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s-allylmercaptocysteine improves alcoholic liver disease partly through a direct modulation of insulin receptor signaling

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Acta Pharmaceutica sinica B 2021年第3期11卷 668-679页

作者： Pingping Luo Ming Zheng Rui Zhang Hong Zhang Yingxia Liu Wei Li Xiaoming sun Qian Yu George LTipoe Jia Xiao Clinical Medicine Research Institute the First Affiliated Hospital of Jinan UniversityGuangzhou 510632China Department of Interventional surgery the First Affiliated Hospital of Jinan UniversityGuangzhou 510632China state Key Discipline of Infectious Diseases Department of Infectious DiseasesShenzhen Third People’s HospitalShenzhen 518000China Faculty of Pharmaceutical sciences Toho UniversityChiba 2748510Japan school of Integrative Pharmacy Institute of Integrative Pharmaceutical ResearchGuangdong Pharmaceutical UniversityGuangzhou 510000China school of Biomedical sciences Li Ka Shing Faculty of Medicinethe University of Hong KongHong Kong 999077China

Alcoholic liver disease(ALD) causes insulin resistance, lipid metabolism dysfunction, and inflammation. We investigated the protective effects and direct regulating target of s-allylmercaptocysteine(sAMC) from aged garlic on liver cell injury. A chronic ethanol-fed ALD in vivo model(the NIAAA model) was used to test the protective functions of sAMC. It was observed that sAMC(300 mg/kg, by gavage method) effectively ameliorated ALD-induced body weight reduction, steatosis,insulin resistance, and inflammation without affecting the health status of the control mice, as demonstrated by histological, biochemical, and molecular biology assays. By using biophysical assays and molecular docking, we demonstrated that sAMC directly targeted insulin receptor(INsR) protein on the cell membrane and then restored downstream IRs-1/AKT/GsK3 b signaling. Liver-specific knock-down in mice and siRNA-mediated knock-down in AML-12 cells of Insr significantly impaired sAMC(250 mmol/L in cells)-mediated protection. Restoration of the IRs-1/AKT signaling partly recovered hepatic injury and further contributed to sAMC’s beneficial effects. Continuous administration of AKT agonist and recombinant IGF-1 in combination with sAMC showed hepato-protection in the mice ***-term(90-day) administration of sAMC had no obvious adverse effect on healthy mice. We conclude that sAMC is an effective and safe hepato-protective complimentary agent against ALD partly through the direct binding of INsR and partial regulation of the IRs-1/AKT/GsK3 b pathway.

关键词： Alcoholic liver disease s-allylmercaptocysteine Insulin receptor Insulin resistance IRs-1 AKT GsK3b safety

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Anti-cancer activities of s-allylmercaptocysteine from aged garlic

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Chinese Journal of Natural Medicines 2019年第1期17卷 43-49页

作者： LV Yi sO Kwok-Fai WONG Nai-Kei XIAO Jia Laboratory of Neuroendocrinology School of Biological SciencesFujian Normal University National Key Disciplines for Infectious Diseases Shenzhen Third People's HospitalThe Second Hospital Affiliated to Southern University of Science and Technology school of Biomedical sciences Li Ka Shing Faculty of MedicineThe University of Hong Kong

While most types of malignancies remain recalcitrant to treatment, application of natural products or their analogs in daily life has offered some hopes as an effective prophylaxis against cancer onset and progression in the past decades. Emerging evidence supports a link between garlic consumption and decreased cancer incidence. Notably, aged garlic extract(AGE) exhibits stronger anti-cancer activities than that of fresh garlic, by virtue of enrichment of several AGE-specific organosulfur compounds, including s-allylmercaptocysteine(sAMC). In this review, we summarize the up-to-date mechanistic pathways associated with the anti-proliferative, anti-metastatic and pro-apoptotic effects of sAMC in various cancer models. Based upon the proven safety and improved understanding on its anti-neoplastic properties, sAMC has gained recognition as a promising daily food supplement for cancer prevention or management.

关键词： Aged garlic s-allylmercaptocysteine Cancer Molecular pathway Reactive oxygen species

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Garlic-derived compound s-allylmercaptocysteine inhibits hepatocarcinogenesis through targeting LRP6/Wnt pathway

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Acta Pharmaceutica sinica B 2018年第4期8卷 575-586页

作者： Jia Xiao Feiyue Xing Yingxia Liu Yi Lv Xiaogang Wang Ming-Tat Ling Hao Gao songying Ouyang Min Yang Jiang Zhu Yu Xia Kwok-Fai so George L.Tipoe state Key Discipline of Infectious Diseases Shenzhen Third People's Hospital Department of Immunobiology Institute of Tissue Transplantation and ImmunologyJinan University school of Biomedical sciences The University of Hong Kong Department of Cell Biology & Institute of Biomedicine Jinan University Australian Prostate Cancer Research Centre-Queensland and Institute of Health and Biomedical Innovation Queensland University of Technology Institute of Traditional Chinese Medicine and Natural Products College of PharmacyJinan University Biomedical Research Center of south China College of Life SciencesFujian Normal University JM Medical (shenzhen) LLC GMH Institute of Central Nervous system Regeneration Jinan University

Whether and how garlic-derived s-allylmercaptocysteine(sAMC) inhibits hepatocellular carcinoma(HCC) is largely unknown. In the current study, the role of low-density lipoprotein receptor(LDLR)-related protein 6(LRP6) in HCC progression and the anti-HCC mechanism of sAMC was examined in clinical sample, cell model and xenograft/orthotopic mouse models. We demonstrated that sAMC inhibited cell proliferation and tumorigenesis, while induced apoptosis of human HCC cells without influencing normal hepatocytes. sAMC directly interacted with Wnt-pathway co-receptor LRP6 on the cell membrane. LRP6 was frequently over-expressed in the tumor tissue of human HCC patients(66.7% of 48 patients) and its overexpression only correlated with the over-expression of β-catenin, but not with age, gender, tumor size, stage and metastasis. Deficiency or over-expression of LRP6 in hepatoma cells could partly mimic or counteract the anti-tumor properties of sAMC, respectively. In vivo administration of sAMC significantly suppressed the growth of Huh-7 xenograft/orthotopic HCC tumor without causing undesirable side effects. In addition, stable down-regulation of LRP6 in Huh-7 facilitated the anti-HCC effects of sAMC. In conclusion, LRP6 can be a potential therapeutic target of HCC. sAMC is a promising specific anti-tumor agent for treating HCC subtypes with Wnt activation at the hepatoma cell surface.

关键词： s-allylmercaptocysteine HCC Wnt LRP6 Human Nude mice

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