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Multidimensional autophagy nano-regulator boosts Alzheimer's disease treatment by improving both extra/intraneuronal homeostasis

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1380-1399页

作者： Yixian Li Peng Yang Ran Meng Shuting Xu Lingling Zhou Kang Qian Pengzhen Wang Yunlong Cheng Dongyu Sheng Minjun Xu Tianying Wang Jing Wu Jinxu Cao Qizhi Zhang Key Laboratory of Smart Drug Delivery Ministry of EducationSchool of PharmacyFudan UniversityShanghai 201203China

Intraneuronal dysproteostasis and extraneuronal microenvironmental abnormalities in Alzheimer’s disease(AD)collectively culminate in neuronal deterioration.In the context of AD,autophagy dysfunction,a multi-link obstacle involving autophagy downregulation and lysosome defects in neurons/microglia is highly implicated in intra/extraneuronal pathological processes.Therefore,multidimensional autophagy regulation strategies co-manipulating“autophagy induction”and“lysosome degradation”in dual targets(neuron and microglia)are more reliable for AD treatment.Accordingly,we designed an RP-1 peptide-modified reactive oxygen species(ROS)-responsive micelles(RT-NM)loading rapamycin or gypenoside XVII.Guided by RP-1 peptide,the ligand of receptor for advanced glycation end products(RAGE),RT-NM efficiently targeted neurons and microglia in AD-affected region.This nanocombination therapy activated the whole autophagy-lysosome pathway by autophagy induction(rapamycin)and lysosome improvement(gypenoside XVII),thus enhancing autophagic degradation of neurotoxic aggregates and inflammasomes,and promoting Aβ phagocytosis.Resultantly,it decreased aberrant protein burden,alleviated neuroinflammation,and eventually ameliorated memory defects in 3×Tg-AD transgenic mice.Our research developed a multidimensional autophagy nano-regulator to boost the efficacy of autophagy-centered AD therapy.

关键词： Autophagy-lysosome pathway Alzheimer’s disease Proteostasis Neuroinflammation Multi-target therapy rapamycin Gypenoside XVII Cascade dual-targeting

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 benefit.In 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 cells.Mechanically,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 arrest.Meanwhile,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 condition.These effects were further validated in xenograft models.In 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

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

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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 disease.rapamycin,an autophagy inducer,has been shown to have neuroprotective effects in Parkinson’s disease.However,the link between rapamycin and ferroptosis in Parkinson’s disease is not entirely clear.In 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 model.The 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 ptosis.The 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 effects.Therefo 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

Dichloroacetic acid and rapamycin synergistically inhibit tumor progression

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2023年第5期24卷 397-405页

作者： Huan CHEN Kunming LIANG Cong HOU Hai-long PIAO CAS Key Laboratory of Separation Science for Analytical Chemistry Dalian Institute of Chemical PhysicsChinese Academy of SciencesDalian 116023China Department of Biochemistry&Molecular Biology School of Life SciencesChina Medical UniversityShenyang 110122China University of Chinese Academy of Sciences Beijing 100049China

Mammalian target of rapamycin(mTOR)controls cellular anabolism,and mTOR signaling is hyperactive in most cancer cells.As a result,inhibition of mTOR signaling benefits cancer patients.rapamycin is a US Food and Drug Administration(FDA)-approved drug,a specific mTOR complex 1(mTORC1)inhibitor,for the treatment of several different types of cancer.However,rapamycin is reported to inhibit cancer growth rather than induce apoptosis.Pyruvate dehydrogenase complex(PDHc)is the gatekeeper for mitochondrial pyruvate oxidation.PDHc inactivation has been observed in a number of cancer cells,and this alteration protects cancer cells from senescence and nicotinamide adenine dinucleotide(NAD^(+))exhaustion.In this paper,we describe our finding that rapamycin treatment promotes pyruvate dehydrogenase E1 subunit alpha 1(PDHA1)phosphorylation and leads to PDHc inactivation dependent on mTOR signaling inhibition in cells.This inactivation reduces the sensitivity of cancer cells'response to rapamycin.As a result,rebooting PDHc activity with dichloroacetic acid(DCA),a pyruvate dehydrogenase kinase(PDK)inhibitor,promotes cancer cells'susceptibility to rapamycin treatment in vitro and in vivo.

关键词： Dichloroacetic acid(DCA) rapamycin Pyruvate dehydrogenase E1 subunit alpha 1(PDHA1) Mammalian target of rapamycin(mTOR)

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

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

Fasting produces antidepressant-like effects via activating mammalian target of rapamycin complex 1 signaling pathway in ovariectomized mice

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Neural Regeneration Research 2023年第9期18卷 2075-2081页

作者： Zi-Qian Cheng Jie Fan Fang-Yi Zhao Jing-Yun Su Qi-Han Sun Ran-Ji Cui Bing-Jin Li Jilin Provincial Key Laboratory on Molecular and Chemical Genetic The Second Hospital of Jilin UniversityChangchunJilin ProvinceChina Jilin Engineering Laboratory for Screening of Antidepressant ChangchunJilin ProvinceChina

Recent studies have shown that a 9-hour fast in mice reduces the amount of time spent immobile in the forced swimming test.Howeve r,whether 9-hour fasting has therapeutic effects in female mice with depressive symptoms has not been established.Therefore,in this study,we simulated perimenopausal depression via an ovariectomy in mice,and subjected them to a single 9-hour fasting 7 days later.We found that the ovariectomy increased the time spent immobile in the forced swimming test,inhibited expression of the mammalian target of rapamycin complex 1 signaling pathway in the hippocampus and prefro ntal cortex,and decreased the density of dendritic spines in the hippocampus.The 9-hour acute fasting alleviated the above-mentioned phenomena.Furthermore,all of the antidepressant-like effects of 9-hour fasting were reve rsed by an inhibitor of the mammalian to rget of rapamycin complex 1.Electrophysiology data showed a remarkable increase in long-term potentiation in the hippocampal CA1 of the ovariectomized mice subjected to fasting compared with the findings in the ovariectomized mice not subjected to fasting.These findings show that the antidepressant-like effects of 9-hour fasting may be related to the activation of the mammalian target of the rapamycin complex 1 signaling pathway and synaptic plasticity in the mammalian hippocampus.Thus,fasting may be a potential treatment for depression.

关键词： antidepressant brain-derived neurotrophic factor dendritic spine fasting hippocampus LTP mTOR complex 1 neural plasticity ovariectomized mice rapamycin

Indirect targeting of MYC sensitizes pancreatic cancer cells to mechanistic target of rapamycin (mTOR) inhibition

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Cancer Communications 2022年第4期42卷 360-364页

作者： Christian Schneeweis Zonera HassanKatja Ascherl Matthias Wirth Stella Koutsouli Felix Orben Lukas Krauß Carolin Schneider Rupert Ollinger Oliver HKrämer Roland Rad Maximilian Reichert Maria SRobles Dieter Saur Günter Schneider Medical Clinic and Polyclinic II Klinikum rechts der IsarTechnical University MunichMunich 81675Germany Department of Hematology Oncology and Tumor ImmunologyCharite-Universitatsmedizin BerlinCorporate Member of Freie Universitat BerlinHumboldt-Universitat zu Berlin and Berlin Institute of HealthBerlin 12203Germany Institute of Medical Psychology and Biomedical Center(BMC) Faculty of MedicineLMU MunichMunich 80336Germany Institute of Molecular Oncology and Functional Genomics TUM School of MedicineTechnical University MunichMunich 81675Germany Department of Toxicology University of Mainz Medical CenterMainz 55131Germany German Cancer Research Center(DKFZ)and German Cancer Consortium(DKTK) Heidelberg 69120Germany Center for Protein Assemblies(CPA) Technical University of MunichGarching 85747Germany Institute for Translational Cancer Research and Experimental Cancer Therapy Technical University MunichMunich 81675Germany Department of General Visceral and Pediatric SurgeryUniversity Medical Center GottingenGottingen 37075Germany

Dear Editor,Pancreatic ductal adenocarcinoma(PDAC)remains a significant health problem with an increase in the incidence and a five-year survival rate of only 10%[1].The Phosphoinositide 3-kinase-protein kinase-B-mechanistic target of rapamycin(PI3K-AKT-mTOR)pathway is a driver pathway in PDAC and an important therapeutic target[2].We[3]and others[4–6]have demonstrated that the mTOR kinase is a therapeutic target in PDAC,and rationally designed mTOR inhibitor(mTORi)-based combination therapies are emerging[2].

关键词： rapamycin therapeutic adenocarcinoma

Real-world five-year outcomes of FlexyRap®cobalt-chromium rapamycin-eluting stents with biodegradable polymer in patients with de-novo coronary artery disease

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World Journal of Cardiology 2023年第3期15卷 84-94页

作者： Nitish Garg Raman Chawla Vivek Tandon Deepak Garg Nilesh Parshottam Preeti Vani Malte Neuss Department of Interventional Cardiology Cardinova HospitalJalandhar 144001India Department of Interventional Cardiology CareMax HospitalJalandhar 144001India Department of Interventional Cardiology EMC HospitalAmritsar 143001India Department of Interventional Cardiology Moga Medicity HospitalMoga 142001India Department of Interventional Cardiology Sunshine Global HospitalSurat 394370India Medical Division Sahajanand Laser Technology Ltd.GandhinagarGujarat382028India

BACKGROUND The use of biodegradable polymer drug-eluting stents(BP-DES)has been proven to minimize restenosis and stent thrombosis.The current post-marketing monitoring was observed at the 5-year clinical outcomes of individuals who had been treated with FlexyRap®DES in the real world.AIM To assess the safety and effectiveness of FlexyRap®DES at the 5-year follow-up in real-world settings.METHODS Findings from a retrospective,multi-center,observational,post-market clinical follow-up study of patients treated with FlexyRap®DES for de novo coronary artery disease(CAD)were reported.During the 12-mo follow-up,the primary endpoint was target lesion failure,which was defined as the composite of cardiovascular death, target vessel myocardial infarction(TV-MI), and clinically driven target lesion revascularization.RESULTS The data of 500 patients received with FlexyRap®DES was obtained at the completion of the surveillance timeline of 5-year.After the implantation of FlexyRap®DES,the device success rate was 100%.Adverse events that led to major bleeding,permanent disability,or death were not experienced in the patients.The major adverse cardiac event rate at 12-mo,3-year,and 5-year follow-up was 1(0.2%),0(0%),and 1(0.2%)respectively with 0(0%)cardiovascular death,2(0.4%)TV-MI,and 0(0%)TLR compositely.Furthermore,late stent thrombosis was found in 2(0.4%)patients at the follow-up of 12-mo,very late stent thrombosis was observed in 2 patients(0.4%)at 3-year follow-up.CONCLUSION FlexyRap®DES was proved to be safe and efficacious in real-world patients with de novo CAD,indicating a lowered rate of cardiac events and stent thrombosis at 5-year follow-up.

关键词： Coronary artery disease Drug-eluting stents Percutaneous coronary intervention rapamycin Sirolimus

rapamycin attenuates bleomycin-induced pulmonary fibrosis in rats and the expression of metalloproteinase-9 and tissue inhibitors of metalloproteinase-1 in lung tissue

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Chinese Medical Journal 2014年第7期127卷 1304-1309页

作者： Jin Xiaoguang Department of Respiratory and Critical Care Medicine Beijing Chao-Yang Hospital Capital Medical University Beijing 100020 China Beijing Institute of Respiratory Medicine Beijing 100020 China Beijing Hospital Beijing 100730 China

Background Idiopathic pulmonary fibrosis （IPF） is the most common and devastating form of interstitial lung disease （ILD） in the clinic.There is no effective therapy except for lung transplantation.rapamycin is an immunosuppressive drug with potent antifibrotic activity.The purpose of this study was to examine the effects of rapamycin on bleomycininduced pulmonary fibrosis in rats and the relation to the expression of metalloproteinase-9 （MMP-9） and tissue inhibitor of metalloproteinase-1 （TIMP-1）.Methods Sprague-Dawley rats were treated with intratracheal injection of 0.3 ml of bleomycin （5 mg/kg） in sterile 0.9％ saline to make the pulmonary fibrosis model.rapamycin was given at a dose of 0.5 mg/kg per gavage,beginning one day before bleomycin instillation and once daily until animal sacrifice.Ten rats in each group were sacrificed at 3,7,14,28 and 56 days after bleomycin administration.Alveolitis and pulmonary fibrosis were semi-quantitatively assessed after HE staining and Masson staining under an Olympus BX40 microscope with an IDA-2000 Image Analysis System.Type Ⅰ and Ⅲ collagen fibers were identified by Picro-sirius-polarization.Hydroxyproline content in lung tissue was quantified by a colorimetric-based spectrophotometric assay,MMP-9 and TIMP-1 were detected by immunohistochemistry and by realtime quantitative reverse transcriptase polymerase chain reaction （RT-PCR）.Results Bleomycin induced alveolitis and pulmonary fibrosis of rats was inhibited by rapamycin.Significant inhibition of alveolitis and hydroxyproline product were demonstrated when daily administration of rapamycin lasted for at least 14 days.The inhibitory efficacy on pulmonary fibrosis was unremarkable until rapamycin treatment lasted for at least 28 days （P ＜0.05）.It was also demonstrated that rapamycin treatment reduced the expression of MMP-9 and TIMP-1 in lung tissue that was increased by bleomycin.Conclusion These results highlight the significance of rapamycin in alleviating alveolitis and pulmonary fibrosis,which is associated with de

关键词： rapamycin pulmonary fibrosis bleomycin metalloproteinase-9 tissue inhibitor ofmetalloproteinase-1