Pub Date : 2025-01-01DOI: 10.1016/j.apsb.2024.09.003
Yutong Tu , Qian Yu , Mengna Li , Lixin Gao , Jialuo Mao , Jingkun Ma , Xiaowu Dong , Jinxin Che , Chong Zhang , Linghui Zeng , Huajian Zhu , Jiaan Shao , Jingli Hou , Liming Hu , Bingbing Wan , Jia Li , Yubo Zhou , Jiankang Zhang
{"title":"DiPTAC: A degradation platform via directly targeting proteasome","authors":"Yutong Tu , Qian Yu , Mengna Li , Lixin Gao , Jialuo Mao , Jingkun Ma , Xiaowu Dong , Jinxin Che , Chong Zhang , Linghui Zeng , Huajian Zhu , Jiaan Shao , Jingli Hou , Liming Hu , Bingbing Wan , Jia Li , Yubo Zhou , Jiankang Zhang","doi":"10.1016/j.apsb.2024.09.003","DOIUrl":"10.1016/j.apsb.2024.09.003","url":null,"abstract":"","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 1","pages":"Pages 661-664"},"PeriodicalIF":14.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.apsb.2024.08.028
Shujun Liu , Shijun Yuan , Meichen Liu , Jinhu Liu , Shunli Fu , Tong Gao , Shuang Liang , Xinyan Huang , Xinke Zhang , Yongjun Liu , Zipeng Zhang , Na Zhang
The underlying cause of low response rates to existing immunotherapies is that tumor cells dominate tumor immune escape through surface antigen deficiency and inducing tumor immunosuppressive microenvironment (TIME). Here, we proposed an in situ tumor cell engineering strategy to disrupt tumor immune escape at the root by restoring tumor cell MHC-I/tumor-specific antigen complex (MHC-I/TSA) expression to promote T-cell recognition and by silencing tumor cell CD55 to increase the ICOSL+ B-cell proportion and reverse the TIME. A doxorubicin (DOX) and dual-gene plasmid (MAC pDNA, encoding both MHC-I/ASMTNMELM and CD55-shRNA) coloaded drug delivery system (LCPN@ACD) with tumor targeting and charge/size dual–conversion properties was prepared. LCPN@ACD-induced ICD promoted DC maturation and enhanced T-cell activation and infiltration. LCPN@ACD enabled effective expression of MHC-I/TSA on tumor cells, increasing the ability of tumor cell recognition and killing. LCPN@ACD downregulated tumor cell CD55 expression, increased the proportion of ICOSL+ B cells and CTLs, and reversed the TIME, thus greatly improving the efficacy of αPD-1 and CAR-T therapies. The application of this in situ tumor cell engineering strategy eliminated the source of tumor immune escape, providing new ideas for solving the challenges of clinical immunotherapy.
{"title":"In situ tumor cell engineering reverses immune escape to enhance immunotherapy effect","authors":"Shujun Liu , Shijun Yuan , Meichen Liu , Jinhu Liu , Shunli Fu , Tong Gao , Shuang Liang , Xinyan Huang , Xinke Zhang , Yongjun Liu , Zipeng Zhang , Na Zhang","doi":"10.1016/j.apsb.2024.08.028","DOIUrl":"10.1016/j.apsb.2024.08.028","url":null,"abstract":"<div><div>The underlying cause of low response rates to existing immunotherapies is that tumor cells dominate tumor immune escape through surface antigen deficiency and inducing tumor immunosuppressive microenvironment (TIME). Here, we proposed an <em>in situ</em> tumor cell engineering strategy to disrupt tumor immune escape at the root by restoring tumor cell MHC-I/tumor-specific antigen complex (MHC-I/TSA) expression to promote T-cell recognition and by silencing tumor cell CD55 to increase the ICOSL<sup>+</sup> B-cell proportion and reverse the TIME. A doxorubicin (DOX) and dual-gene plasmid (MAC pDNA, encoding both MHC-I/ASMTNMELM and CD55-shRNA) coloaded drug delivery system (LCPN@ACD) with tumor targeting and charge/size dual–conversion properties was prepared. LCPN@ACD-induced ICD promoted DC maturation and enhanced T-cell activation and infiltration. LCPN@ACD enabled effective expression of MHC-I/TSA on tumor cells, increasing the ability of tumor cell recognition and killing. LCPN@ACD downregulated tumor cell CD55 expression, increased the proportion of ICOSL<sup>+</sup> B cells and CTLs, and reversed the TIME, thus greatly improving the efficacy of <em>α</em>PD-1 and CAR-T therapies. The application of this <em>in situ</em> tumor cell engineering strategy eliminated the source of tumor immune escape, providing new ideas for solving the challenges of clinical immunotherapy.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 1","pages":"Pages 627-641"},"PeriodicalIF":14.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.apsb.2024.11.006
Lixia Fu , Guoshu Jia , Zhenming Liu , Xiaocong Pang , Yimin Cui
Artificial intelligence (AI) has emerged as a transformative force in healthcare, with applications spanning diagnostics to drug development. However, its integration into drug regulation remains nascent, with varying degrees of adoption and implementation across different regulatory bodies worldwide. This review aims to provide a comprehensive overview of the current state of AI in drug regulation, encapsulating AI-related policies, initiatives, and its practical application in regulatory agencies globally. It further discusses the challenges and future prospects of AI in this field. The findings reveal that numerous agencies have launched action plans and initiatives to incorporate AI, aiming to streamline regulatory processes and enhance data-driven regulatory decision-making. Moreover, AI's deployment in safety surveillance, workflow optimization, and regulatory science research is expanding, highlighting its increasing impact on drug regulation. Nonetheless, key challenges persist, such as data quality and reliability, technical limitations, talent shortage and the absence of standards. The review concludes that interdisciplinary collaboration is crucial to harness AI's full potential in drug regulation and overcoming its current limitations. In the future, AI may become a pivotal catalyst in drug regulation, promising a new era of enhanced scrutiny, efficiency, and innovation that will benefit public health on a global scale.
{"title":"The applications and advances of artificial intelligence in drug regulation: A global perspective","authors":"Lixia Fu , Guoshu Jia , Zhenming Liu , Xiaocong Pang , Yimin Cui","doi":"10.1016/j.apsb.2024.11.006","DOIUrl":"10.1016/j.apsb.2024.11.006","url":null,"abstract":"<div><div>Artificial intelligence (AI) has emerged as a transformative force in healthcare, with applications spanning diagnostics to drug development. However, its integration into drug regulation remains nascent, with varying degrees of adoption and implementation across different regulatory bodies worldwide. This review aims to provide a comprehensive overview of the current state of AI in drug regulation, encapsulating AI-related policies, initiatives, and its practical application in regulatory agencies globally. It further discusses the challenges and future prospects of AI in this field. The findings reveal that numerous agencies have launched action plans and initiatives to incorporate AI, aiming to streamline regulatory processes and enhance data-driven regulatory decision-making. Moreover, AI's deployment in safety surveillance, workflow optimization, and regulatory science research is expanding, highlighting its increasing impact on drug regulation. Nonetheless, key challenges persist, such as data quality and reliability, technical limitations, talent shortage and the absence of standards. The review concludes that interdisciplinary collaboration is crucial to harness AI's full potential in drug regulation and overcoming its current limitations. In the future, AI may become a pivotal catalyst in drug regulation, promising a new era of enhanced scrutiny, efficiency, and innovation that will benefit public health on a global scale.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 1","pages":"Pages 1-14"},"PeriodicalIF":14.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.apsb.2024.11.019
Cheng-Long Gao , Jinqian Song , Haojie Wang , Qinghong Shang , Xin Guan , Gang Xu , Jiayang Wu , Dalei Wu , Yueqin Zheng , Xudong Wu , Feng Zhao , Xindong Liu , Lei Shi , Tao Pang
The innate immune sensor NLRP3 inflammasome overactivation is involved in the pathogenesis of ulcerative colitis. PGAM5 is a mitochondrial phosphatase involved in NLRP3 inflammasome activation in macrophages. However, the role of PGAM5 in ulcerative colitis and the mechanisms underlying PGAM5 regulating NLRP3 activity remain unknown. Here, we show that PGAM5 deficiency ameliorates dextran sodium sulfate (DSS)-induced colitis in mice via suppressing NLRP3 inflammasome activation. By combining APEX2-based proximity labeling focused on PGAM5 with quantitative proteomics, we identify NEK7 as the new binding partner of PGAM5 to promote NLRP3 inflammasome assembly and activation in a PGAM5 phosphatase activity-independent manner upon inflammasome induction. Interfering with PGAM5–NEK7 interaction by punicalagin inhibits the activation of the NLRP3 inflammasome in macrophages and ameliorates DSS-induced colitis in mice. Altogether, our data demonstrate the PGAM5–NEK7 interaction in macrophages for NLRP3 inflammasome activation and further provide a promising therapeutic strategy for ulcerative colitis by blocking the PGAM5–NEK7 interaction.
{"title":"The PGAM5–NEK7 interaction is a therapeutic target for NLRP3 inflammasome activation in colitis","authors":"Cheng-Long Gao , Jinqian Song , Haojie Wang , Qinghong Shang , Xin Guan , Gang Xu , Jiayang Wu , Dalei Wu , Yueqin Zheng , Xudong Wu , Feng Zhao , Xindong Liu , Lei Shi , Tao Pang","doi":"10.1016/j.apsb.2024.11.019","DOIUrl":"10.1016/j.apsb.2024.11.019","url":null,"abstract":"<div><div>The innate immune sensor NLRP3 inflammasome overactivation is involved in the pathogenesis of ulcerative colitis. PGAM5 is a mitochondrial phosphatase involved in NLRP3 inflammasome activation in macrophages. However, the role of PGAM5 in ulcerative colitis and the mechanisms underlying PGAM5 regulating NLRP3 activity remain unknown. Here, we show that PGAM5 deficiency ameliorates dextran sodium sulfate (DSS)-induced colitis in mice <em>via</em> suppressing NLRP3 inflammasome activation. By combining APEX2-based proximity labeling focused on PGAM5 with quantitative proteomics, we identify NEK7 as the new binding partner of PGAM5 to promote NLRP3 inflammasome assembly and activation in a PGAM5 phosphatase activity-independent manner upon inflammasome induction. Interfering with PGAM5–NEK7 interaction by punicalagin inhibits the activation of the NLRP3 inflammasome in macrophages and ameliorates DSS-induced colitis in mice. Altogether, our data demonstrate the PGAM5–NEK7 interaction in macrophages for NLRP3 inflammasome activation and further provide a promising therapeutic strategy for ulcerative colitis by blocking the PGAM5–NEK7 interaction.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 1","pages":"Pages 349-370"},"PeriodicalIF":14.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.apsb.2024.10.005
Jintong Yang , Yiteng Lu , Kexin Hu , Xinchen Zhang , Wei Wang , Deyong Ye , Mingguang Mo , Xin Xiao , Xichen Wan , Yuqing Wu , Shuxian Zhang , He Huang , Zhibei Qu , Yimin Hu , Yu Cao , Jiaxu Hong , Lu Zhou
Dry eye disease (DED) is a prevalent and intractable ocular disease induced by a variety of causes. Elevated sphingomyelin (SM) levels and pro-inflammatory cytokines were detected on the ocular surface of DED patients, particularly in the meibomian glands. Sphingomyelin synthase 2 (SMS2), one of the proteins involved in SM synthesis, would light a novel way of developing a DED therapy strategy. Herein, we report the design and optimization of a series of novel thiophene carboxamide derivatives to afford 14l with an improved highly potent inhibitory activity on SM synthesis (IC50, SMS2 = 28 nmol/L). Moreover, 14l exhibited a notable protective effect of anti-inflammation and anti-apoptosis on human corneal epithelial cells (HCEC) under TNF-α-hyperosmotic stress conditions in vitro, with an acceptable ocular specific distribution (corneas and meibomian glands) and pharmacokinetics (PK) profiles (t1/2, cornea = 1.11 h; t1/2, meibomian glands = 4.32 h) in rats. Furthermore, 14l alleviated the dry eye symptoms including corneal fluorescein staining scores and tear secretion in a dose-dependent manner in mice. Mechanically, 14l reduced the mRNA expression of Tnf-α, Il-1β and Mmp-9 in corneas, as well as the proportion of very long chain SM in meibomian glands. Our findings provide a new strategy for DED therapy based on selective SMS2 inhibitors.
{"title":"Discovery of a novel thiophene carboxamide analogue as a highly potent and selective sphingomyelin synthase 2 inhibitor for dry eye disease therapy","authors":"Jintong Yang , Yiteng Lu , Kexin Hu , Xinchen Zhang , Wei Wang , Deyong Ye , Mingguang Mo , Xin Xiao , Xichen Wan , Yuqing Wu , Shuxian Zhang , He Huang , Zhibei Qu , Yimin Hu , Yu Cao , Jiaxu Hong , Lu Zhou","doi":"10.1016/j.apsb.2024.10.005","DOIUrl":"10.1016/j.apsb.2024.10.005","url":null,"abstract":"<div><div>Dry eye disease (DED) is a prevalent and intractable ocular disease induced by a variety of causes. Elevated sphingomyelin (SM) levels and pro-inflammatory cytokines were detected on the ocular surface of DED patients, particularly in the meibomian glands. Sphingomyelin synthase 2 (SMS2), one of the proteins involved in SM synthesis, would light a novel way of developing a DED therapy strategy. Herein, we report the design and optimization of a series of novel thiophene carboxamide derivatives to afford <strong>14l</strong> with an improved highly potent inhibitory activity on SM synthesis (IC<sub>50, SMS2</sub> = 28 nmol/L). Moreover, <strong>14l</strong> exhibited a notable protective effect of anti-inflammation and anti-apoptosis on human corneal epithelial cells (HCEC) under TNF-<em>α</em>-hyperosmotic stress conditions <em>in vitro</em>, with an acceptable ocular specific distribution (corneas and meibomian glands) and pharmacokinetics (PK) profiles (<em>t</em><sub>1/2, cornea</sub> = 1.11 h; <em>t</em><sub>1/2, meibomian glands</sub> = 4.32 h) in rats. Furthermore, <strong>14l</strong> alleviated the dry eye symptoms including corneal fluorescein staining scores and tear secretion in a dose-dependent manner in mice. Mechanically, <strong>14l</strong> reduced the mRNA expression of <em>Tnf-α</em>, <em>Il-1β</em> and <em>Mmp-9</em> in corneas, as well as the proportion of very long chain SM in meibomian glands. Our findings provide a new strategy for DED therapy based on selective SMS2 inhibitors.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 1","pages":"Pages 392-408"},"PeriodicalIF":14.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.apsb.2024.12.007
Yang Liu , Yinchao Zhang , Huikai Li , Tony Y. Hu
Cancer remains a complex and challenging medical problem, driving extensive research efforts. Despite significant progress in understanding its genetic and molecular aspects, the quest for effective treatments continues. Nanomedicines have shown great potential for revolutionizing cancer treatment by offering targeted and controlled drug delivery, reducing side effects, and improving patient outcomes. Accordingly, nanomedicines have been the focus of extensive research and development for clinical translation. As of September 2024, a search on the ClinicalTrials.gov website using the term “nanoparticles” revealed numerous ongoing and planned clinical trials. Motivated by recent advances in the field, this review explores the current frontier of cancer nanomedicine. Nanomedicines have supported chemotherapy, phototherapy and sonodynamic therapy, nucleic acid therapy, and immunotherapy. However, translating nanomedicines into practice has been challenged by complex interactions between nanoparticles and biological systems, variable permeability and retention of nanoparticles in tumors, safety concerns, difficulty achieving targeted delivery, and issues with scaling up manufacturing. Perspectives on addressing these challenges are offered. Future opportunities for cancer nanomedicines, including modifying the tumor microenvironment, integrating artificial intelligence and big data, and targeting new medical areas, are also discussed. This review underscores the potential of cancer nanomedicines to revolutionize treatment from a clinical standpoint.
{"title":"Recent advances in the bench-to-bedside translation of cancer nanomedicines","authors":"Yang Liu , Yinchao Zhang , Huikai Li , Tony Y. Hu","doi":"10.1016/j.apsb.2024.12.007","DOIUrl":"10.1016/j.apsb.2024.12.007","url":null,"abstract":"<div><div>Cancer remains a complex and challenging medical problem, driving extensive research efforts. Despite significant progress in understanding its genetic and molecular aspects, the quest for effective treatments continues. Nanomedicines have shown great potential for revolutionizing cancer treatment by offering targeted and controlled drug delivery, reducing side effects, and improving patient outcomes. Accordingly, nanomedicines have been the focus of extensive research and development for clinical translation. As of September 2024, a search on the ClinicalTrials.gov website using the term “nanoparticles” revealed numerous ongoing and planned clinical trials. Motivated by recent advances in the field, this review explores the current frontier of cancer nanomedicine. Nanomedicines have supported chemotherapy, phototherapy and sonodynamic therapy, nucleic acid therapy, and immunotherapy. However, translating nanomedicines into practice has been challenged by complex interactions between nanoparticles and biological systems, variable permeability and retention of nanoparticles in tumors, safety concerns, difficulty achieving targeted delivery, and issues with scaling up manufacturing. Perspectives on addressing these challenges are offered. Future opportunities for cancer nanomedicines, including modifying the tumor microenvironment, integrating artificial intelligence and big data, and targeting new medical areas, are also discussed. This review underscores the potential of cancer nanomedicines to revolutionize treatment from a clinical standpoint.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 1","pages":"Pages 97-122"},"PeriodicalIF":14.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.apsb.2024.11.007
Shaobing Li , Juntao Lin , Chengxinqiao Wang , Junhan Liu , Yupeng Wang , Yan Chen , Dongfang Zhou
Elevated glucose metabolism is a prominent characteristic of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA). However, the efficacy of inhibiting a single target of glucose metabolism in FLS using small molecular inhibitors is limited for RA treatment. Herein, the synergistic inhibition of FLS’ survival, proliferation, and activation by combining two glucose metabolism inhibitors, diclofenac (DC) and lonidamine (LND) was first verified. Subsequently, DC and LND were individually conjugated to cystamine-modified hyaluronic acid (HA) to prepare two polymer-prodrug conjugates. A HAP-1 peptide-modified dual polymer-prodrug conjugates-assembled nanoparticles system (HAP−1NPDC+LND) was further tailored in the optimal synergistic ratio for targeted and synergistic metabolic modulation of FLS to alleviate RA symptoms. Upon targeted uptake by FLS in inflamed joints, HAP−1NPDC+LND released DC and LND within the intracellular reductive microenvironment, where DC hinders glucose uptake and LND suppresses glycolytic enzymes to eliminate FLS synergistically. Additionally, the secretion of lactic acid and pro-inflammatory factors from FLS were reduced, thereby disrupting the crosstalk between FLS and pro-inflammatory macrophages. Finally, HAP−1NPDC+LND demonstrated promising efficacy in a mouse model of collagen-induced arthritis (CIA). Overall, this research provides valuable insights into novel therapeutic strategies for the safe and effective of treatment RA through targeted and synergistic metabolic modulation of FLS.
{"title":"Synergistic metabolic modulation of fibroblast-like synoviocytes via targeted dual prodrug nanoparticles to mitigate rheumatoid arthritis","authors":"Shaobing Li , Juntao Lin , Chengxinqiao Wang , Junhan Liu , Yupeng Wang , Yan Chen , Dongfang Zhou","doi":"10.1016/j.apsb.2024.11.007","DOIUrl":"10.1016/j.apsb.2024.11.007","url":null,"abstract":"<div><div>Elevated glucose metabolism is a prominent characteristic of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA). However, the efficacy of inhibiting a single target of glucose metabolism in FLS using small molecular inhibitors is limited for RA treatment. Herein, the synergistic inhibition of FLS’ survival, proliferation, and activation by combining two glucose metabolism inhibitors, diclofenac (DC) and lonidamine (LND) was first verified. Subsequently, DC and LND were individually conjugated to cystamine-modified hyaluronic acid (HA) to prepare two polymer-prodrug conjugates. A HAP-1 peptide-modified dual polymer-prodrug conjugates-assembled nanoparticles system (<sup>HAP−1</sup>NP<sub>DC+LND</sub>) was further tailored in the optimal synergistic ratio for targeted and synergistic metabolic modulation of FLS to alleviate RA symptoms. Upon targeted uptake by FLS in inflamed joints, <sup>HAP−1</sup>NP<sub>DC+LND</sub> released DC and LND within the intracellular reductive microenvironment, where DC hinders glucose uptake and LND suppresses glycolytic enzymes to eliminate FLS synergistically. Additionally, the secretion of lactic acid and pro-inflammatory factors from FLS were reduced, thereby disrupting the crosstalk between FLS and pro-inflammatory macrophages. Finally, <sup>HAP−1</sup>NP<sub>DC+LND</sub> demonstrated promising efficacy in a mouse model of collagen-induced arthritis (CIA). Overall, this research provides valuable insights into novel therapeutic strategies for the safe and effective of treatment RA through targeted and synergistic metabolic modulation of FLS.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 1","pages":"Pages 542-556"},"PeriodicalIF":14.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.apsb.2024.11.001
Luxun Tang , Yu Shi , Qiao Liao , Feng Wang , Hao Wu , Hongmei Ren , Xuemei Wang , Wenbin Fu , Jialing Shou , Wei Eric Wang , Pedro A. Jose , Yongjian Yang , Chunyu Zeng
The neonatal mammalian heart has a remarkable regenerative capacity, while the adult heart has difficulty to regenerate. A metabolic reprogramming from glycolysis to fatty acid oxidation occurs along with the loss of cardiomyocyte proliferative capacity shortly after birth. In this study, we sought to determine if and how metabolic reprogramming regulates cardiomyocyte proliferation. Reversing metabolic reprogramming by carnitine palmitoyltransferase 1 (CPT1) inhibition, using cardiac-specific Cpt1a and Cpt1b knockout mice promoted cardiomyocyte proliferation and improved cardiac function post-myocardial infarction. The inhibition of CPT1 is of pharmacological significance because those protective effects were replicated by etomoxir, a CPT1 inhibitor. CPT1 inhibition, by decreasing poly(ADP-ribose) polymerase 1 expression, reduced ADP-ribosylation of dual-specificity phosphatase 1 in cardiomyocytes, leading to decreased p38 MAPK phosphorylation, and stimulation of cardiomyocyte proliferation. Our present study indicates that reversing metabolic reprogramming is an effective strategy to stimulate adult cardiomyocyte proliferation. CPT1 is a potential therapeutic target for promoting heart regeneration and myocardial infarction treatment.
{"title":"Reversing metabolic reprogramming by CPT1 inhibition with etomoxir promotes cardiomyocyte proliferation and heart regeneration via DUSP1 ADP-ribosylation-mediated p38 MAPK phosphorylation","authors":"Luxun Tang , Yu Shi , Qiao Liao , Feng Wang , Hao Wu , Hongmei Ren , Xuemei Wang , Wenbin Fu , Jialing Shou , Wei Eric Wang , Pedro A. Jose , Yongjian Yang , Chunyu Zeng","doi":"10.1016/j.apsb.2024.11.001","DOIUrl":"10.1016/j.apsb.2024.11.001","url":null,"abstract":"<div><div>The neonatal mammalian heart has a remarkable regenerative capacity, while the adult heart has difficulty to regenerate. A metabolic reprogramming from glycolysis to fatty acid oxidation occurs along with the loss of cardiomyocyte proliferative capacity shortly after birth. In this study, we sought to determine if and how metabolic reprogramming regulates cardiomyocyte proliferation. Reversing metabolic reprogramming by carnitine palmitoyltransferase 1 (CPT1) inhibition, using cardiac-specific <em>Cpt1a</em> and <em>Cpt1b</em> knockout mice promoted cardiomyocyte proliferation and improved cardiac function post-myocardial infarction. The inhibition of CPT1 is of pharmacological significance because those protective effects were replicated by etomoxir, a CPT1 inhibitor. CPT1 inhibition, by decreasing poly(ADP-ribose) polymerase 1 expression, reduced ADP-ribosylation of dual-specificity phosphatase 1 in cardiomyocytes, leading to decreased p38 MAPK phosphorylation, and stimulation of cardiomyocyte proliferation. Our present study indicates that reversing metabolic reprogramming is an effective strategy to stimulate adult cardiomyocyte proliferation. CPT1 is a potential therapeutic target for promoting heart regeneration and myocardial infarction treatment.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 1","pages":"Pages 256-277"},"PeriodicalIF":14.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.apsb.2024.12.004
Yuanchao Zhu , Fei Zhao , Yubing Zhu , Xingang Li , Deshi Dong , Bolin Zhu , Jianchun Li , Xin Hu , Zinan Zhao , Wenfeng Xu , Yang Jv , Dandan Wang , Yingming Zheng , Yiwen Dong , Lu Li , Shilei Yang , Zhiyuan Teng , Ling Lu , Jingwei Zhu , Linzhe Du , Pengfei Jin
Debates persist regarding the efficacy and safety of azvudine, particularly its real-world outcomes. This study involved patients aged ≥60 years who were admitted to 25 hospitals in mainland China with confirmed SARS-CoV-2 infection between December 1, 2022, and February 28, 2023. Efficacy outcomes were all-cause mortality during hospitalization, the proportion of patients discharged with recovery, time to nucleic acid-negative conversion (TNANC), time to symptom improvement (TSI), and time of hospital stay (THS). Safety was also assessed. Among the 5884 participants identified, 1999 received azvudine, and 1999 matched controls were included after exclusion and propensity score matching. Azvudine recipients exhibited lower all-cause mortality compared with controls in the overall population (13.3% vs. 17.1%, RR, 0.78; 95% CI, 0.67–0.90; P = 0.001) and in the severe subgroup (25.7% vs. 33.7%; RR, 0.76; 95% CI, 0.66–0.88; P < 0.001). A higher proportion of patients discharged with recovery, and a shorter TNANC were associated with azvudine recipients, especially in the severe subgroup. The incidence of adverse events in azvudine recipients was comparable to that in the control group (2.3% vs. 1.7%, P = 0.170). In conclusion, azvudine showed efficacy and safety in older patients hospitalized with COVID-19 during the SARS-CoV-2 omicron wave in China.
{"title":"Real-world efficacy and safety of azvudine in hospitalized older patients with COVID-19 during the omicron wave in China: A retrospective cohort study","authors":"Yuanchao Zhu , Fei Zhao , Yubing Zhu , Xingang Li , Deshi Dong , Bolin Zhu , Jianchun Li , Xin Hu , Zinan Zhao , Wenfeng Xu , Yang Jv , Dandan Wang , Yingming Zheng , Yiwen Dong , Lu Li , Shilei Yang , Zhiyuan Teng , Ling Lu , Jingwei Zhu , Linzhe Du , Pengfei Jin","doi":"10.1016/j.apsb.2024.12.004","DOIUrl":"10.1016/j.apsb.2024.12.004","url":null,"abstract":"<div><div>Debates persist regarding the efficacy and safety of azvudine, particularly its real-world outcomes. This study involved patients aged ≥60 years who were admitted to 25 hospitals in mainland China with confirmed SARS-CoV-2 infection between December 1, 2022, and February 28, 2023. Efficacy outcomes were all-cause mortality during hospitalization, the proportion of patients discharged with recovery, time to nucleic acid-negative conversion (<em>T</em><sub>NANC</sub>), time to symptom improvement (<em>T</em><sub>SI</sub>), and time of hospital stay (<em>T</em><sub>HS</sub>). Safety was also assessed. Among the 5884 participants identified, 1999 received azvudine, and 1999 matched controls were included after exclusion and propensity score matching. Azvudine recipients exhibited lower all-cause mortality compared with controls in the overall population (13.3% <em>vs</em>. 17.1%, RR, 0.78; 95% CI, 0.67–0.90; <em>P</em> = 0.001) and in the severe subgroup (25.7% <em>vs</em>. 33.7%; RR, 0.76; 95% CI, 0.66–0.88; <em>P</em> < 0.001). A higher proportion of patients discharged with recovery, and a shorter <em>T</em><sub>NANC</sub> were associated with azvudine recipients, especially in the severe subgroup. The incidence of adverse events in azvudine recipients was comparable to that in the control group (2.3% <em>vs</em>. 1.7%, <em>P</em> = 0.170). In conclusion, azvudine showed efficacy and safety in older patients hospitalized with COVID-19 during the SARS-CoV-2 omicron wave in China.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 1","pages":"Pages 123-132"},"PeriodicalIF":14.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.apsb.2024.11.003
Sai Zhu , Xin Chen , Lijiao Sun , Xiaofeng Li , Yu Chen , Liangyun Li , Xiaoguo Suo , Chuanhui Xu , Minglu Ji , Jianan Wang , Hua Wang , Lei Zhang , Xiaoming Meng , Cheng Huang , Jun Li
Kupffer cells (KCs), as residents and sentinels of the liver, are involved in the formation of hepatic fibrosis (HF). However, the biological functions of circular RNAs (circRNAs) in KCs to HF have not been determined. In this study, the expression levels of circRNAs, microRNAs, and messenger RNAs (mRNAs) in KCs from a mouse model of HF mice were investigated using microarray and circRNA-Seq analyses. circDcbld2 was identified as a candidate circRNA in HF, as evidenced by its up-regulation in KCs. Silver staining and mass spectrometry showed that Wtap and Igf2bp2 bind to cirDcbld2. The suppression of circDcbld2 expression decreased the KC inflammatory response and oxidative stress and inhibited hepatic stellate cell (HSCs) activation, attenuating mouse liver fibrogenesis. Mechanistically, Wtap mediated the N6-methyladenosine (m6A) methylation of circDcbld2, and Igf2bp2 recognized m6A-modified circDcbld2 and increased its stability. circDcbld2 contributes to the occurrence of HF by binding miR-144-3p/Et-1 to regulate the inflammatory response and oxidative stress. These findings indicate that circDcbld2 functions via the m6A/circDcbld2/miR-144-3p/Et-1 axis and may act as a potential biomarker for HF treatment.
{"title":"N6-Methyladenosine modification of circDcbld2 in Kupffer cells promotes hepatic fibrosis via targeting miR-144-3p/Et-1 axis","authors":"Sai Zhu , Xin Chen , Lijiao Sun , Xiaofeng Li , Yu Chen , Liangyun Li , Xiaoguo Suo , Chuanhui Xu , Minglu Ji , Jianan Wang , Hua Wang , Lei Zhang , Xiaoming Meng , Cheng Huang , Jun Li","doi":"10.1016/j.apsb.2024.11.003","DOIUrl":"10.1016/j.apsb.2024.11.003","url":null,"abstract":"<div><div>Kupffer cells (KCs), as residents and sentinels of the liver, are involved in the formation of hepatic fibrosis (HF). However, the biological functions of circular RNAs (circRNAs) in KCs to HF have not been determined. In this study, the expression levels of circRNAs, microRNAs, and messenger RNAs (mRNAs) in KCs from a mouse model of HF mice were investigated using microarray and circRNA-Seq analyses. circDcbld2 was identified as a candidate circRNA in HF, as evidenced by its up-regulation in KCs. Silver staining and mass spectrometry showed that <em>Wtap</em> and <em>Igf2bp2</em> bind to cirDcbld2. The suppression of circDcbld2 expression decreased the KC inflammatory response and oxidative stress and inhibited hepatic stellate cell (HSCs) activation, attenuating mouse liver fibrogenesis. Mechanistically, <em>Wtap</em> mediated the <em>N</em><sup>6</sup>-methyladenosine (m6A) methylation of circDcbld2, and <em>Igf2bp2</em> recognized m6A-modified circDcbld2 and increased its stability. circDcbld2 contributes to the occurrence of HF by binding miR-144-3p/<em>Et-1</em> to regulate the inflammatory response and oxidative stress. These findings indicate that circDcbld2 functions <em>via</em> the m6A/circDcbld2/miR-144-3p/<em>Et-1</em> axis and may act as a potential biomarker for HF treatment.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 1","pages":"Pages 296-313"},"PeriodicalIF":14.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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