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A potent PGK1 antagonist reveals PGK1 regulates the production of IL-1βand IL-6

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Acta Pharmaceutica Sinica B 2022年第11期12卷 4180-4192页

作者： Liping Liao Wenzhen Dang Tingting Lin Jinghua Yu Tonghai Liu Wen Li Senhao Xiao Lei Feng Jing Huang Rong Fu Jiacheng Li Liping Liu Mingchen Wang Hongru Tao Hualiang Jiang Kaixian Chen Xingxing Diao Bing Zhou Xiaoyan Shen Cheng Luo deparment of pharmacology&the Key Laboratory of Smart Drug Delivery Ministry of EeducaionSchool of PharmacyFudan UniversityShanghai 201203China State Key Laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Bejing 10049China School of Pharmaceutical Science and Technology Hangzhou Institute for Advanced StudyUniversity of Chinese Academy of SciencesHangzhou 310024China School of Pharmaceutical Sciences Zhejiang Chinese Medical UniversityHangzhou 310053China

Glycolytic metabolism enzymes have been implicated in the immunometabolism field through changes in metabolic status. PGK1 is a catalytic enzyme in the glycolytic pathway. Here, we set up a high-throughput screen platform to identify PGK1 inhibitors. DC-PGKI is an ATPcompetitive inhibitor of PGK1 with an affinity of Kd= 99.08 nmol/L. DC-PGKI stabilizes PGK1in vitro and in vivo, and suppresses both glycolytic activity and the kinase function of PGK1. In addition,DC-PGKI unveils that PGK1 regulates production of IL-1β and IL-6 in LPS-stimulated ***, inhibition of PGK1 with DC-PGKI results in NRF2(nuclear factor-erythroid factor 2-related factor 2, NFE2L2) accumulation, then NRF2 translocates to the nucleus and binds to the proximity region of Il-1β and Il-6 genes, and inhibits LPS-induced expression of these genes. DC-PGKI ameliorates colitis in the dextran sulfate sodium(DSS)-induced colitis mouse model. These data support PGK1 as a regulator of macrophages and suggest potential utility of PGK1 inhibitors in the treatment of inflammatory bowel disease.

关键词： Glycolysis Phosphoglycerate kinasel Macrophages NRF2 Inflammation

Brain GABA and glutamate levels in workers of two ant species （Hymenoptera： Formicidae）： Interspecific differences and effects of queen presence/absence

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Insect Science 2014年第5期21卷 647-658页

作者： Andrzej Wnuk Wojciech Kostowski Julita Korczynska Anna Szczuka Beata Symonowicz Przemyslaw Bienkowski Pawel Mierzejewski Ewa Joanna Godzinska Laboratory of Ethology Department of Neurophysiology Nencki Institute of Experimental Biology PAS Warsaw Department of pharmacology and Physiology of the Nervous System Institute of Psychiatry and Neurology Warsaw Poland

Presence of amino acid neurotransmitters gamma-aminobutyric acid （GABA） and glutamate （Glu） in ant brains was reported in very few studies. To learn more about factors influencing GABA and Glu levels in ant brains, we applied high-performance liquid chromatography to measure levels of these compounds in single brains of workers of 2 ant species, Myrmica ruginodis （subfamily Myrmicinae） and Formica polyctena （subfamily Formicinae） taken from queenright/queenless colony fragments and tested in dyadic aggression tests consisting of an encounter with a nestrnate, an alien conspecific or a small cricket. Brain glutamate levels were higher than those of GABA in both tested species. Brain GABA levels （in μmol/brain） and GABA ： Glu ratio were higher in M. ruginodis （a submissive species） than in E polyctena （a dominant, aggressive species） in spite of smaller brain weight of M. ruginodis. Brain glutamate levels （in μmol/brain） did not differ between the tested species, which implies that glutamate concentration （in μmol/mg of brain tissue） was higher in M. ruginodis. Queen absence was associated with increased worker brain GABA levels in E polyctena, but not in M. ruginodis. No significant effects of opponent type were discovered. As GABA agonists enhance friendly social behavior in rodents, we hypothesize that elevated brain GABA levels of orphaned workers of *** facilitate the adoption of a new queen. This is the first report providing information on GABA and glutamate levels in single ant brains and documenting the effects of queen presence/absence on brain levels of amino acid neurotransmitters in workers of social Hymenoptera.

关键词： Formica polyctena GABA glutamate interspecific differences Myrmica ruginodis queen

Selectively activate Kv7.4channel in DRN 5-HT neurons reverses depression-like behavior in social defeat model

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Selectively activate Kv7.4channel in DRN 5-HT neurons revers...

The efficacy of tucatinib-based therapeutic approaches for HER2-positive breast cancer

中国神经科学学会第十二届全国学术会议

作者： Chen Zhao Yingzi Wang Li Li Min Su Jing Wang Hailin Zhang deparment of pharmacology Hebei Medical University

Objective It’s well known that serotonergic system originating in dorsal raphe nuclei（DRN） play essential roles in the control of mood, the pharmacotherapy of anxiety and depression. Here we describe the crucial roles of Kv7.4 potassium channels in modulating the excitability of 5-HT neurons in DRN and the development of depressionlike behaviors in social defeat depression models. Methods（1） Whole-cell patch clamp was used to record Kv7 currents and elicited firing activity of DRN 5-HT neurons. And non-invasive loose-seal cell-attached patch clamp was used to record the spontaneous firing activity.（2） Cell types were identified via single-cell PCR.（3） The depression-like behaviors were measured by social interaction test and sucrose preference test. Results（1） Among the subunits of Kv7 channels, Kv7.4 selectively expressed in DRN 5-HT neurons.（2） Fasudil potently augments Kv7.4 current in DRN 5-HT neurons.（3） Kv7.4 activity modulates the excitability of DRN 5-HT neurons.（4） Fasudil reversed the depression-like behaviors in the social defeat models of depression. Conclusion Since the expression of Kv7.4 in the CNS is limited, selectively targeting Kv7.4 channel is likely to produce fewer side effects than non-selective Kv7 channel openers and, thus, Kv7.4 may offer an alternative novel target for treating depression.

关键词： Kv7.4 5-HT DRN social defeat depression-like behavior

来源： cnki会议评论

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Military Medical Research 2022年第5期9卷 628-636页

作者： Zaid Sirhan Anita Thyagarajan Ravi P.Sahu Department of pharmacology and Toxicology Boonshoft School of Medicine Wright State UniversityDaytonOH45435USA

Overexpression of human epidermal growth factor receptor 2 (HER2) occurs in approximately 15–20% of breast cancer cases. HER2 is a member of the epidermal growth factor receptor (EGFR) family with tyrosinase kinase activity, and its overexpression is linked to poor prognosis and shorter progression-free survival (PFS) and overall survival (OS). Among various treatment options, HER2-targeting monoclonal antibodies and tyrosine kinase inhibitors (TKIs) have mostly been applied in recent decades to treat HER2-positive (HER2^(+)) breast cancer patients. Although positive clinical outcomes were documented in both advanced disease and neoadjuvant settings, the development of resistance mechanisms to such approaches has been one of the major challenges with the continuous usage of these drugs. In addition, patients who experience disease progression after treatment with multiple HER2-targeted therapies often have limited treatment options. The Food and Drug Administration (FDA) has recently approved a new TKI (i.e., tucatinib) for use in combination with immunotherapy and/or chemotherapeutic agents for the treatment of advanced-stage/metastatic HER2^(+) breast cancer. This review highlights recent updates on the efficacy of tucatinib-based therapeutic approaches in experimental models as well as in the clinical settings of HER2^(+) breast cancer.

关键词： HER2-positive(HER2^(+)) Breast cancer Targeted therapy Tucatinib Immunotherapy

Enzymatic and metabolic regulation of lysine succinylation

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Genes & Diseases 2020年第2期7卷 166-171页

作者： Annapoorna Sreedhar Elizabeth K.Wiese Taro Hitosugi Department of Molecular pharmacology and experimental Therapeutics Mayo ClinicRochesterMNUSA Division of Oncology Research Mayo ClinicRochesterMNUSA

Lysine succinylation(Ksucc),defined as a transfer of a succinyl group to a lysine residue of a protein,is a newly identified protein post-translational modification^*** chemical modification is reversible,dynamic,and evolutionarily conserved^4 where it has been comprehensively studied in both bacterial and mammalian cells^*** proteins involved in the regulation of various cellular and biological processes have been shown to be heavily succinylated^*** clinical data provides evidence that dysregulation of Ksucc is correlated with the development of several diseases,including cardiovascular diseases and cancer^***,an in-depth understanding of Ksucc and its regulation is important not only for understanding its physiological function but also for developing drug therapies and targeted agents for these *** this review,we highlight some of the recent advances in understanding the role of Ksucc and desuccinylation under physiological and pathological conditions.

关键词： Lysine succinylation Metabolism Post-translational modification SIRT5 Succinyl-CoA

Exosomes derived from differentiated human ADMSC with the Schwann cell phenotype modulate peripheral nerve-related cellular functions

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Bioactive Materials 2022年第8期7卷 61-75页

作者： Bo Liu Yunfan Kong Wen Shi Mitchell Kuss Ke Liao Guoku Hu Peng Xiao Jagadesan Sankarasubramanian Chittibabu Guda Xinglong Wang Yuguo Lei Bin Duan Mary&Dick Holland Regenerative Medicine Program and Division of Cardiology Department of Internal MedicineUniversity of Nebraska Medical CenterOmahaNEUSA Department of pharmacology and experimental Neuroscience University of Nebraska Medical CenterOmahaNEUSA Department of Genetics Cell Biology&AnatomyCollege of MedicineUniversity of Nebraska Medical CenterOmahaNEUSA Department of pharmacology&experimental Neuroscience College of MedicineUniversity of Nebraska Medical CenterOmahaNEUSA Department of Biomedical Engineering Huck Institutes of the Life SciencesSartorius Mammalian Cell Culture FacilityPennsylvania State UniversityUniversity ParkPAUSA Department of Surgery College of MedicineUniversity of Nebraska Medical CenterOmahaNEUSA Department of Mechanical and Materials Engineering University of Nebraska-LincolnLincolnNEUSA

Peripheral nerve regeneration remains a significant clinical challenge due to the unsatisfactory functional recovery and public health ***,especially those derived from mesenchymal stem cells(MSCs),are promising as potential cell-free therapeutics and gene therapy vehicles for promoting neural *** this study,we reported the differentiation of human adipose derived MSCs(hADMSCs)towards the Schwann cell(SC)phenotype(hADMSC-SCs)and then isolated exosomes from hADMSCs with and without differentiation(i.e.,dExo vs uExo).We assessed and compared the effects of uExo and dExo on antioxidative,angiogenic,anti-inflammatory,and axon growth promoting properties by using various peripheral nerve-related *** results demonstrated that hADMSC-SCs secreted more neurotrophic factors and other growth factors,compared to hADMSCs without *** dExo isolated from hADMSC-SCs protected rat SCs from oxidative stress and enhanced HUVEC migration and *** to uExo,dExo also had improved performances in downregulating pro-inflammatory gene expressions and cytokine secretions and promoting axonal growth of sensory neurons differentiated from human induced pluripotent stem ***,microRNA(miRNA)sequencing analysis revealed that exosomes and their parent cells shared some similarities in their miRNA profiles and exosomes displayed a distinct miRNA *** more miRNAs were identified in dExo than in *** upregulated miRNAs,like miRNA-132-3p and miRNA-199b-5p,were highly related to neuroprotection,anti-inflammation,and *** dExo can effectively modulate various peripheral nerve-related cellular functions and is promising for cell-free biological therapeutics to enhance neural regeneration.

关键词： Anti-oxidation Anti-inflammatory Axon growth Neural regeneration microRNA

Withania somnifera: a pre-clinical study on neuroregenerative therapy for stroke

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Neural Regeneration Research 2015年第2期10卷 183-185页

作者： Aparna Raghavan Zahoor A. Shah Department of Medicinal and Biological Chemistry College of Pharmacy and Pharmaceutical Sciences University of Toledo Department of pharmacology and experimental Therapeutics College of Pharmacy and Pharmaceutical Sciences University of Toledo

Stroke management exerts insurmountable societal and economic burden on the patient as well as their caregivers. In the year 2010 alone, the direct and indirect costs of stroke care amounted to 36.5 billion dollars （Go et al., 2014）. Despite concentrated efforts to develop a safe, effective drug for stroke, we have not discovered one since the introduction of recombinant tissue plasminogen activator （rtPA）--the standalone FDA-approved therapy for stroke. While rtPA is highly effective, it needs to be given within 3-4.5 hours of the onset of stroke symptoms （Zivin, 2009）. This is often complicated by the delay in the commencement of treatment due to preliminary inclusion parameters that are required to be ascertained before rtPA administration.

关键词： Withania somnifera a pre-clinical study on neuroregenerative therapy for stroke MCAO PARP WS

Another surprise in receptor binding of *** toxins

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The Innovation 2022年第4期3卷 13-14页

作者： Klaus Aktories Institute of experimental and Clinical pharmacology and Toxicology Medical FacultyUniversity of FreiburgAlbertstr.2579104 FreiburgGermany

Clostridioides difficile(formerly named Clostridium difficile)is the dominant causative agent of a spectrum of illnesses,which frequently occur as the consequence of antibiotic treatment of *** infections(CDIs)causemild to severe diarrhea(so-called antibiotic-associated diarrhea)but also pseudomembranous enterocolitis with complications like toxicmegacolon,bowel perforation,and *** protein toxins are involved in the pathology of CDIs,toxin A(TcdA)and toxin B(TcdB),which are the prototypes of large clostridial glucosylating toxins,and *** ADP-ribosyltransferase *** is most likely the driving toxin responsible for the major pathology of the infection.

关键词： diarrhea pathology colon

Telfairia occidentalis (Cucurbitaceae) pulp extract mitigates rifampicinisoniazid-induced hepatotoxicity in an in vivo rat model of oxidative stress

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Journal of Integrative Medicine 2019年第1期17卷 46-56页

作者： Lucky Legbosi Nwidu Yibala Ibor Oboma experimental pharmacology and Toxicology Faculty of Pharmaceutical Sciences University of Port Harcourt Medical Laboratory Sciences Faculty of Basic Medical Sciences College of Health Sciences Niger Delta University

Objective: Drug-induced liver injury complicates antituberculosis drug treatment and is a leading cause of death worldwide. The aim of this study is to establish the ethnomedicinal claim of hepatoprotective effects of fruit pulp extract of Telfairia occidentalis against rifampicin(RIF) and isoniazid(INH)-induced oxidative stress in ***: T. occidentalis pulp extract(TOPE)(125–500 mg/kg) and silymarin(50 mg/kg) were evaluated in an induced hepatotoxicity model of oxidative stress in Wistar rats by intoxication with RIF and INH(100 mg/kg each) orally for 60 d. Markers indicating oxidative stress and hepatic damage such as alanine aminotransferase(ALT), aspartate aminotransferase(AST) and alkaline phosphatase(ALP) were *** of antioxidant status, including catalase, glutathione reductase, glutathione peroxidase and superoxide dismutase, and marker of lipid peroxidation, malondialdehyde(MDA), were assayed using standard procedures. The hematological profile, lipid profile, serum markers for kidney function and histopathological examination were also ***: Intoxication with RIF and INH markedly reduced the hematological indices and elevated the biochemical enzyme markers(AST, ALT and ALP, P < 0.001) and lipid profile(P < 0.001), while antioxidant biomarkers were significantly(P < 0.01) depressed and MDA was elevated. However, pretreatment with TOPE significantly(P < 0.001) alleviated this alteration and sustained the antioxidant potentials. The histopathological morphology supports the biochemical evidence of ***: Current study is indicative of potential antioxidant activity, hepatoprotective effects and plausible therapeutic alleviation of RIF-INH-induced hepatotoxicity of TOPE in laboratory animals.

关键词： Telfairia occidentalis Pulp extract Oxidative stress Antioxidant Lipid peroxidation Hepatoprotective