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rapamycin reverses ferroptosis by increasing autophagy in MPTP/MPP+-induced models of Parkinson's disease

Neural Regeneration Research 2023年第11期18卷 2514-2519页

作者： Tongyu Liu Peihan Wang Huan Yin Xiangfei Wang Jing Lv Jiang Yuan Jing Zhu Yunfu Wang Department of Neurology Affiliated Taihe HospitalHubei University of MedicineShiyanHubei ProvinceChina Institute of Neuroscience Hubei University of MedicineShiyanHubei ProvinceChina Wudang Mountain Hospital Area of Taihe Hospital Affiliated Hospital of Hubei University of MedicineShiyanHubei ProvinceChina

Parkinson’s disease is a neurodegenerative disorder,and fe rroptosis plays a significant role in the pathological mechanism underlying Parkinson’s ***,an autophagy inducer,has been shown to have neuroprotective effects in Parkinson’s ***,the link between rapamycin and ferroptosis in Parkinson’s disease is not entirely *** this study,rapamycin was administe red to a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson’s disease mouse model and a 1-methyl-4-phenylpyridinium-induced Parkinson’s disease PC12 cell *** results showed that rapamycin improved the behavioral symptoms of Parkinson’s disease model mice,reduced the loss of dopamine neurons in the substantia nigra pars compacta,and reduced the expression of ferroptosis-related indicators(glutathione peroxidase 4,recombinant solute carrier family 7,member 11,glutathione,malondialdehyde,and reactive oxygen species).In the Parkinson’s disease cell model,rapamycin improved cell viability and reduced ferro *** neuroprotective effect of rapamycin was attenuated by a ferroptosis inducer(methyl(1S,3R)-2-(2-chloroacetyl)-1-(4-methoxycarbonylphenyl)-1,3,4,9-tetrahyyridoindole-3-carboxylate)and an autophagy inhibitor(3-methyladenine).Inhibiting ferro ptosis by activating autophagy may be an important mechanism by which rapamycin exerts its neuroprotective *** re,the regulation of ferroptosis and autophagy may provide a therapeutic target for drug treatments in Parkinson’s disease.

关键词： autophagy behavior ferroptosis MPTP Parkinson’s disease PC12 cell rapamycin tyrosine hydroxylase

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rapamycin enhances the anti-tumor activity of cabozantinib in cMet inhibitor-resistant hepatocellular carcinoma

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Frontiers of Medicine 2022年第3期16卷 467-482页

作者： Chao Gao Shenghao Wang Weiqing Shao Yu Zhang Lu Lu Huliang Jia Kejin Zhu Jinhong Chen Qiongzhu Dong Ming Lu Wenwei Zhu Lunxiu Qin Department of General Surgery Huashan HospitalCancer Metastasis InstituteFudan UniversityShanghai 200040China Kanion Research Institute Lianyungang 222002China Institutes of Biomedical Sciences Fudan UniversityShanghai 200040China

Cabozantinib,mainly targeting cMet and vascular endothelial growth factor receptor 2,is the second-line treatment for patients with advanced hepatocellular carcinoma(HCC).However,the lower response rate and resistance limit its enduring clinical *** this study,we found that cMet-low HCC cells showed primary resistance to cMet inhibitors,and the combination of cabozantinib and mammalian target of rapamycin(mTOR)inhibitor,rapamycin,exhibited a synergistic inhibitory effect on the in vitro cell proliferation and in vivo tumor growth of these ***,the combination of rapamycin with cabozantinib resulted in the remarkable inhibition of AKT,extracellular signal-regulated protein kinases,mTOR,and common downstream signal molecules of receptor tyrosine kinases;decreased cyclin D1 expression;and induced cell cycle ***,rapamycin enhanced the inhibitory effects of cabozantinib on the migration and tubule formation of human umbilical vascular endothelial cells and human growth factor-induced invasion of cMet inhibitor-resistant HCC cells under hypoxia *** effects were further validated in xenograft *** conclusion,our findings uncover a potential combination therapy of cabozantinib and rapamycin to combat cabozantinib-resistant HCC.

关键词： hepatocellular carcinoma cabozantinib primary resistance rapamycin

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rapamycin liposome gutta inhibiting fungal keratitis of rats

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International Journal of Ophthalmology(English edition) 2019年第4期12卷 536-541页

作者： Zhen-Hua Zhang Feng Teng Qing-Xiu Sun Shu-Zhen Wang Chao Liu Gui-Qiu Zhao Department of Ophthalmology Qingdao Central Hospital the Second Clinical Hospital of Qingdao University Department of Ophthalmology the Affiliated Hospital of Qingdao University

AIM: To study the therapeutic effect of rapamycin liposome eyedrops on fungal keratitis(FK) and its effect on the expression of monocyte chemotactic protein-1(MCP-1).METHODS: This study adopted the thin film dispersion method to prepare rapamycin liposomes eyedrops, as well as used the orthogonal design to analyze and study main influencing factors that affected the quality of liposomes. Totally 96 healthy Wistar rats were randomly divided into four groups: normal control group(A), FK blank control group(B), FK blank liposomes control group(C), and 30 FK rapamycin liposome treatment group(D). Groups B, C, and D were first prepared as FK animal models. The corneal response was recorded in details on day 1, 3, 5, 7, and 14 after modeling. Six rats were obtained and immunohistochemistry and semi-quantitative reverse transcription polymerase chain reaction(RT-PCR) were used to detect the expression of MCP-1 protein and mRNA, ***: The severity of corneal lesions in the rapamycin treatment group was reduced, and the clinical score of the slit lamp examination was lower than that of Groups B and C(Prapamycin treatment group was significantly inhibited, comparing to that of groups B and C(Prapamycin. rapamycin has a good therapeutic effect on FK. It can reduce FK fungal burden and significantly inhibit the expression of MCP-1 protein and mRNA.

关键词： fungal keratitis rapamycin liposome monocyte chemotactic protein-1 rats

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rapamycin Treatment Attenuates Angiotensin Ⅱ-induced Abdominal Aortic Aneurysm Formation via VSMC Phenotypic Modulation and Down-regulation of ERK1/2 Activity

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2018年第1期38卷 93-100页

作者： Fei-fei LI Xiao-ke SHANG Xin-ling DU Shu CHEN Department of Cardiovascular Surgery Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430022 China

The aim of the present study is to address the effect of rapamycin on abdominal aortic aneurysm（AAA） and the potential mechanisms. A clinically relevant AAA model was induced in apolipoprotein E-deficient（ApoE-/-） mice, in which miniosmotic pump was implanted subcutaneously to deliver angiotensin Ⅱ（Ang Ⅱ） for 14 days. Male ApoE-/-mice were randomly divided into 3 groups： saline infusion, Ang Ⅱ infusion, and Ang Ⅱ infusion plus intraperitoneal injection of rapamycin. The diameter of the supra-renal abdominal aorta was measured by ultrasonography at the end of the infusion. Then aortic tissue was excised and examined by Western blotting and histoimmunochemistry. Ang Ⅱ with or without rapamycin treatment was applied to the cultured vascular smooth muscle cells（VSMCs） in vitro. The results revealed that rapamycin treatment significantly attenuated the incidence of Ang Ⅱinduced-AAA in ApoE-/-mice. Histologic analysis showed that rapamycin treatment decreased disarray of elastin fibers and VSMCs hyperplasia in the medial layer. Immunochemistry staining and Western blotting documented the increased phospho-ERKl/2 and ERK1/2 expression in aortic walls in Ang Ⅱ induced-AAA,as well as in human lesions. Whereas in the rapamycintreated group, decreased phospho-ERK1/2 expression level was detected. Moreover, rapamycin reversed Ang Ⅱ-induced VSMCs phenotypic change both in vivo and in vitro. Based on those results, we confirmed that rapamycin therapy suppressed Ang Ⅱ-induced AAA formation in mice, partially via VSMCs phenotypic modulation and down-regulation of ERK1/2 activity.

关键词： rapamycin abdominal aortic aneurysm angiotensin Ⅱ extracellular signal-regulated kinase vascular smooth muscle cells phenotypic modulation

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rapamycin combined with allogenic immature dendritic cells selectively expands CD4^+CD25^+Foxp3^+ regulatory T cells in rats

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Hepatobiliary & Pancreatic Diseases International 2012年第2期11卷 203-208页

作者： Guo-Ying Wang Qi Zhang Yang Yang Wen-Jie Chen Wei Liu Nan Jiang Gui-Hua Chen chgh1955@*** Liver Transplantation Center Third Affiliated Hospital Transplantation Research Institute Sun Yat-Sen University Organ Transplantation Research Center of Guangdong Province Guangzhou 510630 China

ReferencesReferencesBackgroundDendritic cells (DCs) can initiate the expansion of regulatory T cells (Tregs), which play an indispensable role in inducing transplantation tolerance. Some studies have investigated the effect of the immunosuppressant rapamycin (Rapa) on Tregs in vitro. However, the in vivo effect of Rapa combined with immature DCs (iDCs) on Tregs is unknown. This study was undertaken to determine whether allogenic iDCs combined with a short course of Rapa have the ability to selectively expand the CD4+CD25+Foxp3+ Tregs in a rat *** Norway rats were injected intravenously with 2×106 Lewis iDCs followed by 1 mg/kg per day Rapa intraperitoneally for 7 consecutive days. On day 8, the levels of CD4+CD25+Foxp3+ Treg cells in peripheral blood and spleen cells were analyzed by flow cytometry. IL-2, IL-4, TGF-β1, and IFN-γ levels in serum were assessed by ELISA. The experimental animals were divided into four groups: control, Rapa-treated, iDC-treated, and ***4+CD25+Foxp3+ Tregs comprised 7%-8%of CD4+ T cells in control rats. Rapa combined with iDCs enhanced this percentage in the peripheral blood and spleen. However, the levels of Tregs did not significantly change after treatment with Rapa or iDCs alone. The levels of CD4+CD25?/sup>Foxp3+ T cells and CD4+ CD25+Foxp3?/sup> T cells in CD4+ T cells did not significantly change in the combined group. The TGF-β1 level in serum from the combined group increased significantly compared with the other *** significantly higher percentage of CD4+ CD25+ Foxp3+ Tregs was found in rats treated with allogenic iDCs and a short course of Rapa, along with an increase in the TGF-β1 level in serum. This improved protocol may be a promising therapeutic strategy to increase Tregs, which are beneficial to the induction of peritransplant tolerance.

关键词： dendritic cells regulatory T cells rapamycin

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rapamycin ameliorates experimental autoimmune uveoretinitis by inhibiting Th1/Th2/Th17 cells and upregulating CD4+CD25+ Foxp3 regulatory T cells

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International Journal of Ophthalmology(English edition) 2015年第4期8卷 659-664页

作者： Li-Fei Yuan Guang-Da Li Xin-Jun Ren Hong Nian Xiao-Rong Li Xiao-Min Zhang Tianjin Medical University Eye Hospital & Eye Institute Hebei Eye Hospital Linyi People's Hospital

· AIM: To determine the effects of rapamycin on experimental autoimmune uveoretinitis(EAU) and investigate of role of rapamycin on T cell subsets in the disease.·METHODS: EAU was induced in rats using peptides1169 to 1191 of the interphotoreceptor binding protein(IRBP). rapamycin(0.2 mg/kg/d) was administrated by intraperitoneal injection for a consecutive 7d after immunization. Th1/Th2/Th17 cytokines, TGF-β1, and IL-6produced by lymphocyteswere measured by ELISA, while Th17 cells and CD4 +CD25 + regulatory T cells(Tregs)from rat spleen were detected by flow cytometry.·RESULTS: Intraperitoneal treatment immediately after immunization dramatically ameliorated the clinical course of EAU. Clinical responses were associated with reduced retinal inflammatory cell infiltration and tissue destruction. rapamycin induced suppression of Th1/Th2/Th17 cytokines, including IFN-γ, IL-2, IL-17, IL-4, and IL-10 release from T lymphocytes of EAU rats, in *** also significantly increased TGF-β1production but had no effect on IL-6 productionof T lymphocytes from EAU rats in vitro. Furthermore,rapamycin decreased the ratio of Th17 cells/CD4 +T cells and upregulated Tregs in EAU, as detected by flow cytometry.·CONCLUSION: rapamycin effectively interferes with T cell mediated autoimmune uveitis by inhibiting antigen-specific T cell functions and enhancing Tregs in *** is a promising new alternative as an adjunct corticosteroid-sparing agent for treating uveitis.

关键词： experimental autoimmune uveoretinitis rapamycin regulatory T cells Th1 cells Th2 cells Th17 cells uveitis

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Mammalian target of rapamycin pathway inhibition enhances the effects of 5-aza-dC on suppressing cell proliferation in human gastric cancer cell lines

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Science China(Life Sciences) 2008年第7期51卷 640-647页

作者： SUN DanFeng,TIAN XiaoQing,ZHANG YanJie,CHEN YingXuan,LU Rong,WANG Xia &FANG JingYuan Shanghai Jiao-Tong University Sc0hool of Medicine Renji Hospital,Shanghai Institute of Digestive Disease,Shanghai 200001, China 1. Shanghai Jiao-Tong University Sc0hool of Medicine Renji Hospital Shanghai Institute of Digestive Disease Shanghai 200001 China

The present study aimed to evaluate the relationship between mTOR signaling pathway and DNA methylation in cell survival,cell cycle,gene expression and protein level on human gastric cancer cells. Human gastric cancer cell lines,MKN45 and SGC7901 were treated with 5-aza-dC,rapamycin and/or *** viability was analyzed by *** cycle distribution was evaluated by flow cytometry (FCM).The transcription level of PTEN and p27 Kip1 genes was detected by using real-time *** expressions were detected by Western *** found that cell viability was moderately reduced when treated with 5-aza-dC alone,but remarkably reduced when mTOR pathway was inhibited together (P<0.01).mTOR inhibition enhances the effects of 5-aza-dC on arresting cell cycle at G2 phase in human gastric cancer cell *** expression of PTEN and p27 Kip1 mRNA was remarkably increased in the gastric cancer cells treated with combind drugs(P<0.01).Phosphorylation of Akt,p70S6K and 4E-BP1 were significantly reduced in the cells treated with LY294002 or RAPA(P<0.01),but we failed to find that 5-aza-dC enhance these *** suggested that mTOR inhibition could enhance the effects of 5-aza-dC on suppressing cell proliferation and arresting cell cycle in human gastric cancer cell lines, which might be a potential target for tumor therapy.

关键词： mammalian target of rapamycin rapamycin DNA methylation 5-aza-dC gastric cancer

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Neuroprotective effects of rapamycin on spinal cord injury in rats by increasing autophagy and Akt signaling

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Neural Regeneration Research 2019年第4期14卷 721-727页

作者： Xi-Gong Li Jun-Hua Du Yang Lu Xiang-Jin Lin Department of Orthopedic Surgery The First Affiliated Hospital School of Medicine Zhejiang University

rapamycin treatment has been shown to increase autophagy activity and activate Akt phosphorylation, suppressing apoptosis in several models of ischemia reperfusion injury. However, little has been studied on the neuroprotective effects on spinal cord injury by activating Akt phosphorylation. We hypothesized that both effects of rapamycin, the increased autophagy activity and Akt signaling, would contribute to its neuroprotective properties. In this study, a compressive spinal cord injury model of rat was created by an aneurysm clip with a 30 g closing force. Rat models were intraperitoneally injected with rapamycin 1 mg/kg, followed by autophagy inhibitor 3-methyladenine 2.5 mg/kg and Akt inhibitor IV 1 μg/kg. Western blot assay, immunofluorescence staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay were used to observe the expression of neuronal autophagy molecule Beclin 1, apoptosis-related molecules Bcl-2, Bax, cytochrome c, casp ase-3 and Akt signaling. Our results demonstrated that rapamycin inhibited the expression of mTOR in injured spinal cord tissue and up-regulated the expression of Beclin 1 and phosphorylated-Akt. rapamycin prevented the decrease of bcl-2 expression in injured spinal cord tissue, reduced Bax, cytochrome c and caspase-3 expression levels and reduced the number of apoptotic neurons in injured spinal cord tissue 24 hours after spinal cord injury. 3-Methyladenine and Akt inhibitor IV intervention suppressed the expression of Beclin-1 and phosphorylated-Akt in injured spinal cord tissue and reduced the protective effect of rapamycin on apoptotic neurons. The above results indicate that the neuroprotective effect of rapamycin on spinal cord injury rats can be achieved by activating autophagy and the Akt signaling pathway.

关键词： nerve regeneration rapamycin mammalian target of rapamycin,mTOR autophagy Beclin 1 3-methyladenine acute spinal cord injury apoptosis Bax Akt neural regeneration

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Construction of a mutant of Actinoplanes sp. N902-109 that produces a new rapamycin analog

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Chinese Journal of Natural Medicines 2018年第3期16卷 210-218页

作者： HUANG He GAO Ping ZHAO Qi HU Hai-Feng Shanghai Institute of Pharmaceutical Industry Shanghai 201203 China Institute of Plant Physiology and Ecology Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Shanghai 200032 China

In the present study, we introduced point mutations into Ac_rap A which encodes a polyketide synthase responsible for rapamycin biosynthesis in Actinoplanes sp. N902-109, in order to construct a mutant with an inactivated enoylreductase(ER) domain, which was able to synthesize a new rapamycin analog. Based on the homologous recombination induced by double-strand breaks in chromosome mediated by endonuclease I-SceI, the site-directed mutation in the first ER domain of Ac_rapA was introduced using non-replicating plasmid pL YERIA combined with an I-SceI expression plasmid. Three amino acid residues of the active center, Ala-Gly-Gly, were converted to Ala-Ser-Pro. The broth of the mutant strain SIPI-027 was analyzed by HPLC and a new peak with the similar UV spectrum to that of rapamycin was found. The sample of the new peak was prepared by solvent extraction, column chromatography, and crystallization methods. The structure of new compound, named as SIPI-rapxin, was elucidated by determining and analyzing its MS and NMR spectra and its biological activity was assessed using mixed lymphocyte reaction(MLR). An ER domain–deficient mutant of Actinoplanes sp. N902-109, named as SIPI-027, was constructed, which produced a novel rapamycin analog SIPI-rapxin and its structure was elucidated to be 35, 36-didehydro-27-O-demethylrapamycin. The biological activity of SIPI-rapxin was better than that of rapamycin. In conclusion, inactivation of the first ER domain of rap A, one of the modular polyketide synthase responsible for macro-lactone synthesis of rapamycin, gave rise to a mutant capable of producing a novel rapamycin analog, 35, 36-didehydro-27-O-demethylrapamycin, demonstrating that the enoylreductase domain was responsible for the reduction of the double bond between C-35 and C-36 during rapamycin synthesis.

关键词： Actinoplanes sp. N902-109 rapamycin Structural analog Polyketide synthase Enoylreductase

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A mixed blessing for liver transplantation patients—rapamycin

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Hepatobiliary & Pancreatic Diseases International 2023年第1期22卷 14-21页

作者： Guang-Han Fan Chen-Zhi Zhang Feng-Qiang Gao Xu-Yong Wei Sun-Bin Ling Kai Wang Jian-Guo Wang Shu-Sen Zheng Mehrdad Nikfarjam Xiao Xu Department of Hepatobiliary and Pancreatic Surgery Affiliated Hangzhou First People’s HospitalZhejiang University School of MedicineHangzhou 310006China Zhejiang University School of Medicine Hangzhou 310058China Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province Hangzhou 310006China Institute of Organ Transplantation Zhejiang UniversityHangzhou 310003China State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer MedicineSun Yat-sen University CancerGuangzhou 510060China Westlake Laboratory of Life Sciences and Biomedicine Hangzhou 310024China Department of Hepatobiliary and Pancreatic Surgery The First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China Department of Hepatobiliary and Pancreatic Surgery Shulan(Hangzhou)HospitalHangzhou 310000China NHC Key Laboratory of Combined Multi-Organ Transplantation Hangzhou 310003China Department of Surgery University of MelbourneAustin HealthHeidelbergVIC 3084Australia

Background:Liver transplantation(LT)is an effective treatment option for end-stage liver *** target of rapamycin(m TOR)inhibitors,such as rapamycin,are widely used post *** sources:In this review,we focused on the anti-cancer activities and metabolic side effects of rapamycin after *** literature available on Pub Med for the period of January 1999-September 2022 was *** key words were rapamycin,sirolimus,liver transplantation,hepatocellular carcinoma,diabetes,and lipid metabolism ***:rapamycin has shown excellent effects and is safer than other immunosuppressive *** has exhibited excellent anti-cancer activity and has the potential in preventing hepatocellular carcinoma(HCC)recurrence post *** is closely related to two long-term complications after LT,diabetes and lipid metabolism ***:rapamycin prevents HCC recurrence post LT in some patients,but it also induces metabolic *** use of rapamycin benefits the liver recipients.

关键词： Liver transplantation rapamycin Metabolic disease Hepatocellular carcinoma Tumor recurrence

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