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Enhanced oral drug delivery by mimicking natural amino acid and oligopeptide absorption route

Nano Research 2025年第2期18卷 525-540页

作者： Ruinan Wu Xiaoxing Fan Licheng Wu Liyun Xing Jinxia Kong Zhou Zhou Jingyuan Wen Lian Li Yuan Huang Key Laboratory of drug-Targeting and drug Delivery System of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengdu 610041China School of Pharmacy Faculty of Medical and Health SciencesUniversity of AucklandAuckland 1023New Zealand

Oral delivery of protein and peptide drugs presents considerable challenges due to their susceptibility to digestive enzymes in gastrointestinal(Gl)tract and low efficiency of transepithelial ***,inspired by efficient absorption of protein-based nutrients,we constructed several kinds of oral drug delivery systems by mimicking natural amino acid and oligopeptide absorption *** kinds of amino acids and two kinds of oligopeptides were chosen as targeting ligands to mediate transportation of orally administered nanoparticles(NPs).Liraglutide(Lira),a kind of glucagon like peptide-1(GLP-1)receptor agonist,was used as model *** functionalized NPs could protect Lira from enzymatic degradation in Gl ***,compared with amino acid-modified NPs,oligopeptide-modified NPs exhibited greater transepithelial transport efficiency and were primarily absorbed in the proximal small intestine due to the high expression and transportation mediated by proton coupled oligopeptide transporter 1(PEPT1).These Lira-loaded NPs could effectively control the blood glucose level,reduce plasma lipid level,and repair tissue damage on type 2 diabetic mice and even showed comparable hypoglycemic effects of subcutaneous injection(s.c.)free *** study demonstrates the potential of mimicking natural oligopeptide absorption route to enhance oral delivery of protein and peptide drugs.

关键词： oral drug delivery amino acid absorption route oligopeptide absorption route liraglutide

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Research progress of small-molecule natural medicines for the treatment of ischemic stroke

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Chinese Journal of Natural Medicines 2025年第1期23卷 21-30页

作者： Kui Liu Ling Wang Tao Pang State Key Laboratory of Natural Medicines New Drug Screening and Pharmacodynamics Evaluation Center China Pharmaceutical University

Stroke is the second leading cause of disability and mortality worldwide, imposing a substantial socioeconomic burden on individuals and healthcare systems. Annually, approximately 14 million people experience stroke, with ischemic stroke comprising nearly 85% of cases, of which 10% to 20% involve large vessel occlusions. Currently, recombinant tissue plasminogen activator(tPA) remains the only approved pharmacological intervention. However, its utility is limited due to a narrow therapeutic window and low recanalization rates, making it applicable to only a minority of patients. Therefore, there is an urgent need for novel therapeutic strategies, including pharmacological advancements and combinatory ***-molecule natural medicines, particularly those derived from traditional Chinese herbs,have demonstrated significant therapeutic potential in ischemic stroke management. These compounds exert multiple neuroprotective effects, such as antioxidation, anti-inflammatory action, and inhibition of apoptosis, all of which are critical in mitigating stroke-induced cerebral damage. This review comprehensively examines the pathophysiology of acute ischemic stroke(AIS) and highlights the recent progress in the development of small-molecule natural medicines as promising therapeutic agents for cerebral ischemic stroke.

关键词： Antioxidants Ischemic stroke Natural medicines Neuroinflammation. Small molecule

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Characteristics of β-oxidative and reductive metabolism on the acyl side chain of cinnamic acid and its analogues in rats

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Acta Pharmacologica Sinica 2019年第8期40卷 1106-1118页

作者： Kai-jing Zhao Yang Chen Shi-jin Hong Yi-ting Yang Jiong Xu Han-yu Yang Liang Zhu Ming Liu Qiu-shi Xie Xian-ge Tang Ting-ting Yang Ya-qian Zhou Li Liu Xiao-dong Liu center of drug metabolism and pharmacokinetics School of PharmacyChina Pharmaceutical University

Cinnamic acid and its analogues(pyragrel and ozagrel)undergo chain-shortened(β-oxidative)and reductive metabolism on acyl side *** this study,we characterized the β-oxidative and reductive metabolism on acyl side chain of cinnamic acid and its analogues using primary rat hepatocytes,hepatic mitochondrial,and microsomal systems.A compartmental model including parent compounds and metabolites was developed to characterize in vivo β-oxidative and reductive metabolism following an intravenous dose of parent compounds to *** fitted total in vivo clearance values were further compared with the in vitro values predicted by the well-stirred *** showed that hepatic microsomal CYP450s did not catalyze β-oxidative or reductive metabolism of the three *** to β-oxidation of fatty acids,β-oxidative metabolism on their acyl side chain occurred mainly in mitochondria,which was highly dependent on ATP,CoA and NAD~+.Fatty acids and NADH inhibited the β-oxidative *** metabolism occurred in both mitochondria and *** in mitochondria was ATP-,CoA-,and NAD(P)H-dependent and reversible,which was suppressed by enoyl reductase inhibitor *** in microsomes was ATP-,CoA-,and NADPH-dependent but little affected by *** plasma concentrations of β-oxidative metabolites and reductive metabolites were successfully fitted using the compartmental *** estimated total in vivo clearance values were consistent with those predicted from hepatocytes and organelles,implicating significance of in vitro *** findings demonstrate the roles of hepatic mitochondria and microsomes in β-oxidative and reductive metabolism on acyl side chain of cinnamic acid and its analogues along with their metabolic characteristics.

关键词： antiplatelet drug cinnamic acid pyragrel ozagrel drug metabolism hepatocytes mitochondria microsomes pharmacokinetics in vitro-in vivo correlation

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Chiral phosphoramidite ligand-modulated palladium auto-tandem catalysis for asymmetric dehydrogenative dienylation of imines with α-alkenes

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Science China Chemistry 2025年

作者： Zhong-Sheng Nong Hao-Fan Qian Ying-Chun Chen Pu-Sheng Wang Liu-Zhu Gong Hefei National Research center for Physical Sciences at the Microscale and Department of Chemistry University of Science and Technology of China Key Laboratory of drug Targeting and drug Delivery System (Sichuan University) Ministry of Education and Sichuan Research Center for Drug Precision Industrial Technology West China School of Pharmacy Sichuan University School of Materials and Chemistry Southwest University of Science and Technology

The development of efficient processes allowing rapid access to complex chiral molecules from easily available alkenes is a long-term pursuit in the synthetic chemistry community. Transition metal-catalyzed asymmetric functionalization of allylic C–H bond represents a unique alternative toward this goal. However, enantioselective dehydrogenative transformation of olefins to value-added optically enriched molecules remains yet to be discovered. Here, we report a highly enantioselective dehydrogenative dienylation of imines with unactivated α-alkenes driven by the synergistic action of palladium complex and carboxylic acid. Chiral phosphoramidite ligands turned out to be superior in modulating the performance of palladium autotandem catalysis and allowed a broad range of α-alkenes and imines to be transformed into chiral dienylamines. Mechanistic studies suggest that the dienes could be in situ generated from α-alkenes through a palladium(0)-mediated dehydrogenative process in the presence of excess benzoquinone oxidants, and then participated in the Pd-chiral phosphoramidite-catalyzed intermolecular vinylogous-type addition to the imines activated by the carboxylic acid co-catalyst. Notably, the second β-H elimination occurring in the dienylation event might be the turnover-limiting step.

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Impact of setting distinct target blood glucose levels on endogenous insulin suppression and pharmacodynamics of insulin preparations

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World Journal of Diabetes 2025年第2期16卷 47-54页

作者： Hui Liu Ting Li Xin-Lei Chen Hong-Ling Yu Ye-Rong Yu Department of Endocrinology and metabolism West China Hospital of Sichuan UniversityChengdu 610041Sichuan ProvinceChina Clinical Trial center West China Hospital of Sichuan UniversityChengdu 610041Sichuan ProvinceChina Health Management center General Practice Medical CenterWest China Hospital of Sichuan UniversityChengdu 610041Sichuan ProvinceChina

BACKGROUND Insulin therapy plays a crucial role in managing *** guidelines mandate assessing the pharmacokinetics(PK)and pharmacodynamics(PD)of new insulin formulations with euglycemic clamp techniques before entry into the ***,blood glucose(BG)levels are maintained at 5%below baseline to suppress endogenous insulin secretion in healthy ***,in scenarios where BG baseline is relatively low,maintaining it at 5%below baseline can increase hypoglycemic ***,we adjusted to maintain it at 2.5%below a baseline of<4.00 mmol/*** remains uncertain whether this adjustment impacts endogenous insulin inhibition or the PD of study *** To evaluate and compare the PD and C-peptide status using two different target BG setting *** Data came from euglycemic clamp trials assessing the PK/PD of insulin aspart(IAsp)in healthy *** BG was set at 2.5%below baseline for those with a basal BG of<4.00 mmol/L(group A),and at 5%below baseline for others(group B).The area under the curve(AUC)of IAsp(AUC_(IAsp,0-8 h))and GIR from 0 to 8 hours(AUCGIR,0-8 h)was used to characterize the PK and PD of IAsp,*** C-peptide reduction and PK/PD of IAsp were compared between the two *** Out of 135 subjects,15 were assigned to group A and 120 to group B;however,group B exhibited higher basal Cpeptide(1.59±0.36 vs 1.32±0.42 ng/mL,P=0.006).Following propensity score matching to adjust for basal Cpeptide differences,71 subjects(15 in group A and 56 in group B)were *** significant differences were observed in demographics,IAsp dosage,or clamp *** B showed significantly higher baseline(4.35±0.21 vs 3.91±0.09 mmol/L,P<0.001),target(4.13±0.20 vs 3.81±0.08 mmol/L,P<0.001),and clamped(4.10±0.17 vs 3.80±0.06 mmol/L,P<0.001)BG *** groups exhibited comparable C-peptide suppression(32.5%±10.0%vs 35.6%±12.1%,P=0.370)and similar IAsp activity(AUCGIR,0-8 h:1433±400 vs 1440±397 mg/kg,

关键词： Euglycemic clamp Target glucose setting Healthy subject C-peptide Pharmacodynamics Endogenous insulin secretion

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Spastin and alsin protein interactome analyses begin to reveal key canonical pathways and suggest novel druggable targets

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Neural Regeneration Research 2025年第3期20卷 725-739页

作者： Benjamin R.Helmold Angela Ahrens Zachary Fitzgerald P.Hande Ozdinler Department of Neurology Feinberg School of MedicineNorthwestern UniversityChicagoILUSA center for Molecular Innovation and drug Discovery Center for Developmental TherapeuticsChemistry of Life Processes InstituteNorthwestern UniversityEvanstonILUSA Mesulam center for Cognitive Neurology and Alzheimer’s Disease Feinberg School of MedicineNorthwestern UniversityChicagoILUSA Feinberg School of Medicine Les Turner ALS Center at Northwestern UniversityChicagoILUSA

Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein–protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as “causative” for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and drug Administration–approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.

关键词： ALS2 alsin amyotrophic lateral sclerosis hereditary spastic paraplegia neurodegenerative diseases personalized medicine precision medicine protein interactome protein-protein interactions SPAST spastin

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pharmacokinetics of monoclonal antibodies ]nd Fc-fusion proteins

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Protein & Cell 2018年第1期9卷 15-32页

作者： Liming Liu Department of pharmacokinetics Pharrnacodynamics and Drug Metabolism MRL West Point PA 19486 USA

There are many factors that can influence the pharma- cokinetics （PK） of a mAb or Fc-fusion molecule with the primary determinant being FcRn-mediatad recycling. Through Fab or Fc engineering, IgG-FcRn interaction can be used to generate a variety of therapeutic anti. bodies with significantly enhanced half-life or ability to remove unwanted antigen from circulation, Glycosyla- tion of a mAb or *** protein can have a significant impact on the PK of these molecules, mAb charge can be important and variants with pl values of 1-2 unit difference are likely to impact PK with lower pl values being favorable for a longer ***. Most mAbs display target mediated drug disposition （TMOO）, which can have significant consequences on the study designs of preclinical and clinical studies. The PK of mAb can also be influenced by anti-drug antibody （ADA） response and *** binding, which require careful consideration during the discovery stage, mAbs are primarily absor- bed through the lymphatics via convection and can be conveniently administered by the subcutaneous （sc） route in large doses/volumes with co-formulation of hyaluronidase. The human PK of a mAb can be rea- sonably estimated using cynomolgus monkey data and allometric scaling methods.

关键词： monoclonal antibody (mAb) Fc-fusionprotein pharmacokineUcs FcRn target-mediated drugdisposition (TMDD) glycosylation anti-drug antibody (ADA)human PK prediction

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drug metabolism in drug discovery and development

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Acta Pharmaceutica Sinica B 2018年第5期8卷 721-732页

作者： Zhoupeng Zhang Wei Tang Department of pharmacokinetics Pharmacodynamics and Drug Metabolism Merck Sharp & Dohme Corp. Shanghai ChemPartners

drug metabolism as a discipline plays an important role in drug discovery and development and the effects of drug metabolism on pharmacokinetics(PK), pharmacodynamics(PD), and safety should be carefully considered. This communication provides an overview of common strategies in the area of drug metabolism for improving PK/PD and safety profiles of drug candidates; these include, but are not limited to, collaboration with medicinal chemists on structure–activity relationships(SAR) to overcome high clearance, using deuterium replacement to further optimize a lead, prodrug approaches to circumvent formulation and delivery difficulties, and addressing issues such as species differences in metabolism,drug–drug interactions(DDI) and formation of reactive metabolites.

关键词： Bioactivation drug discovery and development drug metabolism Metabolite pharmacokinetics Pharmacodynamics Safety Toxicity

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Spinal cord injury regenerative therapy development:integration of design of experiments

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Neural Regeneration Research 2025年第9期20卷 2571-2573页

作者： Yuji Okano Hideyuki Okano Yoshitaka Kase Division of CNS Regeneration and drug Discovery International Center for Brain Science(ICBS)Fujita Health UniversityKutsukake-ChoToyoake-ShiAichiJapan Department of Extended Intelligence for Medicine The Ishii-Ishibashi LaboratoryKeio University School of MedicineShinanomachiShinjuku-KuTokyoJapan Keio University Regenerative Medicine Research center Kawasaki-kuKawasaki-shiJapan

Spinal cord injury(SCI)can cause motor and sensory paralysis,and autonomic nervous system disorders including malfunction of urination and defecation,thereby significantly impairing the quality of *** continue to explo re new stem cell strategies for the treatment of paralysis by transpla nting human induced pluripotent stem cell-derived neural ste m/progenitor cells(hiPSCNS/PCs)into spinal cord injured tissues.

关键词： Spinal paralysis injury

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Sequencing and characterizing human mitochondrial genomes in the biobank-based genomic research paradigm

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Science China Life Sciences 2025年

作者： Lintao Luo Mengge Wang Yunhui Liu Jianbo Li Fengxiao Bu Huijun Yuan Renkuan Tang Chao Liu Guanglin He Institute of Rare Diseases West China Hospital of Sichuan UniversitySichuan University Department of Forensic Medicine College of Basic MedicineChongqing Medical University center for Archaeological Science Sichuan University Anti-drug Technology center of Guangdong Province

Human mitochondrial DNA (mtDNA) harbors essential mutations linked to aging,neurodegenerative diseases,and complex muscle *** to its uniparental and haploid inheritance,mtDNA captures matrilineal evolutionary trajectories,playing a crucial role in population and medical ***,critical questions about the genomic diversity patterns,inheritance models,and evolutionary and medical functions of mtDNA remain unresolved or underexplored,particularly in the transition from traditional genotyping to largescale genomic *** review summarizes recent advancements in data-driven genomic research and technological innovations that address these questions and clarify the biological impact of nuclear-mitochondrial segments (NUMTs) and mtDNA variants on human health,disease,and *** propose a streamlined pipeline to comprehensively identify mtDNA and NUMT genomic diversity using advanced sequencing and computational ***-resolved mtDNA sequencing and assembly can distinguish authentic mtDNA variants from NUMTs,reduce diagnostic inaccuracies,and provide clearer insights into heteroplasmy patterns and the authenticity of paternal *** review emphasizes the need for integrative multi-omics approaches and emerging long-read sequencing technologies to gain new insights into mutation mechanisms,the influence of heteroplasmy and paternal inheritance on mtDNA diversity and disease susceptibility,and the detailed functions of NUMTs.

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