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Journal of Pharmaceutical Analysis 2024年第2期14卷 211-224页

作者： Jingjing Wang Qi Su Kun Chen Qing Wu Jiayan Ren Wenjuan Tang Yu Hu Zeren Zhu Cheng Cheng Kaihui Tu Huaizhen He Yanmin Zhang school of pharmacy Health Science CenterXi'an Jiaotong UniversityXi'an710061China

Hepatocellular carcinoma (HCC) is one of the most common tumor types and remains a major clinical challenge. Increasing evidence has revealed that mitophagy inhibitors can enhance the effect of chemotherapy on HCC. However, few mitophagy inhibitors have been approved for clinical use in humans. Pyrimethamine (Pyr) is used to treat infections caused by protozoan parasites. Recent studies have reported that Pyr may be beneficial in the treatment of various tumors. However, its mechanism of action is still not clearly defined. Here, we found that blocking mitophagy sensitized cells to Pyr-induced apoptosis. Mechanistically, Pyr potently induced the accumulation of autophagosomes by inhibiting autophagosome-lysosome fusion in human HCC cells. In vitro and in vivo studies revealed that Pyr blocked autophagosome-lysosome fusion by upregulating BNIP3 to inhibit synaptosomal-associated protein 29 (SNAP29)-vesicle-associated membrane protein 8 (VAMP8) interaction. Moreover, Pyr acted synergistically with sorafenib (Sora) to induce apoptosis and inhibit HCC proliferation in vitro and in vivo. Pyr enhances the sensitivity of HCC cells to Sora, a common chemotherapeutic, by inhibiting mitophagy. Thus, these results provide new insights into the mechanism of action of Pyr and imply that Pyr could potentially be further developed as a novel mitophagy inhibitor. Notably, Pyr and Sora combination therapy could be a promising treatment for malignant HCC.

关键词： Pyrimethamine BNIP3 SNARE Autophagosome-lysosome fusion Hepatocellular carcinoma Sorafenib

Cell Mechanics Regulates the Dynamic Anisotropic Remodeling of Fibril Matrix at Large Scale

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Research 2024年第3期2023卷 401-415页

作者： Mingxing Ouyang Yanling Hu Weihui Chen Hui Li Yingbo Ji Linshuo Qiu Linlin Zhu Baohua Ji Bing Bu Linhong Deng Institute of Biomedical Engineering and health Sciences School of Medical and Health Engineering and School of PharmacyChangzhou UniversityChangzhou213164China Institute of Biomechanics and Applications Department of Engineering MechanicsZhejang UniversityHangzhou310027China.

Living tissues often have anisotropic and heterogeneous organizations, in which developmental processes are coordinated by cells and extracellular matrix modeling. Cells have the capability of modeling matrix in long distance;however, the biophysical mechanism is largely unknown. We investigated the dynamic remodeling of collagen I (COL) fibril matrix by cell contraction with designed patterns of cell clusters. By considering cell dynamic contractions, our molecular dynamics simulations predicted the anisotropic patterns of the observed COL bundling in experiments with various geometrical patterns without spatial limitation. The pattern of COL bundling was closely related to the dynamic remodeling of fibril under cell active contraction. We showed that cell cytoskeletal integrity (actin filaments and microtubules), actomyosin contractions, and endoplasmic reticulum calcium channels acting as force generations and transductions were essential for fiber bundling inductions, and membrane mechanosensory components integrin and Piezo played critical roles as well. This study revealed the underlying mechanisms of the cell mechanics-induced matrix remodeling in large scales and the associated cellular mechanism and should provide important guidelines for tissue engineering in potential biomedical applications.

关键词： contraction Dynamic Matrix

Remodeling the tumor microenvironment by vascular normalization and GSH-depletion for augmenting tumor immunotherapy

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Chinese Chemical Letters 2024年第2期35卷 329-334页

作者： Jin Wang Qingqing Zhang Yanchen Li Xiaoyan Pan Yuanyuan Shan Jie Zhang school of pharmacy Health Science CenterXi'an Jiaotong UniversityXi'an 710061China Department of pharmacy The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'an 710061China

Remodeling tumor microenvironment(TME)is a very promising and effective strategy to enhance the effects of chemotherapy,photodynamic therapy,and *** of tumor vasculature as well as depletion of glutathione(GSH)can improve the ***,we developed a novel therapeutic nanoparticle functional enzyme ultra QDAU5 nanoparticles(FEUQ Nps)based on a fluorescence-on and releasable strategy by combining a vascular normalization inducer,a GSH depleting agent,and an activated *** which the cleavage of disulfide bonds releases active molecules that induce vascular normalization and improve the hypoxic *** addition,it may deplete GSH in cancer cells,thus inducing the production of reactive oxygen species(ROS)and lipid peroxide(LPO)and promoting iron *** may also lead to endoplasmic stress and release of calmodulin,which activates the immune ***,quenched fluorophores are turned on in the presence of galactosidase(GLU)for tumor-specific *** summary,we developed novel therapeutic agent nanoparticles with the function of vascular normalization inducers to achieve specific labeling of hepatocellular carcinoma while exerting efficient antitumor effects in vivo.

关键词： Vascular normalization Tumor microenvironment GSH depletion Ferroptosis Activated immune

Double-layer probiotic encapsulation for enhanced bacteriotherapy against inflammatory bowel disease

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Nano Research 2024年第10期17卷 9103-9110页

作者： Yixin Wang Jun Liu Sichen Yuan Yawen You Quanyin Hu Pharmaceutical Sciences Division School of PharmacyUniversity of Wisconsin-MadisonMadisonWI 53705USA Carbone Cancer Center School of Medicine and Public HealthUniversity of Wisconsin-MadisonMadisonWI 53705USA Wisconsin Center for NanoBioSystems School of PharmacyUniversity of Wisconsin-MadisonMadisonWI 53705USA

Inflammatory bowel disease(IBD)is inflammatory intestinal disorders associated with dysregulated gut *** that leverages bacteria as therapeutics has shown tremendous promise in resolving gut dysbiosis and reducing inflammatory mediators to treat *** delivered probiotics,such as Escherichia coli Nissle 1917(EcN),can produce beneficial ingredients,competitively inhibit the proliferation of pathogens,and promote the restoration of gut microbiome ***,environmental stresses(such as gastric acids)in the gastrointestinal(GI)tract pose an enormous challenge to the probiotics following oral administration,leading to decreases in viability and activity of ***,the inferior mucoadhesive capability of probiotics results in low colonization efficacy,further compromising their therapeutic *** probiotics with functional biomaterials may protect them from elimination and prolong their retention in the GI ***,we developed a facile double-layer electrostatic assembly technique to encapsulate EcN bacteria in protective layers of mucoadhesive chitosan(CS)and immunomodulatory hyaluronic acid(HA)to generate *** biomaterials confer the coated EcN resistance to environmental assault and enhanced mucoadhesion in the GI *** probiotics equipped with the multifunctional shield can thus suppress inflammation and reshape the intestinal microenvironment to enhance therapeutic efficacy for the prevention and treatment of ***,this study presents a novel probiotic coating strategy to augment the outcome of bacteriotherapy to combat IBD.

关键词： probiotics biomaterial coating inflammatory bowel disease mucoadhesion oral administration

Difluoromethyl phenoxathiinium salt: A new general and versatile difluoromethylating reagent with divergent ·CF_(2)H, CF_(2)H^(+), and :CF_(2) reactivities

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Science China Chemistry 2024年第3期67卷 953-962页

作者： Yuan-Qing Gu Hong-Xin Long Dan-Dan Zhang Mei-Feng Ruan Guo-Kai Liu school of pharmacy Shenzhen University Medical SchoolShenzhen UniversityShenzhen 518055China

Development of practical and versatile electrophilic difluoromethylating reagent is still a grand challenge so far due to its inherent instability or low ***,we report the design and synthesis of difluoromethyl phenoxathiinium tetrafluoroborate(PT-CF_(2)H^(+)BF_(4)^(-)) as a novel difluoromethylating reagent,which proves to be a bench-stable,general,powerful and versatile reagent with divergent·CF_(2)H,CF_(2)H^(+),and:CF_(2) *** use of this reagent,we demonstrated a vast array of difluoromethyl radical transfer reactions via diverse pathways involving photocatalyst-free visible-light induction,visible-light photoredox catalysis and visible-light mediation single electron transfer of EDA ***,the green and highly effective CF_(2)H^(+) and:CF_(2) transfer reactions were also readily accomplished.

关键词： difluoromethyl phenoxathiinium salt versatile difluoromethylating reagent difluoromethyl radical difluoromthyl cation difluorocarbene

Combination losartan with hyaluronic acid modified diethyldithiocarbamate loaded hollow copper sulfide nanoparticles for the treatment of breast cancer and metastasis

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Chinese Chemical Letters 2024年第3期35卷 406-414页

作者： Haili Hu Weiwei Zhang Lei Lei Fan Tong Huilin Zhang Yiwei Zhang Wenqin Yang Yilu Tang Ruyi Lin Xue Xia Jiamei Li Shiyong Song Huile Gao Key Laboratory of Drug Targeting and Drug Delivery Systems West China School of PharmacySichuan UniversityChengdu 610041China school of pharmacy Henan UniversityKaifeng 475004China Department of Public health Chengdu Medical CollegeChengdu 610500China

The application of photothermal therapy(PTT)is greatly limited by the low accumulation of photothermal agents,uneven photothermal distribution,and heat endurance of cancer *** still,despite PTT enhances immunogenicity,the anti-tumor immune efficacy is still unsatisfactory due to the inefficient immunogenic cell death(ICD)induction and poor infiltration of immune *** solve the above problems of PTT,we developed hyaluronic acid(HA)modified hollow copper sulfide nanoparticles encapsulating diethyldithiocarbamate(DDTC)to construct a breast tumor targeting and near infrared(NIR)photo-responsive drug delivery system(D-HCuS@HA),which further combined with losartan to improve the accumulation and penetration in the tumor *** irradiation,D-HCuS@HA realized enhanced PTT and released cytotoxic Cu(DDTC)_(2)to eliminate heat endurance tumor cells,thereby enhancing antitumor effect and inducing effective ***,the combination with losartan could remodel the tumor microenvironment,allowing more T cells to infiltrate into the tumor,and significantly inhibiting the occurrence and development of metastatic *** vitro/vivo results revealed the great potential of D-HCuS@HA combined with losartan,which provides a new paradigm for anti-tumor and anti-metastases.

关键词： Targeted drug delivery system Hollow copper sulfide nanoparticles Photothermal therapy Hyaluronic acid Breast cancer Anti-metastasis

Advanced nano drug delivery systems for neuroprotection against ischemic stroke

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Chinese Chemical Letters 2024年第2期35卷 151-162页

作者： Chenchen Xie Jun Liao Ning Zhang Yuhan Sun Yi Li Liyan Xiong Yingnan Zhang Xiaoyan Liu Wei Su Heming Chen Ping Zeng Xiaoqing Zhang Ying Lu Tingfang Wang Chuan Zhang Shanghai Engineering Research Center of Organ Repair School of MedicineShanghai UniversityShanghai 200444China Department of Pharmaceutical Science School of PharmacyNaval Medical UniversityShanghai 200433China Department of pharmacy the International Peace Maternity and Child Health HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200030China school of pharmacy Shanghai Jiao Tong UniversityShanghai 200040China

Ischemic stroke(IS)represents a significant threat to brain health due to its elevated mortality and disability *** efficacy of small-molecule neuroprotective agents has been impeded by challenges associated with traversing the blood-brain barrier(BBB)and limited ***,advanced nano drug delivery systems hold promise for overcoming these obstacles by facilitating efficient transportation across the BBB and maintaining optimal drug *** review aims to explore advanced neuroprotective nano drug delivery systems as a means of effectively administering neuroprotective agents to the brain using pharmaceutical approaches in the treatment of *** examining these systems,researchers and clinicians can gain valuable insights and innovative concepts,illuminating the potential of advanced neuroprotective nano drug delivery *** these advancements can drive the progress of pioneering and efficacious therapeutic interventions for IS.

关键词： Target Blood-brain barrier Ischemic stroke Nano drug delivery Neuroprotection

Divergent defluorocarboxylation of α-CF_(3) alkenes with formate via photocatalyzed selective mono-or triple C-F bond cleavage

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Science China Chemistry 2024年第1期67卷 368-373页

作者： Xing-Yu Wang Pei Xu Wen-Wen Liu Hao-Qiang Jiang Song-Lei Zhu Dong Guo Xu Zhu Jiangsu Key Laboratory of New Drug Research and Clinical pharmacy School of PharmacyXuzhou Medical UniversityXuzhou 22100China

Unprecedented divergent synthesis of gem-difluorovinylacetic acid and glutaric acid derivatives fromα-CF_(3)alkenes with formate as the carbonyl source was *** reaction can undergo selective mono-or triple C-F bond cleavage by simply switching the photocatalyst and hydrogen atom transfer(HAT)catalyst under visible-light-induced conditions at room *** acts as both the C1 source and the reductant through the generation of CO_(2)^(·-)species,which underwent Giese radical addition to electron-deficient alkenes to trigger the consecutive C-F bond cleavage and carboxylation process.

关键词： C-F bond activation defluorocarboxylation carbon dioxide radical anion visible light

Krüppel-like factor 2(KLF2),a potential target for neuroregeneration

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Neural Regeneration Research 2024年第11期19卷 2327-2328页

作者： Surajit Hansda Prateeksha Prateeksha Hiranmoy Das Department of Pharmaceutical Sciences Jerry H.Hodge School of PharmacyTexas Tech University Health Sciences CenterAmarilloTXUSA

Neurological disorders and injuries lead to the impairment or depletion of neurons in terms of quantity,structure,or function,resulting in the loss of cognitive,emotional,and physical abilities in human ***,in turn,accompanies the shortfall of valuable human resources and economic potential,causing a detriment to *** these challenges,therefore,becomes imperative not only from a humanitarian perspective but also as a means of preserving human capital and bolstering economic prosperity.

关键词： companies injuries potential

Progress in experimental models to investigate the in vivo and in vitro antidiabetic activity of drugs

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Animal Models and Experimental Medicine 2024年第3期7卷 297-309页

作者： Yasodha Krishna Janapati Sunil Junapudi school of pharmacy&health Sciences United States International University-AFRICA(USIU-A)NairobiKenya Department of Pharmaceutical Chemistry Geethanjali College of PharmacyKeesaraIndia

Diabetes mellitus is one of the world's most prevalent and complex metabolic disorders,and it is a rapidly growing global public health *** is characterized by hyperglycemia,a condition involving a high blood glucose level brought on by deficiencies in insulin secretion,decreased activity of insulin,or *** effects of diabetes include cardiovascular problems,retinopathy,neuropathy,nephropathy,and vascular alterations in both macro-and micro-blood *** vivo and in vitro models have always been important for investigating and characterizing disease pathogenesis,identifying targets,and reviewing novel treatment options and *** understanding these models is crucial for the researchers so this review summarizes the different experimental in vivo and in vitro model options used to study diabetes and its *** most popular in vivo studies involves the small animal models,such as rodent models,chemically induced diabetogens like streptozotocin and alloxan,and the possibility of deleting or overexpressing a specific gene by knockout and transgenic technologies on these *** models include virally induced models,diet/nutrition induced diabetic animals,surgically induced models or pancreatectomy models,and non-obese *** animals or non-rodent models like porcine(pig),canine(dog),nonhuman primate,and Zebrafish models are also *** in vitro models discussed are murine and human beta-cell lines and pancreatic islets,human stem cells,and organoid *** other enzymatic in vitro tests to assess diabetes include assay of amylase inhibition and inhibition ofα-glucosidase activity.

关键词： animal models diabetes mellitus typeⅠ diabetes mellitus typeⅡ in vitro and in vivo models