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Microbial nucleic acid recognition serves as the major stimulus to an antiviral response, implying a requirement to limit the misrepresentation of self nucleic acids as non-self and the induction of autoinflammation. By systematic screening using a panel of interferon-stimulated genes we identify two siblings and a singleton variably demonstrating severe neonatal anemia, membranoproliferative glomerulonephritis, liver fibrosis, deforming arthropathy and increased anti-DNA antibodies. In both families we identify biallelic mutations in DNASE2 , associated with a loss of DNase II endonuclease activity. We record increased interferon alpha protein levels using digital ELISA, enhanced interferon signaling by RNA-Seq analysis and constitutive upregulation of phosphorylated STAT1 and STAT3 in patient lymphocytes and monocytes. A hematological disease transcriptomic signature and increased numbers of erythroblasts are recorded in patient peripheral blood, suggesting that interferon might have a particular effect on hematopoiesis. These data define a type I interferonopathy due to DNase II deficiency in humans. Nucleic acid sensing is important to ensure that an innate immune response is only mounted against microbial nucleic acid. Here, the authors identify loss-of-function mutations in the DNASE2 gene that cause type I interferon-mediated autoinflammation due to enhanced systemic interferon signaling.

Macrophages contribute to the pathogenesis of rheumatoid arthritis (RA). They can display different states of activation or \"polarization,\" notably the so-called inflammatory \"M1\" and the various alternative \"M2\" polarizations, characterized by distinct functions. Data regarding the effects of RA anti-cytokine biological disease-modifying anti-rheumatic drugs (bDMARDs) on macrophage polarization are scarce. We aimed to assess modulation of macrophage polarization by bDMARDs targeting pro-inflammatory cytokines in RA. We generated monocyte derived macrophages using blood samples from 20 RA patients with active RA and 30 healthy controls. We evaluated the impact on M1 inflammatory macrophages of: etanercept (ETA), adalimumab (ADA), certolizumab (CZP), tocilizumab (TCZ), and rituximab (RTX). We assessed the impact on macrophage polarization using flow cytometry and RTqPCR to study the expression of surface markers and perform functional studies of cytokine production, phagocytosis, and negative feedback control of inflammation. Among evaluated bDMARDs, anti-TNF agents modulated the polarization of inflammatory macrophages by decreasing inflammatory surface markers (CD40, CD80) and favoring alternative markers (CD16, CD163, MerTK). Anti-TNF agents also induced alternative functions in macrophages activated in inflammatory condition with (i) the inhibition of inflammatory cytokines (TNF, IL-6, IL-12), (ii) an increase in phagocytosis. These findings were mechanistically related to an increase in early IL-10 production, responsible for higher negative feedback control of inflammation involving SOCS3 and Gas6. This IL-10 effect was STAT3-dependent. Anti-TNF agents not only inhibit inflammatory functions of macrophages, but also favor resolution of inflammation through polarization toward alternative features specifically involving the IL-10/STAT3 axis.

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.

Pro-survival stress-inducible chaperone HSP110 is the only HSP for which a mutation has been found in a cancer. Multicenter clinical studies demonstrated a direct association between HSP110 inactivating mutation presence and excellent prognosis in colorectal cancer patients. Here, we have combined crystallographic studies on human HSP110 and in silico modeling to identify HSP110 inhibitors that could be used in colorectal cancer therapy. Two molecules (foldamers 33 and 52), binding to the same cleft of HSP110 nucleotide-binding domain, were selected from a chemical library (by co-immunoprecipitation, AlphaScreening, Interference-Biolayer, Duo-link). These molecules block HSP110 chaperone anti-aggregation activity and HSP110 association to its client protein STAT3, thereby inhibiting STAT3 phosphorylation and colorectal cancer cell growth. These effects were strongly decreased in HSP110 knockdown cells. Foldamer’s 33 ability to inhibit tumor growth was confirmed in two colorectal cancer animal models. Although tumor cell death (apoptosis) was noted after treatment of the animals with foldamer 33, no apparent toxicity was observed, notably in epithelial cells from intestinal crypts. Taken together, we identified the first HSP110 inhibitor, a possible drug-candidate for colorectal cancer patients whose unfavorable outcome is associated to HSP110.

Prolonged exposure to extreme humid heat can induce systemic inflammation, organ stress, and hormonal imbalance. While fluid replacement is commonly recommended, its mechanistic efficacy under humid heat stress remains unclear. This study investigated the impact of fluid intake on thermoregulation, inflammation, organ function, and stress signaling during 8 h of humid heat exposure (ambient temperature: 40 °C, relative humidity: 55%) in 32 healthy young adults (20 males and 12 females). Participants completed two randomized trials: limited fluid intake (LFI, 125 mL/h) and full fluid intake (FFI, 375 mL/h). Core temperature (Tcore), inflammatory cytokines (IL-6, IL-1β, IFN-γ, TNF-α), organ stress markers (ALT, BUN), oxidative stress indices (MDA, SOD), and cortisol were assessed pre- and post-exposure. FFI significantly reduced post-exposure Tcore (37.8 ± 0.3 °C vs. 38.1 ± 0.3 °C, p = 0.046), mitigated cytokine elevations, and decreased BUN (blood urea nitrogen), ALT (alanine aminotransferase), and cortisol levels. Western blot analysis of PBMCs revealed that LFI activated NF-κB p65, JNK2, p38, and STAT3α phosphorylation, whereas FFI suppressed these responses. These findings demonstrate that adequate hydration attenuates heat-induced systemic and molecular stress responses. Our results highlight hydration as a key modulator of inflammatory signaling pathways during prolonged heat stress, offering insights into preventive strategies for populations vulnerable to climate-induced extreme heat events.

Glucocorticoids (GC) are a controversial yet commonly used intervention in the clinical management of acute inflammatory conditions, including sepsis or traumatic injury. In the context of major trauma such as surgery, concerns have been raised regarding adverse effects from GC, thereby necessitating a better understanding of how GCs modulate the immune response. Here we report the results of a randomized controlled trial (NCT02542592) in which we employ a high-dimensional mass cytometry approach to characterize innate and adaptive cell signaling dynamics after a major surgery (primary outcome) in patients treated with placebo or methylprednisolone (MP). A robust, unsupervised bootstrap clustering of immune cell subsets coupled with random forest analysis shows profound (AUC = 0.92, p-value = 3.16E-8) MP-induced alterations of immune cell signaling trajectories, particularly in the adaptive compartments. By contrast, key innate signaling responses previously associated with pain and functional recovery after surgery, including STAT3 and CREB phosphorylation, are not affected by MP. These results imply cell-specific and pathway-specific effects of GCs, and also prompt future studies to examine GCs’ effects on clinical outcomes likely dependent on functional adaptive immune responses.

Natural Killer (NK) cell is the first batch of re-constructed cell populations after allogeneic hematopoietic stem cell transplantation (allo-HSCT), and its delayed reconstitution inevitably causes poor outcome. The traditional Chinese medicine Huiyang-Guben decoction (HYGB) has been clinically used in patients undergoing allo-HSCT, but its effect on NK cell reconstruction is still unclear. 40 patients with allo-HSCT therapy were randomly divided into the control group and the HYGB group, and were given oral administration of normal saline or HYGB for 4 weeks before allo-HSCT, respectively. NK cells were cultured and treated with transforming growth factor β (TGF-β) and HYGB in vitro, and cell viability, cell apoptosis, and the function of NK cells were evaluated. Functional verification experiments were performed by knocking down signal transduction molecule 7 (Smad7) in NK cells before TGF-β and HYGB treatment. Clinical data suggested that HYGB intervention decreased the incidence of acute graft-versus-host disease after allo-HSCT, and increased the proportion of NK cell population. Meanwhile, HYGB improved cell viability, restrained apoptotic cell death, and enhanced cell killing activity of NK cells in patients with allo-HSCT. Notably, we found that HYGB significantly increased the expression level of Smad7 and the phosphorylation level of signal transducer and activator of transcription 3 (Stat3) in NK cells from patients with allo-HSCT. Moreover, HYGB alleviated TGF-β-induced NK cell impairment and re-activated the Smad7/Stat3 signaling in vitro, while silencing Smad7 reversed the protective effect of HYGB on TGF-β-treated NK cells. HYGB promotes NK cell reconstruction and improves NK cell function after allo-HSCT through activating the Smad7/Stat3 signaling pathway.

Background Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) that lasts a long time and has a variety of causes. Aim The primary aim of this study was to evaluate pentoxifylline's (PTX) essential function in patients with UC. Methods Fifty-two mild to moderate UC patients who matched the eligibility requirements participated in this clinical study. One gram of mesalamine (t.i.d.) and a placebo were administered to the mesalamine group (n = 26) for a duration of 24 weeks. Mesalamine 1 g t.i.d. and PTX 400 mg two times daily were administered to the PTX group (n = 26) for 24 weeks. A gastroenterologist investigated patients at the start and 6 months after the medication was given to assess disease activity index (DAI) and numeric pain rating scale (NRS). Also, interleukin-6 (IL-6), sphingosine 1 phosphate (S1P), tumor necrosis factor-alpha (TNF-α), and fecal myeloperoxidase (MPO) were measured before and after therapy. Zonula occuldin-1 (ZO-1) and signal transducer and activator of transcription factor-3 (STAT-3) expression was assessed before and after therapy as well as histological assessment. Short Form 36 Health Survey (SF-36), was assessed for each patient before and after 6 months of treatment. Results The PTX group showed statistically lower levels of serum SIP, TNF-α, IL-6, faecal MPO, gene expression of STAT-3, and a significant increase of ZO-1 in comparison with the mesalamine group. DAI and NRS significantly decreased whereas SF-36 significantly increased in the PTX group. Conclusion PTX could alleviate inflammation in patients with UC, so it might be promising adjunctive for patients with UC. Trial registration identifier NCT 05558761.

This study aimed to evaluate the efficacy of bevacizumab maintenance therapy in advanced ovarian cancer and its impact on the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3)/vascular endothelial growth factor A (VEGFA) pathway. A total of 126 patients were enrolled, divided into two groups: control (n=62) and study (n=64). The control group received neoadjuvant chemotherapy, tumor debulking surgery, and postoperative adjuvant chemotherapy. The research group received postoperative bevacizumab maintenance therapy in addition to standard treatment. Results showed that the research group had significantly improved disease control rates (43.75% vs. 24.19%, P=0.0206), objective response rates (76.56% vs. 48.39%, P=0.0011), overall survival (30.45±7.69 months vs. 22.92±7.26 months, P<0.0001) and progression-free survival (16.08±2.46 months vs. 12.08±2.25 months) compared to controls. Bevacizumab also led to lower levels of Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3) and vascular endothelial growth factor A (VEGFA) expression. This therapy demonstrated safety and efficacy, significantly prolonging progression-free survival and overall survival. Cette étude visait à évaluer l'efficacité du traitement d'entretien par bévacizumab chez des patientes atteintes d'un cancer de l'ovaire avancé, ainsi que son impact sur la voie Janus kinase 2 (JAK2)/transducteur du signal et activateur de la transcription 3 (STAT3)/facteur de croissance endothélial vasculaire A (VEGFA). Un total de 126 patientes ont été incluses et réparties en deux groupes : un groupe témoin (n=62) et un groupe d'étude (n=64). Le groupe témoin a reçu une chimiothérapie néoadjuvante, une chirurgie de cytoréduction tumorale et une chimiothérapie adjuvante postopératoire. Le groupe d'étude a, en plus, bénéficié d'un traitement d'entretien au bévacizumab après les soins standards. Les résultats ont montré que le groupe d'étude présentait des taux de contrôle de la maladie significativement améliorés (43,75 % contre 24,19 %, P=0,0206), des taux de réponse objective plus élevés (76,56 % contre 48,39 %, P=0,0011), une survie globale prolongée (30,45 ± 7,69 mois contre 22,92 ± 7,26 mois, P<0,0001) et une survie sans progression plus longue (16,08 ± 2,46 mois contre 12,08 ± 2,25 mois) par rapport au groupe témoin. Le bévacizumab a également réduit les niveaux d'expression de JAK2, STAT3 et VEGFA. Ce traitement s'est révélé sûr et efficace, prolongeant de manière significative la survie sans progression et la survie globale.