Acta Pharmaceutica Sinica. B最新文献

英文中文

Unlocking the healthy human microbiome: Redefining core microbial signatures

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-02-01 DOI: 10.1016/j.apsb.2025.01.001

Shuting Xia , Diya Jiang , Qianyi Zhou , Hairong Lyu , Anita Y. Voigt , Xin Zhou , Zhemin Zhou , Yuan Huang

引用次数: 0

l-[5-11C]Glutamine PET imaging noninvasively tracks dynamic responses of glutaminolysis in non-alcoholic steatohepatitis l-[5-11C]谷氨酰胺 PET 成像无创追踪非酒精性脂肪性肝炎谷氨酰胺分解的动态反应

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-02-01 DOI: 10.1016/j.apsb.2024.07.023

Yiding Zhang , Lin Xie , Masayuki Fujinaga , Yusuke Kurihara , Masanao Ogawa , Katsushi Kumata , Wakana Mori , Tomomi Kokufuta , Nobuki Nengaki , Hidekatsu Wakizaka , Rui Luo , Feng Wang , Kuan Hu , Ming-Rong Zhang

Inhibiting glutamine metabolism has been proposed as a potential treatment strategy for improving non-alcoholic steatohepatitis (NASH). However, effective methods for assessing dynamic metabolic responses during interventions targeting glutaminolysis have not yet emerged. Here, we developed a positron emission tomography (PET) imaging platform using l-[5-¹¹C]glutamine ([¹¹C]Gln) and evaluated its efficacy in NASH mice undergoing metabolic therapy with bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES), a glutaminase 1 (GLS1) inhibitor that intervenes in the first and rate-limiting step of glutaminolysis. PET imaging with [¹¹C]Gln effectively delineated the pharmacokinetics of l-glutamine, capturing its temporal-spatial pattern of action within the body. Furthermore, [¹¹C]Gln PET imaging revealed a significant increase in hepatic uptake in methionine and choline deficient (MCD)-fed NASH mice, whereas systemic therapeutic interventions with BPTES reduced the hepatic avidity of [¹¹C]Gln in MCD-fed mice. This reduction in [¹¹C]Gln uptake correlated with a decrease in GLS1 burden and improvements in liver damage, indicating the efficacy of BPTES in mitigating NASH-related metabolic abnormalities. These results suggest that [¹¹C]Gln PET imaging can serve as a noninvasive diagnostic platform for whole-body, real-time tracking of responses of glutaminolysis to GLS1 manipulation in NASH, and it may be a valuable tool for the clinical management of patients with NASH undergoing glutaminolysis-based metabolic therapy.

抑制谷氨酰胺代谢被认为是改善非酒精性脂肪性肝炎（NASH）的潜在治疗策略。然而，在针对谷氨酰胺分解的干预过程中，评估动态代谢反应的有效方法尚未出现。在此，我们开发了一种使用-[5-C]谷氨酰胺（[C]Gln）的正电子发射断层扫描（PET）成像平台，并评估了其在接受双-2-（5-苯乙酰氨基-1,3,4-噻二唑-2-基）乙基硫醚（BPTES）代谢治疗的 NASH 小鼠中的疗效。BPTES 是一种谷氨酰胺酶 1（GLS1）抑制剂，可干预谷氨酰胺分解的第一步和限速步骤。利用[C]Gln PET 成像可以有效地描述谷氨酰胺的药代动力学，捕捉其在体内的时空作用模式。此外，[C]Gln PET 成像显示，蛋氨酸和胆碱缺乏（MCD）喂养的 NASH 小鼠肝脏摄取量显著增加，而 BPTES 的系统治疗干预降低了 MCD 喂养小鼠肝脏对[C]Gln 的渴求度。这种[C]Gln摄取量的减少与GLS1负担的减少和肝损伤的改善相关，表明BPTES在减轻与NASH相关的代谢异常方面具有疗效。这些结果表明，[C]Gln PET 成像可作为一种无创诊断平台，用于全身实时跟踪谷氨酰胺分解对 NASH 中 GLS1 操作的反应，它可能是对接受谷氨酰胺分解代谢疗法的 NASH 患者进行临床管理的一种有价值的工具。

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引用次数: 0

P2Y14R activation facilitates liver regeneration via CREB/DNMT3b/Dact-2/β-Catenin signals in acute liver failure

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-02-01 DOI: 10.1016/j.apsb.2025.01.004

Mengze Zhou , Yehong Li , Jialong Qian , Xinli Dong , Yanshuo Guo , Li Yin , Chunxiao Liu , Kun Hao , Qinghua Hu

Acute liver failure (ALF) is lack of broadly approved therapeutic strategy except liver transplantation. As a glycogen metabolic intermediate, UDP-glucose (UDP-G) has been considered to accelerate liver repairment. Nevertheless, the role of UDP-G and its receptor P2Y purinoceptor 14 (P2Y₁₄R) in ALF remains unknown. The present study aims to investigate the role and underlying mechanisms of UDP-G/P2Y₁₄R axis in ALF. In this study, hepatic P2Y₁₄R is significantly increased in TAA-induced and partial hepatectomy-induced ALF, while knockout of whole-body P2Y₁₄R aggravates liver failure, manifested by inhibiting β-Catenin-mediated liver regeneration. Consistently, P2Y₁₄R deficiency exhibits impaired liver regeneration in mice suffer partial hepatectomy. Importantly, only hepatocellular specific deletion of P2Y₁₄R (P2Y₁₄R^flox/floxAlb^cre/+) mice shows a similar phenomenon, rather than stellate cell specific deletion of P2Y₁₄R (P2Y₁₄R^flox/floxLrat^cre/+) mice. Mechanistically, P2Y₁₄R induction regulates methylation of Dact-2 through CREB/DNMT3b signals in hepatocytes, subsequently inhibiting the expression of Dact-2 which is a stabilizer of β-Catenin degradation complex, leading to the activation of β-Catenin -mediated liver regeneration. Interestingly, the administration of exogenous UDP-G can accelerate liver regeneration and liver function recovery after partial hepatectomy in hepatocellular carcinoma mice. Together, the findings propose an unrecognized role of P2Y₁₄R in ALF and provide an effective adjuvant strategy for treatment of ALF.

{"title":"P2Y14R activation facilitates liver regeneration via CREB/DNMT3b/Dact-2/β-Catenin signals in acute liver failure","authors":"Mengze Zhou , Yehong Li , Jialong Qian , Xinli Dong , Yanshuo Guo , Li Yin , Chunxiao Liu , Kun Hao , Qinghua Hu","doi":"10.1016/j.apsb.2025.01.004","DOIUrl":"10.1016/j.apsb.2025.01.004","url":null,"abstract":"<div><div>Acute liver failure (ALF) is lack of broadly approved therapeutic strategy except liver transplantation. As a glycogen metabolic intermediate, UDP-glucose (UDP-G) has been considered to accelerate liver repairment. Nevertheless, the role of UDP-G and its receptor P2Y purinoceptor 14 (P2Y<sub>14</sub>R) in ALF remains unknown. The present study aims to investigate the role and underlying mechanisms of UDP-G/P2Y<sub>14</sub>R axis in ALF. In this study, hepatic P2Y<sub>14</sub>R is significantly increased in TAA-induced and partial hepatectomy-induced ALF, while knockout of whole-body P2Y<sub>14</sub>R aggravates liver failure, manifested by inhibiting <em>β</em>-Catenin-mediated liver regeneration. Consistently, P2Y<sub>14</sub>R deficiency exhibits impaired liver regeneration in mice suffer partial hepatectomy. Importantly, only hepatocellular specific deletion of P2Y<sub>14</sub>R (P2Y<sub>14</sub>R<sup><em>flox/flox</em></sup><em>Alb</em><sup><em>cre/+</em></sup>) mice shows a similar phenomenon, rather than stellate cell specific deletion of P2Y<sub>14</sub>R (P2Y<sub>14</sub>R<sup><em>flox/flox</em></sup><em>Lrat</em><sup><em>cre/+</em></sup>) mice. Mechanistically, P2Y<sub>14</sub>R induction regulates methylation of Dact-2 through CREB/DNMT3b signals in hepatocytes, subsequently inhibiting the expression of Dact-2 which is a stabilizer of <em>β</em>-Catenin degradation complex, leading to the activation of <em>β</em>-Catenin -mediated liver regeneration. Interestingly, the administration of exogenous UDP-G can accelerate liver regeneration and liver function recovery after partial hepatectomy in hepatocellular carcinoma mice. Together, the findings propose an unrecognized role of P2Y<sub>14</sub>R in ALF and provide an effective adjuvant strategy for treatment of ALF.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 2","pages":"Pages 919-933"},"PeriodicalIF":14.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143591918","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}

引用次数: 0

Tumor-intrinsic PRMT5 upregulates FGL1 via methylating TCF12 to inhibit CD8+ T-cell-mediated antitumor immunity in liver cancer

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-01-01 DOI: 10.1016/j.apsb.2024.10.016

Jiao Sun , Hongfeng Yuan , Linlin Sun , Lina Zhao , Yufei Wang , Chunyu Hou , Huihui Zhang , Pan Lv , Guang Yang , Ningning Zhang , Wei Lu , Xiaodong Zhang

Protein arginine methyltransferase 5 (PRMT5) acts as an oncogene in liver cancer, yet its roles and in-depth molecular mechanisms within the liver cancer immune microenvironment remain mostly undefined. Here, we demonstrated that disruption of tumor-intrinsic PRMT5 enhances CD8⁺ T-cell-mediated antitumor immunity both in vivo and in vitro. Further experiments verified that this effect is achieved through downregulation of the inhibitory immune checkpoint molecule, fibrinogen-like protein 1 (FGL1). Mechanistically, PRMT5 catalyzed symmetric dimethylation of transcription factor 12 (TCF12) at arginine 554 (R554), prompting the binding of TCF12 to FGL1 promoter region, which transcriptionally activated FGL1 in tumor cells. Methylation deficiency at TCF12-R554 residue downregulated FGL1 expression, which promoted CD8⁺ T-cell-mediated antitumor immunity. Notably, combining the PRMT5 methyltransferase inhibitor GSK591 with PD-L1 blockade efficiently inhibited liver cancer growth and improved overall survival in mice. Collectively, our findings reveal the immunosuppressive role and mechanism of PRMT5 in liver cancer and highlight that targeting PRMT5 could boost checkpoint immunotherapy efficacy.

{"title":"Tumor-intrinsic PRMT5 upregulates FGL1 via methylating TCF12 to inhibit CD8+ T-cell-mediated antitumor immunity in liver cancer","authors":"Jiao Sun , Hongfeng Yuan , Linlin Sun , Lina Zhao , Yufei Wang , Chunyu Hou , Huihui Zhang , Pan Lv , Guang Yang , Ningning Zhang , Wei Lu , Xiaodong Zhang","doi":"10.1016/j.apsb.2024.10.016","DOIUrl":"10.1016/j.apsb.2024.10.016","url":null,"abstract":"<div><div>Protein arginine methyltransferase 5 (PRMT5) acts as an oncogene in liver cancer, yet its roles and in-depth molecular mechanisms within the liver cancer immune microenvironment remain mostly undefined. Here, we demonstrated that disruption of tumor-intrinsic PRMT5 enhances CD8<sup>+</sup> T-cell-mediated antitumor immunity both <em>in vivo</em> and <em>in vitro</em>. Further experiments verified that this effect is achieved through downregulation of the inhibitory immune checkpoint molecule, fibrinogen-like protein 1 (FGL1). Mechanistically, PRMT5 catalyzed symmetric dimethylation of transcription factor 12 (TCF12) at arginine 554 (R554), prompting the binding of TCF12 to FGL1 promoter region, which transcriptionally activated FGL1 in tumor cells. Methylation deficiency at TCF12-R554 residue downregulated FGL1 expression, which promoted CD8<sup>+</sup> T-cell-mediated antitumor immunity. Notably, combining the PRMT5 methyltransferase inhibitor GSK591 with PD-L1 blockade efficiently inhibited liver cancer growth and improved overall survival in mice. Collectively, our findings reveal the immunosuppressive role and mechanism of PRMT5 in liver cancer and highlight that targeting PRMT5 could boost checkpoint immunotherapy efficacy.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 1","pages":"Pages 188-204"},"PeriodicalIF":14.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388017","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}

引用次数: 0

Oxidative stress and inflammation in the pathogenesis of neurological disorders: Mechanisms and implications

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-01-01 DOI: 10.1016/j.apsb.2024.10.004

Umesh Chandra Dash , Nitish Kumar Bhol , Sandeep Kumar Swain , Rashmi Rekha Samal , Prabhat Kumar Nayak , Vishakha Raina , Sandeep Kumar Panda , Rout George Kerry , Asim K. Duttaroy , Atala Bihari Jena

Neuroprotection is a proactive approach to safeguarding the nervous system, including the brain, spinal cord, and peripheral nerves, by preventing or limiting damage to nerve cells and other components. It primarily defends the central nervous system against injury from acute and progressive neurodegenerative disorders. Oxidative stress, an imbalance between the body's natural defense mechanisms and the generation of reactive oxygen species, is crucial in developing neurological disorders. Due to its high metabolic rate and oxygen consumption, the brain is particularly vulnerable to oxidative stress. Excessive ROS damages the essential biomolecules, leading to cellular malfunction and neurodegeneration. Several neurological disorders, including Alzheimer's, Parkinson's, Amyotrophic lateral sclerosis, multiple sclerosis, and ischemic stroke, are associated with oxidative stress. Understanding the impact of oxidative stress in these conditions is crucial for developing new treatment methods. Researchers are exploring using antioxidants and other molecules to mitigate oxidative stress, aiming to prevent or slow down the progression of brain diseases. By understanding the intricate interplay between oxidative stress and neurological disorders, scientists hope to pave the way for innovative therapeutic and preventive approaches, ultimately improving individuals' living standards.

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引用次数: 0

Advances and prospects of RNA delivery nanoplatforms for cancer therapy

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-01-01 DOI: 10.1016/j.apsb.2024.09.009

Mohamed S. Attia, Gregor Kijanka, Nam-Trung Nguyen, Jun Zhang, Hongjie An

Modern oncology is rapidly evolving, driven by recent advances in RNA-based therapeutics. As new emerging cutting-edge technology, mRNA vaccines hold excellent promise for encoding immunostimulatory molecules, tumor-associated antigens, neoantigens, and chimeric antigen receptors for T-cell reprogramming. RNA interference tools enable highly effective post-transcriptional gene silencing that has rapidly progressed towards more tailored antitumor treatments targeting key molecular players in tumor progression and drug resistance. The inherent challenges and limitations of RNA-based tools, such as size, low stability and surface charges hindering direct cell entry, along with the short circulatory half-life and rapid clearance, call for new and improved RNA delivery systems enabling enhanced gene delivery. Nanoplatforms, particularly certain types of lipid, polymeric nanoparticles and inorganic nanoparticles, provide designed means to address the challenges of RNA delivery and cellular uptake. This paper explores the challenges and barriers while giving insight into the future perspective of RNA-based cancer therapeutics in the context of delivery nanoplatforms and the challenges during development.

{"title":"Advances and prospects of RNA delivery nanoplatforms for cancer therapy","authors":"Mohamed S. Attia, Gregor Kijanka, Nam-Trung Nguyen, Jun Zhang, Hongjie An","doi":"10.1016/j.apsb.2024.09.009","DOIUrl":"10.1016/j.apsb.2024.09.009","url":null,"abstract":"<div><div>Modern oncology is rapidly evolving, driven by recent advances in RNA-based therapeutics. As new emerging cutting-edge technology, mRNA vaccines hold excellent promise for encoding immunostimulatory molecules, tumor-associated antigens, neoantigens, and chimeric antigen receptors for T-cell reprogramming. RNA interference tools enable highly effective post-transcriptional gene silencing that has rapidly progressed towards more tailored antitumor treatments targeting key molecular players in tumor progression and drug resistance. The inherent challenges and limitations of RNA-based tools, such as size, low stability and surface charges hindering direct cell entry, along with the short circulatory half-life and rapid clearance, call for new and improved RNA delivery systems enabling enhanced gene delivery. Nanoplatforms, particularly certain types of lipid, polymeric nanoparticles and inorganic nanoparticles, provide designed means to address the challenges of RNA delivery and cellular uptake. This paper explores the challenges and barriers while giving insight into the future perspective of RNA-based cancer therapeutics in the context of delivery nanoplatforms and the challenges during development.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 1","pages":"Pages 52-96"},"PeriodicalIF":14.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388235","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}

引用次数: 0

Drug discovery targeting thyroid hormone receptor β (THRβ) for the treatment of liver diseases and other medical indications 针对甲状腺激素受体 β (THRβ) 的药物研发，用于治疗肝脏疾病和其他医疗适应症

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-01-01 DOI: 10.1016/j.apsb.2024.07.025

Kean Wang , Feiyang Chen , Jiang Wang , Hong Liu

Thyroid hormone receptors (THRs), a crucial nuclear receptor protein family, primarily consist of two categories: α receptors and β receptors. Among them, THRβ is the primary subtype of thyroid hormone that confers benefits to the liver. In the last two decades, there have been efforts to develop THRβ agonists that selectively yield beneficial effects on the liver, such as lowering triglycerides and cholesterol, while reducing adverse effects on the heart, muscle, and bone. This paper systematically reviews strategies to enhance the safety of THRβ agonists for the treatment of MASH, with a focus on improving the selectivity of THRα and increasing the distribution of the drug in the liver. Additionally, we explore the potential application of this target in addressing other medical indications.

甲状腺激素受体（THR）是一个重要的核受体蛋白家族，主要由受体和受体两类组成。其中，THR是对肝脏有益的甲状腺激素的主要亚型。近二十年来，人们一直在努力开发THR激动剂，以选择性地产生对肝脏有益的作用，如降低甘油三酯和胆固醇，同时减少对心脏、肌肉和骨骼的不利影响。本文系统回顾了提高 THR 激动剂治疗 MASH 的安全性的策略，重点是提高 THR 的选择性和增加药物在肝脏中的分布。此外，我们还探讨了这一靶点在其他医疗适应症中的潜在应用。

引用次数: 0

Akkermansia muciniphila-derived acetate activates the hepatic AMPK/SIRT1/PGC-1α axis to alleviate ferroptosis in metabolic-associated fatty liver disease

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-01-01 DOI: 10.1016/j.apsb.2024.10.010

Aoxiang Zhuge , Shengjie Li , Shengyi Han , Yin Yuan , Jian Shen , Wenrui Wu , Kaicen Wang , Jiafeng Xia , Qiangqiang Wang , Yifeng Gu , Enguo Chen , Lanjuan Li

Emerging evidences have indicated the role of ferroptosis in the progression of metabolic-associated fatty liver disease (MAFLD); thus, inhibiting ferroptosis is a promising strategy for the development of MAFLD therapeutics. Recent studies have demonstrated the antioxidative effect of the gut commensal bacterium Akkermansia muciniphila (A. muc); however, whether it can alleviate ferroptosis remains unclear. The current study indicates A. muc intervention efficiently reversed high-fat high-fructose diet (HFHFD)-induced lipid peroxidation and ferroptosis in the liver. These beneficial effects were mediated by activation of the hepatic AMPK/SIRT1/PGC-1α axis, as evidenced by the finding that AMPK deficiency abrogated the amelioration of lipid peroxidation in vitro and in vivo. Furthermore, the short-chain fatty acids (SCFAs) were enriched upon A. muc treatment, and acetate was identified as a key activator of hepatic AMPK signalling. Mechanistically, microbiota-derived acetate was transported to the liver and metabolized to adenosine monophosphate (AMP), which triggered AMPK activation. Furthermore, a colonization assay in germ-free mice confirmed that A. muc mediated antiferroptotic effects in the absence of other microbes. These data indicated that A. muc exerts antiferroptotic effects against MAFLD, at least partially by producing acetate, which activates the hepatic AMPK/SIRT1/PGC-1α axis to alleviate ferroptosis via the inhibition of polyunsaturated fatty acid (PUFA) synthesis.

{"title":"Akkermansia muciniphila-derived acetate activates the hepatic AMPK/SIRT1/PGC-1α axis to alleviate ferroptosis in metabolic-associated fatty liver disease","authors":"Aoxiang Zhuge , Shengjie Li , Shengyi Han , Yin Yuan , Jian Shen , Wenrui Wu , Kaicen Wang , Jiafeng Xia , Qiangqiang Wang , Yifeng Gu , Enguo Chen , Lanjuan Li","doi":"10.1016/j.apsb.2024.10.010","DOIUrl":"10.1016/j.apsb.2024.10.010","url":null,"abstract":"<div><div>Emerging evidences have indicated the role of ferroptosis in the progression of metabolic-associated fatty liver disease (MAFLD); thus, inhibiting ferroptosis is a promising strategy for the development of MAFLD therapeutics. Recent studies have demonstrated the antioxidative effect of the gut commensal bacterium <em>Akkermansia muciniphila</em> (<em>A. muc</em>); however, whether it can alleviate ferroptosis remains unclear. The current study indicates <em>A. muc</em> intervention efficiently reversed high-fat high-fructose diet (HFHFD)-induced lipid peroxidation and ferroptosis in the liver. These beneficial effects were mediated by activation of the hepatic AMPK/SIRT1/PGC-1<em>α</em> axis, as evidenced by the finding that AMPK deficiency abrogated the amelioration of lipid peroxidation <em>in vitro</em> and <em>in vivo</em>. Furthermore, the short-chain fatty acids (SCFAs) were enriched upon <em>A. muc</em> treatment, and acetate was identified as a key activator of hepatic AMPK signalling. Mechanistically, microbiota-derived acetate was transported to the liver and metabolized to adenosine monophosphate (AMP), which triggered AMPK activation. Furthermore, a colonization assay in germ-free mice confirmed that <em>A. muc</em> mediated antiferroptotic effects in the absence of other microbes. These data indicated that <em>A. muc</em> exerts antiferroptotic effects against MAFLD, at least partially by producing acetate, which activates the hepatic AMPK/SIRT1/PGC-1<em>α</em> axis to alleviate ferroptosis <em>via</em> the inhibition of polyunsaturated fatty acid (PUFA) synthesis.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 1","pages":"Pages 151-167"},"PeriodicalIF":14.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388276","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}

引用次数: 0

Facilitation of mucosal healing by estrogen receptor β in ulcerative colitis through suppression of branched-chain amino acid transport and subsequent triggering of autophagy in colonic epithelial cells

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-01-01 DOI: 10.1016/j.apsb.2024.11.014

Yilei Guo , Yanrong Zhu , Jing Zhang , Yue He , Mianjiang Zhao , Haochang Lin , Zhifeng Wei , Yufeng Xia , Yue Dai

Colonic mucosal healing is the ultimate goal of ulcerative colitis (UC) treatment, but it remains difficult to realize. Given the higher incidence of UC in males and the beneficial effect of estrogen on UC, we conducted this study to examine the therapeutic potential of estrogen receptor β (ERβ), the primary ER subtype in colon, on mucosal healing in UC. Our study is the first to report that ERβ activation degree was positively correlated with mucosal healing in patients with UC. Furthermore, ERβ activation enhanced mucosal healing in mice with dextran sulfate sodium-induced and biopsy-induced colonic injuries. Mechanistically, ERβ activation promoted autophagy of colonic epithelial cells by inhibiting branched-chain amino acid transport, leading to focal adhesion kinase (FAK) activation. Activated FAK promoted focal adhesion turnover and colonic epithelial cell migration, ultimately facilitating mucosal healing. ERβ^−/− colitis mice exhibited impaired mucosal healing compared to wild-type littermates, highlighting the crucial effect of ERβ. Importantly, combination with ERβ-agonist diarylpropionitrile enhanced the amelioration of 5-aminosalicylic acid, a standard UC treatment agent, against mouse colitis. These findings attest to the crucial role of ERβ activation in colonic mucosal healing and may further inform the development of novel strategies for UC treatment.

{"title":"Facilitation of mucosal healing by estrogen receptor β in ulcerative colitis through suppression of branched-chain amino acid transport and subsequent triggering of autophagy in colonic epithelial cells","authors":"Yilei Guo , Yanrong Zhu , Jing Zhang , Yue He , Mianjiang Zhao , Haochang Lin , Zhifeng Wei , Yufeng Xia , Yue Dai","doi":"10.1016/j.apsb.2024.11.014","DOIUrl":"10.1016/j.apsb.2024.11.014","url":null,"abstract":"<div><div>Colonic mucosal healing is the ultimate goal of ulcerative colitis (UC) treatment, but it remains difficult to realize. Given the higher incidence of UC in males and the beneficial effect of estrogen on UC, we conducted this study to examine the therapeutic potential of estrogen receptor <em>β</em> (ER<em>β</em>), the primary ER subtype in colon, on mucosal healing in UC. Our study is the first to report that ER<em>β</em> activation degree was positively correlated with mucosal healing in patients with UC. Furthermore, ER<em>β</em> activation enhanced mucosal healing in mice with dextran sulfate sodium-induced and biopsy-induced colonic injuries. Mechanistically, ER<em>β</em> activation promoted autophagy of colonic epithelial cells by inhibiting branched-chain amino acid transport, leading to focal adhesion kinase (FAK) activation. Activated FAK promoted focal adhesion turnover and colonic epithelial cell migration, ultimately facilitating mucosal healing. ER<em>β</em><sup>−/−</sup> colitis mice exhibited impaired mucosal healing compared to wild-type littermates, highlighting the crucial effect of ER<em>β</em>. Importantly, combination with ER<em>β</em>-agonist diarylpropionitrile enhanced the amelioration of 5-aminosalicylic acid, a standard UC treatment agent, against mouse colitis. These findings attest to the crucial role of ER<em>β</em> activation in colonic mucosal healing and may further inform the development of novel strategies for UC treatment.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 1","pages":"Pages 168-187"},"PeriodicalIF":14.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388277","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}

引用次数: 0

Dual activation of GCGR/GLP1R signaling ameliorates intestinal fibrosis via metabolic regulation of histone H3K9 lactylation in epithelial cells

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-01-01 DOI: 10.1016/j.apsb.2024.11.017

Han Liu , Yujie Hong , Hui Chen , Xianggui Wang , Jiale Dong , Xiaoqian Li , Zihan Shi , Qian Zhao , Longyuan Zhou , JiaXin Wang , Qiuling Zeng , Qinglin Tang , Qi Liu , Florian Rieder , Baili Chen , Minhu Chen , Rui Wang , Yao Zhang , Ren Mao , Xianxing Jiang

Intestinal fibrosis is a significant clinical challenge in inflammatory bowel diseases, but no effective anti-fibrotic therapy is currently available. Glucagon receptor (GCGR) and glucagon-like peptide 1 receptor (GLP1R) are both peptide hormone receptors involved in energy metabolism of epithelial cells. However, their role in intestinal fibrosis and the underlying mechanisms remain largely unexplored. Herein GCGR and GLP1R were found to be reduced in the stenotic ileum of patients with Crohn's disease as well as in the fibrotic colon of mice with chronic colitis. The downregulation of GCGR and GLP1R led to the accumulation of the metabolic byproduct lactate, resulting in histone H3K9 lactylation and exacerbated intestinal fibrosis through epithelial-to-mesenchymal transition (EMT). Dual activating GCGR and GLP1R by peptide 1907B reduced the H3K9 lactylation in epithelial cells and ameliorated intestinal fibrosis in vivo. We uncovered the role of GCGR/GLP1R in regulating EMT involved in intestinal fibrosis via histone lactylation. Simultaneously activating GCGR/GLP1R with the novel dual agonist peptide 1907B holds promise as a treatment strategy for alleviating intestinal fibrosis.

{"title":"Dual activation of GCGR/GLP1R signaling ameliorates intestinal fibrosis via metabolic regulation of histone H3K9 lactylation in epithelial cells","authors":"Han Liu , Yujie Hong , Hui Chen , Xianggui Wang , Jiale Dong , Xiaoqian Li , Zihan Shi , Qian Zhao , Longyuan Zhou , JiaXin Wang , Qiuling Zeng , Qinglin Tang , Qi Liu , Florian Rieder , Baili Chen , Minhu Chen , Rui Wang , Yao Zhang , Ren Mao , Xianxing Jiang","doi":"10.1016/j.apsb.2024.11.017","DOIUrl":"10.1016/j.apsb.2024.11.017","url":null,"abstract":"<div><div>Intestinal fibrosis is a significant clinical challenge in inflammatory bowel diseases, but no effective anti-fibrotic therapy is currently available. Glucagon receptor (GCGR) and glucagon-like peptide 1 receptor (GLP1R) are both peptide hormone receptors involved in energy metabolism of epithelial cells. However, their role in intestinal fibrosis and the underlying mechanisms remain largely unexplored. Herein GCGR and GLP1R were found to be reduced in the stenotic ileum of patients with Crohn's disease as well as in the fibrotic colon of mice with chronic colitis. The downregulation of GCGR and GLP1R led to the accumulation of the metabolic byproduct lactate, resulting in histone H3K9 lactylation and exacerbated intestinal fibrosis through epithelial-to-mesenchymal transition (EMT). Dual activating GCGR and GLP1R by peptide 1907B reduced the H3K9 lactylation in epithelial cells and ameliorated intestinal fibrosis <em>in vivo</em>. We uncovered the role of GCGR/GLP1R in regulating EMT involved in intestinal fibrosis <em>via</em> histone lactylation. Simultaneously activating GCGR/GLP1R with the novel dual agonist peptide 1907B holds promise as a treatment strategy for alleviating intestinal fibrosis.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 1","pages":"Pages 278-295"},"PeriodicalIF":14.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388280","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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