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Background Major depressive disorder (MDD) is a prevalent mental health condition, wherein the JAK/STAT signaling pathway serves as a potent cellular mechanism implicated in its pathophysiology. Increased expression of JAK2, STAT3, and subsequently IDO1 genes appears to be linked to depressive symptoms. With their antioxidant capabilities and improved absorption due to the nano formula, selenium nanoparticles could potentially modulate this molecular pathway. This study aimed to assess the impact of nano-selenium supplementation on the expression of JAK2, STAT3, and IDO1 genes in patients with MDD. Methods A triple-blind, randomized, placebo-controlled trial was conducted at the Psychosomatic Clinic of Imam Khomeini Hospital Complex. A total of 50 participants, newly diagnosed with MDD were randomized to either a nano-selenium (55 µg/day) or placebo group for 12 weeks. All participants were receiving their standard treatment (sertraline 50 mg/day). Blood samples were collected at baseline and post-intervention to measure the gene expression using RT-qPCR. Results At the end of the study, both groups showed reductions in JAK2 and STAT3 relative gene expression after 12 weeks ( P  < 0.05). Although the reduction was more in the nano-selenium group, the between-group differences were not statistically significant. Conclusions This study is the first to examine nano-selenium as a novel potential adjunct treatment for MDD. Though the degree of reduction in JAK2 and STAT3 levels was greater within the nano-selenium group, it appears that additional investigations are needed to elucidate its effects. Trial registration The research received approval from the Research Ethics Committees of Iran University of Medical Sciences (Approval ID: IR IUMS.REC.1402.206, dated 2023-06-13) and was duly registered with the Iranian Registry of Clinical Trials (IRCT; registration number: IRCT20091114002709N62, dated 2023-07-29). Graphical Abstract This research represents the first human trial investigating the effects of the nano-selenium formulation on the expression of a key signaling pathway associated with major depressive disorder.

The poor prognosis of clear-cell renal cell carcinoma (ccRCC) patients is due to progression and targeted drug resistance, but the underlying molecular mechanisms need further elucidation. This study examined the biological function and related mechanisms of gankyrin in ccRCC based on the results of our previous study. To this end, in vitro functional experiments; in vivo models of subcutaneous tumor formation, lung metastasis, and orthotopic ccRCC; and antibody chip detection, co-IP, ChIP assays were performed to examine the biological role and molecular mechanisms of gankyrin in ccRCC. Two hundred fifty-six ccRCC patients were randomly divided into training and validation cohorts to examine the prognostic value of gankyrin and other markers through IHC and statistical analyses. We observed that the gankyrin-overexpressing ccRCC cell lines 786-O and 769-P exhibited increased proliferation, invasion, migration, tumorigenicity, and pazopanib resistance and decreased apoptosis, while gankyrin knockdown achieved the opposite results. Mechanistically, gankyrin recruited STAT3 via direct binding, and STAT3 binding to the CCL24 promoter promoted its expression. Reciprocally, an increase in autocrine CCL24 enhanced the expression of gankyrin and STAT3 activation via CCR3 in ccRCC, forming a positive autocrine-regulatory loop. Furthermore, in vivo experimental results revealed that blocking the positive loop through gankyrin knockdown or treatment with the CCR3 inhibitor SB328437 reversed the resistance to pazopanib and inhibited lung metastasis in ccRCC. Moreover, a positive correlation between gankyrin and STAT3 or CCL24 expression in ccRCC specimens was observed, and improved accuracy for ccRCC patient prognosis was achieved by combining gankyrin and STAT3 or CCL24 expression with existing clinical prognostic indicators, including the TNM stage and SSIGN score. In summary, targeting the gankyrin/STAT3/CCL24/CCR3 autocrine-regulatory loop may serve as a remedy for patients with advanced ccRCC, and combining gankyrin and STAT3 or CCL24 expression with the current clinical indicators better predicts ccRCC patient prognosis.

Inflammatory bowel diseases (IBDs) are chronic inflammatory diseases of the gastrointestinal tract, which are clinically present as 1 of the 2 disorders, Crohn's disease (CD) or ulcerative colitis (UC) (Rogler 2004). The immune dysregulation in the intestine plays a critical role in the pathogenesis of IBD, involving a wide range of molecules, including cytokines. The aim of this work was to study the involvement of T-helper 17 (Th17) subset in the bowel disease pathogenesis by the nitric oxide (NO) pathway in Algerian patients with IBD. We investigated the correlation between the proinflammatory cytokines [(interleukin (IL)-17, IL-23, and IL-6] and NO production in 2 groups of patients. We analyzed the expression of messenger RNAs (mRNAs) encoding Th17 cytokines, cytokine receptors, and NO synthase 2 (NOS2) in plasma of the patients. In the same way, the expression of p-signal transducer and activator of transcription 3 (STAT3) and NOS2 was measured by immunofluorescence and immunohistochemistry. We also studied NO modulation by proinflammatory cytokines (IL-17A, IL-6, tumor necrosis factor α, or IL-1β) in the presence or absence of all-trans retinoic acid (At RA) in peripheral blood mononuclear cells (PBMCs), monocytes, and in colonic mucosa cultures. Analysis of cytokines, cytokine receptors, and NOS2 transcripts revealed that the levels of mRNA transcripts of the indicated genes are elevated in all IBD groups. Our study shows a significant positive correlation between the NO and IL-17A, IL-23, and IL-6 levels in plasma of the patients with IBD. Interestingly, the correlation is significantly higher in patients with active CD. Our study shows that both p-STAT3 and inducible NOS expression was upregulated in PBMCs and colonic mucosa, especially in patients with active CD. At RA downregulates NO production in the presence of proinflammatory cytokines for the 2 groups of patients. Collectively, our study indicates that the IL-23/IL-17A axis plays a pivotal role in IBD pathogenesis through the NO pathway.

Background. Chronic heart failure (CHF) is the end stage of cardiac disease with a 5-year mortality rate reaching 50%. Simvastatin is an antioxidant with lipid-lowering effects, which is commonly used to treat CHF. Resistance training is a nondrug treatment for CHF and exerts a positive effect on both the myocardial structure and function. Objective. This study is aimed at exploring the effects and outcomes of simvastatin combined with resistance training on the mitochondrial membrane potential (MMP) of peripheral blood lymphocytes and the Janus kinase/signal transducer and activator of the transcription 3 (JAK/STAT3) signaling pathway in patients with CHF. Methods. One hundred and eleven patients with CHF were allocated to the control group (CNG) (n=55) and intervention group (IG) (n=56) using the random number table method. The CNG received simvastatin treatment only, whereas the IG received simvastatin treatment plus resistance training. Treatment efficacy, diastolic interventricular septal thickness (IVST), left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVDD), MMP fluorescence intensity, JAK mRNA and STAT3 mRNA relative expression levels, serum C-reactive protein (CRP), galectin-3, interleukin-6 (IL-6), N-terminal–probrain natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT), and heart-type fatty acid-binding protein (H-FABP) levels were compared in both groups. Results. After 6 months of treatment, diastolic IVST, LVDD, and serum levels of CRP, galectin-3, IL-6, NT-proBNP, hs-cTnT, and H-FABP decreased in both groups and were lower in the IG than in the CNG (P<0.05), whereas LVEF, JAK and STAT3 mRNA relative expression levels, and MMP fluorescence intensity of peripheral blood lymphocytes were higher in the IG than in the CNG (P<0.05). Conclusion. Simvastatin combined with resistance training improves heart function and reduces myocardial damage as well as the occurrence of adverse cardiac events compared with simvastatin alone. The mechanism may be related to the increase of expression of MMP, JAK, and STAT3, the regulation of MMP and JAK/STAT3 signaling pathways in peripheral lymphocytes, the alleviation of mitochondrial damage, and the inhibition of inflammatory response.

Atopic dermatitis (AD) is an eczematous, pruritic skin disorder with extensive barrier dysfunction and elevated interleukin (IL)-4 and IL-13 signatures. The barrier dysfunction correlates with the downregulation of barrier-related molecules such as filaggrin (FLG), loricrin (LOR), and involucrin (IVL). IL-4 and IL-13 potently inhibit the expression of these molecules by activating signal transducer and activator of transcription (STAT)6 and STAT3. In addition to IL-4 and IL-13, IL-22 and IL-17A are probably involved in the barrier dysfunction by inhibiting the expression of these barrier-related molecules. In contrast, natural or medicinal ligands for aryl hydrocarbon receptor (AHR) are potent upregulators of FLG, LOR, and IVL expression. As IL-4, IL-13, IL-22, and IL-17A are all capable of inducing oxidative stress, antioxidative AHR agonists such as coal tar, glyteer, and tapinarof exert particular therapeutic efficacy for AD. These antioxidative AHR ligands are known to activate an antioxidative transcription factor, nuclear factor E2-related factor 2 (NRF2). This article focuses on the mechanisms by which FLG, LOR, and IVL expression is regulated by IL-4, IL-13, IL-22, and IL-17A. The author also summarizes how AHR and NRF2 dual activators exert their beneficial effects in the treatment of AD.

Skeletal deformities are typical AD-HIES manifestations, which are mainly caused by heterozygous and loss-of-function mutations in Signal transducer and activator of transcription 3 (STAT3). However, the mechanism is still unclear and the treatment strategy is limited. Herein, we reported that the mice with Stat3 deletion in osteoblasts, but not in osteoclasts, induced AD-HIES-like skeletal defects, including craniofacial malformation, osteoporosis, and spontaneous bone fracture. Mechanistic analyses revealed that STAT3 in cooperation with Msh homeobox 1(MSX1) drove osteoblast differentiation by promoting Distal-less homeobox 5( Dlx5) transcription. Furthermore, pharmacological activation of STAT3 partially rescued skeletal deformities in heterozygous knockout mice, while inhibition of STAT3 aggravated bone loss. Taken together, these data show that STAT3 is critical for modulating skeletal development and maintaining bone homeostasis through STAT3-indcued osteogenesis and suggest it may be a potential target for treatments. Autosomal dominant hyper-immunoglobulin E syndrome (AD-HIES) is associated with mutations in STAT3, and clinical manifestations include skeletal deformities. Here, the authors show that inactivation of STAT3 in osteoblast induces AD-HIES-like skeletal defects by impairing osteogenesis, and show that pharmacological STAT3 activation rescues the phenotype.

Key Points The Janus kinases (JAKs) are major activators of signal transducer and activator of transcription (STAT) proteins. JAK–STAT3 signalling is crucial for cancer development in both tumour cells and the tumour microenvironment, and both JAK and STAT3 have emerged as important targets for cancer treatment. Interleukin-6 (IL-6) and several other members of the IL-6 family have a prominent role in JAK–STAT3 activation in cancer. Antibodies that target IL-6 are currently in clinical trials for cancer treatment. However, owing to a multitude of cytokines, growth factors and many other molecules that activate JAK–STAT3, blocking IL-6 and its family members alone is not likely to be sufficient for cancer treatment. Several G-protein-coupled receptors (GPCRs) are found to activate STAT3 through JAKs, leading to cancer progression. GPCRs are more readily druggable than STAT3, which is a transcription factor and therefore difficult to target because it is mostly in the nucleus and lacks enzymatic activity. Although Toll-like receptors (TLRs) are usually associated with immune activation, several of them are overexpressed and could promote cancer via the JAK–STAT3 pathway in both immune cells and tumour cells. The synthetic ligand of TLR9A, CpG oligonucleotide, when linked to small interfering RNA (siRNA) against STAT3, has been shown to be an effective approach to deliver RNA into both immune cells and tumour cells. The CpG–STAT3 siRNA is now poised to enter clinical trials for cancer treatment. Some microRNAs that interact with the JAK–STAT3 pathway are emerging as having crucial roles in regulating cancer-promoting inflammation and oncogenesis. Appropriate microRNAs that can block the JAK–STAT3 pathway could potentially be developed as inhibitors of this pathway with clinical application. Although STAT3 is well known as a transcription factor that defines a gene expression programme in cancer, recent studies have identified surprising roles of STAT3 in mitochondria in cancer. Importantly, STAT3 also contributes to cancer progression by DNA methylation and chromatin topological modulation. The Janus kinases (JAKs) are major activators of signal transducer and activator of transcription (STAT) proteins, and this signalling axis is crucial for cancer development in both tumour cells and the tumour microenvironment. This Review discusses the new roles of JAK–STAT signalling in promoting cancer through inflammation, obesity, stem cells and the pre-metastatic niche, and the potential therapeutic strategies that these roles can offer. The Janus kinases (JAKs) and signal transducer and activator of transcription (STAT) proteins, particularly STAT3, are among the most promising new targets for cancer therapy. In addition to interleukin-6 (IL-6) and its family members, multiple pathways, including G-protein-coupled receptors (GPCRs), Toll-like receptors (TLRs) and microRNAs were recently identified to regulate JAK–STAT signalling in cancer. Well known for its role in tumour cell proliferation, survival, invasion and immunosuppression, JAK–STAT3 signalling also promotes cancer through inflammation, obesity, stem cells and the pre-metastatic niche. In addition to its established role as a transcription factor in cancer, STAT3 regulates mitochondrion functions, as well as gene expression through epigenetic mechanisms. Newly identified regulators and functions of JAK–STAT3 in tumours are important targets for potential therapeutic strategies in the treatment of cancer.

Using an inducible, inflammatory model of breast cellular transformation, we describe the transcriptional regulatory network mediated by STAT3, NF-κB, and AP-1 factors on a genomic scale. These proinflammatory regulators form transcriptional complexes that directly regulate the expression of hundreds of genes in oncogenic pathways via a positive feedback loop. This transcriptional feedback loop and associated network functions to various extents in many types of cancer cells and patient tumors, and it is the basis for a cancer inflammation index that defines cancer types by functional criteria. We identify a network of noninflammatory genes whose expression is well correlated with the cancer inflammatory index. Conversely, the cancer inflammation index is negatively correlated with the expression of genes involved in DNA metabolism, and transformation is associated with genome instability. We identify drugs whose efficacy in cell lines is correlated with the cancer inflammation index, suggesting the possibility of using this index for personalized cancer therapy. Inflammatory tumors are preferentially associated with infiltrating immune cells that might be recruited to the site of the tumor via inflammatory molecules produced by the cancer cells.

Signal transducer and activator of transcription 3 (STAT3) is one of seven STAT family members involved with the regulation of cellular growth, differentiation and survival. STAT proteins are conserved among eukaryotes and are important for biological functions of embryogenesis, immunity, haematopoiesis and cell migration. STAT3 is widely expressed and located in the cytoplasm in an inactive form. STAT3 is rapidly and transiently activated by tyrosine phosphorylation by a range of signalling pathways, including cytokines from the IL‐6 family and growth factors, such as EGF and PDGF. STAT3 activation and subsequent dimer formation initiates nuclear translocation of STAT3 for the regulation of target gene transcription. Four STAT3 isoforms have been identified, which have distinct biological functions. STAT3 is considered a proto‐oncogene and constitutive activation of STAT3 is implicated in the development of various cancers, including multiple myeloma, leukaemia and lymphomas. In this review, we focus on recent progress on STAT3 and osteosarcoma (OS). Notably, STAT3 is overexpressed and associated with the poor prognosis of OS. Constitutive activation of STAT3 in OS appears to upregulate the expression of target oncogenes, leading to OS cell transformation, proliferation, tumour formation, invasion, metastasis, immune evasion and drug resistance. Taken together, STAT3 is a target for cancer therapy, and STAT3 inhibitors represent potential therapeutic candidates for the treatment of OS. Signal transducer and activator of transcription 3 (STAT3) is a member of the STAT protein family, vitally important for eukaryotic cells. We review the molecular structure and function of STAT3 and its isoforms, highlighting signalling pathways for the regulation of gene transcription. A critical appraisal of STAT3 in cancers, such as osteosarcoma, is provided emphasizing potential therapeutic approaches targeting STAT3 and its inhibitors

Delayed or impaired wound healing is a major health issue worldwide, especially in patients with diabetes and atherosclerosis. Here we show that expression of the circular RNA circ-Amotl1 accelerated healing process in a mouse excisional wound model. Further studies showed that ectopic circ-Amotl1 increased protein levels of Stat3 and Dnmt3a. The increased Dnmt3a then methylated the promoter of microRNA miR-17, decreasing miR-17-5p levels but increasing fibronectin expression. We found that Stat3, similar to Dnmt3a and fibronectin, was a target of miR-17-5p. Decreased miR-17-5p levels would increase expression of fibronectin, Dnmt3a, and Stat3. All of these led to increased cell adhesion, migration, proliferation, survival, and wound repair. Furthermore, we found that circ-Amotl1 not only increased Stat3 expression but also facilitated Stat3 nuclear translocation. Thus, the ectopic expressed circ-Amotl1 and Stat3 were mainly translocated to nucleus. In the presence of circ-Amotl1, Stat3 interacted with Dnmt3a promoter with increased affinity, facilitating Dnmt3a transcription. Ectopic application of circ-Amotl1 accelerating wound repair may shed light on skin wound healing clinically. Yang et al. show that expression of the circular RNA circ-Amotl1 accelerated wound healing and increased levels of Stat3 and Dnmt3a. The increased Dnmt3a methylated miR-17 promoter, decreasing miR-17-5p levels but increasing fibronectin expression. Furthermore, circ-Amotl1 facilitated Stat3 nuclear translocation to promote cell activities and wound repair.