Liposarcoma is a typical sarcoma with high degree of recurrence rate and mortality. Ferroptosis, an iron-dependent cell death driven by lipid peroxidation, plays a critical role in tumorigenesis and tumor-suppression. Here, we performed lipidomics to reveal that ursodeoxycholic acid (UDCA) was one of the most significantly downregulated metabolites in sera of retroperitoneal liposarcoma (RLPS) patients compared with healthy subjects. As a drug for treating primary biliary cholangitis, UDCA was found to inhibit the proliferation of liposarcoma cells in vitro and in vivo . Mechanistically, UDCA binds to SLC7A11 to inhibit cystine uptake and impair glutathione de novo synthesis, resulting in ferroptosis through the xCT-GPX4 axis. Moreover, when UDCA and oral MDM2 inhibitor were used together, they showed better tumor-suppression. Overall, this work sheds light on UDCA as a cystine exchange factor by binding to SLC7A11 to induce ferroptosis, providing an effective and promising intervention strategy for RLPS.Funding Information: This work was supported by grants from the National Natural Science Foundation of China (No. 81972223 to WG.L., No. 91957120 to S.-H.L.), the Scientific Research Foundation for Advanced Talents, Xiang’an Hospital of Xiamen University (No. PM20180917008 to W.L.) and the Fundamental Research Funds for the Central Universities (20720210001 to S.-H.L.). Joint laboratory of School of Medicine, Xiamen University-Shanghai Jiangxia Blood Technology CO. LTD (No. XDHT2020010C to WG.L.). China Postdoctoral Foundation (no. 2019M662246 to Xu Kong).Declaration of Interests: The authors declare no conflict of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.Ethics Approval Statement: The present protocols were reviewed and approved by the Ethics Committees of all participating institutions, including the Xiang’an Hospital of Xiamen University (No. XAHLL2021024) and Peking University International Hospital (No. WA2020RW29). All the participants were enrolled and anonymized after approval by the institutional review board. We obtained written informed consent from all participants, except for those we could not contact due to lack of follow-up. In these cases, the institutional review boards at each participating institution granted permission for existing tissue samples to be used for research purposed. None of the samples used in this study came from patients who had opted out of participation.All experimental procedures involving animals were conducted in accordance with the animal protocols approved by the Laboratory Animal Center of Xiamen University and Ethics Committee of Xiamen University (No. XMULAC20190114).
Increasing evidence has solidified the involvement of α-synuclein (α-Syn) and neurotoxins in the pathogenesis of Parkinson's disease (PD), suggesting a combination of genetic and environmental influences. 2,3,5,4'-Tetrahydroxystilbene-2-O-β-D-glucoside (TSG) is one of the main active components extracted from Polygonum multiflorum. The purpose of the present study was to investigate the effects of TSG on α-Syn aggregation, mitochondrial dysfunction, oxidative stress, and apoptosis in vitro. A53T mutant α-synuclein-transfected cells (A53T AS cells) plus MPP+ exposure were used as a complex cell model of PD. The expression of proteins was determined by Western blot assay. Flow cytometry was utilized to measure mitochondrial membrane potential and apoptosis. The results showed that MPP+ exposure for 24 h induced more severe damage in A53T AS cells than in vector control cells. Pretreatment of TSG for 24 h significantly increased the cell viability; decreased lactate dehydrogenase leakage; inhibited α-Syn over-expression and aggregation; elevated mitochondrial membrane potential; decreased reactive oxygen species, Bax/Bcl-2 ratio, and caspase-3 activity; and inhibited apoptosis in A53T AS cells exposed to MPP+. These results suggest that TSG may be an attractive candidate for PD therapy.
This study investigated the prevalence and determinants of hyperuricemia in Chinese type 2 diabetes mellitus (T2DM) patients with central obesity. A multicentric hospital-based cross-sectional study was carried out in Guangdong Province between August 2011 and March 2012. At each hospital, Chinese T2DM patients with central obesity who were aged over 20 years, whose serum uric acid levels were measured, and who had lived in Guangdong Province for >=1 year, were recruited. Hyperuricemia was defined as serum uric acid >420 μmol/L in men and >360 μmol/L in women. Binary logistic regression was used to assess associated risk factors for hyperu-ricemia. A total of 2,917 T2DM patients with central obesity took part. The overall prevalence of hyperuricemia was 32.6% (36.1% for women, 28.4% for men). Binary logistic regression analyses demonstrated that women (OR: 1.576; 95% confidence interval (CI): 1.231, 2.018), high BMI (OR: 1.228; 95% CI: 1.094, 1.379), waist cir-cumference (OR: 1.135; 95% CI: 1.009, 1.276), hypertension (OR: 1.603; 95% CI: 1.263, 2.035), high total cho-lesterol (OR: 1.133; 95% CI: 1.002, 1.281), triglycerides (OR: 1.134; 95% CI: 1.069, 1.203), low HDL-cholesterol (OR: 0.820; 95% CI: 0.677, 0.995) and low estimated glomerular filtration rate (OR: 0.840; 95% CI: 0.815, 0.866) were risk factors associated with hyperuricemia. Hyperuricemia is prevalent in Chinese T2DM patients with central obesity and is significantly positively associated with women, cardiovascular risk factors such as obesity, hypertension and dyslipidemia, and low eGFR. 本研究旨在探讨高尿酸血症在中国2 型糖尿病合并腹型肥胖患者中的患病率，并 分析其相关危险因素。2011 年8 月至2012 年3 月期间，在广东省内进行多中 心、以医院为基础的横断面调查。在广东省内居住满一年且年龄在20 岁以上， 确诊2 型糖尿病合并腹型肥胖且检测血尿酸水平的患者纳入本研究。高尿酸血症 定义：男性血尿酸 >420 μmol/L 或女性血尿酸 >360 μmol/L。采用二分类logistic 回归分析高尿酸血症的危险因素。共2917 名2 型糖尿病合并腹型肥胖的患者纳 入本研究。高尿酸血症的患病率为32.6%(女性为36.1%，男性为28.4%)。二分 类logistic 回归分析显示，女性、高体重指数和腰围、高血压、高总胆固醇和甘 油三酯、低高密度脂蛋白胆固醇和低肾小球滤过率是高尿酸血症的危险因素。 高尿酸血症在中国2 型糖尿病合并腹型肥胖患者中盛行，与女性、心血管危险因 素如肥胖、高血压、血脂異常症和低肾小球滤过率呈显著相关。
Exposure to hepatitis E virus (HEV) bears a high risk of developing chronic infection in immunocompromised patients, including organ transplant recipients and cancer patients. We aim to identify effective anti-HEV therapies through screening and repurposing safe-in-human broad-spectrum antiviral agents. In this study, a safe-in-human broad-spectrum antiviral drug library comprising of 94 agents was used. Upon screening, we identified gemcitabine, a widely used anti-cancer drug, as a potent inhibitor of HEV replication. The antiviral effect was confirmed in a range of cell culture models with genotype 1 and 3 HEV strains. As a cytidine analog, exogenous supplementation of pyrimidine nucleosides effectively reversed the antiviral activity of gemcitabine, but the level of pyrimidine nucleosides per se does not affect HEV replication. Surprisingly, similar to interferon-alpha (IFNα) treatment, gemcitabine activates STAT1 phosphorylation. This subsequently triggers activation of interferon-sensitive response element (ISRE) and transcription of interferon-stimulated genes (ISGs). Cytidine or uridine effectively inhibits gemcitabine-induced activation of ISRE and ISGs. As expected, JAK inhibitor 1 blocked IFNα, but not gemcitabine-induced STAT1 phosphorylation, ISRE/ISG activation, and anti-HEV activity. These effects of gemcitabine were completely lost in STAT1 knockout cells. In summary, gemcitabine potently inhibits HEV replication by triggering interferon-like response through STAT1 phosphorylation but independent of Janus kinases. This represents a non-canonical antiviral mechanism, which utilizes the innate defense machinery that is distinct from the classical interferon response. These results support repurposing gemcitabine for treating hepatitis E, especially for HEV-infected cancer patients, leading to dual anti-cancer and antiviral effects.
Abstract Purpose A meta-analysis was performed to assess the benefits and safety profile of approved immune checkpoint inhibitors in hepatocellular carcinoma patients. Methods Eligible studies were searched from Cochrane, Embase, and PubMed databases based on a well-established strategy. Review manager version 5.4 was employed for data analysis. Results Following the exclusion of ineligible studies, eight studies were included in this meta-analysis. Compared with control group, immune checkpoint inhibitors were associated with improved ORR (OR 3.65, 95% CI 2.82–4.73, P < 0.00001), DCR (OR 1.17, 95% CI 1.02–1.35, P = 0.02), SD (OR 0.72, 95% CI 0.58–0.89, P = 0.002), and more risk of all caused any-grade adverse events (OR 1.64, 95% CI 1.03–2.60, P = 0.004). However, no significant differences were observed in PD (OR 0.96, 95% CI 0.82–1.12, P = 0.59), OS (HR 0.76, 95% CI 0.66–0.87, P = 0.25), PFS (HR 0.74, 95% CI 0.63–0.87, P = 0.24) and all caused grade 3 or 4 adverse events (OR 1.22, 95% CI 0.98–1.52, P = 0.07), treatment-related any grade adverse events (OR 0.99, 95% CI 0.48–2.07, P = 0.98), treatment-related grade 3 or 4 events (OR 1.05, 95% CI 0.81–1.35, P = 0.72) between the two groups. After studies with nivolumab as a monotherapy excluded, patients in the immune checkpoint inhibitor group showed significant improvements in OS (HR 0.67, 95% CI 0.58–0.77, P < 0.00001) and PFS (HR 0.62, 95% CI 0.54–0.71, P < 0.00001). Conclusion Immune checkpoint inhibitors have demonstrated peculiar benefits in the treatment of HCC with an acceptable safety profile. Combining immune checkpoint inhibitors with other medications may be more beneficial for patients with hepatocellular carcinoma.
The details of primary mouse microglial cell culture. Figure S1. Iba-1 immunostaining images and morphology pictures of primary microglias isolated using mild trypsinization. Scale bar = 50 μm (TIF 7.29 mb). Figure S2. Iba-1 immunostaining images and morphology pictures of primary microglia isolated using shaking. The scale bar = 50 μm and arrows refer to the enlarged round cell body. (ZIP 24043 kb)
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