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关键词： Sam68   Inflammation   Inflammatory bowel disease   Arthritis   Cardiovascular disease   TNF   TLR   TCR   BCR  

摘要： Sam68 is a ubiquitously expressed KH-domain containing RNA-binding protein highly studied for its involvement in regulating multiple steps of RNA metabolism. Sam68 also contains multiple protein-protein interaction regions such as proline-rich regions, tyrosine phosphorylation sites, and arginine methylation sites, all of which facilitate its participation as an adaptor protein in multiple signaling pathways, likely independent of its RNA-binding role. This review focuses on providing a comprehensive report on the adaptor roles of Sam68 in inflammatory signaling and inflammatory diseases. The insights presented here have the potential to open new avenues in inflammation research and justify targeting Sam68 to control aberrant inflammatory responses.

关键词： Interleukin-21 (IL-21)   Skin fibrosis   Lung fibrosis   Signal transducer and activator of transcription   (STAT) 3   Systemic sclerosis (SSc)  

摘要： Background: Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy, abnormal inflammation, and fibrosis of the skin and internal organs, notably the skin and lungs, significantly impairing quality of life. There is currently no cure for SSc, and its etiology remains largely unknown, presenting a primary barrier to effective treatment. We investigated the role of interleukin-21 (IL-21) in the pathogenesis of SSc. Methods: We assessed the expression levels of fibrosis-related genes in human dermal fibroblasts exposed to IL-21 and TGF beta. We also induced SSc in wild-type C57BL/6 mice and IL-21 knockout (KO) mice with a C57BL/6 background using bleomycin (Bleomycin). Histological analyses were conducted on skin and lung tissues from these mice. The distribution and expression levels of fibrosis-related proteins in the tissues were examined via immunohistochemistry and quantitative real-time PCR. Furthermore, we measured the frequency of Th1, Th2, and Th17 cells among splenocytes through flow cytometry. Results: IL-21 activation led to STAT3 phosphorylation more than TGF beta in dermal fibroblasts. In IL-21 KO mice with BLM-induced SSc, skin thickness and lung fibrosis were reduced. The absence of IL-21 in these mice resulted in suppressed expression of fibrosis-related genes, including Col1a1, Col1a2, Col3a1, CTGF, alpha-SMA, STAT3, and TGF beta, in the skin and lungs. It also led to a decreased frequency of Th1, Th2, and Th17 cells, as well as a lower Th17/Treg ratio among splenocytes, factors known to contribute to the development of SSc. Conclusions: IL-21 contributes to the development of SSc by promoting the expression of fibrosis-related genes and modulating the levels of CD4+ T cells.

关键词： Quantitative structure-activity relationship   Multi-task transfer learning   Molecular dynamics simulation   Interleukin-1 receptor  

摘要： The human interleukin-1 receptor I (IL-1R1) is a cytokine receptor recognized by interleukin 1(3 (IL-1(3), among other cytokines. Over activation of IL-1R1 has been implicated in various inflammatory conditions. This research aims to identify small-molecule inhibitors targeting the hIL1R1/IL1(3 interaction, employing a multi-task transfer learning approach for quantitative structure-activity relationship (QSAR) modelling. A comprehensive bioactivity dataset from functionally related proteins was utilised to build a robust ensemble machine learning model for predicting IC50 values against the target protein. Despite the availability of antibody-based therapies, the absence of orally available small-molecule inhibitors necessitates their development. By combining model predictions with docking and simulation approaches, the interleukin-1 receptor inhibitor (IRI-1) emerged as a lead compound. It potently inhibited human IL1-R1 with micromolar activity in THP-1 and Saos-2 cells and demonstrated good biocompatibility. Western blot analysis revealed that IRI-1 inhibits IL-1(3-mediated phosphorylation of IL1-R1, JNK, IRAK-4, and ERK in THP-1 cells. Furthermore, molecular dynamics simulations confirmed the structural stability of the protein-ligand complexes. This study highlights the effectiveness of multi-task transfer learning approaches for building robust QSAR models against novel proteins or those with limited bioactivity data, such as hIL-1(3/IL-1R1 protein.

关键词： PCOD   IL-27   IL-38   FGF-21   Metainflammation   Immunoendocrine  

摘要： Background: Polycystic ovary syndrome (PCOS) is a common metabolic/ endocrine disorder seen predominantly in women in their reproductive age, which increases the risk of infertility, endometrial cancer and metabolic disorders. IL-27 and IL-38 are recently discovered, novel anti-inflammatory cytokines whose role in immune- endocrine dysfunction seen in PCOS is largely unknown. Methods: In the present study, we quantified these two cytokines along with markers for meta-inflammation (TNF-alpha, IL-6, IL-1(3, IL-1Ra, IL-10 and TGF-(3) and hormonal dysregulation (insulin, leptin, adiponectin, FGF21, testosterone and DHEA-S) in the serum of PCOS women (n=44), along with age matched controls (n=20), by ELISA. We quantified serum lipid peroxidation, protein peroxidation, and nitrite levels using spectrophotometry. Results: PCOS women had significantly elevated levels of IL-27, IL-38 along with TNF-alpha, IL-6, IL-1Ra, IL-10, FGF21 and adiponectin, and decreased levels of TGF-(3, SDF-1 and leptin. While there is no significant difference with respect to redox markers, nitrite levels were significantly increased in PCOS cases. Conclusion: The increased circulating levels of anti-inflammatory cytokines IL-27 and IL-38 under PCOS conditions warrant further investigation. To the best of our knowledge, this is the first report on IL-38 levels in PCOS.

关键词： Mesenchymal stem cell-exosome   IL-10   TGF-beta signaling pathway   Canonical Wnt/beta-catenin signaling   Chondrogenesis  

摘要： Current treatment approaches cannot exactly regenerate cartilage tissue. Regarding some problems encountered with cell therapy, exosomes are advantageous because of their "cell-free" nature. This study examines the relationship between IL-10 and TGF-beta and Canonical Wnt/beta-catenin signal pathways in human adipose tissue-derived MSCs exosomes (hAT-MSCs-Exos) after in vitro chondrogenic differentiation. Human adipose tissue-derived mesenchymal stem cells (hAT-MSCs) and, as a control group, human fetal chondroblast cells (hfCCs) were differentiated chondrogenically in vitro. Exosome isolation and characterization analyses were performed. Chondrogenic differentiation was shown by Alcian Blue and Safranin O stainings. The expression levels of IL-10, TGF-beta/SMAD signaling pathway genes, and Canonical Wnt/beta-catenin signaling pathway genes, which play an essential role in chondrogenesis, were analyzed by RT-qPCR. Conditioned media cytokine levels were measured by using the TGF-beta and IL-10 ELISA kits. IL-10 expression was upregulated in both chondrogenic differentiated hAT-MSC-Exos (dhAT-MSC-Exos) (p < 0.0001). In the TGF-beta signaling pathway, TGF-beta (p < 0.0001), SMAD2 (p < 0.0001), SMAD4 (p < 0.001), ACAN (p < 0.0001), SOX9 (p < 0.05) and COL1A2 (p < 0.0001) expressions were upregulated in dhAT-MSC-Exos. SMAD3 expression was upregulated in non-differentiated hAT-MSC-Exos. In the Canonical Wnt/beta-catenin signaling pathway, WNT (p < 0.0001) and CTNNB1(p < 0.0001) expressions were upregulated in dhAT-MSC-Exos. AXIN (p < 0.0001) expression was upregulated in non-differentiated hAT-MSC-Exos. TGF-beta and IL-10 levels were higher in dhAT-MSCs) (p < 0.0001). Related to these results, IL-10 may induce TGF-beta/SMAD and Canonical Wnt/beta-catenin signaling pathways in hAT-MSC exosomes obtained after chondrogenic differentiation. Therefore, using these exosomes for cartilage regeneration can lead to the development of treatment methods.

关键词： Axial spondyloarthritis   Psoriatic arthritis   Liver tolerance   bDMARDs   FIB-4  

摘要： Highlights•In axial spondyloarthritis, anti-TNF and anti-IL17 do not increase the FIB-4 score after two years. •In psoriatic arthritis, anti-IL17 but not anti-TNF increases the FIB-4 score after two years.

关键词： choroidal endothelial cells   choroidal neovascularisation   Geraniin   interleukin-10  

摘要： Anti-vascular endothelial growth factor (VEGF) drugs suppress choroidal neovascularisation (CNV), thus improving vision. However, some patients may have a poor response or develop resistance to anti-VEGF drugs. Geraniin (GE), a polyphenol isolated from an herb called Phyllanthus amarus, possesses anti-angiogenic properties. This study aimed to explore the mechanism of action of GE in CNV. GE was found to activate the angiotensin-converting enzyme 2 (ACE2)/angiotensin 1-7 (Ang-[1-7])/MAS1 proto-oncogene, G protein-coupled receptor (MasR)/interleukin-10 (IL-10) pathway in hypoxic human choroidal endothelial cells (HCECs) in vitro and mouse models of laser-induced CNV in vivo. Activation of the ACE2/Ang-(1-7)/MasR/IL-10 pathway by GE attenuated the proliferative, migratory, and tube-forming abilities of hypoxic HCECs and prevented the development of CNV in mice. Notably, GE did not cause ocular or systemic toxicity in mice with CNV. These findings suggest that GE alleviates CNV by activating the ACE2/Ang-(1-7)/MasR/IL-10 pathway in choroidal endothelial cells (CECs).

关键词： Diabetic kidney disease   Albuminuria   Chemerin   TNF-alpha   Diabetes Mellitus   Inflammation  

摘要： Background: Chronic inflammation has been increasingly recognized as an essential pathogenic mechanism for the development and progression of diabetic kidney disease (DKD). Chemerin is an adipokine which has been suggested to be related to inflammation and has been correlated with the development of diabetic complications. We aimed to explore the potential links between chemerin, TNF - alpha, as a marker of systemic inflammation, and the level of albuminuria in patients with type 2 diabetes mellitus (T2DM). Method: The study included 84 patients with T2DM and 10 normoalbuminuric non-diabetic controls. Demographic, clinical and laboratory data including chemerin and TNF-alpha levels were collected. Results: A total of 84 diabetic patients were enrolled, 32 males (38.1 %), with mean age 57.9 +/- 10.7 years. They were divided into 3 groups: A1: 14 with normalbuminuria, A2: 27 with microalbuminuria, and A3: 43 with macroalbuminuria (uACR < 30, 30-300 and > 300 mg/gm respectively). Chemerin and TNF-alpha levels increased with the progress of albuminuria (control: 21.3 (14.7 -77), A1: 794 (683-925), A2: 1150 (962.9 - 1221.5) and A3: 1466 (1197.5 - 2002.5) ng/ml;p < 0.001) and (control: 77.9 (59 - 96.8), A1: 85.2 (71-116.3), A2: 87.3 (81 - 97.5) and A3: 99 (85.1 - 142.5) pg/ml;p = 0.009) respectively. Among the diabetics, a significant association was evident between serum chemerin and serum TNF-alpha (r = 0.53;p < 0.001). On linear stepwise regression analysis, chemerin was significantly associated with TNF-alpha and HbA1c (unstandardized beta 10.881 and 272.68 respectively, p < 0.001);and TNF-alpha was significantly correlated with chemerin, uACR (unstandardized beta 0.059 and 0.004 respectively, p < 0.001) and HbA1c (unstandardized beta -13.699, p = 0.014). Conclusion: Our findings suggest a potential role of chemerin and TNF-alpha in the development and progression of DKD, and thus support the role of the inflammatory pathway. Larger follow up studies are warranted to