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Abstract Background Chronic graft-versus-host disease (cGVHD) is an immune-related disorder that is the most common complication post-allogenic hematopoietic stem cell transplant. Corticosteroids with or without calcineurin inhibitors (CNIs) remain the mainstay of cGVHD treatment for first-line therapy. However, for many patients, cGVHD symptoms cannot be effectively managed and thus require second-line therapy. Currently, there is no approved treatment for second-line cGVHD treatment in China. In this study, belumosudil, a highly selective and potent rho-associated coiled-coil-containing protein kinase-2 inhibitor demonstrated to be effective for cGVHD in the United States and other Western countries, is investigated in patients with cGVHD in China for its overall benefit–risk balance. Methods This multicenter, open-label phase II study evaluated the safety, efficacy, and pharmacokinetics of oral belumosudil 200 mg once daily in cGVHD patients who had been treated with at least one line of systemic therapy in China. The primary endpoint was overall response rate (ORR); each individual patient’s response was assessed by the investigator using the 2014 National Institutes of Health consensus criteria. Secondary endpoints were duration of response (DOR), time to response (TTR), changes in Lee Symptom Scale (LSS) score, organ response rate, corticosteroid dose change, CNI dose change, failure-free survival, time-to-next-treatment, overall survival, and safety. Results Thirty patients were enrolled in the study with a median follow-up time of 12.9 months. ORR was 73.3% (95% confidence interval: 54.1–87.7%) and all responders achieved partial response. Median DOR among responders was not reached and median TTR was 4.3 weeks (range: 3.9–48.1). Fifteen patients (50.0%) achieved clinically meaningful response in terms of reduction in LSS score by ≥ 7 points from baseline. Corticosteroid and CNI dose reductions were reported in 56.7% (17/30) and 35.0% (7/20) of patients, respectively. Most treatment-emergent adverse events (TEAEs) were mild to moderate in severity, with 11 patients (36.7%) experiencing grade ≥ 3 TEAEs. The most common grade ≥ 3 TEAE was pneumonia (n = 5, 16.7%). Conclusions Belumosudil treatment demonstrated a favorable benefit–risk balance in treating cGVHD patients who previously have had standard corticosteroid therapy in China where approved second-line setting is absent. Trial registration ClinicalTrials.gov identifier NCT04930562.

Objective To detect the expressions of X-box binding protein 1 unspliced （xbp1u） and X-box binding protein 1 spliced （xbp1s） mRNA in peripheral blood CD19+B cells of patients with lupus nephritis （LN） and healthy subjects and explore the clinical significance of XBP1 in LN patients. Methods The expression levels of xbp1u and xbp1s in peripheral blood CD19+B cells of 65 LN patients and 30 healthy controls were detected by real-time polymerase chain reaction （RT-PCR）. And the ratio of CD19−CD138+plasma cells/CD19+B cells in peripheral blood was detected by flow cytometry. Results The expression level of xbp1u mRNA in CD19+B cells of active LN group （0.078±0.034） was higher than that in control group（0.035±0.011）（P＜0.05） and in stable group（0.049±0.016）（P＜0.05）. The expression level of xbp1s mRNA in CD19+B cells of active LN group（0.076±0.037）was higher than that in control group（0.022±0.010）（P＜0.05） and stable group（0.043±0.017）（P＜0.05）. The ratio of CD19−CD138+ plasma cells /CD19+B cells in LN group（0.059±0.024）was significantly higher than that in control group （P＜0.01） and stable group （0.073±0.036）（P＜0.05）; XBP1 expression in LN patients was correlated positively with the ratio of CD19−CD138+ plasma cells/CD19+B cells （r value = 0.138 & 0.036）, positively with anti-ds-DNA antibody and systemic lupus erythematosus disease activity index（SLEDAI）score （r value = 0.417 & 0.058） and negatively with hemoglobin and complement C3 （r value = −0.559 & −0.219）. Conclusion The expressions of xbp1u and xbp1s mRNA in peripheral blood mononuclear cells of LN patients in active group are higher than those in healthy group. Both are correlated positively with SLEDAI score and anti-DS DNA antibody. The expression of XBP1 is up-regulated in B cells of LN patients and it is significantly correlated with plasma cells. It implies that XBP1 may participate in the pathogenesis of LN through promoting the differentiation of B cells.

Purpose: To investigate the clinical effects of arthroscopically artificial ligament reconstruction with tensional remnant-repair in patients who are obese, and/or with demand for highly intensive sports, and/or with poor-quality ligament remnants. Methods: A retrospective case series study was performed on patients treated by arthroscopically anterior talofibular ligament (ATFL) reconstruction with tensional remnant repair technique from January 2019 to August 2021. General data, including demographics, surgical time, and postoperative adverse events, were recorded. The American Orthopaedic Foot and Ankle Society score (AOFAS), foot and ankle ability measure (FAAM), visual analog scale (VAS), and anterior talar translation were measured preoperatively and at 6 weeks, 3 months, and 2 years postoperatively. Ultrasonography examination was performed preoperatively and 2 years postoperatively to evaluate the ATFL. Data were analyzed using SPSS 19.0. F test was used to analyze the pre- and postoperative VAS, FAAM, and AOFAS scores. The significance was set at p

Abstract Background G-protein coupled receptors (GPCRs) are recognized as attractive targets for drug therapy. However, it remains poorly understood how GPCRs, except for a few chemokine receptors, regulate the progression of liver fibrosis. Here, we aimed to reveal the role of GPR65, a proton-sensing receptor, in liver fibrosis and to elucidate the underlying mechanism. Methods The expression level of GPR65 was evaluated in both human and mouse fibrotic livers. Furthermore, Gpr65-deficient mice were treated with either bile duct ligation (BDL) for 21 d or carbon tetrachloride (CCl4) for 8 weeks to investigate the role of GPR65 in liver fibrosis. A combination of experimental approaches, including Western blotting, quantitative real-time reverse transcription‑polymerase chain reaction (qRT-PCR), and enzyme-linked immunosorbent assay (ELISA), confocal microscopy and rescue studies, were used to explore the underlying mechanisms of GPR65’s action in liver fibrosis. Additionally, the therapeutic potential of GPR65 inhibitor in the development of liver fibrosis was investigated. Results We found that hepatic macrophages (HMs)-enriched GPR65 was upregulated in both human and mouse fibrotic livers. Moreover, knockout of Gpr65 significantly alleviated BDL- and CCl4-induced liver inflammation, injury and fibrosis in vivo, and mouse bone marrow transplantation (BMT) experiments further demonstrated that the protective effect of Gpr65 knockout is primarily mediated by bone marrow-derived macrophages (BMMs). Additionally, in vitro data demonstrated that Gpr65 silencing and GPR65 antagonist inhibited, while GPR65 overexpression and application of GPR65 endogenous and exogenous agonists enhanced the expression and release of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and transforming growth factor-β (TGF-β), all of which subsequently promoted the activation of hepatic stellate cells (HSCs) and the damage of hepatocytes (HCs). Mechanistically, GPR65 overexpression, the acidic pH and GPR65 exogenous agonist induced up-regulation of TNF-α and IL-6 via the Gαq-Ca2+-JNK/NF-κB pathways, while promoted the expression of TGF-β through the Gαq-Ca2+-MLK3-MKK7-JNK pathway. Notably, pharmacological GPR65 inhibition retarded the development of inflammation, HCs injury and fibrosis in vivo. Conclusions GPR65 is a major regulator that modulates the progression of liver fibrosis. Thus, targeting GPR65 could be an effective therapeutic strategy for the prevention of liver fibrosis.

Introduction The mechanisms underlying the protective effects of atrial natriuretic peptide (ANP) on the gut barrier during traumatic hemorrhagic shock (THS) remain elusive. This study aimed to explore the potential role of ANP in safeguarding against gut barrier dysfunction after THS, focusing on the PLC-γ1/ROS feedback loop. Methods In our THS rat model, we randomly allocated male Sprague-Dawley rats to receive intravenous ANP with or without a concurrent NADPH oxidase/p38 MAPK inhibitor during the shock phase. After 24 h, we assessed circulatory and jejunal ANP, ROS, intestinal tight junction proteins, and apoptosis to evaluate the effects of ANP on the gut barrier and its interplay with intestinal ANP and ROS. Rat small intestinal epithelial cells (IECs) were also treated with ANP and subjected to hypoxia/re-oxygenation injury, with or without PI3K/PLC inhibition, to elucidate the relationship between ANP/ROS signaling and PLC-γ1. Furthermore, we modulated PLC-γ1 expression in these IECs to examine its impact on ROS and ANP production. Results Intravenous ANP administration at 0.025 μg/kg/min during THS significantly increased intestinal ANP and ROS levels at 24 h. ANP treatment enhanced the expression of intestinal tight junction proteins and reduced IEC apoptosis. Inhibition of circulatory ROS diminished intestinal ANP levels, while suppression of circulatory ANP led to a reduction in intestinal ROS. Decreasing PLC-γ1 expression in hypoxia/re-oxygenation-treated IECs resulted in lower ROS and ANP levels, whereas augmenting PLC-γ1 expression did not alter these levels. Additionally, PI3K inhibition markedly decreased PLC-γ1 expression in these cells. Conclusion ANP-induced protection of the intestinal barrier in THS is mediated by an intrinsic PLC-γ1/ROS positive feedback loop. ANP preserves gut barrier integrity and reduces IEC apoptosis through this mechanism. Further studies are warranted to investigate the interaction between IECs and other cellular components within the PLC-γ1/ROS loop.