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High-throughput discovery of highly selective reversible hMAO-B inhibitors based on at-line nanofractionation

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Acta Pharmaceutica Sinica B 2024年第4期14卷 1772-1786页

作者： Yu Fan Jincai Wang Jingyi Jian Yalei Wen Jiahao Li Hao Tian Jacques Crommen Wei Bi Tingting Zhang Zhengjin Jiang Institute of pharmaceutical analysis/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education(MOE)of China/College of pharmacy Jinan UniversityGuangzhou 510632China KU Leuven-University of Leuven Pharmaceutical AnalysisDepartment of Pharmaceutical and Pharmacological SciencesLeuven 3000Belgium Laboratory of Analytical pharmaceutical Chemistry Department of Pharmaceutical SciencesCIRMUniversity of LiegeLiege B-4000Belgium department of Neurology the First Affiliated Hospital of Jinan University/Clinical Neuroscience Institutethe First Affiliated Hospital of Jinan UniversityGuangzhou 510630China

Human monoamine oxidase B(hMAO-B)has emerged as a pivotal therapeutic target for Parkinson's *** to adverse effects and shortage of commercial drugs,there is a need for novel,highly selective,and reversible hMAO-B inhibitors with good blood-brain barrier *** this study,a high-throughput at-line nanofractionation screening platform was established with extracts from Chuanxiong Rhizoma,which resulted in the discovery of 75 active compounds,including phenolic acids,volatile oils,and phthalides,two of which were highly selective novel natural phthalide hMAO-B inhibitors that were potent,selective,reversible and had good blood‒brain *** docking and molecular dynamics simulations elucidated the inhibition ***(IC_(50)=103 nmol/L;SI=645)and neocnidilide(IC_(50)=131 nmol/L;SI=207)demonstrated their excellent potential as hMAO-B *** offset the limitations of deactivating enzymes associated with irreversible hMAO-B inhibitors such as *** SH-SY5Y cell assays,sedanolide(EC_(50)=0.962μmol/L)and neocnidilide(EC_(50)=1.161μmol/L)exhibited significant neuroprotective effects,comparable to the positive drugs rasagiline(EC_(50)=0.896μmol/L)and safinamide(EC_(50)=1.079μmol/L).These findings underscore the potential of sedanolide as a novel natural hMAO-B inhibitor that warrants further development as a promising drug candidate.

关键词： Human monoamine oxidase B inhibitors High-throughput screening At-linenanofractionation Parkinson's disease Cellular neuroprotection Traditional Chinese medicines(TCMs)

Mimotope peptide modified pompon mum-like magnetic microparticles for precise recognition,capture and biotransformation analysis of rituximab in biological fluids

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1317-1328页

作者： Jiawen Yang Aixuan Zhou Minyi Li Qiaoxian He Jingwei Zhou Jacques Crommen Wentao Wang Zhengjin Jiang Qiqin Wang Institute of pharmaceutical analysis College of Pharmacy/State Key Laboratory of Bioactive Molecules and Druggability Assessment/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education(MOE)of ChinaJinan UniversityGuangzhou 510632China Laboratory for the analysis of Medicines Department of Pharmaceutical SciencesCIRMUniversity of LiegeLiege B-4000Belgium SCIEX Shanghai 200050China

Due to low immobilized ligand density,limited binding capacity,and severe interference from serum proteins,developing ideal peptide-based biomaterials for precise recognition and in vivo analysis of biopharmaceuticals remains a huge *** this study,mimotope peptide modified pompon mum-like biomimetic magnetic microparticles(MMPs,3.8μm)that mimic the specific functionalities of CD20 on malignant B cells were developed for the first *** from the numerous ligand binding sites(Ni^(2+))on the pompon mum-like MMPs,these novel materials achieved≥10 times higher peptide ligand densities(>2300 mg/g)and antibody binding capacities(1380 mg/g)compared to previous reported *** the high specificity of the mimotope peptide,rituximab can be precisely recognized and enriched from cell culture media or serum *** also established an LC-MS/MS method using the MMPs for tracking rituximab biotransformation in patient ***,deamidation of Asn55 and Asn33,as well as oxidation of Met81 and Met34 were observed at the key complementarity determining regions of rituximab,which could potentially influence antibody function and require careful ***,these versatile biomimetic MMPs demonstrate superior recognition and enrichment capabilities for target antibodies,offering interesting possibilities for biotransformation analysis of biopharmaceuticals in patient serum.

关键词： Therapeutic monoclonal antibody Mimotope peptide Precise recognition Peptide-based biomaterials Biotransformation Patient serum

Gut microbiome-based thiamine metabolism contributes to the protective effect of one acidic polysaccharide from Selaginella uncinata(Desv.)Spring against inflammatory bowel disease

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Journal of pharmaceutical analysis 2024年第2期14卷 177-195页

作者： Haochen Hui Zhuoya Wang Xuerong Zhao Lina Xu Lianhong Yin Feifei Wang Liping Qu Jinyong Peng department of pharmaceutical analysis College of PharmacyDalian Medical UniversityDalianLiaoning116044China Innovation Materials Research and Development Center Botanee Research InstituteYunnan Botanee Bio-technology Group Co.Ltd.Kunming650106China department of Traditional Chinese Medicine Pharmacology School of PharmacyAnhui University of Chinese MedicineHefei230012China

Inflammatory bowel disease(IBD)is a serious disorder,and exploration of active compounds to treat it is *** acidic polysaccharide named SUSP-4 was purified from Selaginella uncinata(Desv.)Spring,which contained galacturonic acid,galactose,xylose,arabinose,and rhamnose with the main chain structure of→4)-α-d-GalAp-(1→and→6)-β-d-Galp-(1→and the branched structure of→5)-α-l-Araf-(1→.Animal experiments showed that compared with Model group,SUSP-4 significantly improved body weight status,disease activity index(DAI),colonic shortening,and histopathological damage,and elevated occludin and zonula occludens protein 1(ZO-1)expression in mice induced by dextran sulfate sodium salt(DSS).16S ribosomal RNA(rRNA)sequencing indicated that SUSP-4 markedly downregulated the level of Akkermansia and *** results confirmed that SUSP-4 obviously elevated thiamine levels compared with Model mice by adjusting thiamine metabolism,which was further confirmed by a targeted metabolism *** transplantation experiments showed that SUSP-4 exerted an anti-IBD effect by altering the intestinal flora in mice.A mechanistic study showed that SUSP-4 markedly inhibited macrophage activation by decreasing the levels of phospho-nuclear factor kappa-B(p-NF-κB)and cyclooxygenase-2(COX-2)and elevating NF-E2-related factor 2(Nrf2)levels compared with Model *** conclusion,SUSP-4 affected thiamine metabolism by regulating Akkermania and inhibited macrophage activation to adjust NF-κB/Nrf2/COX-2-mediated inflammation and oxidative stress against *** is the first time that plant polysaccharides have been shown to affect thiamine metabolism against IBD,showing great potential for in-depth research and development applications.

关键词： Gut microbiota Inflammatory bowel disease Polysaccharide Selaginella uncinata(Desv.)Spring Thiamine metabolism

Tanshinone IIA ameliorates energy metabolism dysfunction of pulmonary fibrosis using 13C metabolic flux analysis

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Journal of pharmaceutical analysis 2024年第2期14卷 244-258页

作者： Baixi Shan Haoyan Zhou Congying Guo Xiaolu Liu Mingyu Wu Rao Zhai Jun Chen State Key Laboratory of Natural Medicines China Pharmaceutical UniversityNanjing210009China department of Pharmacognosy School of Traditional Chinese PharmacyChina Pharmaceutical UniversityNanjing210009China

Evidence indicates that metabolic reprogramming characterized by the changes in cellular metabolic patterns contributes to the pathogenesis of pulmonary fibrosis (PF). It is considered as a promising therapeutic target anti-PF. The well-documented against PF properties of Tanshinone IIA (Tan IIA) have been primarily attributed to its antioxidant and anti-inflammatory potency. Emerging evidence suggests that Tan IIA may target energy metabolism pathways, including glycolysis and tricarboxylic acid (TCA) cycle. However, the detailed and advanced mechanisms underlying the anti-PF activities remain obscure. In this study, we applied [U-13C]-glucose metabolic flux analysis (MFA) to examine metabolism flux disruption and modulation nodes of Tan IIA in PF. We identified that Tan IIA inhibited the glycolysis and TCA flux, thereby suppressing the production of transforming growth factor-β1 (TGF-β1)-dependent extracellular matrix and the differentiation and proliferation of myofibroblasts in vitro. We further revealed that Tan IIA inhibited the expression of key metabolic enzyme hexokinase 2 (HK2) by inhibiting phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/hypoxia-inducible factor 1α (HIF-1α) pathway activities, which decreased the accumulation of abnormal metabolites. Notably, we demonstrated that Tan IIA inhibited ATP citrate lyase (ACLY) activity, which reduced the collagen synthesis pathway caused by cytosol citrate consumption. Further, these results were validated in a mouse model of bleomycin-induced PF. This study was novel in exploring the mechanism of the occurrence and development of Tan IIA in treating PF using 13C-MFA technology. It provided a novel understanding of the mechanism of Tan IIA against PF from the perspective of metabolic reprogramming.

关键词： Pulmonary fibrosis Tanshinone IIA 13C-metabolic flux analysis Metabolic reprogramming

Saponin Ⅰ from Shuitianqi(Rhizoma Schizocapasae Plantagineae) inhibits metastasis by negatively regulating the transforming growth factor-β1/Smad7 network and epithelial-mesenchymal transition in the intrahepatic metastasis Bagg's Albino/c mouse model

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Journal of Traditional Chinese Medicine 2024年第4期44卷 642-651页

作者： LYU Meixian ZHOU Huan ZHI Limin ZHOU Jinling GAN Rizhi QIN Yanping HE Nengting ZUO Qiqi LI Hao DONG Min LIANG Gang pharmaceutical College Guangxi Medical University department of pharmacy Affiliated Tumor Hospital of Guangxi Medical University Drug clinical trial Facility office the People's Hospital of Guangxi Zhuang Autonomous Region College of pharmacy Guangxi University of Chinese Medicine department of pharmacy the Second Affiliated Hospital of Guangxi Medical University department of pharmacy People's Hospital of Guangxi Hezhou department of pharmacy Guangzhou Women and Children's Medical Center Liuzhou Hospital department of pharmacy First Affiliated Hospital of Gannan Medical University

OBJECTIVE: To examine the influence of Saponin Ⅰ from Shuitianqi(Rhizoma Schizocapasae Plantagineae)(SSPH Ⅰ) on hepatocellular carcinoma(HCC) metastasis,and to elucidate the underlying ***: The intrahepatic metastasis Bagg's Albino/c(BALB/c) mouse model was established with human hepatocellular carcinomas(HepG2) cells, then treated with normal saline(once per day), cisplatin(2 mg/kg, once every 2 d), and SSPH Ⅰ(25, 50, and 75 mg/kg, once per day). Then, we assessed alterations in the hepatic pathology and target protein expressions in the intrahepatic metastasis BALB/c mouse model using a series of molecular biology ***: Based on our analysis, SSPH Ⅰ significantly alleviated hepatocyte necrosis and tumor cells ***, SSPH Ⅰ suppressed extracellular matrix(ECM) degradation and angiogenesis via a decrease in matrix etalloproteinase-2(MMP-2), MMP-9, CD31, CD34,and vascular endothelial growth factor(VEGF) ***, SSPH Ⅰ repressed invasion and metastasis by suppressing the transforming growth factor-β1(TGF-β 1)/Smad7 axis and epithelial-mesenchymal transition(EMT), as evidenced by the scarce TGF-β1, Ncadherin, and Vimentin expressions, and elevated Smad7 and E-cadherin ***: The SSPH Ⅰ-mediated negative regulation of the TGF-β 1/Smad7 axis and EMT are critical for the inhibition of HCC invasion and metastasis.

关键词： Saponin I from Shuitianqi (Rhizoma Schizocapasae Plantagineae) Smad7 protein carcinoma, hepatocellular epithelial-mesenchymal transition transforming growth factor beta1

Nitrosamines crisis in pharmaceuticals Insights on toxicological implications, root causes and risk assessment: A systematic review

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Journal of pharmaceutical analysis 2024年第5期14卷 639-652页

作者： Hemanth P.R.Vikram Tegginamath Pramod Kumar Gunjan Kumar Narasimha M.Beeraka Rajashree Deka Sheik Mohammed Suhail Sandeep Jat Namitha Bannimath Gayatiri Padmanabhan Ravandur S.Chandan Pramod Kumar Bannimath Gurupadayya department of pharmaceutical Chemistry JSS College of Pharmacy MysuruJSS Academy of Higher Education and Research(JSSAHER)Mysuru570015India Xenone Healthcare Pvt.Ltd. New Delhi110076India department of Pharmaceutics JSS College of Pharmacy MysuruJSS Academy of Higher Education and Research(JSSAHER)Mysuru570015India department of Human Anatomy I.M.Sechenov First Moscow State Medical University(Sechenov University)Moscow119991Russian Federation department of Pharmacology Raghavendra Institute of Pharmaceutical Education and Research(RIPER)Ananthapuramu515721India Herman B.Wells Center for Pediatric Research Department of PediatricsIndiana University School of MedicineIndianapolisIN46202USA Animal Physiology and Biochemistry Laboratory Department of ZoologyGauhati UniversityGuwahati781014India department of Pharmacology JSS College of Pharmacy MysuruJSS Academy of Higher Education and Research(JSSAHER)Mysuru570015India department of pharmaceutical analysis National Institute of Pharmaceutical Education and Research(NIPER)-GuwahatiChangsari781101India department of Pharmacology University of GalwayGalwayH91 TK33Ireland

The presence of N-nitroso compounds,particularly N-nitrosamines,in pharmaceutical products has raised global safety concerns due to their significant genotoxic and mutagenic *** systematic review investigates their toxicity in active pharmaceutical ingredients(APIs),drug products,and pharmaceutical excipients,along with novel analytical strategies for detection,root cause analysis,reformulation strategies,and regulatory guidelines for *** review emphasizes the molecular toxicity of N-nitroso compounds,focusing on genotoxic,mutagenic,carcinogenic,and other physiological ***,it addresses the ongoing nitrosamine crisis,the development of nitrosamine-free products,and the importance of sensitive detection methods and precise risk *** comprehensive overview will aid molecular biologists,analytical scientists,formulation scientists in research and development sector,and researchers involved in management of nitrosamine-induced toxicity and promoting safer pharmaceutical products.

关键词： Carcinogenicity Genotoxicity Mutagenicity Molecular toxicity Nitrosamine impurities Nitrosamine drug substance-related impurities

Establishment of NaLuF_(4):15%Tb-based low dose X-PDT agent and its application on efficient antitumor therapy

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International Journal of Minerals,Metallurgy and Materials 2024年第3期31卷 599-610页

作者： Yi Tian Zhiguang Fu Xiaosheng Zhu Chunjing Zhan Jinwei Hu Li Fan Chaojun Song Qian Yang Yu Wang Mei Shi department of Radiation Oncology Xijing HospitalThe Fourth Military Medical UniversityXi’an 710032China department of Oncology Air Force Medical CenterPLAThe Fourth Military Medical UniversityBeijing 100142China department of Tumor Radiotherapy Air Force Medical CenterPLAThe Fourth Military Medical UniversityBeijing 100142China department of Gastroenterology Air Force Hospital of Southern Theater CommandGuangzhou 510062China department of pharmaceutical Chemistry and analysis School of PharmacyThe Fourth Military Medical UniversityXi’an 710032China School of Life Sciences Northwestern Polytechnical UniversityXi’an 710072China Institue of Materia Medica School of PharmacyThe Fourth Military Medical UniversityXi’an 710032China

X-ray excited photodynamic therapy(X-PDT)is the bravo answer of photodynamic therapy(PDT)for deep-seated tumors,as it employs X-ray as the irradiation source to overcome the limitation of light penetration ***,high X-ray irradiation dose caused organ lesions and side effects became the major barrier to X-PDT *** address this issue,this work employed a classic-al co-precipitation reaction to synthesize NaLuF_(4):15%Tb^(3+)(NLF)with an average particle size of(23.48±0.91)nm,which was then coupled with the photosensitizer merocyanine 540(MC540)to form the X-PDT system NLF-MC540 with high production of singlet *** system could induce antitumor efficacy to about 24%in relative low dose X-ray irradiation range(0.1-0.3 Gy).In vivo,when NLF-MC540 irradiated by 0.1 Gy X-ray,the tumor inhibition percentage reached 89.5%±5.7%.The therapeutic mechanism of low dose X-PDT was found.A significant increase of neutrophils in serum was found on the third day after *** immunohistochemical staining of tumor sections,the Ly6G^(+),CD8^(+),and CD11c^(+)cells infiltrated in the tumor microenvironment were *** the bilat-eral tumor model,the NLF-MC540 with 0.1 Gy X-ray irradiation could inhibit both the primary tumor and the distant tumor ***-tected by enzyme linked immunosorbent assay(ELISA),two cytokines IFN-γand TNF-αin serum were upregulated 7 and 6 times than negative control,*** by enzyme linked immune spot assay(ELISPOT),the number of immune cells attributable to the IFN-γand TNF-αlevels in the group of low dose X-PDT were 14 and 6 times greater than that in the negative control group,***,it conclude that low dose X-PDT system could successfully upregulate the levels of immune cells,stimulate the secretion of cy-tokines(especially IFN-γand TNF-α),activate antitumor immunity,and finally inhibit colon tumor growth.

关键词： X-ray excited photodynamic therapy singlet oxygen low dose X-Ray irradiation efficient antitumor therapy anti-tumor immunity

In silico identification of antiviral compounds for the treatment of chikungunya virus infection:qsar modelling and md simulation analysis

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Medicine in Novel Technology and Devices 2024年第2期22卷 102-114页

作者： Hayder M Abdulhamza Muthanna S.Farhan Sara.S Hassan Hany Aqeel Al-Hussainy Amjad Ibrahim Oriabi department of pharmacy Kut University CollegeAlkutWasit52001Iraq department of pharmaceutical Chemistry College of PharmacyUniversity of BaghdadBaghdadIraq Al-Manara College for Medical Sciences Department of PharmacyIraq department of pharmacy Hilla University CollegeBabylonIraq Dr Hany Akeel Institute Iraqi Medical Research CenterBaghdad10001Iraq

Chikungunya virus(CHIKV),transmitted by arthropods,has gained global recognition for its impact on public *** has expanded globally,including Africa,Asia,and the Indian subcontinent,and has a helicase protein in its genome that is crucial for its ***,the study targeted the helicase protein of CHIKV with 745 antiviral compounds using an ML-based QSAR model and molecular *** binders(5279172,78161839,6474310,and 5330286)were selected for MD simulation based on the control(Silvestrol).All compounds had the highest binding scores,with 78161839 showing the most consistent RMSD and the least conformational variation,indicating high *** also showed the lowest binding free energy(ΔG¼31.31 kcal/mol),indicating energetically favourable *** and FEL also depicted the stable complex confirmation of the protein and 78161839 complex during the 100 ns ***,this study aimed to identify helicase function antiviral binders that could be experimentally tested for treating CHIKV.

关键词： Chikungunya virus Machine learning based QSAR Molecular dynamic solution Helicase

Bile acids and coronavirus disease 2019

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Acta Pharmaceutica Sinica B 2024年第5期14卷 1939-1950页

作者： Xiaoru Huang Xuening Liu Zijian Li department of pharmacy Peking University Third HospitalBeijing 100191China department of pharmaceutical Management and Clinical pharmacy College of PharmacyPeking UniversityBeijing 100191China department of Cardiology and Institute of Vascular Medicine Peking University Third HospitalBeijing Key Laboratory of Cardiovascular Receptors ResearchKey Laboratory of Cardiovascular Molecular Biology and Regulatory PeptidesMinistry of HealthState Key Laboratory of Vascular Homeostasis and RemodelingPeking UniversityBeijing 100191China

The coronavirus disease 2019(COVID-19)pandemic,caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has been significantly ***,long-term health effects and prevention strategy remain ***,it is essential to explore the pathophysiological mechanisms and intervention for SARS-CoV-2 *** research indicates a link between COVID-19 and bile acids,traditionally known for facilitating dietary fat *** bile acid ursodeoxycholic acid potentially protects against SARS-CoV-2 infection by inhibiting the farnesoid X receptor,a bile acid nuclear *** activation of G-protein-coupled bile acid receptor,another membrane receptor for bile acids,has also been found to regulate the expression of angiotensin-converting enzyme 2,the receptor through which the virus enters human ***,we review the latest basic and clinical evidence linking bile acids to SARS-CoV-2,and reveal their complicated pathophysiological mechanisms.

关键词： Bile acids COVID-19 Farnesoid X receptor G-protein-coupled bile acid receptor SARS-CoV-2 Angiotensin-converting enzyme 2 Ursodeoxycholic acid Chenodeoxycholic acid