Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is a systemic autoimmune disease characterized by significant renal involvement, yet identifying novel biomarkers for renal complications remains a clinical priority. Metrnl is a recently identified immunomodulatory cytokine implicated in inflammation, but its specific role in AAV has historically been unknown. To address this, this study investigated serum Metrnl levels via ELISA in 37 patients with microscopic polyangiitis (MPA), 17 with granulomatosis with polyangiitis (GPA), and 30 healthy controls (HCs), analysing correlations with clinical parameters such as the Birmingham Vasculitis Activity Score (BVAS) and renal function indicators under false discovery rate (FDR) correction. The results demonstrated that serum Metrnl levels were significantly elevated in both MPA and GPA patients compared to HCs and exhibited a strong positive correlation with BVAS in both subgroups. Crucially, following FDR adjustment, Metrnl levels showed significant correlations with key markers of renal impairment, including creatinine, cystatin C, and estimated glomerular filtration rate (eGFR). Stratification of MPA patients based on renal function (eGFR cut-off: 60 ml/min/1.73 m²) further revealed substantially higher Metrnl levels in those with impaired renal function. Receiver operating characteristic curve analysis indicated superior diagnostic efficacy for Metrnl in identifying AAV with renal involvement [area under the curve (AUC) = 0.8150] compared to diagnosing AAV overall (AUC = 0.7214). Collectively, these findings provide the first evidence that serum Metrnl is elevated in AAV and associated with disease activity and renal dysfunction, suggesting that Metrnl warrants further investigation as a potential biomarker for renal involvement in AAV.

Rheumatoid arthritis (RA), an autoimmune disease, is characterized by synovial hyperplasia, vascular occlusion, and bone erosion. Metrnl, a novel secreted protein linked to inflammatory immune regulation, has been implicated in RA pathogenesis, but its precise mechanisms remain undefined. This study aimed to elucidate Metrnl’s role in RA progression and therapeutic potential. Proteomic analysis was employed to assess Metrnl’s direct effects on RA fibroblast-like synoviocytes (RA-FLS). In vitro, LPS-induced RA-FLS were treated with Metrnl to evaluate proliferation, apoptosis, cell cycle progression, and expression of inflammatory cytokines (IL-6, IL-17, TNF-α) and angiogenic factors (PDGF, VEGF) via PPARγ signaling. Collagen-induced arthritis (CIA) mice models were established to validate therapeutic efficacy, with Micro-CT and histology quantifying joint damage and inflammation. Proteomics results indicated Metrnl’s multidirectional role in coordinating vascular homeostasis and immune-inflammatory network activation. Molecular biological results showed that Metrnl suppressed proliferation, promoted apoptosis, and downregulated IL-6, IL-17, TNF-α, PDGF, and VEGF through PPARγ in LPS-induced RA-FLS cells. In CIA mice, Metrnl mitigated weight loss, reduced swollen joints, and improved behavioral scores. Micro-CT confirmed attenuated cartilage/bone destruction and joint deformities, while histology revealed diminished inflammatory infiltration. Metrnl exerts anti-inflammatory and anti-angiogenic effects in RA by modulating PPARγ signaling, highlighting its dual role in suppressing synovitis and vascular remodeling. These findings propose Metrnl as a novel therapeutic target to impede RA progression, offering insights into its pathological mechanisms. Furthermore, Metrnl mitigates bone erosion and joint deformities, underscoring its broader translational potential for treating bone-related disorders.

Objective:To synthesize current evidence on the bidirectional regulatory mechanisms of the Brain-Gut-Microbiota Axis (BGMA), its perturbation by external factors, and its clinical implications for neurodegenerative, psychiatric, metabolic, and gastrointestinal disorders. Design:Narrative review integrating preclinical and clinical evidence. Data sources:PubMed/Medline, EMBASE, Cochrane Library searches (2000-2023) using keywords: "brain-gut-axis," "microbiota," "dysbiosis," "neuroinflammation," "SCFAs," "neurodegeneration," "psychobiotics." Results:Diet, stress, antibiotics, and environment significantly alter gut microbiota composition (e.g., reducing diversity, shifting Firmicutes/Bacteroidetes (F/B) ratio). Dysbiosis disrupts BGMA communication via: (1) Neural pathways (vagus nerve modulation); (2) Immune activation (cytokine release, neuroinflammation); (3) Microbial metabolites (SCFAs, tryptophan derivatives, TMAO). These disruptions are associated with Alzheimer's disease (reduced Faecalibacterium, amyloid deposition), Parkinson's (elevated TMAO, α-synuclein aggregation), and depression (altered serotonin synthesis), though causality remains to be established in human studies. Conclusion:The BGMA is a critical mediator of systemic health. Dysbiosis contributes to disease pathogenesis through defined neural, immune, and metabolic pathways. Targeting the microbiota offers novel therapeutic strategies. Future research must prioritize translational studies validating microbial biomarkers and interventions in human cohorts.

Background:Ankylosing spondylitis (AS) is an autoimmune disease characterized by bone destruction and abnormal remodeling. Metrnl, a secreted protein involved in inflammation and immune regulation, has recently been linked to bone growth. This study aimed to evaluate serum Metrnl levels in AS patients and explore its bone regulatory mechanisms using cell models and multi-omics analyses. Methods:A total of 275 participants aged 16-60 years were included to measure serum Metrnl levels using Enzyme-Linked-Immunosorbent Assay (ELISA). Correlation and receiver operating characteristic (ROC) curve analyses assessed the diagnostic and predictive value of Metrnl. Mouse pre-osteoblastic MC3T3-E1 cells were treated with recombinant Metrnl (0/10/50 ng/mL) during 28-day osteogenic differentiation. RT-qPCR and alkaline phosphatase (ALP)/Alizarin Red S (ARS) staining was used to evaluate direct osteogenic differentiation effects. Transcriptomic and proteomic studies were conducted to further explore bone metabolism mechanisms. Finally, multi-omics integration analyses identified key pathways and targets. Results:Elevated serum Metrnl levels correlated directly with disease activity markers (CRP, ESR, IL-6) in AS-Active patients, but not in AS-Stable patients. ROC analysis validated Metrnl as a potential auxiliary diagnostic biomarker for high disease activity. In vitro, Metrnl suppressed ALP/OCN expression without altering overall osteogenic differentiation. Transcriptomic and proteomic analyses revealed Metrnl's regulatory effects on osteogenic genes and proteins, emphasizing its role in bone and cartilage development. Bioinformatics highlighted Metrnl's inhibition of endochondral ossification, delaying cartilage development and promoting osteoclast differentiation. Multi-omics integration identified Aspn and Sp7 as key targets in bone remodeling and resorption balance. Conclusions:Metrnl may serve as an additional diagnostic biomarker for AS and as an indicator for monitoring AS disease activity. Besides, Metrnl plays a critical role in regulating cartilage and bone metabolism and maintaining bone homeostasis, providing new insights for the future diagnosis and treatment of bone-related diseases.

Chronic ethanol exposure (CEE) is acknowledged as a significant risk element for cognitive decline and depression, with NLRP3-related neuroinflammation identified as a crucial mechanism driving depression-like behaviors and cognitive impairment induced by CEE. Here, TLR3 is identified as a priming signal that activates NLRP3 inflammasome triggered by CEE via NF-κB p65 nuclear translocation in astrocytes. CEE-induced neuroinflammation, depressive-like behavior and cognitive impairment are alleviated by downregulation of TLR3. Mechanistically, TOLLIP, a negative regulator of TLR3 pathway, is a target gene of RUNX1, a critical transcription factor associated with inflammation. Therefore, CEE triggers NLRP3-related neuroinflammation, cognitive impairment and depressive-like behavior via RUNX1/TOLLIP/TLR3/p65 axis. Neuronal damage serves as the pathological foundation for mental disorders and is closely associated with neuroinflammatory processes. Most TLR3 in the brain is expressed in the astrocytes. Neuronal damage induced by ethanol exposure is alleviated when inflammatory reactions of astrocytes are suppressed by the inhibition of TLR3 pathway. Thus, the study offers significant insights into CEE-induced neuroinflammation and neuronal damage, as well as the relationship between these two phenomena, and offers potential therapeutic strategies.

BACKGROUND:Probiotics can colonize both the human and animal bodies and consist of active microorganisms that are beneficial to health. The use of probiotics has been shown to alleviate certain neurological diseases and disturbances in gut microbiota resulting from chronic ethanol exposure. Research indicates that probiotics can influence the nervous system via the microbial-gut-brain axis, wherein extracellular vesicles secreted by the gut microbiota play a significant role in this process. RESULTS:In this study, we first established a 30-day ethanol exposure and probiotic gavage mouse model, both of which influenced behavior and the composition of gut microbiota. We then extracted gut microbiota-derived extracellular vesicles from the feces of these model mice and injected them into new mice via the tail vein to assess the role of each set of extracellular vesicles. The results indicated that the extracellular vesicles derived from the intestinal microbiota in the ethanol group induced anxiety-like behavior and hippocampal neuroinflammation in the recipient mice. In contrast, the extracellular vesicles secreted by the gut microbiota from the probiotic group mitigated the anxiety-like behavior and neuroinflammation induced by ethanol-influenced extracellular vesicles. CONCLUSIONS:Our study demonstrates that extracellular vesicles secreted by the gut microbiota can influence the nervous system via the microbial-gut-brain axis. Furthermore, we found that the extracellular vesicles secreted by the gut microbiota from the probiotic group exert a beneficial therapeutic effect on anxiety and hippocampal neuroinflammation.

Rheumatoid arthritis (RA) is a chronic autoimmune disease. Its pathological features include synovial inflammation, bone erosion, and joint structural damage. Our previous studies have shown that interleukin (IL)-35 is involved in the pathogenesis of bone loss in RA patients. In this study, we are further evaluating the efficacy of IL-35 on collagen-induced arthritis (CIA) in the mouse model. Male DBA/1J mice (n = 10) were initially immunized, 2 μg/mouse IL-35 was injected intraperitoneally every week for 3 weeks after the establishment of the CIA model. Clinical arthritis, histopathological analysis, and three-dimensional micro‑computed tomography (3D micro‑CT) were determined after the mice were anesthetized on the 42th day. In vitro, RANKL/M-CSF induced mouse preosteoclasts (RAW264.7 cells line) was subjected to antiarthritis mechanism study in the presence of IL-35. The results of clinical arthritis, histopathological analysis, and 3D micro‑CT, the expression of RANK/RANKL/OPG axis, inflammatory cytokines, and osteoclastogenesis-related makers demonstrated decreasing severity of synovitis and bone destruction in the ankle joints after IL-35 treatment. Furthermore, IL-35 attenuated inflammatory cytokine production and the expression of osteoclastogenesis-related makers in a mouse preosteoclasts cell line RAW264.7. The osteoclastogenesis-related makers were significantly reduced in IL-35 treated RAW264.7 cells line after blockage with the JAK/STAT1 signaling pathway. These results demonstrated that IL-35 protein could inhibits osteoclastogenesis and attenuates CIA in mice. We concluded that IL-35 can exhibit anti-osteoclastogenesis effects by reducing the expression of inflammatory cytokines and osteoclastogenesis-related makers, thus alleviating bone destruction in the ankle joint and could be a potential therapeutic target for RA.

BACKGROUND:Chronic ethanol exposure (CEE) is recognized as an important risk factor for depression, and the gut-brain axis has emerged as a key mechanism underlying chronic ethanol exposure-induced anxiety and depression-like behaviors. Short-chain fatty acids (SCFAs), which are the key metabolites generated by gut microbiota from insoluble dietary fiber, exert protective roles on the central nervous system, including the reduction of neuroinflammation. However, the link between gut microbial disturbances caused by chronic ethanol exposure, production of SCFAs, and anxiety and depression-like behaviors remains unclear. METHODS:Initially, a 90-day chronic ethanol exposure model was established, followed by fecal microbiota transplantation model, which was supplemented with SCFAs via gavage. Anxiety and depression-like behaviors were determined by open field test, forced swim test, and elevated plus-maze. Serum and intestinal SCFAs levels were quantified using GC-MS. Changes in related indicators, including the intestinal barrier, intestinal inflammation, neuroinflammation, neurotrophy, and nerve damage, were detected using Western blotting, immunofluorescence, and Nissl staining. RESULTS:Chronic ethanol exposure disrupted with gut microbial homeostasis, reduced the production of SCFAs, and led to anxiety and depression-like behaviors. Recipient mice transplanted with fecal microbiota that had been affected by chronic ethanol exposure exhibited impaired intestinal structure and function, low levels of SCFAs, intestinal inflammation, activation of neuroinflammation, a compromised blood-brain barrier, neurotrophic defects, alterations in the GABA system, anxiety and depression-like behaviors. Notably, the negative effects observed in these recipient mice were significantly alleviated through the supplementation of SCFAs. CONCLUSION:SCFAs not only mitigate damage to intestinal structure and function but also alleviate various lesions in the central nervous system, such as neuroinflammation, and reduce anxiety and depression-like behaviors, which were triggered by transplantation with fecal microbiota that had been affected by chronic ethanol exposure, adding more support that SCFAs serve as a bridge between the gut and the brain.

The thermal errors (TE) of computer numerical control (CNC) in workshop production seriously reduces the productivity. Therefore, to improve the productivity of CNC and enhance production intelligence, an improved adaptive TE compensation model (TECM) is proposed. The model is based on an online temperature measurement system (OTMS), which improves the adaptive learning rate of back-propagation neural network (BPNN) for temperature prediction. Finally, the correlation value between temperature changes and TEs is used for thermal error compensation. The performance verification of the model shows that the proposed OTMS can achieve effective temperature acquisition and processing, and the prediction ability of the improved BPNN is significantly higher than that of other prediction algorithms. Finally, it is found in the test that the improved adaptive TECM can reduce the contour error of workpiece machining to within 0.02×10 -3 mm, the machining accuracy of CNC is significantly improved. The above results show that using the improved adaptive TECM can promote the intelligent development of CNC and improve their machining accuracy, which is of great significance to the development of workshop manufacturing.

Meteorin-like, also known as Metrnl, Meteorin-β, Subfatin, and Cometin, is a novel secreted protein exerting pleiotropic effects on inflammation, immunology, and metabolism. Earlier research on this hormone focused on regulating energy expenditure and glucose homeostasis. Consequently, several studies attempted to characterize the molecule mechanism of Metrnl in glucose metabolism and obesity-related disorders but reported contradictory clinical results. Recent studies gradually noticed its multiple protective functions in inflammatory immune regulations and cardiometabolic diseases, such as inducing macrophage activation, angiogenesis, tissue remodeling, bone formation, and preventing dyslipidemias. A comprehensive understanding of this novel protein is essential to identify its significance as a potential therapeutic drug or a biomarker of certain diseases. In this review, we present the current knowledge on the physiology of Metrnl and its roles in inflammation, immunology, and metabolism, including animal/cell interventional preclinical studies and human clinical studies. We also describe controversies regarding the data of circulation Metrnl in different disease states to determine its clinical application better.

The microbiota-gut-brain axis is a bidirectional regulatory pathway between the brain and the gastrointestinal tract, which plays an important role in maintain homeostasis. Gut microbiota could influence the behavior, cognition, stress response and others via the axis. Depression is a complex psychiatric disease, giving rise to heavy social health and economic burden. In recent years, studies have shown that the gut microbiota are closely linked to the pathophysiological processes of depression. In this article, the interaction and its underlying mechanisms between depression and gut microbiota were summarized.

Ethanol, also known as alcohol, is one of the most common drinks in the world. Chronic ethanol exposure has been reported to induce mental disorders. Ethanol also has a strong effect on the gut microbiota. The gut microbiota has been reported to affect the brain via multiple pathways, including changes in γ-aminobutyric acid (GABA) system, and cause a variety of mental disorders. The GABA system in the cortex is associated with anxiety. However, the role of gut microbiota played in ethanol exposure-induced changes in the GABA system and anxiety is still not clear. We established a 30-day ethanol exposure mouse model and investigated the effects of microbiota using the antibiotic minocycline. Minocycline alleviated ethanol-induced anxiety-like behaviour, dysbiosis of microbiota, intestinal barrier disruption, increased serum endotoxin and interleukin (IL)-6. Minocycline also attenuated ethanol-induced apoptosis and decreased expression of glutamate decarboxylases (GADs) and GABRA1 in the prefrontal cortex. Our results indicated that gut microbiota plays an important role in ethanol-induced anxiety-like behaviour by altering the function of GABA system. In addition, causal mediation analysis showed that endotoxin and IL-6 may mediate the connection between the gut microbiota and the expression of GABAA receptor in the prefrontal cortex.

BackgroundMeteorin-like (Metrnl) is a novel adipokine that is highly expressed in white adipose tissues. Whether Metrnl plays a role in rheumatoid arthritis (RA) remains unclear. In this study, sera from 159 RA patients, 28 osteoarthritis (OA) patients, and 50 healthy individuals were included. The serum levels of Metrnl were measured using an enzyme-linked immunosorbent assay. Clinical parameters, including disease activity score 28 (DAS28), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), rheumatoid factor (RF), antibodies to cyclic citrulline peptide (anti-CCP), inflammatory cytokines, and blood biochemical indices were collected.ResultsMetrnl levels were higher in RA patients compared to OA patients and controls. In the RA group, serum Metrnl levels were positively correlated with DAS28, RF, and CRP levels. However, in the RA group, serum Metrnl levels were not correlated with ESR, anti-CCP, immunoglobulins, and blood biochemical indices.ConclusionThis study showed that Metrnl is involved in the pathogenesis of RA. Increase in serum Metrnl levels is closely related to RA activity.

Chronic ethanol exposure (CEE), which can lead to neuroinflammation, is an increasing risk factor for depression disorder, but the underlying mechanism is not clear. Recent observations have revealed the associations among psychiatric disorders, ethanol exposure and alterations of the gut microbiota. Here, we found that CEE induced depressive-like behavior, which could be alleviated by probiotics and transferred from donor to recipient mice by fecal microbiota transplantation (FMT). Neuroinflammation and the activation of the NLRP3 inflammasome were also observed in recipient mice. The downregulation of NLRP3 in the hippocampus mitigated CEE-induced depressive-like behavior and neuroinflammation but had no significant effect on FMT recipient mice. Moreover, elevated serum inflammatory factors in recipient mice showed a significant mediation effect between the gut microbiota and depressive-like behavior. Together, our study findings indicate that the gut microbiota contributes to both hippocampal NLRP3-mediated neuroinflammation and depressive-like behavior induced by CEE, which may open avenues for potential interventions against CEE-associated psychiatric disorders.

Chronic ethanol exposure (CEE) is associated with greater neurodegenerative effects and an increased risk of depression disorder. The AMPAR is thought to be involved in depression and a reduction in its GluA1 subunit was observed in the mouse hippocampus after CEE. AMPAkines are positive allosteric modulators of the AMPA receptor and have improved depressive-like behavior. However, the role of AMPARs in CEE-induced depressive-like behavior is not clear. It is unclear whether AMPAkines, positive allosteric agonists of AMPARs, protect against ethanol-induced depression. We investigated the effects of CX516 on ethanol-induced depressive-like behavior in a mouse model. CX516 (5 mg/kg) administration alleviated 20% (m/V) ethanol-induced depressive-like behavior in mice. Furthermore, CX516 significantly diminished the inhibition of the ERK1/2-BDNF-TrkB pathway in the hippocampus of ethanol-exposed mice. In addition, CX516 attenuated the levels of pro-inflammatory (IL-6, IL-1β), apoptosis (BAX, BCL-2), and neurodegeneration (FJC) in the mouse hippocampus induced by CEE.

Background: Angiogenesis associates with chondrocytes differentiation in inflammatory arthritis. Interleukin (IL)- 1 beta stimulated SW1353 cells have a phenotype similar to this kind of chondrocytes. IL-17A, a target in T helper 17 (Th17)/IL-17 signaling pathways, was expressed by SW1353 cells. The study aimed to explore the role of IL-35 on angiogenesis in IL-1 beta stimulated SW1353 cells and its related signaling pathways. Methods: Microarray dataset was downloaded from the Gene Expression Omnibus database of arthritis cartilage. The protein-protein interaction (PPI) was analyzed for IL-35, pro-angiogenic factors and the differentially expressed genes (DEGs). We studied the effects of IL-35 on proliferation and apoptosis in IL-1 beta stimulated SW1353 cells using cell counting kit-8 (CCK-8) assay and flow cytometry. The expression of pro-angiogenic factors and IL-17A were assessed by western blot and real-time PCR. Added plumbagin (inhibitor of IL-17A) to repeat the above experiment. The secretion of IL-17A was assessed by ELISA. Results: IL-35, pro-angiogenic factors interacted with DEGs to affect the function of arthritis chondrocytes. IL-35 promoted IL-1 beta-stimulated SW1353 cells proliferation, inhibited apoptosis, and decreased pro-angiogenic molecules and IL-17A expression in a concentration dependent manner. IL-35 inhibited IL-17A secretion in the supernatants of these cells. Blocking the Th17/IL-17 related pathways with plumbagin abolished the effects of IL-35 on IL-1 beta-stimulated SW1353 cells. Conclusion: These results suggested that IL-35 regulated differentiation and pro-angiogenic molecules expression in IL-1 beta stimulated SW1353 cells via Th17/IL-17 related signaling pathways. Our findings may reveal the mechanisms of novel angiogenesis molecules in inflammatory chondrocyte lesion.

Objective Osteoporosis is a common metabolic bone disease mainly involving bone remodeling and blood vessels. The current study aimed to explore the suppressive role of interleukin (IL)-35 in nuclear factor kappa-B ligand receptor activator (RANKL) and macrophage colony stimulating factor (M-CSF)-induced osteoclastogenesis and angiogenesis in osteoclasts. Methods Osteoclasts differentiation were induced by incubation of mouse leukemic monocyte/macrophage cell line RAW264.7 cells in the presence of RANKL and M-CSF and was assessed with tartrate-resistant acid phosphatase (TRAP) staining assay. The viability and apoptosis of RAW264.7 was measured using CCK-8 assay and flow cytometry, respectively. The expression of angiogenic genes and proteins were measured using RT-PCR, Western blots and ELISA. The inhibition of Th17/IL-17 axis was examined using plumbagin, which was demonstrated as an IL-17A related signaling pathway inhibitor. Results IL-35 inhibited the viability of RAW264.7 cells and promoted the apoptosis of RAW264.7 cells in a dose-dependent manner. Furthermore, IL-35 dose-dependently suppressed the expression of angiogenic markers including VEGF and its receptor. The suppressive effect of IL-35 was confirmed through the activation of Th17/IL-17 axis. Conclusions We demonstrated for the first time the immuno-suppressive function of IL-35 on RANKL and M-CSF-induced osteoclastogenesis and angiogenesis through Th17/IL-17 axis. Therapeutic approach involving augmentation of IL-35 regulatory response may serve as a novel treatment option for osteoporosis, especially by suppressing bone resorption and angiogenesis.

We aimed to investigate the effects of interleukin (IL)-35 on proangiogenic factors in IL-1β-pretreated chondrocyte-like SW1353 cells and screen-related genes that participated in osteoarthritis (OA) cartilage with IL-35, proangiogenic factors, and P38 mitogen-activated protein kinase (MAPK) signaling pathway. Different concentrations of IL-35 incubated with IL-1β stimulated SW1353 cells with or without SB203580 (inhibitor of P38 MAPK). Proangiogenic molecule expression was assessed by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Microarray datasets were downloaded from the Gene Expression Omnibus database of OA cartilage. Protein-protein interaction of genes was visualized by Search Tool for the Retrieval Interacting Genes and Cytoscape. Database for Annotation, Visualization, and Integrated Discovery was used to screen biological processes and pathways. IL-35 inhibited mRNA expression of proangiogenic factors in IL-1β-stimulated SW1353 cells through the P38 MAPK signaling pathway. IL-35 inhibited angiopoietin-2 secretion. We found that 8 related genes, 18 biological processes, and 6 pathways may associate with IL-35, P38 MAPK signaling pathway, and cartilage angiogenesis. IL-35 regulated the expression of proangiogenic factors through P38 MAPK signaling pathway in IL-1β-stimulated SW1353 cells. IL-35 and P38 MAPK pathway may participate in neovascularization of cartilage. Our findings may provide molecular mechanisms and possible genes target treatment for OA.

Chronic ethanol exposure can increase the risk of depression. The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor is a key factor in depression and its treatment. The study was conducted to investigate the depressive-like behavior induced by chronic ethanol exposure in mice and to explore the mechanism in cells. To establish the chronic ethanol exposure mouse model, male C57BL/6 N mice were administered 10% (m/V) and 20% (m/V) ethanol as the only choice for drinking for 60 days, 90 days and 180 days. Depressive-like behavior in mice was confirmed by the forced swimming test (FST). Ethanol-induced changes in the mouse hippocampus were indicated by Western blotting, qPCR and Fluoro-Jade C (FJC) staining. We confirmed that 90- and 180-day ethanol exposure can lead to depressive-like mouse behavior, cell apoptosis, neuronal degeneration, a reduction in GluA1 and brain-derived neurotrophic factor (BDNF) expression, and an increase in IL-6 and IL-1 beta in the mouse hippocampus. GluA1 silencing and overexpression models of SH-SY5Y cells were established for further investigation. The cells were treated with 100 mM and 200 mM ethanol for 24 h. Ethanol exposure decreased cell viability and the expression of BDNF and increased the cell apoptosis rate and the expression of BAX, cleaved caspase-3, IL-1 beta and IL-6. GluA1 silencing aggravated ethanol-induced changes in cell viability and apoptosis and the expression of BDNF, BAX and cleaved caspase-3, and GluA1 overexpression attenuated these changes. Neither the silencing nor overexpression of GluA1 had an effect on ethanol-induced increases in IL-1 beta and IL-6. Our results indicated that chronic ethanol exposure induced depressive-like behavior in male C57BL/6 N mice by downregulating GluA1 expression.

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by proliferation and insufficient apoptosis of fibroblast-like synoviocytes (FLSs).The biology and functions of interleukin (IL)-34 are only beginning to be uncovered. We previously demonstrated IL-34 could upregulate the expression of IL-17 in RA patients. In this study, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry of Annexin V and PI staining were performed to assess cell proliferation and apoptosis progression in RA-FLSs after stimulated with increasing concentrations of IL-34, respectively. Inflammatory cytokines and angiogenic factors were measured using quantitative real-time PCR, Western blotting and ELISA. We explored the association between IL-34 and RA-FLS proliferation and apoptosis in the context of RA. Stimulating RA-FLSs with different concentrations of IL-34 significantly promoted the proliferation and inhibited the apoptosis of RA-FLSs in a concentration-dependent manner. Neutralization of IL-17 with the IL-17 inhibitor plumbagin (PB) reduced the effects of IL-34. Proinflammatory cytokine (IL-17A IL-6 and tumor necrosis factor-α, TNF-α) and angiogenic factor (vascular endothelial growth factor, VEGF and hypoxia-inducible factor-1α, HIF-1α) expression was markedly upregulated in RA-FLSs stimulated by IL-34. PB-mediated inhibition of IL-17A also decreased the expression of IL-6, TNF-α, HIF-1α and VEGF in RA-FLSs. Taken together, these findings suggest that targeting IL-34 production in RA-FLSs may be a therapeutic strategy for RA.