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Dysregulation of RNA modification systems in clinical populations with neurocognitive disorders

Neural Regeneration Research 2024年第6期19卷 1256-1261页

作者： Helen M.Knight Merve Demirbugen ?z Adriana PerezGrovas-Saltijeral Division of Cells Organisms and Molecular Genetics School of Life Sciences University of Notingham Department of pharmaceutical Toxicology Faculty of Pharmacy Ankara University

The study of modified RNA known as epitranscriptomics has become increasingly relevant in our understanding of disease-modifying mechanisms. Methylation of N6 adenosine(m6A) and C5 cytosine(m5C) bases occur on mRNAs, tRNA, mt-tRNA, and rRNA species as well as non-coding RNAs. With emerging knowledge of RNA binding proteins that act as writer, reader, and eraser effector proteins, comes a new understanding of physiological processes controlled by these systems. Such processes when spatiotemporally disrupted within cellular nanodomains in highly specialized tissues such as the brain, give rise to different forms of disease. In this review, we discuss accumulating evidence that changes in the m6A and m5C methylation systems contribute to neurocognitive disorders. Early studies first identified mutations within FMR1 to cause intellectual disability Fragile X syndromes several years before FMR1 was identified as an m6A RNA reader protein. Subsequently, familial mutations within the m6A writer gene METTL5, m5C writer genes NSUN2, NSUN3, NSUN5, and NSUN6, as well as THOC2 and THOC6 that form a protein complex with the m5C reader protein ALYREF, were recognized to cause intellectual development disorders. Similarly, differences in expression of the m5C writer and reader effector proteins, NSUN6, NSUN7, and ALYREF in brain tissue are indicated in individuals with Alzheimer’s disease, individuals with a high neuropathological load or have suffered traumatic brain injury. Likewise, an abundance of m6A reader and anti-reader proteins are reported to change across brain regions in Lewy bodies diseases, Alzheimer’s disease, and individuals with high cognitive reserve. m6A-modified RNAs are also reported significantly more abundant in dementia with Lewy bodies brain tissue but significantly reduced in Parkinson’s disease tissue, whilst modified RNAs are misplaced within diseased cells, particularly where synapses are located. In parahippocampal brain tissue, m6A modification is en

关键词： 5-methylcytosine methylation Alzheimer's disease cognitive diseases epitranscriptomics intellectual disability Lewy body diseases N6 adenosine RNA modification

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Probing the dynamic thermodynamic resolution and biological activity of Cu(Ⅱ) and Pd(Ⅱ) complexes with Schiff base ligand derived from proline

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Chinese Chemical Letters 2024年第4期35卷 99-105页

作者： Tao Yu Vadim A.Soloshonok Zhekai Xiao Hong Liu Jiang Wang State Key Laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China School of pharmacy University of Chinese Academy of SciencesBeijing 100049China Department of Organic Chemistry Ⅰ Faculty of ChemistryUniversity of the Basque Country UPV/EHUSan Sebastian 20018Spain IKERBASQUE Basque Foundation for ScienceBilbao 48013Spain School of pharmaceutical Science and Technology Hangzhou Institute for Advanced StudyUCASHangzhou 310024China Lingang Laboratory Shanghai 200031China

Schiff base metal complexes are of great importance in pharmaceutical science owing to their unique chemical properties, which enable them to exhibit diverse biological activities such as anti-bacterial,anti-oxidant, anti-inflammatory, and anti-tumor properties. Furthermore, Schiff base metal complexes can serve as reagents and catalysts in chemical reactions. This review aims to provide an overview of our recently published studies on Cu(Ⅱ) and Pd(Ⅱ) complexes derived from proline Schiff base ligands. We also discuss the potential applications of these metal complexes in the fields of antibacterial and chiral resolution.

关键词： Schiff bases Biological activity Tailor-made amino acids Asymmetric synthesis Chiral tridentate ligands Square-planar Cu(Ⅱ)-complexes Square-planar Pd(Ⅱ)-complexes

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Targeting BCL9/BCL9L enhances antigen presentation by promoting conventional type 1 dendritic cell(cDC1)activation and tumor infiltration

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Signal Transduction and Targeted Therapy 2024年第6期9卷 2804-2818页

作者： Fenglian He Zhongen Wu Chenglong Liu Yuanyuan Zhu Yan Zhou Enming Tian Rina Rosin-Arbesfeld Dehua Yang Ming-Wei Wang Di Zhu Department of Pharmacology Minhang Hospitaland Key Laboratory of Smart Drug DeliveryShanghai Engineering Research Center of Immune TherapySchool of PharmacyFudan UniversityShanghai 201203China The National Center for Drug Screening and the CAS Key Laboratory of Receptor Research Shanghai Institute of Materia MedicaChinese Academy of Sciences(CAS)Shanghai 201203China Department of Microbiology and Immunology Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael Department of Pharmacology School of Basic Medical SciencesFudan UniversityShanghai 200032China Research Center for Deepsea Bioresources SanyaChina Department of Chemistry School of ScienceThe University of TokyoTokyoJapan Engineering Research Center of Tropical Medicine Innovation and Transformation of Ministry of Education School of PharmacyHainan Medical UniversityHaikouChina Shandong Academy of pharmaceutical Science JinanChina

Conventional type 1 dendritic cells(cDC1)are the essential antigen-presenting DC subset in antitumor *** B-cell lymphoma 9 and B-cell lymphoma 9-like(BCL9/BCL9L)inhibits tumor growth and boosts immune responses against ***,whether oncogenic BCL9/BCL9L impairs antigen presentation in tumors is still not completely ***,we show that targeting BCL9/BCL9L enhanced antigen presentation by stimulating cDC1 activation and infiltration into *** inhibition of BCL9/BCL9L with a novel inhibitor hsBCL9z96 or Bcl9/Bcl9l knockout mice markedly delayed tumor growth and promoted antitumor CD8^(+)T cell ***,targeting BCL9/BCL9L promoted antigen presentation in *** is due to the increase of cDC1 activation and tumor infiltration by the XCL1-XCR1 ***,using single-cell transcriptomics analysis,we found that Bcl9/Bcl9l deficient cDC1 were superior to wild-type(WT)cDC1 at activation and antigen presentation via NF-κB/IRF1 ***,we demonstrate that targeting BCL9/BCL9L plays a crucial role in cDC1-modulated antigen presentation of tumor-derived antigens,as well as CD8^(+)T cell activation and tumor *** BCL9/BCL9L to regulate cDC1 function and directly orchestrate a positive feedback loop necessary for optimal antitumor immunity could serve as a potential strategy to counter immune suppression and enhance cancer immunotherapy.

关键词： immunity Targeting markedly

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Associations of PNPLA3 and LEP genetic polymorphisms with metabolic-associated fatty liver disease in Thai people living with human immunodeficiency virus

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World Journal of Hepatology 2024年第3期16卷 366-378页

作者： Kanuengnit Choochuay Punna Kunhapan Apichaya Puangpetch Sissades Tongsima Pornpen Srisawasdi Abhasnee Sobhonslidsuk Somnuek Sungkanuparph Mohitosh Biswas Chonlaphat Sukasem program in Translational Medicine Faculty of Medicine Ramathibodi HospitalMahidol UniversityBangkok 10400Thailand School of pharmacy Walailak UniversityNakhon Si Thammarat 80161Thailand Laboratory for Pharmacogenomics Division of Pharmacogenomics and Personalized MedicineSomdech Phra Debaratana Medical CenterDepartment of PathologyFaculty of Medicine Ramathibodi HospitalMahidol UniversityBangkok 10400Thailand Department of Medical sciences Ministry of Public HealthNonthaburi 11000Thailand National Biobank of Thailand National Center for Genetic Engineering and BiotechnologyPathum Thani 12120Thailand Division of Clinical Chemistry Department of PathologyFaculty of Medicine Ramathibodi HospitalMahidol UniversityBangkok 10400Thailand Division of Gastroenterology and Hepatology Department of MedicineFaculty of Medicine Ramathibodi HospitalMahidol UniversityBangkok 10400Thailand Chakri Naruebodindra Medical Institute Faculty of Medicine Ramathibodi HospitalMahidol UniversitySamut Prakan 10540Thailand Department of pharmacy University of RajshahiRajshahi 6205Bangladesh Pharmacogenomics Clinic Bumrungrad Genomic Medicine InstituteBumrungrad International HospitalBangkok 10110Thailand Research and Development Laboratory Bumrungrad International HospitalBangkok 10110Thailand MRC Centre for Drug Safety Science Department of Pharmacology and TherapeuticsInstitute of SystemsMolecular and Integrative BiologyUniversity of Liverpool Liverpool L693GLUnited Kingdom faculty of pharmaceutical sciences Burapha UniversityChonburi 20131Thailand

BACKGROUND The prevalence of metabolic-associated fatty liver disease(MAFLD)is a growing public health issue in people living with human immunodeficiency virus(PLWH).However,the pathophysiology of MAFLD is still unknown,and the role of genetic variables is only now becoming *** To evaluate the associations of gene-polymorphism-related MAFLD in *** The study employed transient elastography with a controlled attenuation parameter≥248 dB/m to identify MAFLD in patients from a Super Tertiary Hospital in central *** single-nucleotide polymorphisms(SNPs)were genotyped using TaqMan®MGB probe 5'nuclease assays for seven MAFLD-related *** analyses included SNP frequency analysis,Fisher's Exact and Chi-square tests,odds ratio calculations,and multivariable logistic *** The G-allele carriers of PNPLA3(rs738409)exhibited a two-fold rise in MAFLD,increasing by 2.5 times in MAFLD with human immunodeficiency virus *** clinical features and genetic patterns imply that LEP rs7799039 A-allele carriers had a nine times(P=0.001)more significant chance of developing aberrant triglyceride among *** The current study shows an association between PNPLA3 rs738409 and LEP rs7799039 with MAFLD in PLWH.

关键词： PNPLA3 LEP Metabolic-associated fatty liver disease People living with HIV Thai

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An emerging terpolymeric nanoparticle pore former as an internal recrystallization inhibitor of celecoxib in controlled release amorphous solid dispersion beads:Experimental studies and molecular dynamics analysis

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Acta Pharmaceutica Sinica B 2024年第6期14卷 2669-2684页

作者： Jamie Anne Lugtu-Pe Xuning Zhang Sako Mirzaie Hao Han R.Chang Nour AL-Mousawi Kuan Chen Yongqiang Li Anil Kane Daniel Bar-Shalom Xiao Yu Wu Advanced Pharmaceutics and Drug Delivery Laboratory Leslie Dan Faculty of PharmacyUniversity of TorontoToronto M5S 3M2Canada Candoo Pharmatech Company Inc. Mississauga L5N 5M1Canada Department of pharmacy University of CopenhagenCopenhagen DK-2100Denmark Patheon by Thermo Fisher Scientific Toronto Region Operations(TRO)Mississauga L5N 3X4Canada

Solid oral controlled release formulations feature numerous clinical advantages for drug candidates with adequate solubility and dissolution ***,most new chemical entities exhibit poor water solubility,and hence are exempt from such *** combining drug amorphization with controlled release formulation is promising to elevate drug solubility,like other supersaturating systems,the problem of drug recrystallization has yet to be resolved,particularly within the dosage ***,we explored the potential of an emerging,non-leachable terpolymer nanoparticle(TPN)pore former as an internal recrystallization inhibitor within controlled release amorphous solid dispersion(CRASD)beads comprising a poorly soluble drug(celecoxib)reservoir and insoluble polymer(ethylcellulose)*** to conventional pore former,polyvinylpyrrolidone(PVP),TPN-containing membranes exhibited superior structural integrity,less crystal formation at the CRASD bead surface,and greater extent of celecoxib ***-atom molecular dynamics analyses revealed that in the presence of TPN,intra-molecular bonding,crystal formation tendency,diffusion coefficient,and molecular flexibility of celecoxib were reduced,while intermolecular H-bonding was increased as compared to *** work suggests that selection of a pore former that promotes prolonged molecular separation within a nanoporous controlled release membrane structure may serve as an effective strategy to enhance amorphicity preservation inside CRASD.

关键词： Controlled release amorphous solid dispersion Poorly soluble drug Internal recrystallization Membrane-reservoir coated beads Molecular dynamics simulation Effect of pore formers Terpolymer nanogel Drug-polymer interactions

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Encoding and display technologies for combinatorial libraries in drug discovery:The coming of age from biology to therapy

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Acta Pharmaceutica Sinica B 2024年第8期14卷 3362-3384页

作者： Yu Fan Ruibing Feng Xinya Zhang Zhen-Liang Wang Feng Xiong Shuihua Zhang Zhang-Feng Zhong Hua Yu Qing-Wen Zhang Zhang Zhang Yitao Wang Guodong Li Macao Centre for Research and Development in Chinese Medicine State Key Laboratory of Quality Research in Chinese MedicineInstitute of Chinese Medical SciencesUniversity of MacaoMacao SAR 999078China State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoMacao SAR 999078China International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development Ministry of Education(MoE)of People’s Republic of ChinaCollege of PharmacyJinan UniversityGuangzhou 510632China Zhuhai UM Science and Technology Research Institute Zhuhai 519031China Department of pharmacy Guangzhou Red Cross HospitalFaculty of Medical ScienceJinan UniversityGuangzhou 510632China Geriatric Medicine First People’s Hospital of XinXiang and the Fifth Affiliated Hospital of Xinxiang Medical CollegeXinxiang 453100China Shenzhen Innovation Center for Small Molecule Drug Discovery Co. Ltd.Shenzhen 518000China

Drug discovery is a sophisticated process that incorporates scientific innovations and cuttingedge *** to traditional bioactivity-based screening methods,encoding and display technologies for combinatorial libraries have recently advanced from proof-of-principle experiments to promising tools for pharmaceutical hit discovery due to their high screening efficiency,throughput,and resource *** review systematically summarizes the development history,typology,and prospective applications of encoding and displayed technologies,including phage display,ribosomal display,mRNA display,yeast cell display,one-bead one-compound,DNA-encoded,peptide nucleic acidencoded,and new peptide-encoded technologies,and examples of preclinical and clinical *** discuss the progress of novel targeted therapeutic agents,covering a spectrum from small-molecule inhibitors and nonpeptidic macrocycles to linear,monocyclic,and bicyclic peptides,in addition to *** also address the pending challenges and future prospects of drug discovery,including the size of screening libraries,advantages and disadvantages of the technology,clinical translational potential,and market *** review is intended to establish a comprehensive high-throughput drug discovery strategy for scientific researchers and clinical drug developers.

关键词： Drug screening Phage display DNA-encoded chemical libraries Peptide-encoded chemical libraries Clinical drugs

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An edible green algae polysaccharide CRVP from Caulerpa racemosa var. peltate induced apoptosis of liver cancer cells Hepa1-6 by regulating glutathione metabolism

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Food Science and Human Wellness 2024年

作者： Xuewei Xia Heying Zhou Rongxin Zhang Xiaoyong Zhang Baojun Xu Io Nam Wong Riming Huang Guangdong Provincial Key Laboratory of Food Quality and Safety， College of Food Science， South China Agricultural University Department of pharmacy， Guangdong Second Provincial General Hospital Department of Colorectal Surgery， Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South China Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation， College of Marine sciences， South China Agricultural University Food Science and Technology program， BNU-HKBU United International College faculty of Medicine， Macau University of Science and Technology

Algal polysaccharides are an essential active substance in food nutrition and even pharmaceutical activity research due to wide sources， low toxicity， and no side effects. In our previous research， we identified the chemical structure and studied the immunomodulatory mechanism of the polysaccharide CRVP from edible green algae Caulerpa racemosa var. peltata. In this study， we further investigated the cytotoxicity and potential mechanism of CRVP against Hepa1-6 cells. Metabolomics analysis showed that CRVP might affect glutathione metabolism-related pathways. CRVP significantly up-regulated oxidized glutathione （GSSG） and down-regulated reduced glutathione （GSH） in Hepa1-6 cells， increasing the ratio of GSSG to GSH and intracellular reactive oxygen species. The potential anti-liver cancer mechanism is that CRVP may affect redox homeostasis and lead to apoptosis by inhibiting glutathione reductase or System Xc-. Based on the known immunomodulatory mechanism of CRVP， this study can provide a material basis for adjuvant therapeutic nutritional agents with immune-enhancing anti-cancer activity.

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Evaluating the pharmacokinetics of intrapulmonary administered ciprofloxacin solution for respiratory infections using in vivo and in silico PBPK rat model studies

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Chinese Chemical Letters 2023年第1期34卷 230-234页

作者： Changzhi Shi Jelisaveta Ignjatovic Junwei Wang Yi Guo Li Zhang Sandra Cvijic Dongmei Cun Mingshi Yang Wuya College of Innovation Shenyang Pharmaceutical UniversityShenyang 110016China Department of pharmaceutical Technology and Cosmetology University of Belgrade-Faculty of PharmacyBelgrade 11221Serbia Department of pharmacy Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagen DK-2100Denmark

Respiratory antibiotics have been proven clinically beneficial for the treatment of severe lung infections such as Pseudomonas *** a high local concentration of inhaled antibiotics for an extended time in the lung is crucial to ensure an adequate antimicrobial *** this study,we aim to investigate whether an extended exposure of ciprofloxacin(CIP),a model fluoroquinolone drug,in the lung epithelial lining fluid(ELF)could be achieved via a controlled-release formulation *** solutions were intratracheally instilled to the rat lungs at 3 different rates,i.e.,T0h(fast),T2h(medium),and T4h(slow),to mimic different release profiles of inhaled CIP formulations in the ***,the concentration-time profiles of CIP in the plasma and the lung ELF were obtained,respectively,to determine topical exposure index(ELF-Plasma AUC Ratio,EPR).The in silico PBPK model,validated based on the in vivo data,was used to identify the key factors that influence the disposition of CIP in the plasma and *** medium and slow rates groups exhibited much higher EPR than that fast instillation *** ELF AUC of the medium and slow instillation groups were about 200 times higher than their plasma *** contrast,the ELF AUC of the fast instillation group was only about 20 times higher than the plasma *** generated whole-body PBPK rat model,validated by comparison with the in vivo data,revealed that drug pulmonary absorption rate was the key factor that determined pulmonary absorption of *** study suggests that controlled CIP release from inhaled formulations may extend the exposure of CIP in the ELF post pulmonary *** also demonstrates that combining the proposed intratracheal installation model and in silico PBPK model is a useful approach to identify the key factors that influence the absorption and disposition of inhaled medicine.

关键词： Inhalation antibiotics Ciprofloxacin Controlled release PBPK modeling Lung infections

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Antidiabetic effect of combination of fractionated-extracts of Andrographis paniculata and Centella asiatica: In vitro study

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Asian Pacific Journal of Tropical Biomedicine 2018年第11期8卷 527-532页

作者： LOM.Fitrawan R.Ariastuti RR.TjANDrawinata AE.Nugroho S.Pramono master program of pharmaceutical sciences of faculty of pharmacy Universitas Gadjah Mada faculty of pharmacy Universitas Halu Oleo Dexa Laboratories of Biomolecular sciences Department of Pharmacology and Clinical pharmacy Faculty of Pharmacy Universitas Gadjah Mada Department of pharmaceutical Biology Faculty of Pharmacy Universitas Gadjah Mada

Objective: To examine the effect of combination of Andrographis paniculata herb fraction(AHF) and Centella asiatica herb fraction(CHF) on PPAR γ and GLUT4 mRNA expression in 3 T3-L1 adipocyte, and its effect on insulin-stimulated glucose uptake. Methods: 3 T3 L1 adipocyte cells were used to investigate gene expression of PPARy reverse transcription-polymerase chain reaction method. The γ and GLUT4 protein b adipocyte cells were differentiated by using insulin, dexamethasone and 3-isobutyl-1-methylxanthine from 3 T3-L1 cells. Pioglitazone, AHF, CHF and the combination of both herbs were evaluated on glucose uptake activity, PPAR γ and GLUT4 mRNA expressions in 3 T3-L1 adipocyte. Results: The results showed that combination of AHF at 30 μg/mL and CHF at 10 μg/mL could enhance insulin-stimulated glucose uptake. The combination also increased PPAR γ and GLUT4 mR NA expressions significantly in comparison to those of negative control(DMSO). These effects were equal in comparison to those of pioglitazone(0.02 μM) and its single extracts Conclusions: The combination of AHF and CHF can increase glucose uptake and insulin sensitivity through up-regulation of PPAR γ and GLUT4 mRNA expressions in 3 T3-L1 adipocyte.

关键词： Andrographis paniculata Centella asiatica GLUT4 PPAR γ 3T3-L1

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A novel route for the synthesis of androgen receptor antagonist enzalutamide

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Chinese Chemical Letters 2023年第6期34卷 449-453页

作者： Xiangguo Meng Siju Bi Shixin Jin Kai Wu Shanchao Wu Lei Shao Pierre-Antoine Bonnet Chunquan Sheng College of pharmacy Shanghai University of Medicine and Health SciencesShanghai 201318China Department of Medicinal Chemistry School of PharmacySecond Military Medical UniversityShanghai 200433China State Key Lab of Anti-Infectives Shanghai Institute of Pharmaceutical IndustryChina State Institute of Pharmaceutical IndustryShanghai 201203China IBMM Faculty of PharmacyMontpellier UniversityCNRSENSCM34093 Montpellier Cedex 5France

A novel route of enzalutamide was developed in five *** from 4-amino-2-(trifluoromethyl)benzonitrile(7)and Boc-2-aminoisobutyric acid(16),condensation,deprotection,Ullmann coupling,cyclization and amination provided enzalutamide in 41.0%total *** route avoids the using of toxic chemical,unstable intermediate and high-risk *** is a potential efficient and economical procedure for industrialization.

关键词： Enzalutamide Condensation Deprotection Ullmann coupling Cyclization Amination

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