Pub Date : 2025-02-01DOI: 10.1016/j.phrs.2025.107588
Pinglian Yang , Xiaoling Rong , Zhechang Gao , Jiaojiao Wang , Zhiping Liu
Atherosclerosis, a multifactorial progressive inflammatory disease, is the common pathology underlying cardiovascular and cerebrovascular diseases. The macrophage plasticity is involved in the pathogenesis of atherosclerosis. With the advance of metabolomics and epigenetics, metabolites/metabolic and epigenetic modification such as DNA methylation, histone modification and noncoding RNA, play a crucial role in macrophage polarization and the progression of atherosclerosis. Herein, we provide a comprehensive review of the essential role of metabolic and epigenetic regulation, as well as the crosstalk between the two in regulating macrophage polarization in atherosclerosis. We also highlight the potential therapeutic strategies of regulating macrophage polarization via epigenetic and metabolic modifications for atherosclerosis, and offer recommendations to advance our knowledge of the roles of metabolic-epigenetic crosstalk in macrophage polarization in the context of atherosclerosis. Fundamental studies that elucidate the mechanisms by which metabolic and epigenetic regulation of macrophage polarization influence atherosclerosis will pave the way for novel therapeutic approaches.
{"title":"Metabolic and epigenetic regulation of macrophage polarization in atherosclerosis: Molecular mechanisms and targeted therapies","authors":"Pinglian Yang , Xiaoling Rong , Zhechang Gao , Jiaojiao Wang , Zhiping Liu","doi":"10.1016/j.phrs.2025.107588","DOIUrl":"10.1016/j.phrs.2025.107588","url":null,"abstract":"<div><div>Atherosclerosis, a multifactorial progressive inflammatory disease, is the common pathology underlying cardiovascular and cerebrovascular diseases. The macrophage plasticity is involved in the pathogenesis of atherosclerosis. With the advance of metabolomics and epigenetics, metabolites/metabolic and epigenetic modification such as DNA methylation, histone modification and noncoding RNA, play a crucial role in macrophage polarization and the progression of atherosclerosis. Herein, we provide a comprehensive review of the essential role of metabolic and epigenetic regulation, as well as the crosstalk between the two in regulating macrophage polarization in atherosclerosis. We also highlight the potential therapeutic strategies of regulating macrophage polarization via epigenetic and metabolic modifications for atherosclerosis, and offer recommendations to advance our knowledge of the roles of metabolic-epigenetic crosstalk in macrophage polarization in the context of atherosclerosis. Fundamental studies that elucidate the mechanisms by which metabolic and epigenetic regulation of macrophage polarization influence atherosclerosis will pave the way for novel therapeutic approaches.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107588"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142952939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.phrs.2025.107629
Yan Chen , Jing Dai , Peng Chen , Quan Dai , Ya Chen , Yuying Li , Man Lu , Shugang Qin , Qiuju Wang
{"title":"Erratum to the ‘Long non-coding RNAs-sphingolipid metabolism nexus: Potential targets for cancer treatment’ Pharmacol. Res. 210 (December) (2024) 107539","authors":"Yan Chen , Jing Dai , Peng Chen , Quan Dai , Ya Chen , Yuying Li , Man Lu , Shugang Qin , Qiuju Wang","doi":"10.1016/j.phrs.2025.107629","DOIUrl":"10.1016/j.phrs.2025.107629","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107629"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143059309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.phrs.2025.107578
Mingchun Jiang , Jiaxin Chi , Yifan Qiao , Jinpeng Wang , Zhixin Zhang , Jia Liu , Xinhao Sheng , Liangjie Yuan
Ginseng has been commonly used as a traditional Chinese medicine in Asian countries for thousands of years. Ginsenosides are the main pharmacologically active ingredients isolated from ginseng and have neuroprotective effects in the treatment of neurodegenerative disorders, such as Parkinson's disease (PD) and Alzheimer's disease (AD). To summarise and investigate the protective roles of ginsenosides and their underlying mechanisms in PD and AD, we used ‘‘Ginsenoside”, ‘‘Parkinson's disease”, ‘‘Alzheimer's disease”, ‘‘anti-inflammatory”, ‘‘antioxidant”, and ‘‘apoptosis” as keywords to search and extract relevant literature information from scientific databases such as Elsevier, PubMed, and Google Scholar databases. In particular, we used network pharmacology to identify the potential targets of ginsenosides Rg1 and Rb1 in PD and AD. By analysing the existing research advances and network pharmacology results, we found that the neuroprotective effects of ginsenosides, primarily mediated through anti-inflammation, anti-apoptosis and anti-oxidative stress, etc, may be associated with the PI3K/Akt, BDNF/TrkB, MAPKs, NF-κB, Nrf2 and Wnt/β-catenin signalling pathways. This review systematically summarises the different roles and mechanisms of ginsenosides Rg1, Rb1, and rare ginsenosides in PD and AD and provides new strategies for the treatment of neurodegenerative disorders. Network pharmacology provides a new research paradigm for the treatment of PD and AD using Rg1 and Rb1.
{"title":"Ginsenosides Rg1, Rb1 and rare ginsenosides: Promising candidate agents for Parkinson's disease and Alzheimer's disease and network pharmacology analysis","authors":"Mingchun Jiang , Jiaxin Chi , Yifan Qiao , Jinpeng Wang , Zhixin Zhang , Jia Liu , Xinhao Sheng , Liangjie Yuan","doi":"10.1016/j.phrs.2025.107578","DOIUrl":"10.1016/j.phrs.2025.107578","url":null,"abstract":"<div><div>Ginseng has been commonly used as a traditional Chinese medicine in Asian countries for thousands of years. Ginsenosides are the main pharmacologically active ingredients isolated from ginseng and have neuroprotective effects in the treatment of neurodegenerative disorders, such as Parkinson's disease (PD) and Alzheimer's disease (AD). To summarise and investigate the protective roles of ginsenosides and their underlying mechanisms in PD and AD, we used ‘‘Ginsenoside”, ‘‘Parkinson's disease”, ‘‘Alzheimer's disease”, ‘‘anti-inflammatory”, ‘‘antioxidant”, and ‘‘apoptosis” as keywords to search and extract relevant literature information from scientific databases such as Elsevier, PubMed, and Google Scholar databases. In particular, we used network pharmacology to identify the potential targets of ginsenosides Rg1 and Rb1 in PD and AD. By analysing the existing research advances and network pharmacology results, we found that the neuroprotective effects of ginsenosides, primarily mediated through anti-inflammation, anti-apoptosis and anti-oxidative stress, etc, may be associated with the PI3K/Akt, BDNF/TrkB, MAPKs, NF-κB, Nrf2 and Wnt/β-catenin signalling pathways. This review systematically summarises the different roles and mechanisms of ginsenosides Rg1, Rb1, and rare ginsenosides in PD and AD and provides new strategies for the treatment of neurodegenerative disorders. Network pharmacology provides a new research paradigm for the treatment of PD and AD using Rg1 and Rb1.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107578"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142932474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.phrs.2025.107605
Danyue Li , Weilv Xu , Suhui He , Xinyue Li , Yumeng Wang , Qian Lv , Nan Chen , Lu Dong , Feng Guo , Fushan Shi
Most of the pyroptosis inhibitors targeted Gasdermin D (GSDMD) are functioning by restraining GSDMD-N (p30) oligomerization. For the first time, this work discovered a pyroptosis inhibitor taking effect by degrading p30 and GSDMD. As the principal bioactive constituent in Erigeron breviscapus, scutellarin (SCU) assumes a pivotal role in the realm of anti-inflammatory processes. In this study, SCU demonstrated efficacy in hindering pyroptosis mediated by the NOD-like receptor protein 3 (NLRP3) inflammasome, absent in melanoma 2 (AIM2) inflammasome, NLR-family CARD-containing protein 4 (NLRC4) inflammasome, and that activated through the non-canonical pathway. The inhibitory effect is achieved by thwarting apoptosis-associated speck-like protein containing CARD (ASC) oligomerization and inducing the ubiquitin-dependent selective autophagy of p30/GSDMD. Throughout the autophagic process, SCU facilitates selective autophagy of the pyroptosis executor p30/GSDMD through K33-linked polyubiquitination at Lys51 catalyzed by the E3 ligase tripartite motif-containing 21 (TRIM21). This process contributes to the recognition of p30/GSDMD by the cargo receptor sequestosome 1 (SQSTM1)/p62. The characteristic positions SCU as a prospective clinical intervention for a broader spectrum of inflammatory-related disorders.
{"title":"Scutellarin inhibits pyroptosis via selective autophagy degradation of p30/GSDMD and suppression of ASC oligomerization","authors":"Danyue Li , Weilv Xu , Suhui He , Xinyue Li , Yumeng Wang , Qian Lv , Nan Chen , Lu Dong , Feng Guo , Fushan Shi","doi":"10.1016/j.phrs.2025.107605","DOIUrl":"10.1016/j.phrs.2025.107605","url":null,"abstract":"<div><div>Most of the pyroptosis inhibitors targeted Gasdermin D (GSDMD) are functioning by restraining GSDMD-N (p30) oligomerization. For the first time, this work discovered a pyroptosis inhibitor taking effect by degrading p30 and GSDMD. As the principal bioactive constituent in <em>Erigeron breviscapus</em>, scutellarin (SCU) assumes a pivotal role in the realm of anti-inflammatory processes. In this study, SCU demonstrated efficacy in hindering pyroptosis mediated by the NOD-like receptor protein 3 (NLRP3) inflammasome, absent in melanoma 2 (AIM2) inflammasome, NLR-family CARD-containing protein 4 (NLRC4) inflammasome, and that activated through the non-canonical pathway. The inhibitory effect is achieved by thwarting apoptosis-associated speck-like protein containing CARD (ASC) oligomerization and inducing the ubiquitin-dependent selective autophagy of p30/GSDMD. Throughout the autophagic process, SCU facilitates selective autophagy of the pyroptosis executor p30/GSDMD through K33-linked polyubiquitination at Lys51 catalyzed by the E3 ligase tripartite motif-containing 21 (TRIM21). This process contributes to the recognition of p30/GSDMD by the cargo receptor sequestosome 1 (SQSTM1)/p62. The characteristic positions SCU as a prospective clinical intervention for a broader spectrum of inflammatory-related disorders.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107605"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143009539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.phrs.2025.107620
Jiaqi Yao , Yuhong Jiang , Pengcheng Zhang , Yifan Miao , Xiajia Wu , Hang Lei , Zhijun Xie , Yong Tian , Xianlin Zhao , Juan Li , Lv Zhu , Meihua Wan , Wenfu Tang
The necrosis of pancreatic acinar cells is a key molecular event in the progression of acute pancreatitis (AP), with disturbances in mitochondrial energy metabolism considered to be a direct causative factor of acinar cell necrosis. Histidine triad nucleotide-binding protein 2 (HINT2) has been implicated in the development of various diseases, whereas its involvement in the progression of AP remains unclear. This study aims to investigate the role of HINT2 in AP. HINT2 expression in pancreatic tissues was significantly downregulated after AP. The results of glutathione-S-transferase (GST) pull-down and proteomics analyses revealed the involvement of HINT2 in regulating mitochondrial oxidative phosphorylation (OXPHOS) in AP mice. Moreover, lentivirus-mediated HINT2 overexpression not only alleviated AP-induced ATP depletion, but also relieved inflammatory responses and cell necrosis. Mechanistically, HINT2 interacted with cytochrome C oxidase II (MTCO2) to promote mitochondrial OXPHOS, thereby reducing ROS accumulation and inhibiting the activation of inflammatory signaling pathway. Besides, HINT2 act as a direct pharmacological target of Emo to elicit protective effects on AP. Importantly, Emo upregulates the expression of HINT2 and OXPHOS complex proteins and enhances the interaction between HINT2 and MTCO2. Furthermore, CRISPR/Cas9-mediated HINT2 knockout significantly impaired the protective effects of Emo against AP-induced mitochondrial energy metabolism disorders, inflammatory responses, and acinar cell necrosis. Overall, these results uncover a previously unexplored role for HINT2 in maintaining mitochondrial energy metabolism in pancreatic acinar cells and reveals novel mechanism and target for Emo-mediated AP remission.
{"title":"Genetic and pharmacological targeting of HINT2 promotes OXPHOS to alleviate inflammatory responses and cell necrosis in acute pancreatitis","authors":"Jiaqi Yao , Yuhong Jiang , Pengcheng Zhang , Yifan Miao , Xiajia Wu , Hang Lei , Zhijun Xie , Yong Tian , Xianlin Zhao , Juan Li , Lv Zhu , Meihua Wan , Wenfu Tang","doi":"10.1016/j.phrs.2025.107620","DOIUrl":"10.1016/j.phrs.2025.107620","url":null,"abstract":"<div><div>The necrosis of pancreatic acinar cells is a key molecular event in the progression of acute pancreatitis (AP), with disturbances in mitochondrial energy metabolism considered to be a direct causative factor of acinar cell necrosis. Histidine triad nucleotide-binding protein 2 (HINT2) has been implicated in the development of various diseases, whereas its involvement in the progression of AP remains unclear. This study aims to investigate the role of HINT2 in AP. HINT2 expression in pancreatic tissues was significantly downregulated after AP. The results of glutathione-S-transferase (GST) pull-down and proteomics analyses revealed the involvement of HINT2 in regulating mitochondrial oxidative phosphorylation (OXPHOS) in AP mice. Moreover, lentivirus-mediated HINT2 overexpression not only alleviated AP-induced ATP depletion, but also relieved inflammatory responses and cell necrosis. Mechanistically, HINT2 interacted with cytochrome C oxidase II (MTCO2) to promote mitochondrial OXPHOS, thereby reducing ROS accumulation and inhibiting the activation of inflammatory signaling pathway. Besides, HINT2 act as a direct pharmacological target of Emo to elicit protective effects on AP. Importantly, Emo upregulates the expression of HINT2 and OXPHOS complex proteins and enhances the interaction between HINT2 and MTCO2. Furthermore, CRISPR/Cas9-mediated HINT2 knockout significantly impaired the protective effects of Emo against AP-induced mitochondrial energy metabolism disorders, inflammatory responses, and acinar cell necrosis<em>.</em> Overall, these results uncover a previously unexplored role for HINT2 in maintaining mitochondrial energy metabolism in pancreatic acinar cells and reveals novel mechanism and target for Emo-mediated AP remission.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107620"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Correspondence: Improved glycemic and weight control with Dulaglutide addition in SGLT2 inhibitor treated obese type 2 diabetic patients at high cardiovascular risk in a real-world setting. The AWARE-2 study.","authors":"Chang-Yuan Hsu, Che-Wei Chang, Su-Boon Yong, Chin-Yuan Yii","doi":"10.1016/j.phrs.2025.107639","DOIUrl":"10.1016/j.phrs.2025.107639","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"107639"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143123396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.phrs.2025.107589
Jing Long , Hengzhou Lai , Yuqing Huang , Fengming You , Yifang Jiang , Qixuan Kuang
Bone marrow hematopoietic injury encompasses a range of pathological conditions that disrupt the normal function of the hematopoietic system, primarily through the impaired production and differentiation of bone marrow hematopoietic cells. Key pathogenic mechanisms include aging, radiation damage, chemical induction, infection and inflammation, and cross-talk with non-hematopoietic diseases. These pathological factors often lead to myelosuppression and myeloid skewing. Furthermore, we explored the potential and application prospects of natural products in the treatment of bone marrow hematopoietic injury. Natural products, particularly those derived from Chinese herbal medicines and other natural sources, have emerged as promising therapeutic options due to their distinctive mechanisms and minimal side effects. A deeper understanding of the underlying mechanisms of bone marrow hematopoietic injury could illuminate how natural products exert their effects, thereby optimizing treatment strategies and offering safer, more effective options for patients. Future research should leverage emerging technologies to further elucidate the composition and interactions within the bone marrow microenvironment, as well as the specific pathways through which natural products modulate hematopoietic dysfunction.
{"title":"Unraveling the pathogenesis of bone marrow hematopoietic injury and the therapeutic potential of natural products","authors":"Jing Long , Hengzhou Lai , Yuqing Huang , Fengming You , Yifang Jiang , Qixuan Kuang","doi":"10.1016/j.phrs.2025.107589","DOIUrl":"10.1016/j.phrs.2025.107589","url":null,"abstract":"<div><div>Bone marrow hematopoietic injury encompasses a range of pathological conditions that disrupt the normal function of the hematopoietic system, primarily through the impaired production and differentiation of bone marrow hematopoietic cells. Key pathogenic mechanisms include aging, radiation damage, chemical induction, infection and inflammation, and cross-talk with non-hematopoietic diseases. These pathological factors often lead to myelosuppression and myeloid skewing. Furthermore, we explored the potential and application prospects of natural products in the treatment of bone marrow hematopoietic injury. Natural products, particularly those derived from Chinese herbal medicines and other natural sources, have emerged as promising therapeutic options due to their distinctive mechanisms and minimal side effects. A deeper understanding of the underlying mechanisms of bone marrow hematopoietic injury could illuminate how natural products exert their effects, thereby optimizing treatment strategies and offering safer, more effective options for patients. Future research should leverage emerging technologies to further elucidate the composition and interactions within the bone marrow microenvironment, as well as the specific pathways through which natural products modulate hematopoietic dysfunction.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107589"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142952904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.phrs.2025.107587
Ce Chen , Jialin Wang , Mengqin Cheng , Haifeng Xie , Wei Li , Chaofeng Zhang
Pulmonary fibrosis (PF) is a fatal disease with increasing incidence, poor prognosis, and unclear pathogenesis. Our previous research demonstrated the beneficial effects of the natural cyclopeptide Heterophyllin B (HB) in PF. However, the precise mechanism by which HB exerts its effects in PF remains unclear. Our study revealed HB's beneficial effects in alleviating PF symptoms and restoring the intestinal mucosal barrier. Subsequently, the microbiota-dependent antifibrotic efficacy of HB was verified using various delivery routes, antibiotic treatments, and faecal microbiota transplantation. Functionally, 16S rRNA sequencing, untargeted metabolomics, and co-incubation experiments revealed that the antifibrotic efficacy of HB was primarily contingent on the enrichment of Muribaculum intestinale and its metabolite, 3-hydroxybutyric acid. Mechanistically, indoleamine 2,3- dioxygenase 1 (IDO1)-mediated ferroptosis was identified as a pivotal process in initiating PF, and the anti-fibrotic efficacy of HB relies on suppressing IDO1-mediated ferroptosis. Conversely, IDO1 deficiency alleviated the symptoms of bleomycin-induced PF and ferroptosis in mice. Coincidentally, both IDO1 overexpression and ferroptosis were observed in the pulmonary tissue of patients with idiopathic PF. Collectively, this study revealed that HB alleviates PF by eliminating intestinal microecology and metabolism and highlights the feasibility of targeting IDO1 for PF treatment.
{"title":"Muribaculum intestinale-derived 3-hydroxybutyric acid from Heterophyllin B attenuated pulmonary fibrosis through IDO1-mediated ferroptosis","authors":"Ce Chen , Jialin Wang , Mengqin Cheng , Haifeng Xie , Wei Li , Chaofeng Zhang","doi":"10.1016/j.phrs.2025.107587","DOIUrl":"10.1016/j.phrs.2025.107587","url":null,"abstract":"<div><div>Pulmonary fibrosis (PF) is a fatal disease with increasing incidence, poor prognosis, and unclear pathogenesis. Our previous research demonstrated the beneficial effects of the natural cyclopeptide Heterophyllin B (HB) in PF. However, the precise mechanism by which HB exerts its effects in PF remains unclear. Our study revealed HB's beneficial effects in alleviating PF symptoms and restoring the intestinal mucosal barrier. Subsequently, the microbiota-dependent antifibrotic efficacy of HB was verified using various delivery routes, antibiotic treatments, and faecal microbiota transplantation. Functionally, 16S rRNA sequencing, untargeted metabolomics, and co-incubation experiments revealed that the antifibrotic efficacy of HB was primarily contingent on the enrichment of <em>Muribaculum intestinale</em> and its metabolite, 3-hydroxybutyric acid. Mechanistically, indoleamine 2,3- dioxygenase 1 (IDO1)-mediated ferroptosis was identified as a pivotal process in initiating PF, and the anti-fibrotic efficacy of HB relies on suppressing IDO1-mediated ferroptosis. Conversely, IDO1 deficiency alleviated the symptoms of bleomycin-induced PF and ferroptosis in mice. Coincidentally, both IDO1 overexpression and ferroptosis were observed in the pulmonary tissue of patients with idiopathic PF. Collectively, this study revealed that HB alleviates PF by eliminating intestinal microecology and metabolism and highlights the feasibility of targeting IDO1 for PF treatment.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107587"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142952957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.phrs.2025.107596
Jialian Wang , Xingyu Tao , Zhengyang Liu , Yuan Yan , Peifeng Cheng , Bin Liu , Huimin Du , Bailin Niu
Sepsis is a life-threatening syndrome characterized by organ dysfunction caused by a dysregulated host response to infection. Sepsis-associated acute liver injury (SA-ALI) is a frequent and serious complication of sepsis that considerably impacts both short-term and long-term survival outcomes. In intensive care units (ICUs), the mortality rate of patients with SA-ALI remains high, mostly due to the absence of effective early diagnostic markers and suitable therapeutic strategies. Recent studies have demonstrated the importance of non-coding RNAs (ncRNAs) in the development and progression of SA-ALI. This review focuses on the critical roles of ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), in regulating “cytokine storms”, oxidative stress, mitochondrial dysfunction, and programmed cell death in SA-ALI, and summarizes the current state and limitations of existing studies on lncRNAs and circRNAs in SA-ALI. By integrating advancements in high-throughput sequencing technologies, this review provides novel insights into the dual potential of ncRNAs as diagnostic biomarkers and therapeutic targets, offers new ideas for SA-ALI diagnosis and treatment research and highlights potential challenges in clinical translation.
{"title":"Noncoding RNAs in sepsis-associated acute liver injury: Roles, mechanisms, and therapeutic applications","authors":"Jialian Wang , Xingyu Tao , Zhengyang Liu , Yuan Yan , Peifeng Cheng , Bin Liu , Huimin Du , Bailin Niu","doi":"10.1016/j.phrs.2025.107596","DOIUrl":"10.1016/j.phrs.2025.107596","url":null,"abstract":"<div><div>Sepsis is a life-threatening syndrome characterized by organ dysfunction caused by a dysregulated host response to infection. Sepsis-associated acute liver injury (SA-ALI) is a frequent and serious complication of sepsis that considerably impacts both short-term and long-term survival outcomes. In intensive care units (ICUs), the mortality rate of patients with SA-ALI remains high, mostly due to the absence of effective early diagnostic markers and suitable therapeutic strategies. Recent studies have demonstrated the importance of non-coding RNAs (ncRNAs) in the development and progression of SA-ALI. This review focuses on the critical roles of ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), in regulating “cytokine storms”, oxidative stress, mitochondrial dysfunction, and programmed cell death in SA-ALI, and summarizes the current state and limitations of existing studies on lncRNAs and circRNAs in SA-ALI. By integrating advancements in high-throughput sequencing technologies, this review provides novel insights into the dual potential of ncRNAs as diagnostic biomarkers and therapeutic targets, offers new ideas for SA-ALI diagnosis and treatment research and highlights potential challenges in clinical translation.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107596"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.phrs.2025.107608
Laura Grunewald , Lena Andersch , Konstantin Helmsauer , Silke Schwiebert , Anika Klaus , Anton G. Henssen , Teresa Straka , Marco Lodrini , Sebastian G. Wicha , Steffen Fuchs , Falk Hertwig , Frank Westermann , Alice Vitali , Carlotta Caramel , Gabriele Büchel , Martin Eilers , Kathy Astrahantseff , Angelika Eggert , Uta E. Höpken , Johannes H. Schulte , Annette Künkele
Current treatment protocols have limited success against MYCN-amplified neuroblastoma. Adoptive T cell therapy presents an innovative strategy to improve cure rates. However, L1CAM-targeting CAR T cells achieved only limited response against refractory/relapsed neuroblastoma so far. We investigated how oncogenic MYCN levels influence tumor cell response to CAR T cells, as one possible factor limiting clinical success. A MYCN-inducible neuroblastoma cell model was created. L1CAM-CAR T cell effector function was assessed (activation markers, cytokine release, tumor cytotoxicity) after coculture with the model or MYCN-amplified neuroblastoma cell lines. RNA sequencing datasets characterizing the model were compared to publicly available RNA/proteomic datasets. MYCN-directed L1CAM regulation was explored using public ChIP-sequencing datasets. Synergism between CAR T cells and the indirect MYCN inhibitor, MLN8237, was assessed in vitro using the Bliss model and in vivo in an immunocompromised mouse model. Inducing high MYCN levels in the neuroblastoma cell model reduced L1CAM expression and, consequently, L1CAM-CAR T cell effector function in vitro. Primary neuroblastomas possessing high MYCN levels expressed lower levels of both the L1CAM transcript and L1CAM tumor antigen. MLN8237 treatment restored L1CAM tumor expression and L1CAM-CAR T cell effector function. Combining MLN8237 and L1CAM-CAR T cell treatment synergistically enhanced MYCN-overexpressing tumor cytotoxicity in vitro and in vivo concomitant with severe in vivo toxicity. We identify target antigen downregulation as source of resistance against L1CAM-CAR T cells in MYCN-driven neuroblastoma cells. These data suggest that L1CAM-CAR T cell therapy combined with pharmacological MYCN inhibition may benefit patients with MYCN-amplified neuroblastoma.
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