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关键词： agomelatine   inflammation   insulin resistance   kidney injury   necroptosis   obesity  

摘要： Obesity is a risk factor for chronic kidney disease. The expansion of adipose tissues in obesity induces insulin resistance and low-grade systemic inflammation, promoting kidney damage. Our previous studies have demonstrated that agomelatine (AGOM) exerts renoprotective effects in experimental models of obesity and insulin resistance through various mechanisms, including the attenuation of ER stress and oxidative stress. This study aimed to further explore the effects of agomelatine on renal inflammation, insulin signaling, and necroptosis in obese, insulin-resistant rats. Obesity was induced in rats with a high-fat diet for 16 weeks, followed by 4 weeks of treatment with 20 mg kg-1 day-1 of AGOM or 10 mg kg-1 day-1 of pioglitazone (PIO). The results showed that insulin resistance was improved after treatment with AGOM and PIO, as demonstrated by the reduction in fasting plasma glucose, insulin, and HOMA-IR. Both treatments restored the levels of renal insulin signaling proteins. Moreover, AGOM inhibited TNF alpha, TNFR1, NF-& kgreen;B, COX2, and IL1 beta, which attenuated the necroptosis-related proteins RIPK3 and MLKL. AGOM also prevented kidney DNA fragmentation, as detected by the TUNEL assay. In an obese condition, the level of the tight junction protein claudin-1 (CLDN1) was enhanced after being treated with AGOM. In conclusion, the novel mechanisms associated with AGOM and involved in limiting kidney injury were the inhibition of the TNF alpha/NF-& kgreen;B/p-RIPK3 pathway and a reduction in inflammation and necroptosis. This suggested that AGOM could be an effective treatment for inhibiting kidney dysfunction in cases of obesity and insulin resistance. These findings open new avenues for the management of renal dysfunction, with implications for personalized medicine.

关键词： Macrophage   Immune regulation   IL-10   Epigenetics   Ubiquitination   Airway allergy  

摘要： The pathogenesis of many immune disorders is linked to regulatory macrophage dysfunction. The mechanism underlying it is unclear. The objective of this study is to examine the mechanism by which the PRKN ubiquitin protein ligase (PRKN) inhibits the development of regulatory macrophages (Mreg). In this study, dust mite antigens were used as the specific allergens to establish an airway allergy (AA) mouse model. Flow cytometry cell sorting was used to isolate macrophages from the airway tissues. According to the results, the Prkn gene inhibition led to an increase in the number of Mregs in macrophages. Mregs demonstrated the capacity to suppress Th2 polarization, in which IL-10 played a critical role. Pan macrophages isolated from Prkn-deficient mice were more capable of suppressing the activities of other immune cells. PRKN was required for maintaining the hyperubiquitous status of signal transducer and transcriptional activator-3 (STAT3) in macrophages. Exposure to dust mite antigen increased the expression of PRKN in macrophages. IL-10 suppressed PRKN in macrophages by inducing its promoter hypermethylation. PRKN inhibition mitigated the experimental AA. To sum up, PRKN maintains the hyper ubiquitous status of STAT3 and restricts the expression of IL-10 in macrophages, which compromises their immune suppressive functions. Inhibition of PRKN increases Mreg development and mitigates AA. The data suggest that the regulation of Mreg has translation potential to be used in the treatment of immune disorders such as AA.

关键词： Gene expression   GF   Hepapoietin A   Psoriasis   Scatter factor  

摘要： Hidradenitis suppurativa (HS) is a chronic inflammatory disease that is difficult to control, and its mechanism remains unclear. Hepatocyte GF (HGF) has been reported to be significantly upregulated in the serum and skin of patients with HS, especially in the lesions with tunnels. In this study, we examined the transcriptome of HGF-treated keratinocytes and compared it with genetic profiling of HS lesions. HGF was highly expressed in HS skin, especially in the deep dermis, compared with that in healthy controls, and its source was mainly fibroblasts. HGF upregulated more genes in keratinocytes than IL-17A or TNF-a, and these genes included multiple epithelial-mesenchymal transition-related genes. Differentially expressed genes in HGF-stimulated keratinocytes were involved in activation of epithelial-mesenchymal transition-related pathways. These HGF-induced genes were significantly upregulated in HS lesions compared with those in healthy skin and nonlesions and were more strongly associated with HS tunnels. In summary, HGF was highly expressed in HS and induced epithelial-mesenchymal transition-related genes in keratinocytes;HGF-induced genes were highly associated with gene profiling of HS with tunnels, suggesting that HGF may be involved in HS tunnel formation through epithelial-mesenchymal transition.

关键词： Carbothioamide   X-ray diffraction   Thiazole   Cell cytotoxicity   Anti-inflammatory   Anti-oxidant   Molecular docking   MD simulation  

摘要： In this study, tetrahydronaphthalene carbothioamides 2, characterized by spectroscopic methods and X-ray diffraction studies, were used to develop a series of novel tetrahydronaphthalenone-coupled thiazole derivatives 3. The synthesized thiazole hybrids were evaluated for in-vitro anti-inflammatory activity against lipopolysaccharide (LPS)-induced inflammation in RAW264.7 macrophage cells. Notably, compound 3f demonstrated the most potent anti-inflammatory effect by significantly reducing the expression of pro-inflammatory mediators, including nitric oxide species (IC50 = 62.93 mu M) and tumor necrosis factor-alpha (TNF-alpha) (67.50 mu M). Additionally, 3f inhibited cyclooxygenase-2 (COX-2) (IC50 = 73.18 mu M compared to celecoxib 41.21 mu M) expression in a dose-dependent manner. The antioxidant activity of newly generated derivatives was also assessed using the DPPH assay, with compounds 3a, 3b, and 3c showing the highest inhibition rates of 69.94%, 68.82%, and 64.77% at 100 mu g/mL, respectively. Molecular docking studies targeting the active site of Human Peroxiredoxin 5 (PDB ID: 1HD2) and COX-2 (PDB ID: 4M11) were conducted to explore the potential interactions of these compounds with the receptor. Molecular dynamics (MD) simulation predicted the stability of the protein-ligand complex.

摘要： Whereas acute inflammation plays an important role in both tissue damage and repair, chronic inflammation favors tissue injury. Monocytes contribute to this deleterious effect by secreting proinflammatory cytokines. Amini et al. propose a novel mechanism involving adenosine triphosphate-induced purinergic P2X purinoceptor 7 receptor activation, which leads to calcium ion-dependent mitochondrial reactive oxygen species production, triggering interleukin-1 alpha release by monocytes. This stimulates kidney immune cell infiltration and fibrosis in chronic kidney disease and promotes adverse cardiac remodeling following myocardial infarction.

关键词： abatacept   IFN-gamma   inhibitor of differentiation 2   rheumatoid arthritis   T cell  

摘要： Purpose This research investigates the role of inhibitor of differentiation 2 (Id2) in the synthesis of pro-inflammatory cytokines, specifically interferon-gamma (IFN-gamma) and interleukin-17 (IL-17), by various subsets of T cells, and its pathogenic role in rheumatoid arthritis (RA). Methods Flow cytometry was employed to assess T-cell activation and Id2 expression in 72 RA patients and 23 healthy controls. In vitro, peripheral blood mononuclear cells were treated with either an Id2 inhibitor or a T-cell co-stimulation inhibitor. An in vivo collagen-induced arthritis (CIA) model was established using T-cell-specific Id2 knockout mice. Additionally, follow-up observations were conducted among treated RA patients. Results T-cell activation levels in RA synovial fluid were significantly elevated. A positive correlation was found between increased IFN-gamma and Id2 expression. In vitro, antagonising Id2 reduced IFN-gamma production after T-cell activation. T-cell-specific Id2 knockout mice exhibited a diminished occurrence and severity of CIA, along with a significant decrease in IFN-gamma expression. Clinical monitoring indicated that Id2-induced circulating T-cell IFN-gamma expression significantly decreased following treatment with the T-cell activation inhibitor abatacept. Conclusion The data suggest that high Id2 expression is a critical regulator of pro-inflammatory cytokine upregulation, particularly IFN-gamma, by hyperactivated T cells in RA, potentially exacerbating the disease. Inhibiting Id2 expression or function may offer new therapeutic approaches for RA joint inflammation. Key points Pro-inflammatory cytokines are significantly upregulated in the synovial fluid T cells in rheumatoid arthritis patients. The expression of pro-inflammatory cytokine interferon-gamma (IFN-gamma) positively correlates with the high expression of inhibitor of differentiation 2 (Id2). The inhibition or ablation of Id2 can effectively suppress IFN-gamma production and the onset

摘要： Macrophages stimulated by lipopolysaccharide (LPS) generate mitochondria-derived reactive oxygen species (mtROS) that act as antimicrobial agents and redox signals;however, the mechanism of LPS-induced mitochondrial superoxide generation is unknown. Here we show that LPS-stimulated bone-marrow-derived macrophages produce superoxide by reverse electron transport (RET) at complex I of the electron transport chain. Using chemical biology and genetic approaches, we demonstrate that superoxide production is driven by LPS-induced metabolic reprogramming, which increases the proton motive force (triangle p), primarily as elevated mitochondrial membrane potential (Delta psi m) and maintains a reduced CoQ pool. The key metabolic changes are repurposing of ATP production from oxidative phosphorylation to glycolysis, which reduces reliance on F1FO-ATP synthase activity resulting in a higher triangle p, while oxidation of succinate sustains a reduced CoQ pool. Furthermore, the production of mtROS by RET regulates IL-1 beta release during NLRP3 inflammasome activation. Thus, we demonstrate that ROS generated by RET is an important mitochondria-derived signal that regulates macrophage cytokine production.

关键词： AbATE   antibody for tolerance in recently diagnosed type 1 diabetes   ABL1   abelson murine leukemia viral oncogene homolog 1   AC   adenylate cyclase   ADCC   antibody-dependent cell-mediated cytotoxicity   ADR   α   2A-adrenergic receptor   AICD   ATG activation-induced cell death   AMPK   AMP-activated protein kinase   AP   action potentials   APC   antigen-presenting cells   ATG   anti-thymocyte globulins   AUC   area under the curve   cAMP   cyclic adenosine monophosphate   CAR   coxsackie and adenovirus receptor   CCKB   cholecystokinin   CDC   complement-dependent cytotoxicity   ChREBP   carbohydrate response-element binding protein   CNS   central nervous system   CRAC   Ca2+ release-activated Ca2+ channel   CTLA4Ig   cytotoxic T-lymphocyte associated protein Ig   CXCL10   interferon gamma-inducible protein 10 kDa   DPP4   dipeptidyl peptidase-4   DPP-4i   DPP4 inhibitor   DRD   D2-like dopamine receptor   DXM   dextromethorphan   EBV   Epstein-Barr virus   ER   endoplasmic reticulum   FOXO1   forkhead box O1   GABA   γ   -aminobutyric acid   GAD65 Alum   Alum-formulated human recombinant GAD65   GAD65   glutamic acid decarboxylase 65   GCSF   granulocyte colony-stimulating factor   GIP   insulinotropic polypeptide   GLP-1   glucagon-like peptide-1   GPCR   G protein-coupled receptor   GSIS   glucose-induced insulin secretion   GSK3   β   glycogen synthase kinase 3   β   H+   hydrogen   HLA   human leukocyte antigen   ICOS   inducible T-cell co-stimulator   IFN-   γ   interferon gamma   IGF-1   insulin-growth factor 1   IGFBP3   IGF-binding protein 3   IgG2   immunoglobulin G2   IL-1R   IL-1 receptors   ILP   insulin like peptide   IR   insulin receptor   IRAK-1   interleukin-1 receptor-associated serine/threonine kinase 1   IRF-1   interferon gamma regulatory factor-1   JAK   Janus kinase   K+   potassium   KATP   ATP-sensitive potassium channel   KV   voltage-gated potassium channels   mAb   monoclonal antibody   mDPP-4   membrane-bound dipeptidyl peptidase-4   NFAT   nuclear factor of activated T-cells   NKA   Na+/K+ ATPase   NMDAR   glutamate N-Methyl-D-Aspartate receptors   NOD   non-obese diabetic   PC1/3   prohormone convertase 1/3   PCD   programmed cell death   PD-1   programmed death protein   PDX1   pancreatic duodenal homeobox-1 protein   PHA   ph  

摘要： After a century of extensive scientific investigations, there is still no curative or disease-modifying treatment available that can provide long-lasting remission for patients diagnosed with type 1 diabetes (T1D). Although T1D has historically been regarded as a classic autoimmune disorder targeting and destroying pancreatic islet 3-cells, significant research has recently demonstrated that 3-cells themselves also play a substantial role in the disease's progression, which could explain some of the unfavorable clinical outcomes. We offer a thorough review of scientific and clinical insights pertaining to molecular mechanisms behind pathogenesis and the different therapeutic interventions in T1D covering over 20 possible pharmaceutical intervention treatments. The interventions are categorized as immune therapies, treatments targeting islet endocrine dysfunctions, medications with dual modes of action in immune and islet endocrine cells, and combination treatments with a broader spectrum of activity. We suggest that these collective findings can provide a valuable platform to discover new combinatorial synergies in search of the curative disease-modifying intervention for T1D. Significance Statement: This research delves into the underlying causes of T1D and identifies critical mechanisms governing 3-cell function in both healthy and diseased states. Thus, we identify specific pathways that could be manipulated by existing or new pharmacological interventions. These interventions fall into several categories: (1) immunomodifying therapies individually targeting immune cell processes, (2) interventions targeting 3-cells, (3) compounds that act simultaneously on both immune cell and 3-cell pathways, and (4) combinations of compounds simultaneously targeting immune and 3-cell pathways. (c) 2025 The Authors. Published by Elsevier Inc. on behalf of American Society for Pharmacology and Experimental Therapeutics. This is an open access article under the CC BY license (htt

关键词： Cystic fibrosis   P. aeruginosa   IL-17 cytokines   Patient-derived nasal cells   Airway immune response  

摘要： Background: Lungs of people with Cystic Fibrosis (pwCF) are characterized by chronic inflammation and infection with P. aeruginosa. High levels of IL-17 A and F have been observed in sputum of pwCF and the interleukin-17(IL17) family (A-to-F) has been suggested to play a key role in CF pulmonary disease. Methods: We measured mRNA levels of IL-17 receptors (IL-17R) by RT-qPCR in CF bronchial epithelial (CFBE) cultured cells upon infection with P. aeruginosa PAO1 strain or clinical exoproducts (EXO) isolated from pwCF. We measured IL-17 mRNA expression by RT-qPCR and the release of cytokines by ELISA and Bioplex from CF primary nasal epithelial (HNE) cultured cells. Results: Infection of CFBE cells with PAO1 or EXO isolated from 15 pwCF significantly increased mRNA expression of all IL-17R, except IL-17RD. Infection of HNE cells with EXO isolated from the correspondent donor significantly increased the mRNA levels of all the IL-17 cytokines and receptors, except for IL-17D and IL-17RD, and the release of the cytokines IL-17 A, IL-17B, IL-17C, IL-17E and IL-17F. HNE exposed to IL-17 A and F were induced to release pro-inflammatory cytokines (IL-1R, IL-6, TNF-alpha), neutrophil chemokines (IL-8, G-CSF) and cytokines known to be involved in chloride and bicarbonate secretion, together with mucin upregulation (IL-4, IL-13). Conclusion: These results highlight a wider expression of IL-17 family member in respiratory epithelial cells, which can play a role as an autocrine inflammatory amplification loop in CF airways. These in-vitro studies using patient-derived cultures underline the relevant role of IL-17 family members in CF pulmonary immune response.