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Inhibitory role of peroxiredoxin 2 in LRRK2 kinase activity induced cellular pathogenesis

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The Journal of Biomedical Research 2020年第2期34卷 103-113页

作者： Kang Yan Wenfeng Zhang Xu Han Fei Chang Yongjian Liu Jiangsu Key Laboratory of Xenotransplantation School of Basic Medical ScienceNanjing Medical UniversityNanjingJiangsu 211166China Department of Pharmacology&Chemical Biology University of Pittsburgh School of MedicinePittsburghPA 15216USA

Parkinson’s disease(PD) is a major neurodegenerative disease. One of the known genetic contributors to PD pathogenesis is leucine-rich repeat kinase 2(LRRK2) whose mutations with elevated kinase activity could lead to both familial and sporadic PD. However, how the pathogenic kinase activity of LRRK2 is regulated remains largely unclear. Here we report that peroxiredoxin 2(Prx2) was identified as a novel interacting protein to LRRK2 with preferential expression in dopaminergic neurons over other Prx proteins. We also confirmed that Prx2 interacted with LRRK2 through its COR domain and its overexpression significantly decreased the kinase activity of mutant LRRK2. Functionally, overexpressed Prx2 rescued the transfected cells from LRRK2 mutant induced apoptotic processes. Importantly, overexpressed Prx2 reversed the altered subcellular distribution of cationindependent mannose 6-phosphate receptor(CI-M6 PR) induced by PD-mutant LRRK2. Our results suggest that,by interacting with LRRK2, Prx2 may play an inhibitory role in the LRRK2 mediated cellular toxicity in PD by inhibiting its kinase activity.

关键词： peroxiredoxin 2 LRRK2 Parkinson's disease

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Transgenic overexpression of steroid sulfatase alleviates cholestasis

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Liver Research 2017年第1期1卷 63-69页

作者： Mengxi Jiang Meishu Xu Songrong Ren Kyle W.Selcer Wen Xie Center for Pharmacogenetics Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA department of Biological Sciences Duquesne UniversityPittsburghPAUSA Department of Pharmacology&Chemical Biology University of PittsburghPittsburghPAUSA

Background and Aim:Sulfotransferase(SULT)-mediated sulfation and steroid sulfatase(STS)-mediated desulfation represent two critical mechanisms that regulate the chemical and functional homeostasis of endogenous and exogenous molecules.STS catalyzes the hydrolysis of steroid sulfates to form hydroxysteroids.Oxygenated cholesterol derivative oxysterols are known to be endogenous ligands of the liver X receptor(LXR),a nuclear receptor with anti-cholestasis activity,whereas the sulfated oxysterols antagonize LXR signaling.The conversion of sulfated oxysterols to their non-sulfated counterparts is catalyzed by STS.The aim of this study is to determine whether STS can alleviate cholestasis by increasing the activity of LXR.Methods:Liver-specific STS transgenic mice were created and subject to the lithocholic acid(LCA)-induced model of cholestasis.Results:Transgenic overexpression of STS in the liver promoted bile acid elimination and alleviated LCAinduced cholestasis.The protective effect of the STS transgene was associated with the activation of LXR and induction of LXR target genes,likely because of the increased conversion of the antagonistic oxysterol sulfates to the agonistic oxysterols.Conclusions:STS has a novel function in controlling the homeostasis of bile acids by regulating endogenous LXR ligands.

关键词： Steroid sulfatase Bile acid Toxicity Cholestasis Liver X receptor

Leelamine suppresses cMyc expression in prostate cancer cells in vitro and inhibits prostate carcinogenesis in vivo

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Journal of Cancer Metastasis and Treatment 2021年第1期7卷 242-253页

作者： Krishna B.Singh Eun-Ryeong Hahm Shivendra V.Singh Department of Pharmacology&Chemical Biology University of Pittsburgh School of MedicinePittsburghPennsylvaniaPA15261USA UPMC Hillman Cancer Center University of Pittsburgh School of MedicinePittsburghPennsylvaniaPA 15213USA

Aim:Leelamine(LLM)inhibits the growth of human prostate cancer cells but the underlying mechanism is not fully understood.The present study was undertaken to determine the effect of LLM on cMyc,which is overexpressed in a subset of human prostate cancers.Methods:The effect of LLM on cMyc expression and activity was determined by western blotting/confocal microscopy and luciferase reporter assay,respectively.A transgenic mouse model of prostate cancer(Hi-Myc)was used to determine the chemopreventive efficacy of LLM.Results:Exposure of androgen-sensitive(LNCaP)and castration-resistant(22Rv1)human prostate cancer cells to LLM resulted in downregulation of protein and mRNA levels of cMyc.Overexpression of cMyc partially attenuated LLM-mediated inhibition of colony formation,cell viability,and cell migration in 22Rv1 and/or PC-3 cells.LLM treatment decreased protein levels of cMyc targets(e.g.,lactate dehydrogenase),however,overexpression of cMyc did not attenuate these effects.A trend for a decrease in the expression level of cMyc protein was discernible in 22Rv1 xenografts from LLM-treated mice compared with control mice.LLM treatment(10 mg/kg body weight,5 times/week)was well-tolerated by Hi-Myc transgenic mice.The incidence of high-grade prostatic intraepithelial neoplasia,adenocarcinoma in situ,and microinvasion were lower in LLM-treated Hi-Myc mice but the difference was not statistically significant.Conclusion:The present study reveals that LLM inhibits cMyc expression in human prostate cancer cells in vitro but concentrations higher than 10 mg/kg may be required to achieve chemoprevention of prostate cancer.

关键词： Prostate cancer cMyc leelamine chemoprevention

Environmental toxicant-induced maladaptive mitochondrial changes:A potential unifying mechanism in fatty liver disease?

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Acta Pharmaceutica Sinica B 2021年第12期11卷 3756-3767页

作者： Regina D.Schnegelberger Anna L.Lang Gavin E.Arteel Juliane I.Beier Department of Pharmacology&Chemical Biology University of PittsburghPittsburghPA 15213USA department of Neurology University of Miami Miller School of MedicineMiamiFL 33136USA department of Medicine Division of GastroenterologyHepatology&NutritionUniversity of PittsburghPittsburghPA 15213USA Pittsburgh Liver Research Center University of PittsburghPittsburghPA 15213USA department of Environmental&Occupational Health University of PittsburghPittsburghPA 15213USA

Occupational and environmental exposures to industrial chemicals are well known to cause hepatotoxicity and liver injury.However,despite extensive evidence showing that exposure can lead to disease,current research approaches and regulatory policies fail to address the possibility that subtle changes caused by low level exposure to chemicals may also enhance preexisting conditions.In recent years,the conceptual understanding of the contribution of environmental chemicals to liver disease has progressed significantly.Mitochondria are often target of toxicity of environmental toxicants resulting in multisystem disorders involving different cells,tissues,and organs.Here,we review persistent maladaptive changes to mitochondria in response to environmental toxicant exposure as a mechanism of hepatotoxicity.With better understanding of the mechanism(s) and risk factors that mediate the initiation and progression of toxicant-induced liver disease,rational targeted therapy can be developed to better predict risk,as well as to treat or prevent this disease.

关键词： Organochlorines Metals Persistent organic pollutants TASH Liver disease Hepatotoxicity Mitochondrial maladaptation Mitohormesis

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Sulfation of chondroitin and bile acids converges to antagonize Wnt/β-catenin signaling and inhibit APC deficiency-induced gut tumorigenesis

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1241-1256页

作者： Pengfei Xu Yue Xi Jong-Won Kim Junjie Zhu Min Zhang Meishu Xu Songrong Ren Da Yang Xiaochao Ma Wen Xie Center for Pharmacogenetics and department of Pharmaceutical Sciences University of PittsburghPittsburghPA 15261USA department of Hepatobiliary and Pancreatic Surgery Zhongnan Hospital of Wuhan UniversitySchool of Pharmaceutical SciencesWuhan UniversityWuhan 430071China Department of Pharmacology&Chemical Biology University of PittsburghPittsburghPA 15261USA

Sulfation is a crucial and prevalent conjugation reaction involved in cellular processes and mammalian physiology.3’-Phosphoadenosine 5’-phosphosulfate(PAPS)synthase 2(PAPSS2)is the primary enzyme to generate the universal sulfonate donor PAPS.The involvement of PAPSS2-mediated sulfation in adenomatous polyposis coli(APC)mutation-promoted colonic carcinogenesis has not been reported.Here,we showed that the expression of PAPSS2 was decreased in human colon tumors along with cancer stages,and the lower expression of PAPSS2 was correlated with poor prognosis in advanced colon cancer.Gut epithelial-specific heterozygous Apc deficient and Papss2-knockout(Apc^(Δgut-Het)Papss2^(Δgut))mice were created,and the phenotypes were compared to the spontaneous intestinal tumorigenesis of Apc^(Δgut-Het)mice.Apc^(Δgut-Het)Papss2^(Δgutmice) were more sensitive to gut tumorigenesis,which was mechanistically accounted for by the activation of Wnt/β-catenin signaling pathway due to the suppression of chondroitin sulfation and inhibition of the farnesoid X receptor(FXR)-transducin-like enhancer of split 3(TLE3)gene regulatory axis.Chondroitin sulfate supplementation in Apc^(Δgut-Het)Papss2^(Δgutmice) alleviated intestinal tumorigenesis.In summary,we have uncovered the protective role of PAPSS2-mediated chondroitin sulfation and bile acids-FXR-TLE3 activation in the prevention of gut carcinogenesis via the antagonization of Wnt/β-catenin signaling.Chondroitin sulfate may be explored as a therapeutic agent for Papss2 deficiency-associated colonic carcinogenesis.

关键词： Colon cancer APC Wnt/b-catenin PAPSS2 Chondroitin sulfate Sulfation Bile acids FXR

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Small-molecule chemical probes for the potential therapeutic targets in alcoholic liver diseases

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Liver Research 2023年第3期7卷 177-188页

作者： Ashish Dogra Feng Li Center for Drug Discovery Department of Pathology&ImmunologyBaylor College of MedicineHoustonTXUSA NMR and Drug Metabolism Core Advanced Technology CoresBaylor College of MedicineHoustonTXUSA department of Biochemistry&Molecular pharmacology&chemical biology Baylor College of MedicineHoustonTXUSA

Alcoholic liver disease(ALD)encompasses a range of conditions resulting from prolonged and excessive alcohol consumption,causing liver damage such as alcoholic fatty liver,inflammation,fibrosis,and cirrhosis.Alcohol consumption contributes to millions of deaths each year.So far,the effective treatments for ALD are limited.To date,the most effective treatment for ALD is still prevention by avoiding excessive alcohol consumption,and only few specialized medicines are in the market for the treatment of patients suffering from ALD.Small molecules targeting various pathways implicated in ALD pathogenesis can potentially be used for effective therapeutics development.In this review,we provide a concise overview of the latest research findings on potential therapeutic targets,specifically emphasizing small-molecule interventions for the treatment and prevention of ALD.

关键词： Alcoholic liver disease(ALD) Signaling pathways Pathogenesis Therapeutic target chemical probe Small-molecule probe

Targeting adenosine receptor 2B in triple negative breast cancer

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Journal of Cancer Metastasis and Treatment 2018年第1期4卷 171-177页

作者： Carola A.Neumann Kevin Levine Steffi Oesterreich Department of Pharmacology&Chemical Biology University of Pittsburgh Medical Center Hillman Cancer CenterWomens Cancer Research CenterMagee Womens Research InstitutePittsburghPA 15213USA department of Pathology University of PittsburghPittsburghPA 15261USA

In the review“Role of adenosine in tumor progression:focus on A2B receptor as potential therapeutic target”,Sorrentino and Morello make a compelling case for considering adenosine 2B receptor(A2BR)as a target in cancer therapy(J Cancer Metastasis Treat 2017;3:127-38).A large body of evidence has accumulated suggesting A2BR to play an active role in tumor immune suppression and metastasis.Thus,this commentary will discuss the intriguing possibility of targeting A2BR in specific breast cancers that express high levels of A2BR and attract infiltrating immune cells.

关键词： breast cancer Cancer

Metal-organic frameworks as effective sensors and scavengers for toxic environmental pollutants

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National Science Review 2022年第7期9卷 162-180页

作者： Avishek Karmakar Ever Velasco Jing Li department of Chemistry and chemical biology Rutgers University

Metal-organic frameworks(MOFs) constructed from a rich library of organic struts and metal ions/clusters represent promising candidates for a wide range of applications.The unique structure,porous nature,easy tunability and processability of these materials make them an outstanding class of materials for tackling serious global problems relating to energy and environment.Among them,environmental pollution is one aspect that has increased at an alarming rate in the past decade or so.With rapid urbanization and industrialization,toxic environmental pollutants are constantly released and accumulated leading to serious contamination in water bodies and thereby having adverse effects on human health.Recent studies have shown that many toxic pollutants,as listed by the World Health Organization and the US Environmental Protection Agency,can be sele ctively detecte d,captured,sequestered and removed by MOFs from air and aquatic systems.Most of these sensing/capture processes in MOFs are quantifiable and effective for even a trace amount of the targeted chemical species.The functional sites(ligands and metals) play a critical role in such recognition processes and offer an extensive scope of structural tunability for guest(pollutants,toxic entities) recognition.Whereas on the one hand,the underlying mechanisms governing such sensing and capture are important,it is also crucial to identify MOFs that are best suited for commercial applications for the future.In this review article,we provide an overview of the most recent progress in the sensing,capture and removal of various common toxic pollutants,including neutral and ionic,inorganic and organic species,with brief dis cussions on the mechanism and efficacy of selected MOFs.

关键词： metal-organic framework detoxification luminescent sensing pollution environmental remediation

Low-intensity walking as mild medication for pressure control in prehypertensive and hypertensive subjects:how far shall we wander?

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Acta Pharmacologica Sinica 2019年第8期40卷 1119-1126页

作者： Qin Lu Sheng-ming Wang Yi-xiao Liu Hong Chen Rui Zhang Wen-hui Zhang Yuan-yuan Zou Jia-wei Zhou Xin-yi Guo Ying Zhang Teng-Li Huang Yu-hang Liu Si-qi Zhang Kyosuke Yamanishi Hiromichi Yamanishi Hideaki Higashino Haruki Okamura department of pharmacology and chemical biology Shanghai Jiao Tong University School of Medicine Hirakata Ryoikuen

Successful prevention and treatment of hypertension depend on the appropriate combination of antihypertensive drug therapy and nondrug lifestyle modification.While most hypertension guidelines recommend moderate-to high-intensity exercise,we decided to explore a mild yet effective type of exercise to add to hypertension management,especially in populations with complications or frailty.After comparing the short-term cardiovascular effects of low-speed walking versus high-speed walking for 3 kilometers(km)(3 km/h versus 6 km/h)in young,healthy volunteers,we delivered low-speed walking(low-intensity walking,2.5 metabolic equivalents of task,METs)as exercise therapy in 42 prehypertensive and 43 hypertensive subjects.We found that one session of 3 km low-intensity walking exerted a transient pressure-lowering effect as well as a mild negative chronotropic effect on heart rate in both the prehypertensive and hypertensive subjects;these short-term benefits on blood pressure and heart rate were accompanied by a brief increase in urine β-endorphin output.Then we prescribed regular low-intensity walking with a target exercise dose(exercise volume)of 500-1000 METs-min/week(50-60 min/day and 5-7 times/week)in hypertensive subjects in addition to their daily activities.Regular low-intensity walking also showed mild but significant blood pressure-lowering and heart rate-reducing effects in 7 hypertensive subjects within two months.It is hypothesized that regular low-intensity exercise of the necessary dose could be taken as a pragmatic and supplementary medication for hypertension management.

关键词： hypertension prehypertension exercise medication low-intensity walking metabolic equivalent of task blood pressure heart rate urine β-endorphin