Acta Pharmaceutica Sinica. B最新文献

{"title":"Engineering cellular dephosphorylation boosts (+)-borneol production in yeast","authors":"Haiyan Zhang ,&nbsp;Peng Cai ,&nbsp;Juan Guo ,&nbsp;Jiaoqi Gao ,&nbsp;Linfeng Xie ,&nbsp;Ping Su ,&nbsp;Xiaoxin Zhai ,&nbsp;Baolong Jin ,&nbsp;Guanghong Cui ,&nbsp;Yongjin J. Zhou ,&nbsp;Luqi Huang","doi":"10.1016/j.apsb.2024.12.039","DOIUrl":"10.1016/j.apsb.2024.12.039","url":null,"abstract":"<div><div>(+)-Borneol, the main component of \"Natural Borneol\" in the Chinese Pharmacopoeia, is a high-end spice and precious medicine. Plant extraction cannot meet the increasing demand for (+)-borneol, while microbial biosynthesis offers a sustainable supply route. However, its production was extremely low compared with other monoterpenes, even with extensively optimizing the mevalonate pathway. We found that the key challenge is the complex and unusual dephosphorylation reaction of bornyl diphosphate (BPP), which suffers the side-reaction and the competition from the cellular dephosphorylation process, especially lipid metabolism, thus limiting (+)-borneol synthesis. Here, we systematically optimized the dephosphorylation process by identifying, characterizing phosphatases, and balancing cellular dephosphorylation metabolism. For the first time, we identified two endogenous phosphatases and seven heterologous phosphatases, which significantly increased (+)-borneol production by up to 152%. By engineering BPP dephosphorylation and optimizing the MVA pathway, the production of (+)-borneol was increased by 33.8-fold, which enabled the production of 753 mg/L under fed-batch fermentation in shake flasks, so far the highest reported in the literature. This study showed that rewiring dephosphorylation metabolism was essential for high-level production of (+)-borneol in <em>Saccharomyces cerevisiae</em>, and balancing cellular dephosphorylation is also helpful for efficient biosynthesis of other terpenoids since all whose biosynthesis involves the dephosphorylation procedure.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 2","pages":"Pages 1171-1182"},"PeriodicalIF":14.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143591879","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}

{"title":"Intestinal stearoyl-coenzyme A desaturase-inhibition improves obesity-associated metabolic disorders","authors":"Yangliu Xia ,&nbsp;Yang Zhang ,&nbsp;Zhipeng Zhang ,&nbsp;Nana Yan ,&nbsp;Vorthon Sawaswong ,&nbsp;Lulu Sun ,&nbsp;Wanwan Guo ,&nbsp;Ping Wang ,&nbsp;Kristopher W. Krausz ,&nbsp;Oksana Gavrilova ,&nbsp;James M. Ntambi ,&nbsp;Haiping Hao ,&nbsp;Tingting Yan ,&nbsp;Frank J. Gonzalez","doi":"10.1016/j.apsb.2024.11.022","DOIUrl":"10.1016/j.apsb.2024.11.022","url":null,"abstract":"<div><div>Stearoyl-coenzyme A desaturase 1 (SCD1) catalyzes the rate-limiting step of <em>de novo</em> lipogenesis and modulates lipid homeostasis. Although numerous SCD1 inhibitors were tested for treating metabolic disorders both in preclinical and clinic studies, the tissue-specific roles of SCD1 in modulating obesity-associated metabolic disorders and determining the pharmacological effect of chemical SCD1 inhibition remain unclear. Here a novel role for intestinal SCD1 in obesity-associated metabolic disorders was uncovered. Intestinal SCD1 was found to be induced during obesity progression both in humans and mice. Intestine-specific, but not liver-specific, SCD1 deficiency reduced obesity and hepatic steatosis. A939572, an SCD1-specific inhibitor, ameliorated obesity and hepatic steatosis dependent on intestinal, but not hepatic, SCD1. Mechanistically, intestinal SCD1 deficiency impeded obesity-induced oxidative stress through its novel function of inducing metallothionein 1 in intestinal epithelial cells. These results suggest that intestinal SCD1 could be a viable target that underlies the pharmacological effect of chemical SCD1 inhibition in the treatment of obesity-associated metabolic disorders.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 2","pages":"Pages 892-908"},"PeriodicalIF":14.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143591916","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}

{"title":"Circadian clock regulates immune checkpoint inhibitor efficacy","authors":"Yining Niu ,&nbsp;Motao Zhu","doi":"10.1016/j.apsb.2025.01.011","DOIUrl":"10.1016/j.apsb.2025.01.011","url":null,"abstract":"","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 2","pages":"Pages 1183-1185"},"PeriodicalIF":14.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143591880","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}

{"title":"Enhanced radiotheranostic targeting of integrin α5β1 with PEGylation-enabled peptide multidisplay platform (PEGibody): A strategy for prolonged tumor retention with fast blood clearance","authors":"Siqi Zhang ,&nbsp;Xiaohui Ma ,&nbsp;Jiang Wu ,&nbsp;Jieting Shen ,&nbsp;Yuntao Shi ,&nbsp;Xingkai Wang ,&nbsp;Lin Xie ,&nbsp;Xiaona Sun ,&nbsp;Yuxuan Wu ,&nbsp;Hao Tian ,&nbsp;Xin Gao ,&nbsp;Xueyao Chen ,&nbsp;Hongyi Huang ,&nbsp;Lu Chen ,&nbsp;Xuekai Song ,&nbsp;Qichen Hu ,&nbsp;Hailong Zhang ,&nbsp;Feng Wang ,&nbsp;Zhao-Hui Jin ,&nbsp;Ming-Rong Zhang ,&nbsp;Kuan Hu","doi":"10.1016/j.apsb.2024.07.006","DOIUrl":"10.1016/j.apsb.2024.07.006","url":null,"abstract":"<div><div>Peptide-based radiopharmaceuticals targeting integrin <em>α</em>5<em>β</em>1 show promise for precise tumor diagnosis and treatment. However, current peptide-based radioligands that target <em>α</em>5<em>β</em>1 demonstrate inadequate <em>in vivo</em> performance owing to limited tumor retention. The use of PEGylation to enhance the tumor retention of radiopharmaceuticals by prolonging blood circulation time poses a risk of increased blood toxicity. Therefore, a PEGylation strategy that boosts tumor retention while minimizing blood circulation time is urgently needed. Here, we developed a PEGylation-enabled peptide multidisplay platform (PEGibody) for PR_b, an <em>α</em>5<em>β</em>1 targeting peptide. PEGibody generation involved PEGylation and self-assembly. [⁶⁴Cu]QM-2303 PEGibodies displayed spherical nanoparticles ranging from 100 to 200 nm in diameter. Compared with non-PEGylated radioligands, [⁶⁴Cu]QM-2303 demonstrated enhanced tumor retention time due to increased binding affinity and stability. Importantly, the biodistribution analysis confirmed rapid clearance of [⁶⁴Cu]QM-2303 from the bloodstream. Administration of a single dose of [¹⁷⁷Lu]QM-2303 led to robust antitumor efficacy. Furthermore, [⁶⁴Cu]/[¹⁷⁷Lu]QM-2303 exhibited low hematological and organ toxicity in both healthy and tumor-bearing mice. Therefore, this study presents a PEGibody-based radiotheranostic approach that enhances tumor retention time and provides long-lasting antitumor effects without prolonging blood circulation lifetime. The PEGibody-based radiopharmaceutical [⁶⁴Cu]/[¹⁷⁷Lu]QM-2303 shows great potential for positron emission tomography imaging-guided targeted radionuclide therapy for <em>α</em>5<em>β</em>1-overexpressing tumors.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 2","pages":"Pages 692-706"},"PeriodicalIF":14.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141612756","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}

{"title":"DELIVER: The core principles for the clinic translation of nanomedicines","authors":"Chuan Hu ,&nbsp;Xinling He ,&nbsp;Huile Gao ,&nbsp;Jinming Zhang","doi":"10.1016/j.apsb.2025.01.014","DOIUrl":"10.1016/j.apsb.2025.01.014","url":null,"abstract":"","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 2","pages":"Pages 1196-1198"},"PeriodicalIF":14.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143591915","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}

{"title":"Integrated evidence chain-based effectiveness evaluation of traditional Chinese medicines (Eff-iEC): A demonstration study","authors":"Ye Luo ,&nbsp;Xu Zhao ,&nbsp;Ruilin Wang ,&nbsp;Xiaoyan Zhan ,&nbsp;Tianyi Zhang ,&nbsp;Tingting He ,&nbsp;Jing Jing ,&nbsp;Jianyu Li ,&nbsp;Fengyi Li ,&nbsp;Ping Zhang ,&nbsp;Junling Cao ,&nbsp;Jinfa Tang ,&nbsp;Zhijie Ma ,&nbsp;Tingming Shen ,&nbsp;Shuanglin Qin ,&nbsp;Ming Yang ,&nbsp;Jun Zhao ,&nbsp;Zhaofang Bai ,&nbsp;Jiabo Wang ,&nbsp;Aiguo Dai ,&nbsp;Xiaohe Xiao","doi":"10.1016/j.apsb.2024.12.024","DOIUrl":"10.1016/j.apsb.2024.12.024","url":null,"abstract":"<div><div>Addressing the enduring challenge of evaluating traditional Chinese medicines (TCMs), the integrated evidence chain-based effectiveness evaluation of TCMs (Eff-iEC) has emerged. This paper explored its capacity through a demonstration study that evaluated the effectiveness evidence of six commonly used anti-hepatic fibrosis Chinese patent medicines (CPMs), including Biejiajian Pill (BP), Dahuang Zhechong Pill (DZP), Biejia Ruangan Compound (BRC), Fuzheng Huayu Capsule (FHC), Anluo Huaxian Pill (AHP), and Heluo Shugan Capsule (HSC), using both Eff-iEC and the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. The recognition of these CPMs within the TCM academic community was also assessed through their inclusion in relevant medical documents. Results showed that the evidence of BRC and FHC received higher assessments in both Eff-iEC and GRADE system, while the assessments for others varied. Analysis of community recognition revealed that Eff-iEC more accurately reflects the clinical value of these CPMs, exhibiting superior evaluative capabilities. By breaking through the conventional pattern of TCMs effectiveness evaluation, Eff-iEC offers a novel epistemology that better aligns with the clinical realities and reasoning of TCMs, providing a coherent methodology for clinical decision-making, new drug evaluations, and health policy formulation.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 2","pages":"Pages 909-918"},"PeriodicalIF":14.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143591917","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}

{"title":"Resistance to antibody–drug conjugates: A review","authors":"Sijia Li ,&nbsp;Xinyu Zhao ,&nbsp;Kai Fu ,&nbsp;Shuangli Zhu ,&nbsp;Can Pan ,&nbsp;Chuan Yang ,&nbsp;Fang Wang ,&nbsp;Kenneth K.W. To ,&nbsp;Liwu Fu","doi":"10.1016/j.apsb.2024.12.036","DOIUrl":"10.1016/j.apsb.2024.12.036","url":null,"abstract":"<div><div>Antibody–drug conjugates (ADCs) are antitumor drugs composed of monoclonal antibodies and cytotoxic payload covalently coupled by a linker. Currently, 15 ADCs have been clinically approved worldwide. More than 100 clinical trials at different phases are underway to investigate the newly developed ADCs. ADCs represent one of the fastest growing classes of targeted antitumor drugs in oncology drug development. It takes advantage of the specific targeting of tumor-specific antigen by antibodies to deliver cytotoxic chemotherapeutic drugs precisely to tumor cells, thereby producing promising antitumor efficacy and favorable adverse effect profiles. However, emergence of drug resistance has severely hindered the clinical efficacy of ADCs. In this review, we introduce the structure and mechanism of ADCs, describe the development of ADCs, summarized the latest research about the mechanisms of ADC resistance, discussed the strategies to overcome ADCs resistance, and predicted biomarkers for treatment response to ADC, aiming to contribute to the development of ADCs in the future.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 2","pages":"Pages 737-756"},"PeriodicalIF":14.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143591791","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}

{"title":"Topical adhesive spatio-temporal nanosystem co-delivering chlorin e6 and HMGB1 inhibitor glycyrrhizic acid for in situ psoriasis chemo-phototherapy","authors":"Lijun Su ,&nbsp;Yixi Zhu ,&nbsp;Xuebo Li ,&nbsp;Di Wang ,&nbsp;Xiangyu Chen ,&nbsp;Zhen Liu ,&nbsp;Jingjing Li ,&nbsp;Chen Zhang ,&nbsp;Jinming Zhang","doi":"10.1016/j.apsb.2024.12.020","DOIUrl":"10.1016/j.apsb.2024.12.020","url":null,"abstract":"<div><div>Recently, photodynamic therapy (PDT) has gained considerable attention as a promising therapeutic approach for the treatment of psoriasis. Unfortunately, the activation of high mobility group box 1 protein (HMGB1) by PDT triggers innate and adaptive immune responses, which exacerbate skin inflammation. Herein, we combined glycyrrhizic acid (GA), a natural anti-inflammatory compound and immunomodulator derived from the herb <em>Glycyrrhiza uralensis</em> Fisch., with PDT actuated by the photosensitizer chlorin e6 (Ce6) by co-loading them in GA-based lipid nanoparticles coated with a catechol-modified quaternary chitosan salt (GC NPs/QCS-C). GC NPs/QCS-C exhibited high drug loading efficacy, uniform size distribution, an ideal topical adhesive property, enhanced skin retention and penetration in psoriasis-like lesions, and high intracellular uptake in epidermal cells compared with the counterparts. Subsequently, the transdermal administration of GC NPs/QCS-C followed by near-infrared laser radiation in an imiquimod-induced psoriasis-like mouse model significantly ameliorated psoriasis symptoms, promoted the apoptosis of hyperproliferative epidermal cells, and alleviated the inflammatory cascade. The significant therapeutic outcomes of GC NPs/QCS-C were attributed to the synergistic effects of GA and PDT on modulating immune cell recruitment and inhibiting dendritic cell maturation. Our results demonstrated that the topical bio-adhesive nanosystem that combines GA and Ce6 offers a synergistic chemo-phototherapeutic strategy for psoriasis treatment.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 2","pages":"Pages 1126-1142"},"PeriodicalIF":14.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143591800","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}

{"title":"Deubiquitinase JOSD2 alleviates colitis by inhibiting inflammation via deubiquitination of IMPDH2 in macrophages","authors":"Xin Liu ,&nbsp;Yi Fang ,&nbsp;Mincong Huang ,&nbsp;Shiliang Tu ,&nbsp;Boan Zheng ,&nbsp;Hang Yuan ,&nbsp;Peng Yu ,&nbsp;Mengyao Lan ,&nbsp;Wu Luo ,&nbsp;Yongqiang Zhou ,&nbsp;Guorong Chen ,&nbsp;Zhe Shen ,&nbsp;Yi Wang ,&nbsp;Guang Liang","doi":"10.1016/j.apsb.2024.12.012","DOIUrl":"10.1016/j.apsb.2024.12.012","url":null,"abstract":"<div><div>Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract, which increases the incidence of colorectal cancer (CRC). In the pathophysiology of IBD, ubiquitination/deubiquitination plays a critical regulatory function. Josephin domain containing 2 (JOSD2), a deubiquitinating enzyme, controls cell proliferation and carcinogenesis. However, its role in IBD remains unknown. Colitis mice model developed by dextran sodium sulfate (DSS) or colon tissues from individuals with ulcerative colitis and Crohn's disease showed a significant upregulation of JOSD2 expression in the macrophages. JOSD2 deficiency exacerbated the phenotypes of DSS-induced colitis by enhancing colon inflammation. DSS-challenged mice with myeloid-specific JOSD2 deletion developed severe colitis after bone marrow transplantation. Mechanistically, JOSD2 binds to the C-terminal of inosine-5′-monophosphate dehydrogenase 2 (IMPDH2) and preferentially cleaves K63-linked polyubiquitin chains at the K134 site, suppressing IMPDH2 activity and preventing activation of nuclear factor kappa B (NF-<em>κ</em>B) and inflammation in macrophages. It was also shown that JOSD2 knockout significantly exacerbated increased azoxymethane (AOM)/DSS-induced CRC, and AAV6-mediated JOSD2 overexpression in macrophages prevented the development of colitis in mice. These outcomes reveal a novel role for JOSD2 in colitis through deubiquitinating IMPDH2, suggesting that targeting JOSD2 is a potential strategy for treating IBD.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 2","pages":"Pages 1039-1055"},"PeriodicalIF":14.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143591850","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}

{"title":"Unlocking the healthy human microbiome: Redefining core microbial signatures","authors":"Shuting Xia ,&nbsp;Diya Jiang ,&nbsp;Qianyi Zhou ,&nbsp;Hairong Lyu ,&nbsp;Anita Y. Voigt ,&nbsp;Xin Zhou ,&nbsp;Zhemin Zhou ,&nbsp;Yuan Huang","doi":"10.1016/j.apsb.2025.01.001","DOIUrl":"10.1016/j.apsb.2025.01.001","url":null,"abstract":"","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 2","pages":"Pages 1189-1192"},"PeriodicalIF":14.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143591882","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}