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Introduction: Changes in plasma concentrations of anti-inflammatory cytokines, such as interleukin-6 (IL-6) and IL-10, after acute resistance exercise (RE) have been widely explored. Whether observed changes in plasma cytokine concentration correspond to the activation of anti-inflammatory signaling pathways in immune cells after acute RE is unknown. This study aimed to determine if changes in plasma cytokines after acute RE resulted in the activation of anti-inflammatory signaling pathways in peripheral blood mononuclear cells (PBMC)., Methods: Healthy young males (N = 16; age = 23.5 ± 2.7 yr; BMI = 22.4 ± 1.7 kg·m-2) participated in a single session of whole-body RE (4 sets of 4 different exercises at 70% 1-repetition maximum with the last set to failure) and a sedentary control (CON) condition in a randomized crossover design. Blood samples were collected at several time points before and after the exercise bout., Results: Higher plasma IL-6, IL-10, and IL-1 RA concentrations were observed after RE compared with CON. Phosphorylation of STAT3 and protein expression of SOCS3 in PBMC were increased in RE compared with CON. The elevation of plasma IL-6, but not IL-10, coincided with the activation of STAT3 signaling in PBMC., Conclusions: These results highlight a potential mechanism by which RE may exert anti-inflammatory actions in circulating immune cells., (Copyright © 2024 by the American College of Sports Medicine.)

Long non-coding RNAs (lncRNAs) have emerged as pivotal regulators in numerous biological processes, including macrophage-mediated inflammatory responses, which play a critical role in the progress of diverse diseases. This study focuses on the regulatory function of lncRNA brain and reproductive organ-expressed protein (BRE) antisense RNA 1 (BRE-AS1) in modulating the inflammatory activation of monocytes/macrophages. Employing the THP-1 cell line as a model, we demonstrate that lipopolysaccharide (LPS) treatment significantly upregulates BRE-AS1 expression. Notably, specific knockdown of BRE-AS1 via siRNA transfection enhances LPS-induced expression of interleukin (IL)-6 and IL-1β, while not affecting tumor necrosis factor (TNF)-α levels. This selective augmentation of pro-inflammatory cytokine production coincides with increased phosphorylation of Janus kinase (JAK)2 and signal transducer and activator of transcription (STAT)3. Furthermore, BRE-AS1 suppression results in the downregulation of suppressor of cytokine signaling (SOCS)3, an established inhibitor of the JAK2/STAT3 pathway. Bioinformatics analysis identified binding sites for miR-30b-5p on both BRE-AS1 and SOCS3 mRNA. Intervention with a miR-30b-5p inhibitor and a synthetic RNA fragment that represents the miR-30b-5p binding site on BRE-AS1 attenuates the pro-inflammatory effects of BRE-AS1 knockdown. Conversely, a miR-30b-5p mimic replicated the BRE-AS1 attenuation outcomes. Our findings elucidate the role of lncRNA BRE-AS1 in modulating inflammatory activation in THP-1 cells via the miR-30b-5p/SOCS3/JAK2/STAT3 signaling pathway, proposing that manipulation of macrophage BRE-AS1 activity may offer a novel therapeutic avenue in diseases characterized by macrophage-driven pathogenesis., (© 2024. The Author(s).)

Obesity and poverty disproportionally affect African American persons. Epigenetic mechanisms could partially explain the association between socioeconomic disadvantage and body mass index (BMI). We examined the extent to which epigenetic mechanisms mediate the effect of socioeconomic status (SES) on BMI. Using data from African American adults from the Atherosclerosis Risk in Communities (ARIC) Study (n = 2664, mean age = 57 years), education, income, and occupation were used to create a composite SES score at visit 1 (1987-1989). We conducted two methylation-wide association analyses to identify associations between SES (visit 1), BMI and cytosine-phosphate-guanine (CpG) sites measured at a subsequent visit (1990-1995). We then utilized structural equation modeling (SEM) to test whether identified sites mediated the association between earlier SES and BMI in sex-stratified models adjusted for demographic and risk factor covariates. Independent replication and meta-analyses were conducted using the Jackson Heart Study (JHS, n = 874, mean age 51 years, 2000-2004). Three CpG sites near MAD1L1, KDM2B, and SOCS3 (cg05095590, cg1370865, and cg18181703) were suggestively associated (P-value < 1.3×10-5) in ARIC and at array-wide significance (P-value < 1.3×10-7) in a combined meta-analysis of ARIC with JHS. SEM of these three sites revealed significant indirect effects in females (P-value < 5.8×10-3), each mediating 7%-20% of the total effect of SES on BMI. Nominally significant indirect effects were observed for two sites near MAD1L1 and KDM2B in males (P-value < 3.4×10-2), mediating -17 and -22% of the SES-BMI effect. These results provide further evidence that epigenetic modifications may be a potential pathway through which SES may "get under the skin" and contribute to downstream health disparities., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Acetaminophen (APAP, also known as paracetamol) is a commonly used antipyretic and analgesic that is considered safe to use during pregnancy. However, a growing body of research indicates that gestational administration of APAP increased the risk of neurodevelopmental, reproductive and genitourinary disorders in offspring, alongside impairments in placental development. Notably, over-dosed APAP exhibits direct toxicity to endothelial cells, but there is very limited research investigating the impact of APAP on placental angiogenesis, a gap we aim to address in this study. Pregnant mice were gavaged with APAP (15, 50 and 150 mg/kg/d) from embryonic day 11.5 (E11.5) to E13.5. Administration of 150 mg/kg/d APAP leads to low birth weight (LBW) of the offspring and disordered vascular structures within the labyrinthine (Lab) layer of the placenta. This disruption is accompanied by a significant increase in Suppressor of Cytokine Signaling 3 (SOCS3) level, a negative regulator of the Janus kinase signal transducer 1 and activator of the transcription 3 (JAK1/STAT3) signaling. Meanwhile, Human umbilical vein endothelial Cells (HUVECs) with the treatment of 3 mM APAP exhibited reduced cell viability, whereas 1 mM APAP significantly affected the proliferation, migration, invasion and angiogenic capacities of HUVECs. Further, SOCS3 was up-regulated in HUVECs, accompanied by inhibition of JAK1/STAT3 pathways. Knocking-down SOCS3 in HUVECs restored the nuclear translocation of STAT3 and efficiently promoted cellular capacity of tube formation. Overall, short-term maternal administration of overdosed APAP impairs angiogenic capacities of fetal endothelial cells via SOCS3/JAK1/STAT3 pathway in the mouse placenta. This study reveals that overdose of APAP during pregnancy may adversely affect placental angiogenesis, emphasizing the importance of adhering to the safe principles of smallest effective dose for the shortest required durations., Competing Interests: Declaration of Competing Interest All authors declare that they have no known competing financial interest or personal relationships that could have appeared to influence., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Single Nucleotide Variant (SNVs) affect gene expression as well as protein structure and activity, leading to reduced signaling capabilities and ultimately, increasing cancer risk. SOCS3 (suppressor of cytokine signaling 3), a critical tumor suppressor providing a substantial part in the feedback loop of the JAK/STAT pathway, is abnormally suppressed in various cancer. This study aims to screen non-coding and potentially deleterious coding SNVs in the SOCS3 gene. We performed six programs: PredictSNP1.0 (predicting Deleterious nsSNVs), ConSurf (analyzing sequence conservation), ModPred (analyzing SNVS in PTMs sites), I-Mutant and MUpro (to analyze SNVs effecting protein stability), and molecular docking and molecular dynamics (MD) (to assess the consequences of SOCS3 genetic variations on JAK interactions) for coding regions and three programs (UTRSite, SNP2TFBS, miRNA SNP) (to analyze SNVs effecting the gene expression) in non-coding regions, respectively. After screening 2786 SOCS3 SNVs, we found 10 SNVs, as well as 49 SNPs that change the function of non-coding areas. Out of 10 selected nsSNVs, 3 SNVs (W48R, R71C, N198S) predicted to be the most damaging by all the software programs, as well as one nsSNV (R194W) could be highly deleterious from Molecular Docking analysis combined with MD Simulations. Our findings propose a procedure for studying the structure-related consequences of SNVs on protein function in the future.Communicated by Ramaswamy H. Sarma.

Spinal cord injury (SCI) is a serious injury to the central nervous system. Previous studies have discovered that the development of SCI is associated with gene expression. The purpose of this study was to explore the significance of lncRNA TSIX in SCI and its underlying mechanism involved. An in vivo SCI mice model and an in vitro hypoxia-treated HT22 cells model were applied in this study. TSIX and SOCS3 expression in SCI tissues was measured by qRT-PCR, western blot and FISH assay. LV-sh-TSIX was injected into SCI mice intrathecally or subjected to HT22 cells to access the consequent alteration in inflammation response, cell apoptosis and functional recovery through ELISA, immunohistochemistry, TUNEL, flow cytometry assays and BMS scores. Then, the underlying mechanism of TSIX was analyzed by bioinformatics analysis and then confirmed by RIP, RNA pull-down and dual-luciferase reporter assay. It was identified that TSIX was up-regulated in HT22 cells under hypoxia operation and spinal cord tissues of SCI mice. TSIX knockdown improved the lesion size and BMS score and inhibited inflammation and cell apoptosis. MiR-30a was identified as a target for TSIX and SOCS3, and TSIX binds to miR-30a by competing with SOCS3, thereby counteracting miR-30a-mediated SOCS3 inhibition. In addition, LV-sh-TSIX effects were significantly overturned by miR-30a inhibition or SOCS3 over-expression. Knockdown of TSIX improved functional recovery and attenuated the inflammation response and cell apoptosis via miR-30a/SOCS3 axis. These results may provide a potential novel insight for SCI treatment.

Background: Angiogenesis plays a critical protective role in myocardial ischemia-reperfusion injury (MIRI); however, therapeutic targeting of associated genes remains constrained. To bridge this gap, we conducted bioinformatics analysis to identify pivotal angiogenesis-related genes in MIRI, potentially applicable for preventive and therapeutic interventions., Methods: We collected two mouse heart I/R expression datasets (GSE61592 and GSE83472) from Gene Expression Omnibus, utilizing the Limma package to identify differentially expressed genes (DEGs). Angiogenesis-related genes (ARGs) were extracted from GeneCards, and their overlap with DEGs produced differentially expressed ARGs (ARDEGs). Further analyses included Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and disease ontology to explore biological functions. Weighted gene correlation network analysis (WGCNA) was used to investigate molecular modules linked to MIRI. Additionally, a protein-protein interaction (PPI) network was constructed to pinpoint hub genes relevant to MIRI. Receiver operating characteristic curves were used to assess the diagnostic efficacy of these hub genes for MIRI. An ischemia-reperfusion injury model was established using human cardiac microvascular endothelial cells (HCMECs), with the expression of hub genes validated within this experimental framework., Results: We identified 47 ARDEGs, 41 upregulated and 6 downregulated. PPI network analysis revealed suppressor of cytokine signaling 3 ( Socs3 ), C-X-C motif chemokine ligand 1 ( Cxcl1 ), interleukin 1 beta ( Il1b ), and matrix metallopeptidase 9 ( Mmp9 ) as hub genes. Receiver operating characteristic (ROC) curve analysis demonstrated strong diagnostic potential for Socs3 , Cxcl1 , Il1b , and Mmp9 . In vitro validation corroborated the mRNA and protein expression predictions., Conclusions: Our study highlights the pivotal role of Socs3 , Cxcl1 , Il1b , and Mmp9 in MIRI development, their significance in immune cell infiltration, and their diagnostic accuracy. These findings offer valuable insights for MIRI diagnosis and treatment, presenting potential molecular targets for future research., (© 2024 The Author(s). Published by IMR Press.)

Spinal microglial polarization plays a crucial role in the pathological processes of neuropathic pain following peripheral nerve injury. Accumulating evidence suggests that milk fat globule epidermal growth factor-8 (MFG-E8) exhibits anti-inflammatory effect and regulates microglial polarization through the integrin β3 receptor. However, the impact of MFG-E8 on microglial polarization in the context of neuropathic pain has not yet been investigated. In this study, we evaluated the effect of MFG-E8 on pain hypersensitivity and spinal microglial polarization following spared nerve injury (SNI) of the sciatic nerve in mice. We determined the molecular mechanisms underlying the effects of MFG-E8 on pain hypersensitivity and spinal microglial polarization using pain behavior assessment, western blot (WB) analysis, immunofluorescence (IF) staining, quantitative polymerase chain reaction (qPCR), enzyme-linked immunosorbent assay (ELISA), and small interfering RNA (siRNA) transfection. Our findings indicate that SNI significantly increased the levels of MFG-E8 and integrin β3 expressed in microglia within the spinal cord of mice. Additionally, we observed that intrathecal injection of recombinant human MFG-E8 (rhMFG-E8) alleviated SNI induced-mechanical allodynia and thermal hyperalgesia. Furthermore, the results suggested that rhMFG-E8 facilitated M2 microglial polarization and ameliorated neuroinflammation via integrin β3/SOCS3/STAT3 pathway in the spinal cord of mice with SNI. Importantly, these effects were negated by integrin β3 siRNA, or SOCS3 siRNA. These results demonstrate that MFG-E8 ameliorates peripheral nerve injury induced-mechanical allodynia and thermal hyperalgesia by driving M2 microglial polarization and mitigating neuroinflammation mediated by integrin β3/SOCS3/STAT3 pathway in the spinal cord of mice. MFG-E8 may serve as a promising target for the treatment of neuropathic pain., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Accumulating evidence has demonstrated that M1 microglial polarization and neuroinflammation worsen the development of neuropathic pain. However, the mechanisms underlying microglial activation during neuropathic pain remain incompletely understood. Myeloid-epithelial-reproductive tyrosine kinase (Mer), which is a member of the Tyro-Axl-Mer (TAM) family of receptor tyrosine kinases, plays a crucial role in the regulation of microglial polarization. However, the effect of Mer on microglial polarization during neuropathic pain has not been determined. In this study, western blotting, immunofluorescence analysis, quantitative polymerase chain reaction (qPCR), and enzyme-linked immunosorbent assay (ELISA) were used to examine the role of Mer in pain hypersensitivity and microglial polarization in rats with chronic constriction injury (CCI) of the sciatic nerve. The results indicated that Mer expression in microglia was prominently increased in the spinal cords of rats subjected to CCI. Furthermore, treatment with recombinant protein S (PS, an activator of Mer) alleviated mechanical allodynia and thermal hyperalgesia, promoted the switch in microglia from the M1 phenotype to the M2 phenotype, and ameliorated neuroinflammation in rats subjected to CCI. However, the use of suppressor of cytokine signalling 3 (SOCS3) siRNA abolished these changes. These results indicated that Mer regulated M1/M2 microglial polarization and neuroinflammation and may be a potential target for treating neuropathic pain., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Due to the urgent need to create appropriate treatment techniques, which are currently unavailable, LPS-induced sepsis has become a serious concern on a global scale. The primary active component in the pathophysiology of inflammatory diseases such as sepsis is the Gram-negative bacterial lipopolysaccharide (LPS). LPS interacts with cell surface TLR4 in macrophages, causing the formation of reactive oxygen species (ROS), TNF-α, IL-1β and oxidative stress. It also significantly activates the MAPKs and NF-κB pathway. Excessive production of pro-inflammatory cytokines is one of the primary characteristic features in the onset and progression of inflammation. Cytokines mainly signal through the JAK/STAT pathway. We hypothesize that blocking of TLR4 along with TNFR1 might be beneficial in suppressing the effects of STAT1/STAT3 due to the stimulation of SOCS3 proteins. Prior to the LPS challenge, the macrophages were treated with antibodies against TLR4 and TNFR1 either individually or in combination. On analysis of the macrophage populations by flowcytometry, it was seen that receptor blockade facilitated the phenotypic shift of the M1 macrophages towards M2 resulting in lowered oxidative stress. Blocking of TLR4/TNFR1 upregulated the SOCS3 and mTOR expressions that enabled the transition of inflammatory M1 macrophages towards the anti-inflammatory M2 phenotype, which might be crucial in curbing the inflammatory responses. Also the reduction in the production of inflammatory cytokines such as IL-6, IL-1β due to the reduction in the activation of the STAT1 and STAT3 molecules was observed in our combination treatment group. All these results indicated that neutralization of both TLR4 and TNFR1 might provide new insights in establishing an alternative therapeutic strategy for LPS-sepsis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

TLRs are the most thoroughly studied group of pattern-recognition receptors that play a central role in innate immunity. Among them, TLR10 (CD290) remains the only TLR family member without a known ligand and clearly defined functions. One major impediment to studying TLR10 is its absence in mice. A recent study on TLR10 knock-in mice demonstrated its intrinsic inhibitory role in B cells, indicating that TLR10 is a potential drug target in autoimmune diseases. In this study, we interrogated the expression and function of TLR10 in human plasmacytoid dendritic cells (pDCs). We have seen that primary human pDCs, B cells, and monocytes constitutively express TLR10. Upon preincubation with an anti-TLR10 Ab, production of cytokines in pDCs was downregulated in response to stimulation with DNA and RNA viruses. Upon further investigation into the possible mechanism, we documented phosphorylation of STAT3 upon Ab-mediated engagement of TLR10. This leads to the induction of inhibitory molecule suppressor of cytokine signaling 3 (SOCS3) expression. We have also documented the inhibition of nuclear translocation of transcription factor IFN regulatory factor 7 (IRF7) in pDCs following TLR10 engagement. Our data provide the (to our knowledge) first evidence that TLR10 is constitutively expressed on the surface of human pDCs and works as a regulator of their innate response. Our findings indicate the potential of harnessing the function of pDCs by Ab-mediated targeting of TLR10 that may open a new therapeutic avenue for autoimmune disorders., (Copyright © 2024 by The American Association of Immunologists, Inc.)

Objective: The objective of this study is to explore the functions and mechanisms of the LncRNA-KCNQ1OT1/miR-29a-3p/SOCS3 molecular pathway in the context of unexplained recurrent spontaneous abortion (URSA)., Methods: We conducted qRT-PCR to assess the levels of LncRNA-KCNQ1OT1, miR-29a-3p, and SOCS3 in both abortion tissues from women who experienced URSA and healthy early pregnant women. A dual-luciferase assay was employed to investigate whether miR-29a-3p targets SOCS3. Furthermore, RNA IP and RNA Pull-Down assays were employed to confirm the interaction between KCNQ1OT1 and SOCS3 with miR-29a-3p. RNA FISH was used to determine the cellular localization of KCNQ1OT1. Additionally, trophoblast cells (HTR8/SVneo) were cultured and the CCK-8 assay was utilized to assess cell proliferation, while flow cytometry was employed to analyze cell apoptosis., Results: Compared to abortion tissues obtained from healthy early pregnant individuals, those from women who experienced URSA displayed a notable downregulation of KCNQ1OT1 and SOCS3, accompanied by an upregulation of miR-29a-3p. Suppression of KCNQ1OT1 resulted in the inhibition of cell proliferation and the facilitation of apoptosis in HTR8/SVneo cells. Our findings suggest that KCNQ1OT1 may exert a regulatory influence on SOCS3 through a competitive binding mechanism with miR-29a-3p. Notably, KCNQ1OT1 exhibited expression in both the cytoplasm and nucleus, with a predominant localization in the cytoplasm. Furthermore, we observed a negative regulatory relationship between miR-29a-3p and SOCS3, as the miR-29a-3p mimic group demonstrated significantly reduced cell proliferation and an increased rate of apoptosis when compared to the negative control (NC mimic) group. Additionally, the SOCS3 Vector group exhibited a substantial improvement in proliferation capability and a marked reduction in the apoptosis rate in comparison to the NC Vector group. The miR-29a-3p mimic + SOCS3 Vector group demonstrated a remarkable enhancement in proliferation and a reduction in apoptosis when compared to the miR-29a-3p mimic group., Conclusion: The competitive binding of miR-29a-3p to LncRNA-KCNQ1OT1 appears to result in the elevation of SOCS3 expression, consequently fostering the proliferation of trophoblast cells while concomitantly suppressing apoptosis.

Tuberculosis (TB) remains a leading cause of mortality among individuals coinfected with HIV, characterized by progressive pulmonary inflammation. Despite TB's hallmark being focal granulomatous lung lesions, our understanding of the histopathological features and regulation of inflammation in HIV & TB coinfection remains incomplete. In this study, we aimed to elucidate these histopathological features through an immunohistochemistry analysis of HIV & TB co-infected and TB patients, revealing marked differences. Notably, HIV & TB granulomas exhibited aggregation of CD68 + macrophage (Mφ), while TB lesions predominantly featured aggregation of CD20+ B cells, highlighting distinct immune responses in coinfection. Spatial transcriptome profiling further elucidated CD68+ Mφ aggregation in HIV & TB, accompanied by activation of IL6 pathway, potentially exacerbating inflammation. Through multiplex immunostaining, we validated two granuloma types in HIV & TB versus three in TB, distinguished by cell architecture. Remarkably, in the two types of HIV & TB granulomas, CD68 + Mφ highly co-expressed IL6R/pSTAT3, contrasting TB granulomas' high IFNGRA/SOCS3 expression, indicating different signaling pathways at play. Thus, activation of IL6 pathway may intensify inflammation in HIV & TB-lungs, while SOCS3-enriched immune microenvironment suppresses IL6-induced over-inflammation in TB. These findings provide crucial insights into HIV & TB granuloma formation, shedding light on potential therapeutic targets, particularly for granulomatous pulmonary under HIV & TB co-infection. Our study emphasizes the importance of a comprehensive understanding of the immunopathogenesis of HIV & TB coinfection and suggests potential avenues for targeting IL6 signaling with SOCS3 activators or anti-IL6R agents to mitigate lung inflammation in HIV & TB coinfected individuals.

Aims: Chronic obstructive pulmonary disease (COPD) is marked by irreversible airflow limitations stemming from small airway constriction and lung emphysema. The advancement of COPD is greatly influenced by the M1 polarization of macrophages. The mechanisms governing macrophage polarization in inflammation conditions in COPD are not yet fully understood., Methods: To investigate the interplay between exosomes triggered by cigarette smoke and the polarization of macrophages, we utilized a combination of flow cytometry, quantitative real-time reverse transcription PCR, and western blot analysis., Results: Our research reveals that cigarette smoke (CS) exposure induces the secretion of exosomes from human bronchial epithelial cells, with exosomal miR-221-3p identified as a key player in modulating the polarization of M1 macrophages. The evidence indicates that cigarette smoke promotes exosome secretion in these cells, with exosomal miR-221-3p targeting SOCS3 and regulating the STAT3 signaling pathway to facilitate M1 macrophage polarization., Conclusions: This research delves into the molecular pathways through which miR-221-3p facilitates the polarization of M1 macrophages, presenting a groundbreaking approach for potential targeted therapy in COPD.

Background: circRNAs have been shown to participate in diverse diseases; however, their role in oral submucous fibrosis (OSF), a potentially malignant disorder, remains obscure. Our preliminary experiments detected the expression of circRNA mitochondrial translation optimization 1 homologue (circMTO1) in OSF tissues (n = 20) and normal mucosa tissues (n = 20) collected from Hunan Xiangya Stomatological Hospital, and a significant decrease of circMTO1 expression was showed in OSF tissues. Therefore, we further explored circMTO1 expression in OSF., Methods: Target molecule expression was detected using RT-qPCR and western blotting. The migration and invasion of buccal mucosal fibroblasts (BMFs) were assessed using wound healing and Transwell assays. The interaction between miR-30c-5p, circMTO1, and SOCS3 was evaluated using dual luciferase, RNA immunoprecipitation (RIP), and RNA pull-down assays. The colocalisation of circMTO1 and miR-30c-5p was observed using fluorescence in situ hybridisation (FISH)., Results: circMTO1 and SOCS3 expression decreased, whereas miR-30c-5p expression increased in patients with OSF and arecoline-stimulated BMFs. Overexpression of circMTO1 effectively restrained the fibroblast-myofibroblast transition (FMT), as evidenced by the increase in expression of Coll I, α-SMA, Vimentin, and the weakened migration and invasion functions in BMFs. Mechanistic studies have shown that circMTO1 suppresses FMT by enhancing SOCS3 expression by sponging miR-30c-5p and subsequently inactivating the FAK/PI3K/AKT pathway. FMT induced by SOCS3 silencing was reversed by the FAK inhibitor TAE226 or the PI3K inhibitor LY294002., Conclusion: circMTO1/miR-30c-5p/SOCS3 axis regulates FMT in arecoline-treated BMFs via the FAK/PI3K/AKT pathway. Expanding the sample size and in vivo validation could further elucidate their potential as therapeutic targets for OSF., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Decidualisation of the endometrium is a key event in early pregnancy, which enables embryo implantation. Importantly, the molecular processes impairing decidualisation in obese mothers are yet to be characterised. We hypothesise that impaired decidualisation in obese mice is mediated by the upregulation of leptin modulators, the suppressor of cytokine signalling 3 (SOCS3) and the protein tyrosine phosphatase non-receptor type 2 (PTPN2), together with the disruption of progesterone (P4)-signal transducer and activator of transcription (STAT3) signalling. After feeding mice with chow diet (CD) or high-fat diet (HFD) for 16 weeks, we confirmed the downregulation of P4 and oestradiol (E2) steroid receptors in decidua from embryonic day (E) 6.5 and decreased proliferation of stromal cells from HFD. In vitro decidualised mouse endometrial stromal cells (MESCs) and E6.5 deciduas from the HFD showed decreased expression of decidualisation markers, followed by the upregulation of SOCS3 and PTPN2 and decreased phosphorylation of STAT3. In vivo and in vitro leptin treatment of mice and MESCs mimicked the results observed in the obese model. The downregulation of Socs3 and Ptpn2 after siRNA transfection of MESCs from HFD mice restored the expression level of decidualisation markers. Finally, DIO mice placentas from E18.5 showed decreased labyrinth development and vascularisation and fetal growth restricted embryos. The present study revealed major defects in decidualisation in obese mice, characterised by altered uterine response to E2 and P4 steroid signalling. Importantly, altered hormonal response was associated with increased expression of leptin signalling modulators SOCS3 and PTPN2. Elevated levels of SOCS3 and PTPN2 were shown to molecularly affect decidualisation in obese mice, potentially disrupting the STAT3-PR regulatory molecular hub., (© 2024. Crown.)

Numerous natural bioactive compounds extracted from Chinese medicines have been proved to be promising and potent agents in the treatment of ischemic stroke. Hydroxysafflor yellow A (HSYA), separated from Carthamus tinctorius, has increasingly attracted attention for its broad spectrum of pharmacological effects, especially of its neuroprotective action. Our previous studies revealed that HSYA plays significant beneficial roles in a dose-dependent manner in rats with focal cerebral ischemia. However, treatment with higher doses of HSYA appeared to bring about adverse reactions in the rats. In present study, we adopted tenuigenin (TEN), extracted from the Polygala tenuifolia root, in combination with HSYA to optimize the therapeutic strategy against ischemic stroke, and further explored the underlying mechanisms of action of the combination in vivo and in vitro. We firstly confirmed the pharmacological efficacies of co-treatment of HSYA and TEN in middle cerebral ischemia occlusion (MCAO) rats and observed the synergistic improvement of infarct volume, cerebral edema, and morphology of neuron cell body. Behavioral experiments indicated that combination of HSYA and TEN could synergistically improve motor and cognitive function in MCAO rats. We also observed increased viability and suppressed cell apoptosis after HSYA and TEN co-treatments in the oxygen-glucose deprivation/reperfusion (OGD/R) SH-SY5Y cells. Furthermore, JAK2/STAT3 and SOCS3 signaling interaction was demonstrated to be a critical responsor to the co-treatment of HSYA and TEN. In the subsequent experiments with silencing SOCS3 in OGD/R-exposed cells, we found that HSYA and TEN might suppress JAK2/STAT3 pathway through different regulatory mechanisms targeting SOCS3-negative feedback signaling. HSYA seemed to impose excessive activation of JAK2/STAT3 to trigger SOCS3-negative feedback signaling, while TEN appeared to provoke SOCS3 inhibitory feedback role directly to further attenuate JAK2-mediated signaling. Collectively, HSYA and TEN might modulate the crosstalk between JAK2/STAT3 and SOCS3 signaling pathways in different manners that eventually contributed to their synergistic therapeutic effects against cerebral ischemic stroke., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Several blinding diseases affecting the retina and optic nerve are exacerbated by or caused by dysregulated inflammation and oxidative stress. These diseases include uveitis, age related macular degeneration, diabetic retinopathy and glaucoma. Consequently, despite their divergent symptoms, treatments that reduce oxidative stress and suppress inflammation may be therapeutic. The production of inflammatory cytokines and their activities are regulated by a class of proteins termed Suppressors of Cytokine Signaling (SOCS). SOCS1 and SOCS3 are known to dampen signaling via pathways employing Janus kinases and signal transducer and activator of transcription proteins (JAK/STAT), Toll-like Receptors (TLR), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), mitogen activated kinase (MAPK) and NLR family pyrin domain containing 3 (NLRP3). We have developed cell-penetrating peptides from the kinase inhibitory region of the SOCS1 and SOCS3 (denoted as R9-SOCS1-KIR and R9-SOCS3-KIR) and tested them in retinal pigment epithelium (RPE) cells and in macrophage cell lines. SOCS-KIR peptides exhibited anti-inflammatory, anti-oxidant and anti-angiogenic properties. In cell culture, both Th1 and Th17 cells were suppressed together with the inhibition of other inflammatory markers. We also observed a decrease in oxidants and a simultaneous rise in neuroprotective and anti-oxidant effectors. In addition, treatment prevented the loss of gap junction proteins and the ensuing drop in transepithelial electrical resistance in RPE cells. When tested in mouse models by eye drop instillation, they showed protection against autoimmune uveitis, as a prophylactic as well as a therapeutic. Mice with endotoxin-induced uveitis were protected by eye drop administration as well. R9-SOCS3-KIR was particularly effective against the pathways acting through STAT3, e.g. IL-6 and VEGF-A mediated responses that lead to macular degeneration. Eye drop administration of R9-SOCS3-KIR stimulated production of antioxidant effectors and reduced clinical symptoms in mouse model of oxidative stress that replicates the RPE injury occurring in AMD. Because these peptides suppress multiple pathogenic stimuli and because they can be delivered topically to the cornea, they are attractive candidates for therapeutics for uveitis, macular degeneration, diabetic retinopathy and glaucoma., Competing Interests: CA and HJ are listed as inventors in a patent held by the University of Florida for the technology involving R9-SOCS3-KIR peptide. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ahmed, Johnson and Lewin.)

Introduction: SOCS3 (suppressor of cytokine signaling 3) protein is a crucial regulator of cytokine-induced inflammation, and its administration has been shown to have therapeutic effects. Recently, we designed a chimeric proteomimetic of SOCS3, mimicking the interfacing regions of a ternary complex composed of SOCS3, JAK2 (Janus kinase 2) and gp130 (glycoprotein 130) proteins. The derived chimeric peptide, KIRCONG chim, demonstrated limited mimetic function owing to its poor water solubility., Methods: We report investigations concerning a PEGylated variant of KIRCONG mimetic, named KIRCONG chim, bearing a PEG (Polyethylene glycol) moiety as a linker of noncontiguous SOCS3 regions. Its ability to bind to the catalytic domain of JAK2 was evaluated through MST (MicroScale Thermophoresis), as well as its stability in biological serum assays. The structural features of the cyclic compounds were investigated by CD (circular dichroism), nuclear magnetic resonance (NMR), and molecular dynamic (MD) studies. To evaluate the cellular effects, we employed a PLGA-nanoparticle as a delivery system after characterization using DLS and SEM techniques., Results: KIRCONG chim PEG-revealed selective penetration into triple-negative breast cancer (TNBC) MDA-MB-231 cells with respect to the human breast epithelial cell line (MCF10A), acting as a potent inhibitor of STAT3 phosphorylation., Discussion: Overall, the data indicated that miniaturization of the SOCS3 protein is a promising therapeutic approach for aberrant dysregulation of JAK/STAT during cancer progression., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 La Manna et al.)

Autophagy is central to the benefits of longevity signaling programs and to hematopoietic stem cell (HSC) response to nutrient stress. With age, a subset of HSCs increases autophagy flux and preserves regenerative capacity, but the signals triggering autophagy and maintaining the functionality of autophagy-activated old HSCs (oHSCs) remain unknown. Here, we demonstrate that autophagy is an adaptive cytoprotective response to chronic inflammation in the aging murine bone marrow (BM) niche. We find that inflammation impairs glucose uptake and suppresses glycolysis in oHSCs through Socs3-mediated inhibition of AKT/FoxO-dependent signaling, with inflammation-mediated autophagy engagement preserving functional quiescence by enabling metabolic adaptation to glycolytic impairment. Moreover, we show that transient autophagy induction via a short-term fasting/refeeding paradigm normalizes glycolytic flux and significantly boosts oHSC regenerative potential. Our results identify inflammation-driven glucose hypometabolism as a key driver of HSC dysfunction with age and establish autophagy as a targetable node to reset oHSC regenerative capacity., Competing Interests: Declaration of interests E.P. is a member of the Cell Stem Cell advisory board., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Systemic sclerosis (SSc) poses a significant challenge in autoimmunology, characterized by the development of debilitating fibrosis of skin and internal organs. The pivotal role of dysregulated T cells, notably the skewed polarization toward Th2 cells, has been implicated in the vascular damage and progressive fibrosis observed in SSc. In this study, we explored the underlying mechanisms by which cannabinoid receptor 2 (CB2) highly selective agonist HU-308 restores the imbalance of T cells to alleviate SSc. Using a bleomycin-induced SSc (BLM-SSc) mouse model, we demonstrated that HU-308 effectively attenuates skin and lung fibrosis by specifically activating CB2 on CD4 + T cells to inhibit the polarization of Th2 cells in BLM-SSc mice, which was validated by Cnr2-specific-deficient mice. Different from classical signaling downstream of G protein-coupled receptors (GPCRs), HU-308 facilitates the expression of SOCS3 protein and subsequently impedes the IL2/STAT5 signaling pathway during Th2 differentiation. The deficiency of SOCS3 partially mitigated the impact of HU-308. Analysis of a cohort comprising 80 SSc patients and 82 healthy controls revealed an abnormal elevation in the Th2/Th1 ratio in SSc patients. The proportion of Th2 cells showed a significant positive correlation with mRSS score and positivity of anti-Scl-70. Administration of HU-308 to PBMCs and peripheral CD4 + T cells from SSc patients led to the upregulation of SOCS3, which effectively suppressed the aberrantly activated STAT5 signaling pathway and the proportion of CD4 + IL4 + T cells. In conclusion, our findings unveil a novel mechanism by which the CB2 agonist HU-308 ameliorates fibrosis in SSc by targeting and reducing Th2 responses. These insights provide a foundation for future therapeutic approaches in SSc by modulating Th2 responses., Competing Interests: Declaration of competing interest B.L. is a cofounder of Biotheus Inc. and chairman of its scientific advisory board. The other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Circular RNAs (circRNAs) have been progressively recognized as critical regulators in the pathology and pathophysiology of central nervous system disease. However, the potential role of circRNAs in intracerebral hemorrhage (ICH) is still largely unclear. Here, we demonstrate that circTrim37 expression was significantly upregulated at 3 days after ICH by circular RNA microarray and qPCR assays. Overexpression of circTrim37 could significantly ameliorate brain injury volume, brain edema, neurologic deficits, and inflammation in vivo after ICH. CircTrim37 promotes M2 polarization while restrains M1 polarization in vitro. Furthermore, circTrim37 acts as an endogenous sponge for miR-30c-5p, thereby inhibiting miR-30c-5p activity, leading to the upregulation of SOCS3 and making the balance of microglial response towards an M2 phenotype. Taken together, our results indicate the participation of circTrim37 and its coupling mechanism in ICH and provide a novel therapeutic target for ICH., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Disturbances in intestinal immune homeostasis predispose susceptible individuals to type 1 diabetes (T1D). G-protein-coupled receptor 41 (GPR41) is a receptor for short-chain fatty acids (SCFAs) mainly produced by gut microbiota, which plays key roles in maintaining intestinal homeostasis. In this study, we investigated the role of GPR41 in the progression of T1D. In non-obese diabetic (NOD) mice, we found that aberrant reduction of GPR41 expression in the pancreas and colons was associated with the development of T1D. GPR41-deficient (Gpr41 -/- ) mice displayed significantly exacerbated streptozotocin (STZ)-induced T1D compared to wild-type mice. Furthermore, Gpr41 -/- mice showed enhanced gut immune dysregulation and increased migration of gut-primed IFN-γ + T cells to the pancreas. In bone marrow-derived dendritic cells from Gpr41 -/- mice, the expression of suppressor of cytokine signaling 3 (SOCS) was significantly inhibited, while the phosphorylation of STAT3 was significantly increased, thus promoting dendritic cell (DC) maturation. Furthermore, adoptive transfer of bone marrow-derived dendritic cells (BMDC) from Gpr41 -/- mice accelerated T1D in irradiated NOD mice. We conclude that GPR41 is essential for maintaining intestinal and pancreatic immune homeostasis and acts as a negative regulator of DC maturation in T1D. GPR41 may be a potential therapeutic target for T1D., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Neurogenesis as a potential strategy to improve the consequences of intracerebral hemorrhage (ICH). The current study investigates the effects of withaferin A (WFA) in combination with leptin (LEP) on ICH and neurogenesis mechanisms. LEP levels were dramatically reduced on days 7 and 14 following ICH insults in mice, but continuous WFA therapy significantly improved the potency of intrinsic LEP on day 14 after ICH. Furthermore, WFA combined with LEP enhances intrinsic neurogenesis and lessen motor deficits and long-term cognitive outcomes after ICH. In parallel, leptin deficiency in ob/ob mice limits enhancement of neurogenesis following ICH in response to WFA combined with LEP treatment. Importantly, the functional recovery conferred by WFA combined with LEP after ICH was inhibited by neurogenesis suppression. Mechanistically, this study unveiled that the signal transducer and activator of transcription-3 (STAT3) / suppressor of cytokine signaling-3 (SOCS3) pathway is a critical signaling pathway through which WFA combined with LEP treatment promotes intrinsic neurogenesis after ICH. Collectively, the results of this study elucidate the neuroprotective effects of WFA and LEP in ICH, and highlight a potential approach for ICH cell therapy., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background : Chronic rhinosinusitis (CRS) is an inflammatory condition classified into chronic rhinosinusitis with nasal polyps (CRSwNP) and chronic rhinosinusitis without nasal polyps (CRSsNP). Th cells manage inflammatory cells in CRS. Suppressor of Cytokine Signaling (SOCS) proteins regulate Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway in Th cells by polarizing toward Th1, Th2, and Th17 cells. This study evaluated the levels of SOCS1,3,5 in CRS patients to find associations with Th cells. Methods : In this cross-sectional study, 20 CRSwNP patients, 12 CRSsNP patients, and 12 controls participated. The infiltration of CD4 + T cells was determined using immunohistochemistry. The expression of specific transcription factors and SOCS proteins was assessed using real-time PCR. Cytokine levels were evaluated using ELISA. SOCS protein levels were investigated using western blot analysis. Results : The expression of SOCS3 increased in the CRSwNP group compared to CRSsNP and control groups ( p <0.001). SOCS3 protein levels increased in the CRSwNP group compared to CRSsNP ( p <0.05) and control ( p <0.001) groups. Although there was a significant difference in SOCS5 expression between CRSsNP and control groups, SOCS5 protein levels were significantly different between CRSsNP and control ( p <0.001) and CRSwNP ( p <0.05) groups. Conclusions : Targeted therapies may be suggested for CRS by modulating SOCS3 and SOCS5 proteins that are responsible for polarization of Th cells toward Th2 or Th1 cells, respectively. JAK-STAT pathway targeting, which encompasses numerous cells, can be limited to SOCS proteins to more effectively orchestrate Th cell differentiation., (Copyright ©2024, Yale Journal of Biology and Medicine.)

SOCS are a family of negative inhibitors of the molecular cascades induced by cytokines, growth factors and hormones. At molecular level, SOCS proteins inhibit the kinase activity of specific sets of receptor-associated Janus Activated Kinases (JAKs), thereby suppressing the propagation of intracellular signals. Of the eight known members, SOCS1 and SOCS3 inhibit activity of JAKs mainly induced by cytokines and can play key roles in regulation of inflammatory and immune responses. SOCS1 and SOCS3 are the most well-characterized SOCS members in skin inflammatory diseases, where their inhibitory activity on cytokine activated JAKs and consequent anti-inflammatory action has been widely investigated in epidermal keratinocytes. Structurally, SOCS1 and SOCS3 share the presence of a N-terminal domain containing a kinase inhibitory region (KIR) motif able to act as a pseudo-substrate for JAK and to inhibit its activity. During the last decades, the design and employment of SOCS1 and SOCS3-derived peptides mimicking KIR domains in experimental models of dermatoses definitively established a strong anti-inflammatory and ameliorative impact of JAK inhibition on skin inflammatory responses. Herein, we discuss the importance of the findings collected in the past on SOCS1 and SOCS3 function in the inflammatory responses associated to skin immune-mediated diseases and malignancies, for the development of the JAK inhibitor drugs. Among them, different JAK inhibitors have been introduced in the clinical practice for treatment of atopic dermatitis and psoriasis, and others are being investigated for skin diseases like alopecia areata and vitiligo., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Morelli, Madonna and Albanesi.)

Background: Yishen-Tongbi Decoction (YSTB), a traditional Chinese prescription, has been used to improve syndromes of rheumatoid arthritis (RA) for many years. Previous research has shown that YSTB has anti-inflammatory and analgesic properties. However, the underlying molecular mechanism of the anti-RA effects of YSTB remains unclear., Purpose and Study Design: The purpose of this research was to investigate how YSTB affected mice with collagen-induced arthritis (CIA) and RAW264.7 cells induced with lipopolysaccharide (LPS)., Results: The findings show that YSTB could significantly improve the clinical arthritic symptoms of CIA mice (mitigate paw swelling, arthritis score, thymus and spleen indices, augment body weight), downregulated expression of pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), IL-6 and IL-17, while upregulated the level of anti-inflammatory like IL-10 and transforming growth factor-β (TGF-β). Meanwhile, YSTB inhibits bone erosion and reduces inflammatory cell infiltration, synovial proliferation, and joint destruction in CIA mice. In addition, we found that YSTB was able to suppress the LPS-induced inflammation of RAW264.7 cells, which was ascribed to the suppression of nitric oxide (NO) production and reactive oxygen species formation (ROS). YSTB also inhibited the production of inducible nitric oxide synthase and reduced the releases of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 in LPS-induced RAW264.7 cells. Furthermore, the phosphorylation expression of JAK2, JAK3, STAT3, p38, ERK and p65 protein could be suppressed by YSTB, while the expression of SOCS3 could be activated., Conclusion: Taken together, YSTB possesses anti-inflammatory and prevention bone destruction effects in RA disease by regulating the JAK/STAT3/SOCS3 signaling pathway., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xu, Jiao, Wu, Yu, Liu, Zhang and Chen.)

Leptin regulates lipid metabolism, maximizing insulin sensitivity; however, peripheral leptin resistance is not fully understood, and its contribution to metabolic dysfunction-associated steatotic liver disease (MASLD) is unclear. This study evaluated the contribution of the leptin axis to MASLD in humans. Forty-three participants, mostly female (86.04%), who underwent cholecystectomy were biopsied. Of the participants, 24 were healthy controls, 8 had MASLD, and 11 had metabolic dysfunction-associated steatohepatitis (MASH). Clinical and biochemical data and the gene expression of leptin, leptin receptor ( LEPR ), suppressor of cytokine signaling 3 ( SOCS3 ), sterol regulatory element-binding transcription factor 1 ( SREBF1 ), stearoyl-CoA desaturase-1 ( SCD1 ), and patatin-like phospholipase domain-containing protein 2 ( PNPLA2 ), were determined from liver and adipose tissue. Higher serum leptin and LEPR levels in the omental adipose tissue (OAT) and liver with MASH were found. In the liver, LEPR was positively correlated with leptin expression in adipose tissue, and SOCS3 was correlated with SREBF1-SCD1 . In OAT, SOCS3 was correlated with insulin resistance and transaminase enzymes ( p < 0.05 for all. In conclusion, we evidenced the correlation between the peripheral leptin resistance axis in OAT-liver crosstalk and the complications of MASLD in humans.

Background: Diabetic nephropathy (DN) is a life-threatening renal disease and needs urgent therapies. Wogonin is renoprotective in DN. This study aimed to explore the mechanism of how wogonin regulated high glucose (HG)-induced renal cell injury., Methods: Diabetic mice (db/db), control db/m mice, and normal glucose (NG)- or HG-treated human tubule epithelial cells (HK-2) were used to evaluate the levels of suppressor of cytokine signaling 3 (SOCS3), Toll-like receptor 4 (TLR4), inflammation and fibrosis. Lentivirus was used to regulate SOCS3 and TLR4 expressions. After oral gavage of wogonin (10 mg/kg) or vehicle in db/db mice, histological morphologies, blood glucose, urinary protein, serum creatinine values (Scr), blood urea nitrogen (BUN), superoxide dismutase (SOD), glutathione (GSH), and reactive oxygen species (ROS) were assessed. RT-qPCR and Western blot evaluated inflammation and fibrosis-related molecules., Results: HG exposure induced high blood glucose, severe renal injuries, high serumal Src and BUN, low SOD and GSH, and increased ROS. HG downregulated SOCS3 but upregulated TLR4 and JAK/STAT, fibrosis, and inflammasome-related proteins. Wogonin alleviated HG-induced renal injuries by decreasing cytokines, ROS, Src, and MDA and increasing SOD and GSH. Meanwhile, wogonin upregulated SOCS3 and downregulated TLR4 under HG conditions. Wogonin-induced SOCS3 overexpression directly decreased TLR4 levels and attenuated JAK/STAT signaling pathway-related inflammation and fibrosis, but SOCS3 knockdown significantly antagonized the protective effects of wogonin. However, TLR4 knockdown diminished SOCS3 knockdown-induced renal injuries., Conclusion: Wogonin attenuates renal inflammation and fibrosis by upregulating SOCS3 to inhibit TLR4 and JAK/STAT pathway., (© 2024. The Author(s).)

The fetal development of organs and functions is vulnerable to perturbation by maternal inflammation which may increase susceptibility to disorders after birth. Because it is not well understood how the placenta and fetus respond to acute lung- inflammation, we characterize the response to maternal pulmonary lipopolysaccharide exposure across 24 h in maternal and fetal organs using multi-omics, imaging and integrative analyses. Unlike maternal organs, which mount strong inflammatory immune responses, the placenta upregulates immuno-modulatory genes, in particular the IL-6 signaling suppressor Socs3. Similarly, we observe no immune response in the fetal liver, which instead displays metabolic changes, including increases in lipids containing docosahexaenoic acid, crucial for fetal brain development. The maternal liver and plasma display similar metabolic alterations, potentially increasing bioavailability of docosahexaenoic acid for the mother and fetus. Thus, our integrated temporal analysis shows that systemic inflammation in the mother leads to a metabolic perturbation in the fetus., (© 2024. The Author(s).)

Purpose: Despite lung cancer is one of the leading causes of cancer-related deaths, it remains hard to discover effective diagnostic and therapeutic approaches. Moreover, the five-year survival rate is relatively lower than other tumors. So urgent needs for finding a new theranostic target to treat lung cancer effectively. This study aims to present SOCS3 and NOD2 proteins as novel targets for diagnosis and therapy., Methods: We first confirmed SOCS3 expression level in patients' tissues. Then, we applied knockdown and overexpression of SOCS3 on lung cancer cell lines and performed proliferation, migration, and invasion assay. After that, we found NOD2 is a target of SOCS3 and introduced overexpression of NOD2 to A549 for verifying reduced tumorigenicity of lung cancer cells., Results: We identified protein expression level of SOCS3 was frequently higher in tumor tissues than adjacent normal tissues. Truly, overexpression of SOCS3 promoted proliferation, migration, and invasion capacity of lung cancer cells. We found that SOCS3 interacts with NOD2 and SOCS3 ubiquitinates NOD2 directly. Furthermore, lung cancer tissues with higher SOCS3 expression showed lower NOD2 expression. We confirmed overexpression of NOD2 leads to suppressed tumorigenicity of lung cancer cells, and these effects occurred through MAPK pathway., Conclusion: Collectively, our work reveals novel roles of SOCS3 in lung tumorigenesis and proposes SOCS3 as a promising biomarker candidate for therapeutic and diagnostic target for lung cancer., (© 2023. Springer Nature Switzerland AG.)

LPS induced sepsis is a complex process involving various immune cells and signaling molecules. Dysregulation of macrophage polarization and ROS production contributed to the pathogenesis of sepsis. PGP is a transmembrane transporter responsible for the efflux of a number of drugs and also expressed in murine macrophages. Natural products have been shown to decrease inflammation and expression of efflux transporters. However, no treatment is currently available to treat LPS induced sepsis. Verapamil and Tangeretin also reported to attenuate lipopolysaccharide-induced inflammation. However, the effects of verapamil or tangeretin on lipopolysaccharide (LPS)-induced sepsis and its detailed anti-inflammatory mechanism have not been reported. Here, we have determined that verapamil and tangeretin protects against LPS-induced sepsis by suppressing M1 macrophages populations and also through the inhibition of P-glycoprotein expression via downregulating STAT1/STAT3 and upregulating SOCS3 expression in macrophages. An hour before LPS (10 mg/kg) was administered; mice were given intraperitoneal injections of either verapamil (5 mg/kg) or tangeretin (5 mg/kg). The peritoneal macrophages from different experimental groups of mice were isolated. Hepatic, pulmonary and splenic morphometric analyses revealed that verapamil and tangeretin decreased the infiltration of neutrophils into the tissues. Verapamil and tangeritin also enhanced the activity of SOD, CAT, GRX and GSH level in all the tissues tested. verapamil or tangeretin pre-treated mice shifted M1 macrophages to M2 type possibly through the inhibition of P-glycoprotein expression via downregulating STAT1/STAT3 and upregulating SOCS3 expression. Hence, both these drugs have shown protective effects in sepsis via suppressing iNOS, COX-2, oxidative stress and NF-κB signaling in macrophages. Therefore, in our study we can summarize that mice were treated with either Vera or Tan before LPS administration cause an elevated IL-10 by the macrophages which enhances the SOCS3 expression, and thereby able to limits STAT1/STAT3 inter-conversion in the macrophages. As a result, NF-κB activity is also getting down regulated and ultimately mitigating the adverse effect of inflammation caused by LPS in resident macrophages. Whether verapamil or tangeretin offers such protection possibly through the inhibition of P-glycoprotein expression in macrophages needs clarification with the bio availability of these drugs under PGP inhibited conditions is a limitation of this study., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Type 2 diabetes (DM2) is an increasingly prevalent disease that challenges tuberculosis (TB) control strategies worldwide. It is significant that DM2 patients with poor glycemic control (PDM2) are prone to developing tuberculosis. Furthermore, elucidating the molecular mechanisms that govern this susceptibility is imperative to address this problem. Therefore, a pilot transcriptomic study was performed. Human blood samples from healthy controls (CTRL, HbA1c < 6.5%), tuberculosis (TB), comorbidity TB-DM2, DM2 (HbA1c 6.5-8.9%), and PDM2 (HbA1c > 10%) groups (n = 4 each) were analyzed by differential expression using microarrays. We use a network strategy to identify potential molecular patterns linking the differentially expressed genes (DEGs) specific for TB-DM2 and PDM2 (p-value < 0.05, fold change > 2). We define OSM, PRKCD, and SOCS3 as key regulatory genes (KRGs) that modulate the immune system and related pathways. RT-qPCR assays confirmed upregulation of OSM, PRKCD, and SOCS3 genes (p < 0.05) in TB-DM2 patients (n = 18) compared to CTRL, DM2, PDM2, or TB groups (n = 17, 19, 15, and 9, respectively). Furthermore, OSM, PRKCD, and SOCS3 were associated with PDM2 susceptibility pathways toward TB-DM2 and formed a putative protein-protein interaction confirmed in STRING. Our results reveal potential molecular patterns where OSM, PRKCD, and SOCS3 are KRGs underlying the compromised immune response and susceptibility of patients with PDM2 to develop tuberculosis. Therefore, this work paved the way for fundamental research of new molecular targets in TB-DM2. Addressing their cellular implications, and the impact on the diagnosis, treatment, and clinical management of TB-DM2 could help improve the strategy to end tuberculosis for this vulnerable population., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rotavirus is the main cause of acute diarrhea in children up to five years of age. In this regard, probiotics are commonly used to treat or prevent gastroenteritis including viral infections. The anti-rotavirus effect of Bifidobacterium longum and Chlorella sorokiniana , by reducing viral infectivity and improving IFN-type I response, has been previously reported. The present study aimed to study the effect of B. longum and/or C. sorokiniana on modulating the antiviral cellular immune response mediated by IFN-γ, IL-10, SOCS3, STAT1, and STAT2 genes in rotavirus-infected cells. To determine the mRNA relative expression of these genes, HT-29 cells were treated with B. longum and C. sorokiniana alone or in combination, followed by rotavirus infection. In addition, infected cells were treated with B. longum and/or C. sorokiniana . Cellular RNA was purified, used for cDNA synthesis, and amplified by qPCR. Our results demonstrated that the combination of B. longum and C. sorokiniana stimulates the antiviral cellular immune response by upregulating IFN-γ and may block pro-inflammatory cytokines by upregulating IL-10 and SOCS3. The results of our study indicated that B. longum , C. sorokiniana , or their combination improve antiviral cellular immune response and might modulate pro-inflammatory responses.

Objective: Hyperuricaemia is necessary for gout. High urate concentrations have been linked to inflammation in mononuclear cells. Here, we explore the role of the suppressor of cytokine signaling 3 (SOCS3) in urate-induced inflammation., Methods: Peripheral blood mononuclear cells (PBMCs) from gout patients, hyperuricemic and normouricemic individuals were cultured for 24h with varying concentrations of soluble urate, followed by 24h restimulation with lipopolysaccharides (LPS)±monosodium urate (MSU) crystals. Transcriptomic profiling was performed using RNA-Sequencing. DNA methylation was assessed using Illumina Infinium® MethylationEPIC BeadChip system (EPIC array). Phosphorylation of signal transducer and activator of transcription 3 (STAT3) was determined by flow cytometry. Cytokine responses were also assessed in PBMCs from patients with JAK2 V617F tyrosine kinase mutation., Results: PBMCs pre-treated with urate produced more interleukin-1beta (IL-1β) and interleukin-6 (IL-6) and less interleukin-1 receptor anatagonist (IL-1Ra) after LPS simulation. In vitro, urate treatment enhanced SOCS3 expression in control monocytes but no DNA methylation changes were observed at the SOCS3 gene. A dose-dependent reduction in phosphorylated STAT3 concomitant with a decrease in IL-1Ra was observed with increasing concentrations of urate. PBMCs with constitutively activated STAT3 (JAK2 V617F mutation) could not be primed by urate., Conclusion: In vitro, urate exposure increased SOCS3 expression, while urate priming, and subsequent stimulation resulted in decreased STAT3 phosphorylation and IL-1Ra production. There was no evidence that DNA methylation constitutes a regulatory mechanism of SOCS3. Elevated SOCS3 and reduced pSTAT3 could play a role in urate-induced hyperinflammation since urate priming had no effect in PBMCs from patients with constitutively activated STAT3., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Differential activation of macrophages is associated with poor progression of breast cancer (BC). Many reports have elucidated the important involvement of exosomes produced by cancer cells in remodeling the macrophage activation phenotype to promote tumor expansion and invasion. However, the underlying mechanisms by which exosomes secreted by BC cells facilitate macrophage M2 polarization remain enigmatic and worth exploring. In this study, quantitative real-time PCR (RT-qPCR) was used to investigate miR-191-5p expression in BC tumor tissues and cells. Cell counting kit 8 (CCK-8), transwell, and flow cytometry were applied to assess the functional role of miR-191-5p in BC. Isolated nano-vesicles were identified using transmission electron microscopy and western blotting. We also observed that miR-191-5p was significantly elevated in BC clinical samples and that inhibition of miR-191-5p hindered the growth and metastasis of BC cells. Importantly, BC cells successfully accelerated macrophage M2-like polarization by directly transferring exosomes to macrophages, resulting in increased miR-191-5p levels in macrophages. Mechanistically, exosomal miR-191-5p directly inhibited the suppressors of cytokine signaling 3 (SOCS3) expression in macrophages and aggravated macrophage M2 polarization. Similarly, si-SOCS3 transfected macrophages boosted BC cell migration and invasion in a positive feedback manner. Overall, our results manifested a pro-growth and pro-metastatic role between the two cells by elucidating the crucial role of exosomal miR-191-5p in stimulating M2 macrophage polarization and mediating communication between BC cells and macrophages. These findings opened up new horizons for the development of BC therapeutic strategies., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Pathological ocular angiogenesis has long been associated with myeloid cell activation. However, the precise cellular and molecular mechanisms governing the intricate crosstalk between the immune system and vascular changes during ocular neovascularization formation remain elusive. In this study, we demonstrated that the absence of the suppressor of cytokine signaling 3 (SOCS3) in myeloid cells led to a substantial accumulation of microglia and macrophage subsets during the neovascularization process. Our single-cell RNA sequencing data analysis revealed a remarkable increase in the expression of the secreted phosphoprotein 1 (Spp1) gene within these microglia and macrophages, identifying subsets of Spp1-expressing microglia and macrophages during neovascularization formation in angiogenesis mouse models. Notably, the number of Spp1-expressing microglia and macrophages exhibited further elevation during neovascularization in mice lacking myeloid SOCS3. Moreover, our investigation unveiled the Spp1 gene as a direct transcriptional target gene of signal transducer and activator of transcription 3. Importantly, pharmaceutical activation of SOCS3 or blocking of SPP1 resulted in a significant reduction in pathological neovascularization. In conclusion, our study highlights the pivotal role of the SOCS3/STAT3/SPP1 axis in the regulation of pathological retinal angiogenesis., Competing Interests: Declaration of interests Y.S. and T.W. are inventors on patent applications relating to this work filed by Boston Children’s Hospital., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Obesity induces insulin resistance and chronic inflammation, impacting human health. The relationship between obesity, gut microbiota, and regulatory mechanisms has been studied extensively. Dendrobium officinale polysaccharide (DOP), a traditional Chinese herbal medicine, potentially reduces insulin resistance. However, the mechanism through which DOP affects gut microbiota and alleviates obesity-induced insulin resistance in rats requires further investigation., Results: The current study aimed to assess the impact of DOP on gut microbiota and insulin resistance in rats on a high-fat diet. The results revealed that DOP effectively reduced blood lipids, glucose disorders, oxidative stress, and inflammatory infiltration in the liver of obese Sprague Dawley rats. This was achieved by downregulating SOCS3 expression and upregulating insulin receptor substrate-1 (IRS-1) by regulating the JAK/STAT/SOCS3 signaling pathway. Notably, DOP intervention enhanced the abundance of beneficial gut microbiota and reduced harmful microbiota. Correlation analysis demonstrated significant associations among intestinal microbiota, SOCS3-mediated IRS-1 expression, and inflammatory factors., Conclusion: Dendrobium officinale polysaccharide regulated the gut microbiota, enhanced IRS-1 expression, and mitigated liver injury and insulin resistance due to a high-fat diet. These findings depict the potential anti-insulin resistance properties of DOP and offer further evidence for addressing obesity and its complications. © 2023 Society of Chemical Industry., (© 2023 Society of Chemical Industry.)

Cyanogramide (AC14), a novel alkaloid, isolated from the fermentation broth of the marine-derived Actinoalloteichus cyanogriseus. However, the exact role of AC14 in inflammatory bowel disease (IBD) is poorly understood. Our results demonstrated that AC14 exhibited significant inhibition of IL-6 release in THP-1 cells and a "Caco-2/THP-1" coculture system after stimulation with LPS for 24 h. However, no significant effect on TNF-α production was observed. Furthermore, in 2.5 % DSS-induced colitis mice, AC14 treatment led to improvement in body weight, colon length, and intestine mucosal barrier integrity. AC14 also suppressed serum IL-6 production and modulated dysregulated microbiota in the mice. Mechanistically, AC14 was found to inhibit the phosphorylation of Janus kinase (JAK) 2 and signal transducers and activators of transcription (STAT) 3, while simultaneously elevating the expression of suppressor of cytokine signaling (SOCS) 3, both in vivo and in vitro. These findings suggest that AC14 exerts its suppressive effects on IL-6 production in DSS-induced IBD mice through the JAK2-STAT3-SOCS3 signaling pathway. Our study highlights the potential of AC14 as a therapeutic agent for the treatment of IBD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Impaired polarization of M1 to M2 macrophages has been reported in diabetic wounds. We aimed to improve this polarization by down-regulation of expression of the "Suppressor of Cytokine Signaling 3" (SOCS3) gene in macrophages. Two oligodeoxynucleotide (ASO) sequences were designed against SOC3 mRNA and were loaded to mannosylated-polyethyleneimine (Man-PEI). The optimum N/P ratio for Man-PEI-ASO was determined to be 8 based on loading efficiency, particle size, zeta potential, cellular uptake and cytotoxicity assay. pH stability of ASO in Man-PEI-ASO and its protection from DNase I was confirmed. After in vitro treatment of macrophages with Man-PEI-ASO, SOCS3 was downregulated, SOCS1 upregulated, and SOCS1/SOCS3 ratio increased. Also, expressions of macrophage markers of M2 (IL-10, Arg1, CD206) increased and those of M1 (IL-1β, NOS2, CD68) decreased, and secretion of pro-inflammatory cytokines (TNF-α and IL-1β) decreased while that of anti-inflammatory cytokine IL-4 increased. All suggested a polarization into M2 phenotype. Finally, the Man-PEI-ASO was loaded in hydrogel and applied to a diabetic wound model in mice. It improved the healing to the level observed in non-diabetic wounds. We show that using antisense sequences against SOC3 mRNA, macrophage polarization could be directed into the M2 phenotype and healing of diabetic wound could be highly improved., Competing Interests: Declaration of competing interest Samadikuchaksaraei and Amoupour are inventors and owners of a patent related to this project, which has been filed in the Iranian Intellectual Property Office, but has not been licensed yet. Samadikuchaksaraei is shareholder and CEO of Baztarmim Company, which is mainly focused on production of tissue engineering products. Other authors have no conflicts of interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Mycobacterium tuberculosis (Mtb) infection leads to upregulation of Suppressors of Cytokine signaling (SOCS) expression in host macrophages (Mϕ). SOCS proteins inhibit cytokine signaling by negatively regulating JAK/STAT. We investigated this host-pathogen dialectic at the level of transcription. We used phorbol-differentiated THP-1 Mϕ infected with Mtb to investigate preferential upregulation of some SOCS isoforms that are known to inhibit signaling by IFN-γ, IL-12, and IL-6. We examined time kinetics of likely transcription factors and signaling molecules upstream of SOCS transcription, and survival of intracellular Mtb following SOCS upregulation. Our results suggest a plausible mechanism that involves PGE2 secretion during infection to induce the PKA/CREB axis, culminating in nuclear translocation of C/EBPβ to induce expression of SOCS1. Mtb-infected Mϕ secreted IL-10, suggesting a mechanism of induction of STAT3, which may subsequently induce SOCS3. We provide evidence of temporal variation in SOCS isoform exspression and decay. Small-interfering RNA-mediated knockdown of SOCS1 and SOCS3 restored the pro-inflammatory milieu and reduced Mtb viability. In mice infected with Mtb, SOCS isoforms persisted across Days 28-85 post infection. Our results suggest that differential temporal regulation of SOCS isoforms by Mtb drives the host immune response towards a phenotype that facilitates the pathogen's survival., Competing Interests: Declaration of competing interest None of the authors have any conflict of interest to declare., (Copyright © 2023 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.)

Objectives: As a tumor suppressor gene, SOCS3 inhibits the growth of tumor cells by regulating JAK/STAT signaling pathway through negative feedback. This study aimed to investigate the biological function and mechanism of SOCS3 methylation mediated by DNMTs in the development of AML., Methods: Bone marrow samples were collected from 70 AML patients and 20 healthy volunteers. The expression and methylation status of each gene were detected by RT-qPCR, western blot and MS-PCR, and the growth and apoptosis rate of leukemia cell lines were detected by CCK-8 and flow cytometry. The effects of changes in SOCS3 gene expression and methylation status of AML cell lines were observed by gene transfection and gene knockdown., Results: The methylation rate of SOCS3 in AML initial treatment group was significantly higher than that in the remission group and the normal control group (60% vs. 0%, 0%). The expression of SOCS3 in the SOCS3 methylation group was significantly lower than that in the non-methylated group and control group, while the expression of DNMT1, DNMT3a, p-JAK2, p-STAT3 and p-STAT5 were significantly higher than those in the non-methylated group and control group. Demethylation treatment, SOCS3 transfection and DNMT3a knockdown could up-regulate the expression of SOCS3, which decreased the proliferation and increased the apoptosis of leukemia cell lines., Conclusion: SOCS3 methylation mediated by DNMTs promotes the occurrence and development of AML and can be used as a potential biomarker for the diagnosis and efficacy evaluation of AML., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Protein arginine methyltransferases (PRMTs) modulate diverse cellular processes, including stress responses. The present study explored the role of Prmt7 in protecting against menopause-associated cardiomyopathy. Mice with cardiac-specific Prmt7 ablation (cKO) exhibited sex-specific cardiomyopathy. Male cKO mice exhibited impaired cardiac function, myocardial hypertrophy, and interstitial fibrosis associated with increased oxidative stress. Interestingly, female cKO mice predominantly exhibited comparable phenotypes only after menopause or ovariectomy (OVX). Prmt7 inhibition in cardiomyocytes exacerbated doxorubicin (DOX)-induced oxidative stress and DNA double-strand breaks, along with apoptosis-related protein expression. Treatment with 17β-estradiol (E2) attenuated the DOX-induced decrease in Prmt7 expression in cardiomyocytes, and Prmt7 depletion abrogated the protective effect of E2 against DOX-induced cardiotoxicity. Transcriptome analysis of ovariectomized wild-type (WT) or cKO hearts and mechanical analysis of Prmt7-deficient cardiomyocytes demonstrated that Prmt7 is required for the control of the JAK/STAT signaling pathway by regulating the expression of suppressor of cytokine signaling 3 (Socs3), which is a negative feedback inhibitor of the JAK/STAT signaling pathway. These data indicate that Prmt7 has a sex-specific cardioprotective effect by regulating the JAK/STAT signaling pathway and, ultimately, may be a potential therapeutic tool for heart failure treatment depending on sex., (© 2024. The Author(s).)

Background: Polycystic ovary syndrome (PCOS) is a frequent and complicated endocrine disease that remains a major reason for infertility. Bushenhuoluo Decotion (BSHLD) has been validated to exhibit curative effects on PCOS. This study was aimed to explore the potential mechanism underlying the therapeutic action of BSHLD., Methods: PCOS rat model was induced by dehydroepiandrosterone (DHEA). Serum hormone and cytokines levels and ovarian pathological alterations were measured to assess ovarian function. Exosomes (Exos) were identified by Transmission electron microscopy and Nanoparticle Tracking Analysis. RT-qPCR, Western blotting, immunohistochemical staining, and immunofluorescence staining were performed to detect molecule expressions. Proliferation and pyroptosis of granulosa cells (GCs) were evaluated by CCK-8 and flow cytometry, respectively. The binding relationship between miR-30a-5p and suppressor of cytokine signaling 3 (SOCS3) was verified by dual luciferase reporter and RIP assays., Results: BSHLD treatment improved serum hormone abnormality, insulin sensitivity, and ovarian morphologic changes of PCOS rats. Moreover, BSHLD treatment restrained the excessive autophagy and pyroptosis in ovarian tissues of PCOS rats. Moreover, BSHLD reduced the expression of miR-30a-5p in serum, serum-derived Exos, and ovarian tissues, thus inhibiting autophagy and NLRP3-mediated pyroptosis in GCs. Mechanistically, SOCS3 was proved as a target of miR-30a-5p and could activate mTOR/P70S6K pathway to repress autophagy. The inhibitory effect of miR-30a-5p deficiency on autophagy and pyroptosis of GCs was attenuated by rapamycin., Conclusion: Collectively, BSHLD suppressed autophagy and pyroptosis to improve POCS by regulating exosomal miR-30a-5p/SOCS3/mTOR signaling., (© 2024. The Author(s).)

In vivo studies identifying a role of TLR2 in septic arthritis models are lacking. TNF-α played as the most important proinflammatory cytokine, and connected directly to the pathogenesis of bacterial arthritis. IL-1β is another central mediator cytokine in arthritis. It is therefore reasonable to question the role of neutralization of endogenous TNF-α and IL-1β along with TLR2 and associated downstream signaling as crucial mediators in the S. aureus -induced inflammatory arthritis. In reaction to an injury or a pathogen encounter, innate immune cells serve as the initial line of defense. TLR2 mediated entry of S. aureus into macrophage cells initiates an array of inflammatory cascades. After macrophage cell gets activated at the site inflammation, they generate elevated number of cytokines which includes TNF-α, IL-1β. This cytokines signals through STAT1/STAT3 mediated pathways. Thus, aim of this study was to discover how This bone damage could be altered by altering the STAT/STAT3/SOCS3 ratio by blocking TLR2, a particular S. aureus binding site, in conjunction with the use of IL-1 and TNF- antibodies for neutralizing endogenous IL-1β and TNF-α. Additionally, the role of local macrophages in therapy of arthritis was investigated in synovial and Splenic tissue. To comprehend the inflammatory milieu within the system, ROS and other antioxidant enzymes, along with the expression of mTOR in macrophage cells, were also taken into consideration. The detrimental impact of bacterial burden on synovial joints was reduced by simultaneously inhibiting TLR2, TNF-α, and IL-1β. Lowered IFN-γ decreases its sensitivity to STAT1 and lowered IL-6 reduces STAT3 expressions. Whereas, elevated IL-10 enhances SOSC3 expression, which thereby able to limits STAT1/STAT3 inter-conversion. As a result, NF-κB activity was downregulated., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Suppressor of cytokine signaling 3 (SOCS3) plays a significant role in the process of myocardial adaptation to chronic hypoxia. SOCS3 finely regulates cell signaling cross-talk that occurs between NF-κB and STAT3 during the compensatory protective response. However, the role and mechanism of SOCS3 in hypoxic cardiomyocytes are not fully understood. In the study, we investigated the effect of SOCS3 on the p65 and STAT3 signaling pathways and further examined the potential molecular mechanism involved in regulating apoptosis. Our data showed that SOCS3 silencing could upregulate Ac-p65, p-p65, and p-STAT3 expression in nuclear extracts of H9c2 cells that received hypoxic treatment for 24, 48, and 72 h. SOCS3 silencing also remarkably increased the DNA-binding activity of the p65 motif in hypoxic cultivated H9c2 cells. We also found that SOCS3 knockdown increased cleaved-caspase-3, Bax, and PUMA expression and decreased cleaved PARP and Bcl-2 in expression in hypoxic H9c2 cells. Silencing of SOCS3 caused an increase in LDH leakage from injured cardiomyocytes and reduced cell viability under conditions of hypoxic stress. Furthermore, SOCS3 silencing enhanced the apoptosis of H9c2 cells at 72 h of hypoxia. These findings suggest that knockdown of SOCS3 leads to excessive activation of the NF-κB pathway, which, in turn, might promote apoptosis under conditions of chronic hypoxia., (© 2023. The Author(s) under exclusive licence to University of Navarra.)

Liver cancer stem cells (LCSCs) contribute to tumor recurrence and cancer cell proliferation in patients with hepatocellular carcinoma (HCC). METTL3-catalyzed m 6 A modification is relevant to the cancer stem cell (CSC) phenotype, including LCSCs. LCSCs were isolated from MHCC-97H and HepG2 cells through flow cytometry. UALCAN data were used to analyze the expression of METTL3 in liver hepatocellular carcinoma (LIHC) tissues. Loss- and gain-of-function experiments were utilized to assess the biological effects of METTL3 and SOCS3 on the proliferation and stemness phenotypes in vitro and in vivo. The mechanisms underlying the impact of METTL3 were explored using qPCR, MeRIP-qPCR, dual-luciferase reporter, and western blot assays. METTL3 was significantly upregulated in LIHC tissues according to the UALCAN database. METTL3 was highly expressed in LIHC and was significantly correlated with individual cancer stage, tumor grade and lymph node metastasis. Patients with low METTL3 expression had a longer overall survival time based on the data from UALCAN. In addition, the level of METTL3 was enhanced in LCSCs and decreased in non-LCSCs compared to HCC cells. Moreover, overexpression of METTL3 stimulated the proliferation and stemness of LCSCs in vitro and in vivo, while loss of METTL3 impeded it. Bioinformatics analysis combined with validation experiments determined that m 6 A was modified by METTL3-targeting SOCS3 mRNA. METTL3 had side effects regarding the stability of SOCS3 mRNA. SOCS3 overexpression impaired and SOCS3 depletion facilitated the development of LCSCs via the JAK2/STAT3 pathway. Furthermore, METTL3 depletion suppressed proliferation and stemness in LCSCs, which was restored by SOCS3 knockdown or colivelin treatment. We discovered that METTL3 facilitated the stemness and tumorigenicity of LCSCs by modifying SOCS3 mRNA with m 6 A., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Establishing a balance between Th1 and Th2 subsets and M1- and M2-type macrophages is essential for the control of Leishmania infection. The suppressors of cytokine secretion (SOCS) proteins, particularly SOCS1 and SOCS3, play a significant role in regulating cytokine-triggered signaling pathways, thereby impacting the macrophage-and effector T-cell mediated antileishmanial immune response. In addition to the pro-inflammatory cytokines, Leishmania-derived lipophosphoglycan (LPG) and CpG-DNA interact with TLR2 and TLR9 to trigger SOCS expression. The aberrant levels of SOCS1 and SOCS3 expression in Leishmania-infected macrophages impair macrophage-T-cell interaction perturbing the balance in macrophage subsets polarization. This hinders macrophage apoptosis and macrophage-mediated leishmanicidal activity, both support the establishment of infection and parasite replication. Furthermore, aberrant SOCS3 levels in T-cells disrupt Th1 differentiation and aid in parasite replication, lesion development, and pathological immune responses. Strategically, selective modulation of SOCS expression and function in immune effector cells may reduce parasite survival and prevent disease progression., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Leptin resistance is induced via leptin signaling blockade by chronic overstimulation of the leptin receptor and intracellular signaling defect or increased hypothalamic inflammation and suppressor of cytokine signaling (SOCS)-3 expression. High-fat diet triggers leptin resistance induced by at least two independent causes: first, the limited ability of peripheral leptin to activate hypothalamic signaling transducers and activators of transcription (STAT) signaling and secondly a signaling defect in leptin-responsive hypothalamic neurons. Central leptin resistance is dependent on decreased leptin transport efficiency across the blood brain barrier (BBB) rather than hypothalamic leptin insensitivity. Since the hypothalamic phosphorylated STAT3 (pSTAT3) represents a sensitive and specific readout of leptin receptor-B signaling, the assessment of pSTAT3 levels is the gold standard. Hypertriglyceridemia is one of important factors to inhibit the transport of leptin across BBB in obesity. Mismatch between high leptin and the amount of leptin receptor expression in obesity triggers brain leptin resistance via increasing hypothalamic inflammation and SOCS-3 expression. Therapeutic strategies that regulate the passage of leptin to the brain include the development of modifications in the structure of leptin analogues as well as the synthesis of new leptin receptor agonists with increased BBB permeability. In the hyperleptinemic state, polyethylene glycol (PEG)-modified leptin is unable to pass through the BBB. Peripheral histone deacetylase (HDAC) 6 inhibitor, tubastatin, and metformin increase central leptin sensitization. While add-on therapy with anagliptin, metformin and miglitol reduce leptin concentrations, the use of long-acting leptin analogs, and exendin-4 lead to the recovery of leptin sensitivity. Contouring surgery with fat removal, and bariatric surgery independently of the type of surgery performed provide significant improvement in leptin concentrations. Although approaches to correcting leptin resistance have shown some success, no clinically effective application has been developed to date. Due to the impairment of central and peripheral leptin signaling, as well as the extensive integration of leptin-sensitive metabolic pathways with other neurons, the effectiveness of methods used to eliminate leptin resistance is extremely limited., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Background: LncRNAs perform a crucial impact on microglia's activation in Parkinson's disease (PD). Here, our purpose was to probe the function and involved mechanism of lncRNA SOX21-AS1 on microglial activation in PD., Methods: Mice were treated with MPTP, and BV2 cells were treated with LPS/ATP to build PD animal and cell models. Genes' expression was measured using RT-qPCR, immunoblotting, and IHC stain. ELISA was applied for testing inflammatory factors' levels. Cell viability and apoptosis were tested using kits. RIP and RNA pull-down assay were utilized for monitoring the bond of SOX21-AS1 to EZH2, and ChIP was applied for affirming the bond between EZH2 and SOCS3's promoter., Results: The expression of SOX21-AS1 and SOCS3 was abnormal in PD cell and animal models. Inhibition of SOX21-AS1 repressed LPS/ATP-induced activation in BV2 cells and nerve damage caused by activated BV2 cells, alleviating the pathological features of PD mice. Further studies found that SOX21-AS1 epigenetically inhibited SOCS3 by recruiting EZH2 to SOCS3 promoter. SOX21-AS1 overexpression partially offset the repressive impact of SOCS3 enhancement on BV2 cell activation and the protective effect on nerve cells., Conclusion: SOX21-AS1 enhances LPS/ATP-induced activation of BV2 cells and nerve damage caused by activated BV2 cells though recruiting EZH2 to SOCS3's promoter, thereby alleviating PD progression. Our research supplies new potential target for curing PD., (© 2024 S. Karger AG, Basel.)