Acta Pharmaceutica Sinica. B最新文献

{"title":"Future prospects in clinical translation of inorganic nanoparticles","authors":"Ke Xu , Ying Liu , Chunying Chen","doi":"10.1016/j.apsb.2024.08.001","DOIUrl":"10.1016/j.apsb.2024.08.001","url":null,"abstract":"","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 11","pages":"Pages 5082-5084"},"PeriodicalIF":14.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142186918","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":"Activation of pregnane X receptor sensitizes alcoholic steatohepatitis by transactivating fatty acid binding protein 4","authors":"Yiwen Zhang ,&nbsp;Bingfang Hu ,&nbsp;Shaoxing Guan ,&nbsp;Pan Li ,&nbsp;Yingjie Guo ,&nbsp;Pengfei Xu ,&nbsp;Yongdong Niu ,&nbsp;Yujin Li ,&nbsp;Ye Feng ,&nbsp;Jiewen Du ,&nbsp;Jun Xu ,&nbsp;Xiuchen Guan ,&nbsp;Jingkai Gu ,&nbsp;Haiyan Sun ,&nbsp;Min Huang","doi":"10.1016/j.apsb.2024.08.029","DOIUrl":"10.1016/j.apsb.2024.08.029","url":null,"abstract":"<div><div>Alcoholic steatohepatitis (ASH) is a liver disease characterized by steatosis, inflammation, and necrosis of the liver tissue as a result of excessive alcohol consumption. Pregnane X receptor (PXR) is a xenobiotic nuclear receptor best known for its function in the transcriptional regulation of drug metabolism and disposition. Clinical reports suggested that the antibiotic rifampicin, a potent human PXR activator, is a contraindication in alcoholics, but the mechanism was unclear. In this study, we showed that the hepatic expression of fatty acid binding protein 4 (FABP4) was uniquely elevated in ASH patients and a mouse model of ASH. Pharmacological inhibiting FABP4 attenuated ASH in mice. Furthermore, treatment of mice with the mouse PXR agonist pregnenolon-16<em>α</em>-carbonitrile (PCN) induced the hepatic and circulating levels of FABP4 and exacerbated ASH in a PXR-dependent manner. Our mechanism study established FABP4 as a transcriptional target of PXR. Treatment with andrographolide, a natural compound and dual inhibitor of PXR and FABP4, alleviated mice from ASH. In summary, our results showed that the PXR–FABP4 gene regulatory axis plays an important role in the progression of ASH, which may have accounted for the contraindication of rifampicin in patients of alcoholic liver disease. Pharmacological inhibition of PXR and/or FABP4 may have its promise in the clinical management of ASH.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 11","pages":"Pages 4776-4788"},"PeriodicalIF":14.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142187069","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":"Systemic and dynamic immune landscape of Omicron-infected subjects treated with Lianhua Qingwen capsules","authors":"Shijun Chen ,&nbsp;Fuxiang Wang ,&nbsp;Yuanlong Lin ,&nbsp;Yinyin Xie ,&nbsp;Ruihong Zhang ,&nbsp;Juan Chen ,&nbsp;Niu Qiao ,&nbsp;Tong Yin ,&nbsp;Yun Tan ,&nbsp;Hai Fang ,&nbsp;Hongzhou Lu ,&nbsp;Zhu Chen ,&nbsp;Shanhe Yu ,&nbsp;Jiang Zhu ,&nbsp;Zhenhua Jia ,&nbsp;Saijuan Chen","doi":"10.1016/j.apsb.2024.09.011","DOIUrl":"10.1016/j.apsb.2024.09.011","url":null,"abstract":"","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 11","pages":"Pages 5074-5078"},"PeriodicalIF":14.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142707030","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":"A phosphoglycerate mutase 1 allosteric inhibitor restrains TAM-mediated colon cancer progression","authors":"Cheng Wang ,&nbsp;Minghao Zhang ,&nbsp;Shunyao Li ,&nbsp;Miaomiao Gong ,&nbsp;Ming-yu Luo ,&nbsp;Mo-cong Zhang ,&nbsp;Jing-Hua Zou ,&nbsp;Ningxiang Shen ,&nbsp;Lu Xu ,&nbsp;Hui-min Lei ,&nbsp;Ling Bi ,&nbsp;Liang Zhu ,&nbsp;Zhengting Wang ,&nbsp;Hong-zhuan Chen ,&nbsp;Lu Zhou ,&nbsp;Ying Shen","doi":"10.1016/j.apsb.2024.09.007","DOIUrl":"10.1016/j.apsb.2024.09.007","url":null,"abstract":"<div><div>Colorectal cancer (CRC) is a prevalent malignant tumor often leading to liver metastasis and mortality. Despite some success with PD-1/PD-L1 immunotherapy, the response rate for colon cancer patients remains relatively low. This is closely related to the immunosuppressive tumor microenvironment mediated by tumor-associated macrophages (TAMs). Our previous work identified that a phosphoglycerate mutase 1 (PGAM1) allosteric inhibitor, HKB99, exerts a range of anti-tumor activities in lung cancer. Here, we found that upregulation of <em>PGAM1</em> correlates with increased levels of M2-like tumor-associated macrophages (TAMs) in human colon cancer samples, particularly in liver metastatic tissues. HKB99 suppressed tumor growth and metastasis in cell culture and syngeneic tumor models. M2-polarization, induced by colon cancer cell co-culture, was reversed by HKB99. Conversely, the increased migration of colon cancer cells by M2-TAMs was remarkably restrained by HKB99. Notably, a decrease in TAM infiltration was required for the HKB99-mediated anti-tumor effect, along with an increase in CD8⁺ T cell infiltration. Moreover, HKB99 improved the efficacy of anti-PD-1 treatment in syngeneic tumors. Overall, this study highlights HKB99's inhibitory activity in TAM-mediated colon cancer progression. Targeting PGAM1 could lead to novel therapeutic strategies and enhance the effectiveness of existing immunotherapies for colon cancer.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 11","pages":"Pages 4819-4831"},"PeriodicalIF":14.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142706959","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":"Colon-specific controlled release of oral liposomes for enhanced chemo-immunotherapy against colorectal cancer","authors":"Mengya Niu ,&nbsp;Yihan Pei ,&nbsp;Tiantian Jin ,&nbsp;Junxiu Li ,&nbsp;Liming Bai ,&nbsp;Cuixia Zheng ,&nbsp;Qingling Song ,&nbsp;Hongjuan Zhao ,&nbsp;Yun Zhang ,&nbsp;Lei Wang","doi":"10.1016/j.apsb.2024.09.015","DOIUrl":"10.1016/j.apsb.2024.09.015","url":null,"abstract":"<div><div>A colon-specific drug delivery system has great potential for the oral administration of colorectal cancer. However, the uncontrollable <em>in vivo</em> fate of liposomes makes their effectiveness for colonic location, and intratumoral accumulation remains unsatisfactory. Here, an oral colon-specific drug delivery system (CBS-CS@Lipo/Oxp/MTZ) was constructed by covalently conjugating <em>Clostridium butyricum</em> spores (CBS) with drugs loaded chitosan (CS)-coated liposomes, where the model chemotherapy drug oxaliplatin (Oxp) and anti-anaerobic bacteria agent metronidazole (MTZ) were loaded. Following oral administration, CBS germinated into <em>Clostridium butyricum</em> (CB) and colonized in the colon. Combined with colonic specifically <em>β</em>-glucosidase responsive degrading of CS, dual colon-specific release of liposomes was achieved. And the accumulation of liposomes at the CRC site furtherly increased by 2.68-fold. Simultaneously, the released liposomes penetrated deep tumor tissue <em>via</em> the permeation enhancement effect of CS to kill localized intratumoral bacteria. Collaborating with blocking the translocation of intestinal pathogenic bacteria from lumen to tumor with the gut microbiota modulation of CB, the intratumoral pathogenic bacteria were eliminated fundamentally, blocking their recruitment to immunosuppressive cells. Furtherly, synchronized with lipopolysaccharide (LPS) released from MTZ-induced dead <em>Fusobacterium nucleatum</em> and the tumor-associated antigens produced by Oxp-caused immunogenic dead cells, they jointly enhanced tumor infiltration of CD8⁺ T cells and reactivated robust antitumor immunity.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 11","pages":"Pages 4977-4993"},"PeriodicalIF":14.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142706966","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":"Combination of anti-inflammatory therapy and RNA interference by light-inducible hybrid nanomedicine for osteoarthritis treatment","authors":"Li Qiao ,&nbsp;Zhiyao Li ,&nbsp;Bowen Li ,&nbsp;Fu Zhang ,&nbsp;Zhuo Yao ,&nbsp;Chongzhi Wu ,&nbsp;Honglin Tang ,&nbsp;Qi Pan ,&nbsp;Peihua Shi ,&nbsp;Yuan Ping","doi":"10.1016/j.apsb.2024.06.009","DOIUrl":"10.1016/j.apsb.2024.06.009","url":null,"abstract":"<div><div>Osteoarthritis (OA) is a type of highly prevalent heterogeneous degenerative disease that leads to joint pain, deformity, the destruction of articular cartilage, and eventual disability. The current treatment strategies for OA often suffer from systemic side effects, poor anti-inflammatory efficacy, and persistent pain. To address these issues, we develop light-inducible nanomedicine that enables the co-delivery of anti-inflammatory drug (diacerein, DIA) and small interfering RNA (siRNA) targeting nerve growth factor (NGF) for pain relief to enhance the therapeutic efficacy of OA. The nanomedicine is based on poly(<em>β</em>-amino-ester)-coated gold nanocages (AuNCs), which is further incorporated with the phase-change material (lauric acid/stearic acid, LA/SA). Following intra-articular (IA) injection <em>in vivo</em>, the nanomedicine displays high degree of drug accumulation and retention in the joint lesion of OA mouse models. The photothermal effect, induced by AuNCs, not only promotes DIA and siRNA release, but also upregulates the expression of heat shock protein 70 (HSP-70) to resist the apoptosis of chondrocytes in the inflammatory condition. The internalization of both DIA and siRNA results in strong anti-inflammatory and pain-relieving effects, which greatly contribute to the joint repair of OA mice. This study offers a promising combination strategy for OA treatment.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 11","pages":"Pages 5008-5025"},"PeriodicalIF":14.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141528594","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":"GPR17 modulates anxiety-like behaviors via basolateral amygdala to ventral hippocampal CA1 glutamatergic projection","authors":"Ruizhe Nie,&nbsp;Xinting Zhou,&nbsp;Jiaru Fu,&nbsp;Shanshan Hu,&nbsp;Qilu Zhang,&nbsp;Weikai Jiang,&nbsp;Yizi Yan,&nbsp;Xian Cao,&nbsp;Danhua Yuan,&nbsp;Yan Long,&nbsp;Hao Hong,&nbsp;Susu Tang","doi":"10.1016/j.apsb.2024.08.005","DOIUrl":"10.1016/j.apsb.2024.08.005","url":null,"abstract":"<div><div>Anxiety disorders are one of the most epidemic and chronic psychiatric disorders. An incomplete understanding of anxiety pathophysiology has limited the development of highly effective drugs against these disorders. GPR17 has been shown to be involved in multiple sclerosis and some acute brain injury disorders. However, no study has investigated the role of GPR17 in psychiatric disorders. In a well-established chronic restraint stress (CRS) mouse model, using a combination of pharmacological and molecular biology techniques, viral tracing, <em>in vitro</em> electrophysiology recordings, <em>in vivo</em> fiber photometry, chemogenetic manipulations and behavioral tests, we demonstrated that CRS induced anxiety-like behaviors and increased the expression of GPR17 in basolateral amygdala (BLA) glutamatergic neurons. Inhibition of GPR17 by cangrelor or knockdown of GPR17 by adeno-associated virus in BLA glutamatergic neurons effectively improved anxiety-like behaviors. Overexpression of GPR17 in BLA glutamatergic neurons increased the susceptibility to anxiety-like behaviors. What's more, BLA glutamatergic neuronal activity was required for anxiolytic-like effects of GPR17 antagonist and GPR17 modulated anxiety-like behaviors <em>via</em> BLA to ventral hippocampal CA1 glutamatergic projection. Our study finds for the first and highlights the new role of GPR17 in regulating anxiety-like behaviors and it might be a novel potential target for therapy of anxiety disorders.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 11","pages":"Pages 4789-4805"},"PeriodicalIF":14.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142186922","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":"Novel benzothiazole derivatives target the Gac/Rsm two-component system as antibacterial synergists against Pseudomonas aeruginosa infections","authors":"Jun Liu ,&nbsp;Wenfu Wu ,&nbsp;Jiayi Hu ,&nbsp;Siyu Zhao ,&nbsp;Yiqun Chang ,&nbsp;Qiuxian Chen ,&nbsp;Yujie Li ,&nbsp;Jie Tang ,&nbsp;Zhenmeng Zhang ,&nbsp;Xiao Wu ,&nbsp;Shumeng Jiao ,&nbsp;Haichuan Xiao ,&nbsp;Qiang Zhang ,&nbsp;Jiarui Du ,&nbsp;Jianfu Zhao ,&nbsp;Kaihe Ye ,&nbsp;Meiyan Huang ,&nbsp;Jun Xu ,&nbsp;Haibo Zhou ,&nbsp;Junxia Zheng ,&nbsp;Pinghua Sun","doi":"10.1016/j.apsb.2024.08.002","DOIUrl":"10.1016/j.apsb.2024.08.002","url":null,"abstract":"<div><div>The management of antibiotic-resistant, bacterial biofilm infections in skin wounds poses an increasingly challenging clinical scenario. <em>Pseudomonas aeruginosa</em> infection is difficult to eradicate because of biofilm formation and antibiotic resistance. In this study, we identified a new benzothiazole derivative compound, <strong>SN12</strong> (IC₅₀ = 43.3 nmol/L), demonstrating remarkable biofilm inhibition at nanomolar concentrations <em>in vitro</em>. In further activity assays and mechanistic studies, we formulated an unconventional strategy for combating <em>P. aeruginosa</em>-derived infections by targeting the two-component (Gac/Rsm) system. Furthermore, <strong>SN12</strong> slowed the development of ciprofloxacin and tobramycin resistance. By using murine skin wound infection models, we observed that <strong>SN12</strong> significantly augmented the antibacterial effects of three widely used antibiotics—tobramycin (100-fold), vancomycin (200-fold), and ciprofloxacin (1000-fold)—compared with single-dose antibiotic treatments for <em>P. aeruginosa</em> infection <em>in vivo</em>. The findings of this study suggest the potential of <strong>SN12</strong> as a promising antibacterial synergist, highlighting the effectiveness of targeting the two-component system in treating challenging bacterial biofilm infections in humans.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 11","pages":"Pages 4934-4961"},"PeriodicalIF":14.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142186923","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":"Nanomedicine regulating PSC-mediated intercellular crosstalk: Mechanisms and therapeutic strategies","authors":"Hui Wang ,&nbsp;Liang Qi ,&nbsp;Han Han ,&nbsp;Xuena Li ,&nbsp;Mengmeng Han ,&nbsp;Lei Xing ,&nbsp;Ling Li ,&nbsp;Hulin Jiang","doi":"10.1016/j.apsb.2024.07.007","DOIUrl":"10.1016/j.apsb.2024.07.007","url":null,"abstract":"<div><div>Pancreatic fibrosis (PF) is primarily distinguished by the stimulation of pancreatic stellate cells (PSCs) and excessive extracellular matrix deposition, which is the main barrier impeding drug delivery and distribution. Recently, nanomedicine, with efficient, targeted, and controllable drug release characteristics, has demonstrated enormous advantages in the regression of pancreas fibrotic diseases. Notably, paracrine signals from parenchymal and immune cells such as pancreatic acinar cells, islet cells, pancreatic cancer cells, and immune cells can directly or indirectly modulate PSC differentiation and activation. The intercellular crosstalk between PSCs and these cells has been a critical event involved in fibrogenesis. However, the connections between PSCs and other pancreatic cells during the progression of diseases have yet to be discussed. Herein, we summarize intercellular crosstalk in the activation of PSCs and its contribution to the development of common pancreatic diseases, including pancreatitis, pancreatic cancer, and diabetes. Then, we also examine the latest treatment strategies of nanomedicine and potential targets for PSCs crosstalk in fibrosis, thereby offering innovative insights for the design of antifibrotic nanomedicine. Ultimately, the enhanced understanding of PF will facilitate the development of more precise intervention strategies and foster individually tailored therapeutic approaches for pancreatic diseases.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 11","pages":"Pages 4756-4775"},"PeriodicalIF":14.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141697144","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":"Nonalcoholic steatohepatitis increases plasma retention of sorafenib-glucuronide in a mouse model by altering hepatocyte hopping","authors":"Erica Toth ,&nbsp;Hui Li ,&nbsp;Kayla Frost ,&nbsp;Paxton Sample ,&nbsp;Joseph Jilek ,&nbsp;Siennah Greenfield ,&nbsp;Dahea You ,&nbsp;Danielle Kozlosky ,&nbsp;Michael Goedken ,&nbsp;Mary F. Paine ,&nbsp;Lauren Aleksunes ,&nbsp;Nathan Cherrington","doi":"10.1016/j.apsb.2024.09.004","DOIUrl":"10.1016/j.apsb.2024.09.004","url":null,"abstract":"<div><div>Hepatocyte hopping is the hepatocyte-to-sinusoid-to-hepatocyte shuttling that increases the efficiency of hepatic elimination of xenobiotics. This phenomenon is mediated <em>via</em> efflux of hepatic metabolites by Mrp3 and reuptake by Oatp transporters in sequential hepatocytes until eventual biliary efflux by Mrp2. Sorafenib-glucuronide (SFB-G), the major metabolite of sorafenib (SFB), undergoes hepatocyte hopping, leading to efficient biliary elimination. Nonalcoholic steatohepatitis (NASH) alters the functioning of transporters involved in hepatocyte hopping. The purpose of this study was to quantify the effect of NASH on the three drug disposition processes of hepatocyte hopping. Male FVB and C57BL/6 wild-type (WT), <em>Oatp1a/1b</em> cluster knockout (O^−/−), and Mrp2 knockout (<em>Mrp2</em>^−/−) mice were fed a methionine and choline deficient (MCD) diet to induce NASH. Mice were administered 10 mg/kg SFB <em>via</em> oral gavage and concentrations of SFB and SFB-G in plasma quantified using liquid-chromatography tandem mass spectrometry. Compared to WT, plasma area under the concentration-time curve (AUC) of SFB-G increased by 108-fold in the O^–/–-C group and by 345-fold in the <em>Mrp2</em>^–/–-C group. In the WT-NASH group, up-regulation of Mrp3 and decreased Mrp2 function, along with reduced Oatp uptake, elevated SFB-G AUC by 165-fold. SFB-G AUC in the O^–/–-NASH group increased by 108-fold compared to WT-C (3.2-fold compared to O^–/–-C). SFB-G AUC in the <em>Mrp2</em>^–/–-NASH group increased by 450-fold (1.2-fold compared to Mrp2^–/–-C). Taken together, the mislocalization of Mrp2 in NASH is a major contributor to the decrease in SFB-G biliary efflux, but decreased Oatp uptake and enhanced sinusoidal efflux also limit the contribution of downstream hepatocytes, resulting in plasma retention that recapitulates the altered pharmacokinetics observed in human NASH.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 11","pages":"Pages 4874-4882"},"PeriodicalIF":14.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142706967","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}