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Synovial hyperplasia, a profound alteration in the structure of synovial tissue, is the basis for cumulative joint destruction in rheumatoid arthritis (RA). It is generally accepted that controlling synovial hyperplasia can delay the progression of RA. As one of the most intensively studied isoforms of acid-sensing ion channels (ASICs), ASIC1a contributes to various physiopathologic conditions, including RA, due to its unique property of being permeable to Ca2+. However, the role and the regulatory mechanisms of ASIC1a in synovial hyperplasia are poorly understood. Here, rats induced with adjuvant arthritis (AA) and human primary synovial fibroblasts were used in vivo and in vitro to investigate the role of ASIC1a in the proliferation of RA synovial fibroblasts (RASFs). The results show that the expression of ASIC1a was significantly increased in synovial tissues and RASFs obtained from patients with RA as well as in the synovium of rats with AA. Moreover, extracellular acidification improved the ability of RASFs colony formation and increased the expression of proliferation cell nuclear antigen (PCNA) and Ki67, which was abrogated by the specific ASIC1a inhibitor psalmotoxin-1 (PcTX-1) or ASIC1a-short hairpin RNA (ASIC1a-shRNA), suggesting that extracellular acidification promotes the proliferation of RASFs by activating ASIC1a. In addition, the activation of c-Raf and extracellular signal-regulated protein kinases (ERKs) signaling was blocked with PcTX-1 or ASIC1a-shRNA and the proliferation of RASFs was further inhibited by the ERK inhibitor (U0126), indicating that ERK/MAPK signaling contributes to the proliferation process of RASFs promoted by the activation of ASIC1a. These findings gave us an insight into the role of ASIC1a in the proliferation of RASFs, which may provide solid foundation for ASIC1a as a potential target in the treatment of RA.

Circular RNAs (circRNAs), a new class of endogenous non-coding RNAs (ncRNAs), are highly stable and exhibit tissue-specific expression. Accumulating evidence has indicated that circRNAs play crucial roles in the development and progression of multiple diseases. Notably, circRNAs, important epigenetic modulators of gene expression in inflammation and autoimmune regulation, have a close association with the pathogenesis of rheumatoid arthritis (RA). RA, one of the most common systemic autoimmune diseases, is characterized by synovial hyperplasia and inflammation, and cartilage and bone destruction. Here, we focus on the roles of circRNAs in macrophage, synovial tissues, fibroblast-like synoviocytes (FLSs), and cartilage tissues in pathogenesis and progression of RA, highlighting the potential of circRNAs in the blood as diagnostic biomarkers, and aiming at providing new insights into the diagnosis and therapy of this disease.

Nesfatin-1, a newly identified energy-regulating peptide, is widely expressed in the central and peripheral tissues, and has a variety of physiological activities. A large number of recent studies have shown that nesfatin-1 exhibits antioxidant, anti-inflammatory, and anti-apoptotic properties and is involved in the occurrence and progression of various diseases. This review summarizes current data focusing on the therapeutic effects of nesfatin-1 under different pathophysiological conditions and the mechanisms underlying its antioxidant, anti-inflammatory, and anti-apoptotic activities.

Highlights • Severe acute pancreatitis with SIRS and MODS causes high mortality. • First SAP concurrent with ruptured cerebral aneurysm case was reported in this article. • Inflammation-induced blood-brain barrier impairment leads to cerebrovascular injury. • Possible mechanism includes neuroinflammation and inflammation-induced vessel damage., Introduction With high incidence and mortality, severe acute pancreatitis (SAP) is an inflammatory disease of pancreas. When concurrent with systemic inflammatory response syndrome (SIRS), multiple organ failure syndrome (MODS) or pancreatic encephalopathy (PE), it will significantly augment the mortal rate. Herein, we report the first SAP case complicated with fatal rupture of cerebral aneurysm and pre-existing cerebral arteriovenous malformation; meanwhile, numerous examinations indicated the occurrence of SIRS and MODS. Case presentation A 34-year-old male was admitted for these complaints of fixed and continuous epigastric distending pain, nausea and vomiting for nearly 6 h after his greasy lunch. Imaging and experimental examinations indicated SAP concurrent with SIRS and MODS in this patient. Conventional therapies stabled him, but he developed unconscious for fatal rupture of cerebral aneurysm based on cerebral magnetic resonance imaging results. Subsequent treatments failed and this patient died from lethal systemic complications. Discussion After reviewed relevant literature in detail, we unveil the potential mechanisms in this case that systemic inflammation initiated by necrotic tissues of pancreas will disrupt blood-brain barrier (BBB), increase BBB permeability, trigger neuroinflammation and eventually damage cerebral vascular. Conclusion Therefore, to prevent lethal complications of PE or cerebral hemorrhage (CM) in severe pancreatitis, more attentions are recommended to be paid on identifying inflammation-induced brain dysfunction and applying prompt anti-inflammatory therapies.

Shuo Zhang,1 Genxiang Rong,2 Yayun Xu,3 Juehua Jing1 1Department of Orthopedics, The Second Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China; 2Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China; 3Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, People’s Republic of ChinaCorrespondence: Juehua JingDepartment of Orthopedics, The Second Affiliated Hospital of Anhui Medical University, 678 Furong Road, Hefei, Anhui, 230032, People’s Republic of ChinaEmail jjhhu@sina.comBackground: Adipocytokines have been proven to be involved in the progression of autoimmune diseases, including rheumatoid arthritis (RA). Nesfatin-1, a newly discovered adipokine, has recently been reported to possess potent anti-inflammatory, antiapoptotic, and antioxidative properties. However, its role in RA has not yet been reported. Therefore, this study aimed to determine nesfatin-1 levels in the synovium and synovial fluid (SF) of patients with RA and examine their correlation with clinical manifestations and proinflammatory cytokine levels.Methods: Synovium and SF samples were collected from patients with RA and non-RA patients during joint surgery. Immunohistochemistry was used to measure nesfatin-1 protein expression in the synovium. Enzyme-linked immunosorbent assay was used to measure nesfatin-1, interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) levels in the synovium and SF. Pearson correlation analysis was used to evaluate the correlations between nesfatin-1 levels, RA clinical features, and proinflammatory cytokines. The diagnostic value of synovium nesfatin-1 for RA was assessed using receiver operating characteristic (ROC) curve analysis.Results: The results showed that nesfatin-1, IL-1β, and TNF-α levels in the synovium were significantly higher in patients with RA than in controls, with age and body mass index as covariates. Moreover, the results of Pearson correlation analysis showed that nesfatin-1 levels were positively correlated with IL-1β and TNF-α levels in the synovium of patients with RA. Furthermore, there was a positive relationship between synovium nesfatin-1 levels and rheumatoid factor in patients with RA. Additionally, the results of the ROC curve analysis revealed an area under the curve of 0.733 with 77.5% sensitivity and 60.0% specificity for synovium nesfatin-1 in discriminating patients with RA from controls.Conclusion: These findings suggest that increased nesfatin-1 levels in the synovium may be associated with proinflammatory cytokines and RA severity.Keywords: rheumatoid arthritis, adipocytokine, nesfatin-1, synovium, synovial fluid, pro-inflammatory cytokines

The management of acute pancreatitis (AP) remains a challenge to clinicians worldwide for limited effective interventions. Retinoid orphan receptor gamma t (RORγt) is a therapeutic target for several diseases; however, it is unclear whether inhibiting RORγt can ameliorate AP. The relative expression of RORγt, IL-17 and IL-23 in the peripheral blood mononuclear cells of AP patients was measured by RT-PCR. An AP mouse model was induced by ceruletide, and SR1001 was injected before ceruletide administration. RORγt+ cells, T helper 17 cells (Th17), regulatory T cells (Tregs) and γδ T cells were assessed in the pancreas and spleen by flow cytometry. Higher RORγt expression in patients indicated the potential role of RORγt in AP progression. Analyses of the IL-17/IL-23 axis confirmed its role. SR1001 significantly alleviated AP histologically in the mouse model. Serum levels of amylase, IL-6, TNFalpha, IL-17 and IL-23 decreased upon SR1001 treatment. SR1001 selectively decreased the number of RORγt+, Th17, Tregs and γδ T cells in the pancreas but not the spleen. Collectively, these results showed that SR1001 exerted therapeutic effects on AP by suppressing IL-17-secreting Th17 and γδ T cells in the pancreas. Thus, SR1001 may be a promising drug for the treatment of AP in the clinic.

Acid-sensing ion channel 1a (ASIC1a) is a member of the extracellular H+-activated cation channel family. Emerging evidence has suggested that ASIC1a plays a crucial role in the pathogenesis of rheumatoid arthritis (RA). Specifically, ASIC1a could promote inflammation, synovial hyperplasia, articular cartilage, and bone destruction; these lead to the progression of RA, a chronic autoimmune disease characterized by chronic synovial inflammation and extra-articular lesions. In this review, we provided a brief overview of the molecular properties of ASIC1a, including the basic biological characteristics, tissue and cell distribution, channel blocker, and factors influencing the expression and function, and focused on the potential therapeutic targets of ASIC1a in RA and possible mechanisms of blocking ASIC1a to improve RA symptoms, such as regulation of apoptosis, autophagy, pyroptosis, and necroptosis of articular cartilage, and synovial inflammation and invasion of fibroblast-like cells in synovial tissue.

Liver Hepatocellular Carcinoma (LIHC) is the fifth widely occurred carcinoma, which is thought to be the second primary contributor of carcinoma-associated death. There are almost 788,000 death tolls worldwide. Solute carrier family 41 member 3 (SLC41A3) is a member of solute carrier family 41, and it is the key point of numerous researches. Our research attempted to explore the links between SLC41A3 and LIHC through public databases. Higher expression of SLC41A3 displayed an intimate association with higher pathological stages and poorer prognosis. GO and KEGG analysis revealed the possible regulatory pathways of SLC41A3. Additionally, we carried out cell functional experiments to determine the expression of SLC41A3 in the cell lines of LIHC, as well as the effects of its silence on cell proliferation, migration, and invasion. Our data showed that SLC41A3 was greatly increased in the cell lines of LIHC. Moreover, silencing SLC41A3 impeded LIHC cell proliferation, migration, and invasion in vitro. Collectively, our study demonstrated that highly expressed SLC41A3 was a probable indication of LIHC occurrence, and SLC41A3 could be regarded as a prospective target in the treatment of LIHC.

Xiaoyu Hang,1,2 Zhenyu Zhang,1,2 Ruowen Niu,1,2 Chen Wang,1,2 Jing Yao,1,2 Yayun Xu,1,2 Jingjing Tao,1,2 Lanlan Li,1,2 Feihu Chen1,2 1Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei, 230032, People’s Republic of China; 2The Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, 230032, People’s Republic of ChinaCorrespondence: Feihu ChenSchool of Pharmacy, Anhui Medical University, No. 81 Meishan Road, Hefei, 230032, Anhui Province, People’s Republic of ChinaTel/Fax +86 551651611166Email chenfeihu@ahmu.edu.cnPurpose: The severity of rheumatoid arthritis (RA) in women is generally lower than that in men. RA is mediated, at least in part, by the protective effects of estradiol. However, the mechanisms underlying the protective effect of estradiol on RA are still unclear. Recent studies have demonstrated that activation of acid-sensing ion channel 1a (ASIC1a) by tissue acidosis plays an important role in the injury of cartilage in RA. Here, we assessed the effects of estradiol on acid-mediated cartilage injury both in vitro and in vivo and explored the involvement of ASIC1a in RA and its underlying mechanism.Methods: Cultured primary articular chondrocytes were subjected to acidosis-mediated injury in vitro. Beclin1, LC3, p62, GPER1, and ASIC1a expression was detected through Western blotting, quantitative real-time PCR, and immunofluorescence analysis. Adjuvant arthritis (AA) was induced in rats through intradermal immunization by injecting 0.25 mL heat-killed mycobacteria (10 mg/mL) suspended in complete Freund’s adjuvant into the left hind metatarsal footpad. The levels of estrogen and related inflammatory factors in the serum were measured using enzyme-linked immunosorbent assay. The expression of ASIC1a and autophagy-related proteins was detected through immunohistochemical analysis and Western blot.Results: Treatment of primary articular chondrocytes with estradiol decreased the expression of ASIC1a and autophagy level. The symptoms of cartilage damage and levels of inflammatory cytokines in the serum were reduced after estradiol treatment in the rats with AA. In addition, estradiol treatment reduced ASIC1a expression via the PI3K-AKT-mTOR pathway, among which G-protein coupled estradiol receptor 1 (GPER1) plays a regulatory role. Finally, the level of autophagy in chondrocytes was decreased by the selective ASIC1a blocker psalmotoxin-1 (PCTX-1).Conclusion: Estradiol can protect the cartilage of rats with AA against acidosis-mediated damage and autophagy by suppressing ASIC1a expression through GPER1.Keywords: rheumatoid arthritis, estradiol, GPER1, ASIC1a, autophagy, PI3K-AKT-mTOR

Acid-sensing ion channels (ASICs) are members of the degenerin/epithelial sodium channel superfamily. They are extracellular pH sensors that are activated by protons. Among all ASICs, ASIC1a is one of the most intensively studied isoforms because of its unique ability to be permeable to Ca2+. In addition, it is considered to contribute to various pathophysiological conditions. As a membrane proton receptor, the number of ASIC1a present on the cell surface determines its physiological and pathological functions, and this number partially depends on protein synthesis, degradation, and membrane trafficking processes. Recently, several studies have shown that various factors affect these processes. Therefore, this review elucidated the major factors and underlying molecular mechanisms affecting ASIC1a protein expression and membrane trafficking.

Injury risk curves (IRCs) represent the quantification of risk of adverse outcomes, such as a bone fracture, quantified by a biomechanical metric such as force or deflection. From a biomechanical perspective, they are crucial in crashworthiness studies to advance human safety. In clinical settings, they can be used as an assistive tool to aid in the decision-making process for surgical or conservative treatment. The estimation of risk corresponding to a level of biomechanical metric is done using a regression technique, such as a parametric survival regression model. As with any statistical procedure, error measures are computed for the IRC, representing the quality of the estimated risk. For example, confidence intervals (CIs) are recommended by the International Standards Organization, and the normalized confidence interval width (NCIW) is computed based on the width of the CI. This is a surrogate for the quality of the risk curve. A 95% CI means that if the same experiment were hypothetically repeated 100 times, at least 95 of the computed CIs should contain the true risk curve. Such an interpretation is problematic in most biomechanical contexts as rarely the same experiment is repeated. The notion that a wider confidence interval implies a poorer quality risk curve can be misleading. This article considers the evaluation of CIs and its implications in biomechanical settings for safety engineering and clinical practice. Alternatives are suggested for future studies.

High mortality is associated with exclusively metastasis within the peritoneal cavity among patients with epithelial ovarian cancer that is the most lethal gynecologic cancer. There is an unmet need to develop more effective therapies to prevent metastasis of peritoneal cancer. Multicellular spheroid formation, during which cancer cells migrate and adhere to tumor-associated macrophages, is a critical step of ovarian cancer metastasis. Here, we showed that vitamin C inhibited spheroid formation and metastasis in ID8 ovarian cancer-bearing mice. We further found that vitamin C treatment decreased the levels of M2 macrophages in tumor nodules and suppressed the epithelial-mesenchymal transition (EMT). In vitro studies revealed that vitamin C inhibited proliferation, arrested cell cycle, attenuated migration, and prevented the spheroid formation of ID8 ovarian cancer cells. Vitamin C induced apoptosis of ID8 cells, which was confirmed by membrane potential collapse, cytosolic calcium overload, ATP depletion, and caspase-3 activation in vitamin C-treated cells. Intriguingly, vitamin C treatment caused striking morphological change and apoptosis of macrophages. The presented proof of concept study strategically identifies new anticancer mechanisms of vitamin C.

Objectives:Engaging in sexual risk behaviour can be a maladaptive strategy for international students to deal with stress. This study examined the role of poor mental health in mediating the relati...

The presence and extent of cribriform pattern of prostate cancer portend recurrence and cancer death. The relative expressions within this morphology of the prognostically adverse loss of PTEN, and the downstream inactivation of cell cycle inhibitor p27/Kip1 had been uncertain. In this study, we examined 52 cases of cribriform cancer by immunohistochemistry for PTEN, p27, and CD44 variant (v)7/8, and a subset of 17 cases by chromogenic in situ hybridization (ISH) using probes for PTEN or CDKN1B (gene for p27). The fractions of epithelial pixels positive by immunohistochemistry and ISH were digitally assessed for benign acini, high-grade prostatic intraepithelial neoplasia, and 8 morphologic patterns of cancer. Immunostaining results demonstrated that (1) PTEN loss was significant for fused small acini, cribriform-central cells, small cribriform acini, and Gleason grade 5 cells in comparison with other acini; (2) p27 loss was significant only for cribriform-peripheral cells and borderline significant for fused small acini in comparison with benign acini; and (3) CD44v7/8 showed expression loss in cribriform-peripheral cells; other comparisons were not significant. ISH showed that cribriform cancer had significant PTEN loss normalized to benign acini (P