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Analysis of the combined effect of rs699 and rs5051 on angiotensinogen expression and hypertension

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Chronic Diseases and Translational Medicine 2024年第2期10卷 102-117页

作者： Nicholas R.Powell Tyler Shugg Jacob Leighty Matthew Martin Rolf P.Kreutz Michael T.Eadon Dongbing Lai Tao Lu Todd C.Skaar Division of Clinical pharmacology Department of MedicineSchool of MedicineIndiana UniversityIndianapolisIndianaUSA Department of pharmacology and toxicology School of MedicineIndiana UniversityIndianapolisIndianaUSA Department of Cardiology School of MedicineKrannert Institute of CardiologyIndiana UniversityIndianapolisIndianaUSA Division of Nephrology Department of MedicineSchool of MedicineIndiana UniversityIndianapolisIndianaUSA Department of Medical and Molecular Genetics School of MedicineIndiana UniversityIndianapolisIndianaUSA

Background Hypertension(HTN)involves genetic variability in the renin-angiotensin system and influences antihypertensive *** previously reported that angiotensinogen(AGT)messenger RNA(mRNA)is endogenously bound by miR-122-5p and rs699 A>G decreases reporter mRNA in the microRNA functional-assay *** AGT promoter variant rs5051 C>T is in linkage disequilibrium(LD)with rs699 A>G and increases AGT *** independent effect of these variants is understudied due to their LD therefore we aimed to test the hypothesis that increased AGT by rs5051 C>T counterbalances AGT decreased by rs699 A>G,and when these variants occur independently,it translates to HTN-related *** We used in silico,in vitro,in vivo,and retrospective models to test this *** In silico,rs699 A>G is predicted to increase miR-122-5p binding affinity by 3%.Mir-eCLIP results show rs699 is 40–45 nucleotides from the strongest microRNA-binding site in the AGT ***,rs699 A>G increases AGT mRNA in an AGT-plasmid-cDNA HepG2 expression ***-Tissue Expression(GTEx)and UK Biobank analyses demonstrate liver AGT expression and HTN phenotypes are not different when rs699 A>G occurs independently from rs5051 C>***,GTEx and the in vitro experiments suggest rs699 A>G confers cell-type-specific effects on AGT mRNA abundance,and suggest paracrine renal renin-angiotensin-system perturbations could mediate the rs699 A>G associations with *** We found that rs5051 C>T and rs699 A>G significantly associate with systolic blood pressure in Black participants in the UK Biobank,demonstrating a fourfold larger effect than in White *** studies are warranted to determine if altered antihypertensive response in Black individuals might be due to rs5051 C>T or rs699 A>*** like this will help clinicians move beyond the use of race as a surrogate for genotype.

关键词： angiotensinogen genetic and genomic medicine hypertension rs699

Hepatitis B virus infection, infertility, and assisted reproduction

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2024年第8期25卷 672-685页

作者： Lingjian ZHANG Fangfang ZHANG Zhiyuan MA Jie JIN Department of Infectious Diseases Affiliated Hangzhou First People’s HospitalSchool of MedicineZhejiang UniversityHangzhou 310003China Women’s Hospital School of MedicineZhejiang UniversityHangzhou 310003China Key Laboratory of Clinical Cancer pharmacology and toxicology Research of Zhejiang Province Affiliated Hangzhou First People’s HospitalZhejiang University School of MedicineHangzhou 310003China

Background:Hepatitis B virus(HBV)is one of the most widespread viruses worldwide and a major cause of hepatitis,cirrhosis,and hepatocellular *** studies have revealed the impacts of HBV infection on *** increasing number of infertile couples with chronic hepatitis B(CHB)virus infection choose assisted reproductive technology(ART)to meet their fertility *** the high prevalence of HBV,the effects of HBV infection on assisted reproduction treatment remain limited and ***:The aim of this study was to provide a comprehensive overview of the effect of HBV infection on fertility and discuss its effects on pregnancy outcomes,vertical transmission,pregnancy complications,and viral activity during ART ***:We conducted a literature search in PubMed for studies on HBV infection and ART published from 1996 to ***:HBV infection negatively affected fertility in both males and *** research shows that HBV infection may increase the risk of pregnancy complications in couples undergoing assisted reproduction *** impact of HBV infection on the pregnancy outcomes of ART is still *** evidence does not support that ART increases the risk of vertical transmission of HBV,while relevant studies are *** the development of ART,the risk of HBV reactivation(HBVr)is increasing,especially due to the wide application of immunosuppressive ***:Regular HBV infection screening and HBVr risk stratification and management are essential to prevent HBVr during *** determination of optimal strategy and timing of prophylactic anti-HBV therapy during ART still needs further investigation.

关键词： Assisted reproductive technology(ART) Hepatitis B virus(HBV) Immunosuppressive agent Pregnancy

Hydroxychloroquine in SARS-CoV-2 infection:Understanding the misadventure

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Journal of Acute Disease 2024年第2期13卷 45-52页

作者： David Banji Otilia J F Banji Department of pharmacology&toxicology College of PharmacyJazan UniversitySaudi Arabia Department of Clinical Pharmacy College of PharmacyJazan UniversitySaudi Arabia

The widespread outbreak of SARS-CoV-2 was declared a public health emergency by the World Health Organization and various governments *** prompted the implementation of stringent infection control measures to curb the spread of the *** this,the medical community faced the challenge of treating the virus without specific therapies or a vaccine,leading to reliance on empirical treatment *** this context,hydroxychloroquine,an antimalarial and antirheumatic drug,gained attention as a potential treatment *** its theoretical benefits,such as inhibiting viral entry,reducing inflammation,and modulating immune responses,empirical studies yielded inconsistent *** indicated a potential for symptom relief,while others showed no significant improvement in patient *** initial enthusiasm waned as the lack of substantial evidence led to revoking its Emergency Use Authorization,and several clinical trials were prematurely *** review in question critically examines the factors contributing to the ineffectiveness of hydroxychloroquine in treating SARS-CoV-2 infection,highlighting the complexities of drug repurposing during a rapidly evolving pandemic.

关键词： SARS-CoV-2 Hydroxychloroquine Pharmacogenomics TLR signaling Cardiotoxicity

Narciclasine induces colon carcinoma cell apoptosis by inhibiting the IL-17A/Act1/TRAF6/NF-kB signaling pathway

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Genes & Diseases 2024年第5期11卷 428-441页

作者： Huiming Deng Qiang Liu Siman Yu Lifan Zhong Lianfang Gan Huiquan Gu Qianru Wang Ruxin Cheng Yong Liu Li Liu Ling Huang Ronghua Xu Department of Gastrointestinal Surgery Huazhong University of Science and Technology Union Shenzhen HospitalShenzhenGuangdong 518000China Research Center for Drug Safety Evaluation of Hainan Province HaikouHainan 571199China Department of pharmacology Hainan Medical UniversityHaikouHainan 571199China Department of Pathology Guangzhou Panyu Central HospitalGuangzhouGuangdong 511400China Hainan Province Key Laboratory for Drug Preclinical Study of pharmacology and toxicology Research Hainan Medical UniversityHaikouHainan 571199China Hainan Center for Drug and Medical Device Evaluation and Service Hainan Medical Products AdministrationHaikouHainan 570216China

IL-17 A is a promoter of colorectal cancer initiation and *** is a polyhydroxy alkaloid compound isolated from Narcissus plants,which has potent anti-inflammatory and antitumor *** effects of narciclasine on colorectal tumors were evaluated,with a focus on IL-17 *** reduced the growth of HCT-116 and SW-480 colon cancer cells in vitro and in vivo in murine *** results of flow cytometry on JC-1 and Annexin V/PI revealed that narciclasine significantly reduced the mitochondrial membrane potential and induced apoptosis,findings confirmed by western blotting results of reduced Bcl2 and enhanced Bax expression,as well as accumulation of cleaved Caspase-3,Caspase-8,Caspase-9,and cytoplasmic *** narciclasine incubation,IL-17 A,Act1,and TRAF6 were down-regulated,while p-P65(Ser536)accumulated in the cytoplasm,a finding confirmed by laser scanning confocal ***17A substitution could partly reverse these narciclasine effects while they were elevated by IL17A ***,IL-17 A,Act1,and TRAF6 were significantly expressed to greater extents in human colorectal cancer compared to normal adjacent tissue specimens and were closely linked with a poor *** study provided evidence that narciclasine may be a useful therapeutic drug for colorectal cancer treatment through its actions in down-regulating the L-17A/Act1/TRAF6/NF-kB anti-apoptotic signaling pathway.

关键词： Act1 Apoptosis Colonrectal cancer IL-17A Narciclasine NF-kB

mRNA vaccine technology for infectious diseases and beyond

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Science China Life Sciences 2024年第10期67卷 2267-2270页

作者： Pei Hao Xiao Li Xuan Li Wu Zhong Key Laboratory of Molecular Virology and Immunology Shanghai Institute of Immunity and InfectionChinese Academy of Sciences University of Chinese Academy of Sciences Changchun Veterinary Research Institute Chinese Academy of Agricultural Sciences Key Laboratory of Synthetic Biology CAS Center for Excellence in Molecular Plant SciencesInstitute of Plant Physiology and EcologyChinese Academy of Sciences National Engineering Research Center for the Emergency Drug Beijing Institute of Pharmacology and Toxicology

The rise of mRNA vaccine technology Vaccines stand as one of the most significant medical advancements, playing a crucial role in the prevention of infectious diseases and the improvement of global health. The triumph of smallpox vaccination stands as a towering achievement in the annals of healthcare, leading to the complete elimination of a oncedevastating disease and showcasing the efficacy of vaccination methods.

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Understanding the Novel Approach of Nanoferroptosis for Cancer Therapy

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Nano-Micro Letters 2024年第9期16卷 501-556页

作者： Afsana Sheikh Prashant Kesharwani Waleed H.Almalki Salem Salman Almujri Linxin Dai Zhe‑Sheng Chen Amirhossein Sahebkar Fei Gao Department of Pharmaceutics School of Pharmaceutical Education and ResearchJamia HamdardNew Delhi 110062India Department of pharmacology and toxicology Faculty of PharmacyUmm Al-Qura UniversityMakkahSaudi Arabia Department of pharmacology College of PharmacyKing Khalid University61421 Asir‑AbhaSaudi Arabia State Key Laboratory of Southwestern Chinese Medicine Resources Pharmacy SchoolChengdu University of Traditional Chinese MedicineChengdu 611130People’s Republic of China Department of Pharmaceutical Sciences College of Pharmacy and Health SciencesSt.John’s UniversityNew York 11439USA Biotechnology Research Center Pharmaceutical Technology InstituteMashhad University of Medical SciencesMashhadIran Applied Biomedical Research Center Mashhad University of Medical SciencesMashhadIran

As a new form of regulated cell death,ferroptosis has unraveled the unsolicited theory of intrinsic apoptosis resistance by cancer *** molecular mechanism of ferroptosis depends on the induction of oxidative stress through excessive reactive oxygen species accumulation and glutathione depletion to damage the structural integrity of *** to their high loading and structural tunability,nanocarriers can escort the delivery of ferro-therapeutics to the desired site through enhanced permeation or retention effect or by active *** review shed light on the necessity of iron in cancer cell growth and the fascinating features of ferroptosis in regulating the cell cycle and ***,we discussed the effect of ferroptosis-mediated therapy using nanoplatforms and their chemical basis in overcoming the barriers to cancer therapy.

关键词： Ferroptosis Nanoparticles Ferrotherapy Cancer Genes Nanotechnology Toxicity Reactive oxygen species

Low-frequency Stimulation at the Subiculum Prevents Extensive Secondary Epileptogenesis in Temporal Lobe Epilepsy

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Neuroscience Bulletin 2024年第5期40卷 564-576页

作者： Yujia Shen Yiwei Gong Xiaoli Da Shajing Gao Shuo Zhang Minjuan Sun Yuanzhi Yang Xiaoyun Qiu Menghan Li Yang Zheng Fan Fei Yi Wang Zhong Chen Cenglin Xu Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province School of Pharmaceutical ScienceZhejiang Chinese Medical UniversityHangzhou310053China Institute of pharmacology and toxicology NHC and CAMS Key Laboratory of Medical NeurobiologyCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou310058China Department of Neurology First Affiliated Hospital of Zhejiang Chinese Medical UniversityHangzhou310003China Department of Pharmacy The First Affiliated Hospital of Zhejiang Chinese Medical UniversityHangzhou310003China

Secondary epileptogenesis is characterized by increased epileptic susceptibility and a tendency to generate epileptiform activities outside the primary *** is one of the major resultants of pharmacoresistance and failure of surgical outcomes in epilepsy,but still lacks effective ***,we aimed to test the effects of low-frequency stimulation(LFS)at the subiculum for secondary epileptogenesis in a mouse ***,secondary epileptogenesis was simulated at regions both contralateral and ipsilateral to the primary focus by applying successive kindling *** kindled at the right CA3 showed higher seizure susceptibilities at both the contralateral CA3 and the ipsilateral entorhinal cortex and had accelerated kindling processes compared with naive *** at the ipsilateral subiculum during the primary kindling progress at the right CA3 effectively prevented secondary epileptogenesis at both the contralateral CA3 and the ipsilateral entorhinal cortex,characterized by decreased seizure susceptibilities and a retarded kindling process at those secondary *** application along with the primary epileptogenesis was ***,the effects of LFS on secondary epileptogenesis were associated with its inhibitory effect at the secondary focus through interfering with the enhancement of synaptic connections between the primary and secondary *** results imply that LFS at the subiculum is an effective preventive strategy for extensive secondary epileptogenesis in temporal lobe epilepsy and present the subiculum as a target with potential translational importance.

关键词： Secondary epileptogenesis Low-frequency stimulation Subiculum Temporal lobe epilepsy

The NORE1A/RASSF5 Tumor Suppressor Forms a Complex with GSK-3β to Regulate β-Catenin

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Journal of Biosciences and Medicines 2024年第8期12卷 60-75页

作者： M. Lee Schmidt Howard Donninger Geoffrey J. Clark Department pharmacology and toxicology University of Louisville Louisville USA US Worldmeds LouisvilleUSA Department of Medicine University of Louisville Louisville USA Experimental Therapeutics Program James Graham Brown Cancer Center University of Louisville Louisville USA

NORE1A (RASSF5) is a tumor suppressor of the RASSF family that is often down-regulated in human tumors. NORE1A has multiple roles in controlling cellular homeostasis, one of them being regulating levels of β-catenin by binding and modulating the ubiquitin ligase substrate recognition factor β-TrCP. β-catenin is a major executor of the Wnt pathway. The ubiquitin SCF-β-TrCP ligase complex acts on a phospho-degron site in β-catenin that can be phosphorylated by GSK-3β. We now show that in addition to binding β-TrCP, NORE1A also promotes the phosphorylation of the β-catenin phospho-degron by complexing with the kinase GSK-3β. Indeed, NORE1A enhances the formation of a GSK-3β/β-TrCP complex. A structural mutant of NORE1A that retains β-TrCP binding but will no longer interact with GSK-3β inhibits the β-catenin degrading action of NORE1A. The GSK-3β interaction with NORE1A plays an important role in the biology of NORE1A as a GSK-3β inhibitor blocks NORE1A induced senescence. Thus, we identify a new role for the tumor suppressor NORE1A: The regulation of GSK-3β. GSK-3β has many other substrates including multiple transcription factors and co-activators such as p53 and the Hippo component TAZ. The work implies that NORE1A may be able to influence all of them via this new kinase scaffolding interaction.

关键词： RAS NORE1A RASSF5 GSK-3β Beta Catenin HIPPO

Hepatoprotective effects of Xiaoyao San formula on hepatic steatosis and inflammation via regulating the sex hormones metabolism

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World Journal of Hepatology 2024年第7期16卷 1051-1066页

作者： Xiao-Li Mei Shu-Yi Wu Si-Lan Wu Xiao-Lin Luo Si-Xing Huang Rui Liu Zhe Qiang Department of pharmacology and toxicology Sichuan-Chongqing Joint Key Laboratory of New Chinese Medicine Creation LaboratoryChongqing Academy of Chinese Materia MedicaChongqing 400061China College of Chinese Medicine Chongqing College of Traditional Chinses MedicineChongqing 402760China Department of Oncology The Second Affiliated Hospital of Chongqing Medical UniversityChongqing 400010China College of Pharmacy Chongqing Medical UniversityChongqing 400010China

BACKGROUND The modified Xiaoyao San(MXS)formula is an adjuvant drug recommended by the National Health Commission of China for the treatment of liver cancer,which has the effect of preventing postoperative recurrence and metastasis of hepatocellular carcinoma and prolonging patient ***,the molecular mechanisms underlying that remain *** To investigate the role and mechanisms of MXS in ameliorating hepatic injury,steatosis and *** A choline-deficient/high-fat diet-induced rat nonalcoholic steatohepatitis(NASH)model was used to examine the effects of MXS on lipid accumulation in primary *** tissues were collected for western blotting and immunohisto chemistry(IHC)*** accumulation and hepatic fibrosis were detected using oil red staining and Sirius red *** serum samples were collected for biochemical assays and NMR-based metabonomics *** inflammation/lipid metabolism-related signaling and regulators in liver tissues were also detected to reveal the molecular mechanisms of MXS against *** MXS showed a significant decrease in lipid accumulation and inflammatory response in hepatocytes under metabolic *** western blotting and IHC results indicated that MXS activated AMPK pathway but inhibited the expression of key regulators related to lipid accumulation,inflammation and hepatic fibrosis in the pathogenesis of *** metabonomics analysis systemically indicated that the arachidonic acid metabolism and steroid hormone synthesis are the two main target metabolic pathways for MXS to ameliorate liver inflammation and hepatic ***,we found that MXS protected against NASH by attenuating the sex hormone-related metabolism,especially the metabolism of male *** MXS ameliorates inflammation and hepatic steatosis of NASH by inhibiting the metabolism of male *** male hormone related metabolic pathways may be the potential therapeutic app

关键词： Hepatic steatosis Inflammation Sex hormone metabolism Male hormone Phosphatase and tensin homolog deleted on chromosome ten