral infection, advanced age, being male, and the presence of the HLA-DQ2 haplotype. Clonal rearrangements in the TCR-β and γ genes have been reported in all EATL morphological variants with distinctive immunophenotypic characteristics. Although EATL can occur de novo, individuals with RCDII are at a higher risk of developing EATL. The cells of origin of EATL has been postulated to be normal small intestinal intraepithelial T-lymphocytes (IELs), and more recent evidence suggests a link between innate precursor IELs and EATL derived from refractory coeliac disease type II (RCDII). The immune microenvironment of mucosal cells within the small intestine enhances the process of neoplastic transformation of IELs into EATL. Cytokines such as IL-15 can activate and crucially deregulate the JAK-STAT signaling pathway by binding to receptors on the surface of IELs. Furthermore, mutations in the JAK/STAT pathway have been associated with RCDII-derived EATL. [ABSTRACT FROM AUTHOR]

Dry eye syndrome (DES) is a chronic ocular disease that induces epithelial damage to the cornea by decreasing tear production and quality. Adequate treatment options have not been established for severe DES such as Sjogren's syndrome due to complicated pathological conditions. To solve this problem, we focused on the conditioned medium of human adipose-derived mesenchymal stem cells (hAdMSC-CM), which have multiple therapeutic properties. Here, we showed that hAdMSC-CM suppressed Benzalkonium Chloride (BAC)-induced cytotoxicity and inflammation in human corneal epithelial cells (hCECs). In addition, hAdMSC-CM increased the expression level and regulated the localisation of barrier function-related components, and improved the BAC-induced barrier dysfunction in hCECs. RNA-seq analysis and pharmacological inhibition experiments revealed that the effects of hAdMSC-CM were associated with the TGFβ and JAK-STAT signalling pathways. Moreover, in DES model rats with exorbital and intraorbital lacrimal gland excision, ocular instillation of hAdMSC-CM suppressed corneal epithelial damage by improving barrier dysfunction of the cornea. Thus, we demonstrated that hAdMSC-CM has multiple therapeutic properties associated with TGFβ and JAK-STAT signalling pathways, and ocular instillation of hAdMSC-CM may serve as an innovative therapeutic agent for DES by improving corneal barrier function. [ABSTRACT FROM AUTHOR]