Qigu Yao

Zhejiang University

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Hongcui Cao

Hubei University of Medicine

Jiong Yu

First Affiliated Hospital Zhejiang University

Wenyi Chen

Third Affiliated Hospital of Southern Medical University

Lanjuan Li

National Clinical Research Center for Digestive Diseases

Xudong Feng

First Affiliated Hospital of Kunming Medical University

Feiqiong Gao

Zhejiang University

Qiaoling Pan

First Affiliated Hospital Zhejiang University

Jiahang Zhou

First Affiliated Hospital Zhejiang University

Yingduo Yu

First Affiliated Hospital Zhejiang University

Jiaqi Zhu

Zhejiang University

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Zhejiang University

First Affiliated Hospital Zhejiang University

National Clinical Research Center for Digestive Diseases

State Key Laboratory of Diagnosis and Treatment of Infectious Diseases

Zhejiang Chinese Medical University

Chinese Academy of Sciences

Wenzhou Medical University

University of Chinese Academy of Sciences

Blood Center of Zhejiang Province

Chinese Academy of Medical Sciences & Peking Union Medical College

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Dyslipidemia and Non-Alcoholic Fatty Liver Disease Due to a Somatic Mutation in <i>HIF2A</i>

Feiqiong Gao Qigu Yao Jiaqi Zhu Wenyi Chen Xudong Feng

Background: Hypoxia-inducible factor-2α (HIF-2α) is a transcription factor responsible for regulating genes related to angiogenesis and metabolism. This study aims to explore the effect of a previously unreported mutation c.C2473T (p.R825S) in the C-terminal transactivation domain (CTAD) of HIF-2α that we detected in tissue of patients with liver disease.Methods: We sequenced available liver and matched blood samples obtained during partial liver resection or liver transplantation performed for clinical indications including hepatocellular carcinoma and liver failure. We also generated and evaluated both a transgenic mouse model with the same mutation identified in the patients and derived cell lines for dyslipidemia and hepatic lipid accumulation using Further, we used lipidomics to assess hepatic lipid metabolism in the mouse model.Findings: We identified a mutation in the CTAD of HIF-2α (c.C2473T; p.R825S) in 5 of 356 liver samples obtained from patients with hepatopathy and dyslipidemia. We found that introduction of this mutation into the mouse model led to an elevated triglyceride level, lipid droplet accumulation in liver of the mutant mice and in their extracted primary hepatocytes, and increased transcription of genes related to hepatic fatty acid transport and synthesis in the mutant compared to the control groups. In mutant mice and cells, the protein levels of nuclear HIF-2α and its target perilipin-2 (PLIN2), a lipid droplet-related gene, were also elevated. Decreased lipophagy was observed in mutant groups.Interpretation: Our study defines a subpopulation of dyslipidemia that is caused by this HIF-2α mutation. This may have implications for personalized treatment.Funding: This work was supported by Key Research and Development Project of Zhejiang Province (No. 2022C03G2013730), National Key R&D Program of China (2020YFA0113003), Fundamental Research Funds for the Central Universities (No. 2022ZFJH003) and Research Project of Jinan Microecological Biomedicine Shandong Laboratory (No. JNL-2022026C).Declaration of Interest: The authors declare that they have no competing interests.Ethical Approval: All participants signed written informed consent. And this study was approved by the ethics committee of the The First Affiliated Hospital of Zhejiang University School of Medicine .

Dyslipidemia

Steatohepatitis

Alcoholic fatty liver

10.2139/ssrn.4401718

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Citations (1)

The efficacy and safety of combined immune checkpoint inhibitors (nivolumab plus ipilimumab): a systematic review and meta-analysis

World Journal of Surgical Oncology (2020)

Jingjie Chen Shengnan Li Qigu Yao Nannan Du Xiaojun Fu

Currently, nivolumab and ipilimumab are the most widely used immune checkpoint inhibitors. We performed a meta-analysis to evaluate the efficacy and treatment-related adverse events (TRAEs) of nivolumab plus ipilimumab therapy in cancer treatment. We examined data from PubMed, Web of Science, EBSCO, and Cochrane Library. Eleven articles fulfilled our criteria, which we divided into 3 groups: nivolumab plus ipilimumab versus nivolumab (the dose used for monotherapy is 3 mg/kg), nivolumab plus ipilimumab versus ipilimumab (the dose used for monotherapy is 3 mg/kg), and nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (N1I3) versus nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (N3I1). We measured the complete response (CR), partial response (PR), objective response rate (ORR), and TRAEs in any grade and grade 3 or higher. The overall effect estimate favored the combined immunotherapy group in terms of the ORR (RR: 1.40, p < 0.001) and PR (RR: 1.50, p < 0.001) than nivolumab alone. Compared with ipilimumab alone, the combined immunotherapy group had better CR (RR: 4.89, p < 0.001), PR (RR: 2.75, p < 0.001), and ORR (RR: 3.31, p < 0.001). Finally, N1I3 showed better PR (RR: 1.35, p = 0.006) and ORR (RR: 1.21, p = 0.03) than N3I1. The incidence of any TRAEs was similar between both groups (RR: 1.05, p = 0.06). However, the incidence of serious adverse events (grade 3 or higher) was lower in group N3I1 than group N1I3 (RR: 1.51, p < 0.001). This meta-analysis showed that the curative effect of nivolumab plus ipilimumab was better than that of nivolumab or ipilimumab monotherapy. In the combined immunotherapy group, N1I3 was more effective than N3I1. Although the side effects were slightly increased in N1I3 group, overall safety was acceptable.

10.1186/s12957-020-01933-5

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The efficacy and safety of combined immune checkpoint inhibitors (nivolumab plus ipilimumab): a systematic review and meta-analysis

Research Square (Research Square) (2020)

Lihu Gu Shengnan Li Nannan Du Qigu Yao Xiaojun Fu

Abstract Background: Currently, nivolumab and ipilimumab are the most widely used immune checkpoint inhibitors. We performed a meta-analysis to evaluate the efficacy and treatment-related adverse events (TRAEs) of nivolumab-ipilimumab combination therapy in cancer treatment. Methods: We examined data from PubMed, Web of science, EBSCO and Cochrane library. Eleven articles fulfilled our criteria, which we divided into 3 groups; nivolumab and ipilimumab versus ipilimumab, nivolumab and ipilimumab versus ipilimumab and nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (N1I3) versus nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (N3I1). We measured the complete response (CR), partial response (PR), objective response rate (ORR) and TRAEs in any grade and grade 3 or higher. Results: Compared with ipilimumab alone, the combined immunotherapy had better CR (RR: 4.89, p <0.001), PR (RR: 2.75, p <0.001), and ORR (RR: 3.31, p <0.001). The overall effect estimate favored the combined immunotherapy group in terms of the ORR (RR: 1.40, p <0.001) and PR (RR: 1.50, p <0.001) than nivolumab alone. Finally, N1I3 showed better PR (RR: 1.35, p =0.006) and ORR (RR: 1.21, p =0.03) than N3I1. The incidence of any TRAEs was similar between the both groups (RR: 1.05, p =0.06). However, the incidence of serious adverse events (grade 3 or higher) were lower in group N3I1 than group N1I3 (RR: 1.51, p <0.001). Conclusion: This meta-analysis showed that the curative effect of nivolumab plus ipilimumab was better than that of ipilimumab or nivolumab monotherapy. In the combination group, N1I3 combination was more effective than N3I1. Although the side effects were slightly increased in group N1I3, the overall safety was acceptable.

10.21203/rs.3.rs-17064/v1

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Comparison of tenofovir versus entecavir on reducing incidence of hepatocellular carcinoma in chronic hepatitis B patients: A systematic review and meta‐analysis

Journal of Gastroenterology and Hepatology (2020)

Lihu Gu Qigu Yao Zefeng Shen Ying He Derry Minyao Ng

Studies had shown that tenofovir (TDF) and entecavir (ETV) are widely used as the first-line therapy to inhibit hepatitis B virus replication, which can reduce the risk of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients, but it was unclear which nucleos(t)ide analogue was most effective. Therefore, we performed a meta-analysis and a systematic review to compare the incidence of HCC in CHB patients who are either on TDF or ETV.For this study, the following databases were searched for clinical trials published from its inception until November 2019: PubMed, Web of Science, MEDLINE, Embase, and Cochrane Library.A total of 11 eligible studies were selected, including 70 864 patients. The meta-analysis showed that TDF was superior to ETV with regard to the incidence of HCC, the incidence of death or transplantation, and virologic response. There were no significant differences in terms of biochemical response and loss of seroconversion response among the entire cohort.The conclusion was that CHB patients treated with TDF had a reduced incidence of HCC compared with patients treated with ETV.

Entecavir

Hepatitis B

Tenofovir

10.1111/jgh.15036

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Citations (28)

Stem cell therapy for Crohn’s disease: systematic review and meta-analysis of preclinical and clinical studies

Stem Cell Research & Therapy (2021)

Ruo Wang Qigu Yao Wenyi Chen Feiqiong Gao Pan Li

Abstract Background We explored whether stem cell therapy was effective for animal models and patients with Crohn’s disease (CD). Methods We searched five online databases. The relative outcomes were analyzed with the aid of GetData Graph Digitizer 2.26 and Stata 16.0 software. The SYRCLE risk of bias tool and the MINORS tool were used to assess study quality. Results We evaluated 46 studies including 28 animal works ( n = 567) and 18 human trials ( n = 360). In the animal studies, the disease activity index dramatically decreased in the mesenchymal stem cell (MSC) treatment groups compared to the control group. Rats and mice receiving MSCs exhibited longer colons [mice: standardized mean difference (SMD) 2.84, P = 0.000; rats: SMD 1.44, P = 0.029], lower histopathological scores (mice: SMD − 4.58, p = 0.000; rats: SMD − 1.41, P = 0.000) and lower myeloperoxidase levels (SMD − 6.22, P = 0.000). In clinical trials, stem cell transplantation reduced the CD activity index (SMD − 2.10, P = 0.000), the CD endoscopic index of severity (SMD − 3.40, P = 0.000) and simplified endoscopy score for CD (SMD − 1.71, P = 0.000) and improved the inflammatory bowel disease questionnaire score (SMD 1.33, P = 0.305) compared to control values. CD patients maintained high remission rates for 3–24 months after transplantation. Conclusions Stem cell transplantation is a valuable supplementary therapy for CD.

Stem Cell Therapy

10.1186/s13287-021-02533-0

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Citations (68)

Comparison between acupuncture and antidepressant therapy for the treatment of poststroke depression

Medicine (2021)

Lincheng Zhang Bing Chen Qigu Yao Weiyan Chen Weinan Yang

Abstract Background: In this paper, a systematic review and meta-analysis of published randomized controlled trials (RCTs) was conducted to compare the efficacies of acupuncture and antidepressant therapy for the treatment of poststroke depression (PSD). Methods: The research team searched RCTs published on PubMed; Medline; Cochrane library; Chinese National Knowledge Infrastructure (CNKI); Wanfang; Embase; Scopus, and Sinomed from their respective establishments to January 2019. We evaluated the Hamilton Depression Rating Scale (HAMD) scores, Treatment Emergent Symptom Scale (TESS) scores, National Institute of Health Stroke Scale (NIHSS) scores, and total clinical efficacy using fixed effects models. Results: Fourteen RCTs, representing a total of 1124 patients, were studied. Results showed that acupuncture was more effective in improving HAMD scores at 3 weeks after administration (mean difference [MD] = −1.17, 95%CI = −2.18 to −0.16), at 4 weeks (MD = −4.44, 95% CI = −5.64 to −3.23), at 6 weeks (MD = −1.02, 95% CI = −1.68 to −0.36), and at 8 weeks (MD = −4.33, 95% CI = −4.96 to −3.70). Similarly, acupuncture more dramatically decreased NIHSS scores (MD = −2.31, 95% CI = −2.53 to −2.09), and TESS scores (MD = −4.70, 95% CI = −4.93 to −4.48) than conventional Western medicinal therapy. Further, the total clinical efficacy in the acupuncture group was significantly higher than in the antidepressants group (risk ratio [RR] = 1.15, 95% CI = 1.08–1.21). Conclusions: The results of this study suggest that acupuncture not only can reduce the severity of PSD, but also has significant effects on decreasing the appearance of other adverse events.

Depression

Post-Stroke Depression

10.1097/md.0000000000025950

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Citations (3)

Mesenchymal stem cells protect against ferroptosis via exosome-mediated stabilization of SLC7A11 in acute liver injury

Cell Death and Disease (2022)

Feiyan Lin Wenyi Chen Jiahang Zhou Jiaqi Zhu Qigu Yao

Abstract Mesenchymal stem cells (MSCs) have attracted interest for their potential to alleviate liver injury. Here, the protective effect of MSCs on carbon tetrachloride (CCl 4 )-induced acute liver injury (ALI) was investigated. In this study, we illustrated a novel mechanism that ferroptosis, a newly recognized form of regulated cell death, contributed to CCl 4 -induced ALI. Subsequently, based on the in vitro and in vivo evidence that MSCs and MSC-derived exosomes (MSC-Exo) treatment achieved pathological remission and inhibited the production of lipid peroxidation, we proposed an MSC-based therapy for CCl 4 -induced ALI. More intriguingly, treatment with MSCs and MSC-Exo downregulated the mRNA level of prostaglandin-endoperoxide synthase 2 ( Ptgs2 ) and lipoxygenases ( LOXs ) while it restored the protein level of SLC7A11 in primary hepatocytes and mouse liver, indicating that the inhibition of ferroptosis partly accounted for the protective effect of MSCs and MSC-Exo on ALI. We further revealed that MSC-Exo-induced expression of SLC7A11 protein was accompanied by increasing of CD44 and OTUB1. The aberrant expression of ubiquitinated SLC7A11 triggered by CCl 4 could be rescued with OTUB1-mediated deubiquitination, thus strengthening SLC7A11 stability and thereby leading to the activation of system X C − to prevent CCl 4 -induced hepatocyte ferroptosis. In conclusion, we showed that MSC-Exo had a protective role against ferroptosis by maintaining SLC7A11 function, thus proposing a novel therapeutic strategy for ferroptosis-induced ALI.

Exosome

10.1038/s41419-022-04708-w

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Citations (124)

Efficacy and safety of transjugular intrahepatic portosystemic shunt (TIPS) created using covered stents of different diameters: A systematic review and meta-analysis

Diagnostic and Interventional Imaging (2020)

Zongzhang Huang Qigu Yao Jianping Zhu Ying He Yanghao Chen

Hepatic Encephalopathy

Covered stent

10.1016/j.diii.2020.11.004

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Citations (22)

Prolonged resident nanoparticles effectively treat acute lung injury via the selective upregulation of intracellular hydrogen peroxide

Nano Today (2024)

Beiduo Wang Yanping Xu Qigu Yao Liang Song Min Liang

10.1016/j.nantod.2024.102278

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ROS-responsive nanoparticle delivery of obeticholic acid mitigate primary sclerosing cholangitis

Journal of Controlled Release (2024)

Qigu Yao Beiduo Wang Jiong Yu Qiaoling Pan Yingduo Yu

Primary sclerosing cholangitis (PSC) is a challenging cholestatic liver disease marked by progressive bile duct inflammation and fibrosis that has no FDA-approved therapy. Although obeticholic acid (OCA) has been sanctioned for PSC, its clinical utility in PSC is constrained by its potential hepatotoxicity. Here, we introduce a novel therapeutic construct consisting of OCA encapsulated within a reactive oxygen species (ROS)-responsive, biodegradable polymer, further cloaked with human placenta-derived mesenchymal stem cell (hP-MSC) membrane (MPPFTU@OCA). Using PSC patient-derived organoid models, we assessed its cellular uptake and cytotoxicity. Moreover, using a PSC mouse model induced by 3,5-diethoxycarbonyl-1,4-dihydro-collidine (DDC), we demonstrated that intravenous administration of MPPFTU@OCA not only improved cholestasis via the FXR-SHP pathway but also reduced macrophage infiltration and the accumulation of intracellular ROS, and alleviated mitochondria-induced apoptosis. Finally, we verified the ability of MPPFTU@OCA to inhibit mitochondrial ROS thereby alleviating apoptosis by measuring the mitochondrial adenosine triphosphate (ATP) concentration, ROS levels, and membrane potential (ΔΨm) using H 2 O 2 -stimulated PSC-derived organoids. These results illuminate the synergistic benefits of integrating an ROS-responsive biomimetic platform with OCA, offering a promising therapeutic avenue for PSC. ROS-responsive and self-positioning biomimetic nanoparticle delivery of obeticholic acid mitigates primary sclerosing cholangitis via mitochondria-induced apoptosis. • ROS-responsive PPFTU material loaded with OCA alleviated hepatobiliary damage. • MSC membrane encapsulation enables powerful targeting of the liver and inflammation. • Organoids and animal models reveal that MPPFTU@OCA mitigates disease progression via mitochondrial-induced apoptosis.

Obeticholic acid

Mitochondrial ROS

10.1016/j.jconrel.2024.08.006

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