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.
{"title":"Targeting MYCN upregulates L1CAM tumor antigen in MYCN-dysregulated neuroblastoma to increase CAR T cell efficacy","authors":"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","doi":"10.1016/j.phrs.2025.107608","DOIUrl":"10.1016/j.phrs.2025.107608","url":null,"abstract":"<div><div>Current treatment protocols have limited success against <em>MYCN-</em>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 <em>MYCN</em>-amplified neuroblastoma cell lines. RNA sequencing datasets characterizing the model were compared to publicly available RNA/proteomic datasets. MYCN-directed <em>L1CAM</em> regulation was explored using public ChIP-sequencing datasets. Synergism between CAR T cells and the indirect MYCN inhibitor, MLN8237, was assessed <em>in vitro</em> using the Bliss model and <em>in vivo</em> 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 <em>in vitro</em>. Primary neuroblastomas possessing high <em>MYCN</em> levels expressed lower levels of both the <em>L1CAM</em> 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 <em>in vitro</em> and <em>in vivo</em> concomitant with severe <em>in vivo</em> 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 <em>MYCN</em>-amplified neuroblastoma.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107608"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143009541","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.2025.107617
Lulu Zhang , Yi Zheng , Mingyan Shao , Aiping Chen , Meiyi Liu , Wenlong Sun , Tianxing Li , Yini Fang , Yang Dong , Shipeng Zhao , Hui Luo , Juan Feng , Qi Wang , Lingru Li , Yanfei Zheng
Metabolic-associated fatty liver disease (MAFLD) is a chronic, progressive disorder characterized by hepatic steatosis and excessive lipid accumulation. Its high global adult prevalence (approximately 50.7 %) is a significant concern worldwide. However, FDA-approved therapeutic drugs remains lacking. Qigui Jiangzhi Formula (QGJZF) shows promise in treating MAFLD by effectively decreasing lipid levels and improving hepatic steatosis, however its mechanisms remain unclear. This study investigated QGJZF’s effects in high-fat diet-induced zebrafish and golden hamsters, and in palmitate (PA) and oleic acid (OA) - induced HepG2 cells, using the SymMap database to identify potential targets and pathways of QGJZF in MAFLD and AlphaFold algorithms to predict protein structures. In vivo, QGJZF significantly alleviated hepatic lipid deposition. Intriguingly, QGJZF decreased lipid droplets and its levels are negative correlated with the numbers of autolysosomes, indicating that QGJZF’s mechanism of ameliorating liver lipid deposition may be related to the regulation of autophagy. QGJZF upregulated the expressions of phosphorylated -Adenosine 5‘-monophosphate (AMP) - activated protein kinase (p-AMPK), Sirtuin deacetylase 1 (SIRT1) and Transcription factor EB (TFEB), accompanied by the changes in autophagy-related proteins. In vitro, QGJZF inhibited the lipid deposition in PA/OA-stimulated HepG2 cells, and its effect was blocked by an autophagy inhibitor Baf-A1, which was mediated through upregulation of TFEB and its mediated autophagy-lysosomal pathway. Moreover, cotreatment with AMPK inhibitor Compound C, the regulation of QGJZF on TFEB, SIRT1, autophagy-related protein levels, and lipid deposition were reversed. Network pharmacology identified the PRKAA2 (AMPK) and SIRT1 as key hub targets. Futher analysis of their structures using AlphaFold3 algorithms, yielded high-ranking scores of 0.97 and 0.93, respectively. Liquid chromatography-mass spectrometry combined with molecular docking expounded its five compounds in QGJZF binding to AMPK protein. These findings suggest that QGJZF as a therapeutic agent in augmenting autophagy-facilitated lipid clearance for the management of MAFLD via AMPK/SIRT1-TFEB axis.
{"title":"AlphaFold-based AI docking reveals AMPK/SIRT1-TFEB pathway modulation by traditional Chinese medicine in metabolic-associated fatty liver disease","authors":"Lulu Zhang , Yi Zheng , Mingyan Shao , Aiping Chen , Meiyi Liu , Wenlong Sun , Tianxing Li , Yini Fang , Yang Dong , Shipeng Zhao , Hui Luo , Juan Feng , Qi Wang , Lingru Li , Yanfei Zheng","doi":"10.1016/j.phrs.2025.107617","DOIUrl":"10.1016/j.phrs.2025.107617","url":null,"abstract":"<div><div>Metabolic-associated fatty liver disease (MAFLD) is a chronic, progressive disorder characterized by hepatic steatosis and excessive lipid accumulation. Its high global adult prevalence (approximately 50.7 %) is a significant concern worldwide. However, FDA-approved therapeutic drugs remains lacking. Qigui Jiangzhi Formula (QGJZF) shows promise in treating MAFLD by effectively decreasing lipid levels and improving hepatic steatosis, however its mechanisms remain unclear. This study investigated QGJZF’s effects in high-fat diet-induced zebrafish and golden hamsters, and in palmitate (PA) and oleic acid (OA) - induced HepG2 cells, using the SymMap database to identify potential targets and pathways of QGJZF in MAFLD and AlphaFold algorithms to predict protein structures. <em>In vivo,</em> QGJZF significantly alleviated hepatic lipid deposition. Intriguingly, QGJZF decreased lipid droplets and its levels are negative correlated with the numbers of autolysosomes, indicating that QGJZF’s mechanism of ameliorating liver lipid deposition may be related to the regulation of autophagy. QGJZF upregulated the expressions of phosphorylated -Adenosine 5‘-monophosphate (AMP) - activated protein kinase (p-AMPK), Sirtuin deacetylase 1 (SIRT1) and Transcription factor EB (TFEB), accompanied by the changes in autophagy-related proteins. <em>In vitro</em>, QGJZF inhibited the lipid deposition in PA/OA-stimulated HepG2 cells, and its effect was blocked by an autophagy inhibitor Baf-A1, which was mediated through upregulation of TFEB and its mediated autophagy-lysosomal pathway. Moreover, cotreatment with AMPK inhibitor Compound C, the regulation of QGJZF on TFEB, SIRT1, autophagy-related protein levels, and lipid deposition were reversed. Network pharmacology identified the PRKAA2 (AMPK) and SIRT1 as key hub targets. Futher analysis of their structures using AlphaFold3 algorithms, yielded high-ranking scores of 0.97 and 0.93, respectively. Liquid chromatography-mass spectrometry combined with molecular docking expounded its five compounds in QGJZF binding to AMPK protein. These findings suggest that QGJZF as a therapeutic agent in augmenting autophagy-facilitated lipid clearance for the management of MAFLD via AMPK/SIRT1-TFEB axis.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107617"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143009735","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.2025.107600
Dong-mei Xue, Dan-ni Wang, Jia Yuan, Lan Yao, Ying Bian
{"title":"Sailing south from regulations to strategies: Macau as a promising gateway for the export of proprietary Chinese medicines to ASEAN countries","authors":"Dong-mei Xue, Dan-ni Wang, Jia Yuan, Lan Yao, Ying Bian","doi":"10.1016/j.phrs.2025.107600","DOIUrl":"10.1016/j.phrs.2025.107600","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107600"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143009472","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.2025.107616
Hee-Geun Jo , Jihye Seo , Eunhye Baek , Donghun Lee
<div><h3>Background</h3><div>Notwithstanding progress in conventional medicine (CM), the management of rheumatoid arthritis (RA) continues to be problematic due to factors such as limited patient response to treatment and restricted medication access. This study aimed to evaluate the extent to which East Asian herbal medicine with CM combination therapy (EACM) provides additional benefits in effectiveness and safety.</div></div><div><h3>Methods</h3><div>We conducted a comprehensive search across 11 databases in English, Chinese, Korean, and Japanese for randomized controlled trials. The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, using the American College of Rheumatology (ACR) 20/50/70 Response Criteria and the incidence of adverse events (AEI) as primary outcomes. This meta-analysis was performed using a random-effects model. The quality of each study was assessed according to the RoB 2. Of the 1036 full-text articles screened, 415 were included in the review.</div></div><div><h3>Results</h3><div>This review included data from 37,839 participants. EACM was associated with higher ACR responses: ACR 20 (RR: 1.2332; 95 % CI: 1.1852–1.2831, p < 0.0001), ACR 50 (RR: 1.3782; 95 % CI: 1.2936–1.4684, p < 0.0001), and ACR 70 (RR: 1.7084; 95 % CI: 1.5555–1.8762, p < 0.0001), as well as a favorable AEI (OR: 0.3977; 95 % CI: 0.3476–0.4551, p < 0.0001), indicating both better efficacy and safety compared to CM alone. These patterns were consistent across eight secondary outcomes measuring pain, inflammation, and disease activity in RA. Subgroup analyses showed that EACM's effects were independent of the control CM type. Through a comprehensive analysis of a polyherbal prescription dataset, we identified 18 key herbs and 16 significant combination rules, further supported by relevant preclinical evidence. These herbs and synergistic herbal combinations were anticipated to be the most pharmacologically influential in contributing to the meta-analysis outcomes, as substantiated by analytical metrics including network topology and intricate association pattern evaluations.</div></div><div><h3>Conclusions</h3><div>The findings suggest that EACM may serve as a valuable complementary strategy for RA patients insufficiently managed by CM alone. In particular, given that the ACR index integrates multiple aspects of RA patients, the results are expected to provide valuable complementary decision support for the management of RA patients who do not respond well to CM therapy, both for medical and economic reasons. Additionally, the key herbs derived through the multifaceted analysis, which actively reflect clinicians' implicit preferences for prescribing EACMs, may serve as important hypotheses for further research and clinical application. However, additional qualitative and quantitative improvements in research are needed for more definitive conclusions. Further analysis of the herbal prescriptions p
{"title":"Exploring the benefits and prescribing informations of combining East Asian herbal medicine with conventional medicine in the treatment of rheumatoid arthritis: A systematic review and multifaceted analysis of 415 randomized controlled trials","authors":"Hee-Geun Jo , Jihye Seo , Eunhye Baek , Donghun Lee","doi":"10.1016/j.phrs.2025.107616","DOIUrl":"10.1016/j.phrs.2025.107616","url":null,"abstract":"<div><h3>Background</h3><div>Notwithstanding progress in conventional medicine (CM), the management of rheumatoid arthritis (RA) continues to be problematic due to factors such as limited patient response to treatment and restricted medication access. This study aimed to evaluate the extent to which East Asian herbal medicine with CM combination therapy (EACM) provides additional benefits in effectiveness and safety.</div></div><div><h3>Methods</h3><div>We conducted a comprehensive search across 11 databases in English, Chinese, Korean, and Japanese for randomized controlled trials. The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, using the American College of Rheumatology (ACR) 20/50/70 Response Criteria and the incidence of adverse events (AEI) as primary outcomes. This meta-analysis was performed using a random-effects model. The quality of each study was assessed according to the RoB 2. Of the 1036 full-text articles screened, 415 were included in the review.</div></div><div><h3>Results</h3><div>This review included data from 37,839 participants. EACM was associated with higher ACR responses: ACR 20 (RR: 1.2332; 95 % CI: 1.1852–1.2831, p < 0.0001), ACR 50 (RR: 1.3782; 95 % CI: 1.2936–1.4684, p < 0.0001), and ACR 70 (RR: 1.7084; 95 % CI: 1.5555–1.8762, p < 0.0001), as well as a favorable AEI (OR: 0.3977; 95 % CI: 0.3476–0.4551, p < 0.0001), indicating both better efficacy and safety compared to CM alone. These patterns were consistent across eight secondary outcomes measuring pain, inflammation, and disease activity in RA. Subgroup analyses showed that EACM's effects were independent of the control CM type. Through a comprehensive analysis of a polyherbal prescription dataset, we identified 18 key herbs and 16 significant combination rules, further supported by relevant preclinical evidence. These herbs and synergistic herbal combinations were anticipated to be the most pharmacologically influential in contributing to the meta-analysis outcomes, as substantiated by analytical metrics including network topology and intricate association pattern evaluations.</div></div><div><h3>Conclusions</h3><div>The findings suggest that EACM may serve as a valuable complementary strategy for RA patients insufficiently managed by CM alone. In particular, given that the ACR index integrates multiple aspects of RA patients, the results are expected to provide valuable complementary decision support for the management of RA patients who do not respond well to CM therapy, both for medical and economic reasons. Additionally, the key herbs derived through the multifaceted analysis, which actively reflect clinicians' implicit preferences for prescribing EACMs, may serve as important hypotheses for further research and clinical application. However, additional qualitative and quantitative improvements in research are needed for more definitive conclusions. Further analysis of the herbal prescriptions p","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107616"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040819","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}
Natural resources have been used for food and medicine since the beginning of human civilization, and they have always been a low-cost, easily accessible source for individuals. Northeast region of India (NER) represents a significant portion of India's flora and fauna. Marginality, fragility, inaccessibility, ethnicity, and cultural diversity thrived in the region, resulting in the richest reservoir of genetic variation of bioresources. Several bitter plants are used by the locals as both food and medicine to treat a variety of diseases. These medicinal plants are an excellent source of chemically diverse biologically active phytometabolites. There have been few efforts to raise awareness about health benefits of bitter plant resources abound in this region that may provides opportunities for their sustainable utilization. Understanding the structural features of plant derived bitterants in relationship with specific bitter receptor will provide research prospects to identify biomolecules with health benefits. In this context the present review is intended to deliver phyto-pharmacological aspects of bitter plant resources of NER together with detailed understanding of possible association between plant derived phytometabolites as bitter agonists with extraoral bitter receptors.
{"title":"Therapeutics of bitter plants from Northeast region of India and their pharmacological and phytochemical perspectives","authors":"Bhaskar Das , Bharat Gopalrao Somkuwar , Sushil Kumar Chaudhary , Evanylla Kharlyngdoh , Careen Liza Pakyntein , Kishor Basor , Jitendra Kumar Shukla , Pardeep Kumar Bhardwaj , Pulok Kumar Mukherjee","doi":"10.1016/j.phrs.2025.107626","DOIUrl":"10.1016/j.phrs.2025.107626","url":null,"abstract":"<div><div>Natural resources have been used for food and medicine since the beginning of human civilization, and they have always been a low-cost, easily accessible source for individuals. Northeast region of India (NER) represents a significant portion of India's flora and fauna. Marginality, fragility, inaccessibility, ethnicity, and cultural diversity thrived in the region, resulting in the richest reservoir of genetic variation of bioresources. Several bitter plants are used by the locals as both food and medicine to treat a variety of diseases. These medicinal plants are an excellent source of chemically diverse biologically active phytometabolites. There have been few efforts to raise awareness about health benefits of bitter plant resources abound in this region that may provides opportunities for their sustainable utilization. Understanding the structural features of plant derived bitterants in relationship with specific bitter receptor will provide research prospects to identify biomolecules with health benefits. In this context the present review is intended to deliver phyto-pharmacological aspects of bitter plant resources of NER together with detailed understanding of possible association between plant derived phytometabolites as bitter agonists with extraoral bitter receptors.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107626"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143059334","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.2024.107566
Ruohan Zhao , Jingwen Wang , Sookja Kim Chung , Baojun Xu
Depression is one of the most common psychological disorders, and due to its high prevalence and mortality rates, it imposes a significant disease burden. Contemporary treatments for depression involve various synthetic drugs, which have limitations such as side effects, single targets, and slow onset of action. Unlike synthetic medications, phytochemicals offer the benefits of a multi-target and multi-pathway mode of treatment for depression. In this literature review, we describe the pharmacological actions, experimental models, and clinical trials of the antidepressant effects of various phytochemicals. Additionally, we summarize the potential mechanisms by which these phytochemicals prevent depression, including regulating neurotransmitters and their receptors, the HPA axis, inflammatory responses, managing oxidative stress, neuroplasticity, and the gut microbiome. Phytochemicals exert therapeutic effects through multiple pathways and targets, making traditional Chinese medicine (TCM) a promising adjunctive antidepressant for the prevention, alleviation, and treatment of depression. Therefore, this review aims to provide robust evidence for subsequent research into developing phytochemical resources as effective antidepressant agents.
{"title":"New insights into anti-depression effects of bioactive phytochemicals","authors":"Ruohan Zhao , Jingwen Wang , Sookja Kim Chung , Baojun Xu","doi":"10.1016/j.phrs.2024.107566","DOIUrl":"10.1016/j.phrs.2024.107566","url":null,"abstract":"<div><div>Depression is one of the most common psychological disorders, and due to its high prevalence and mortality rates, it imposes a significant disease burden. Contemporary treatments for depression involve various synthetic drugs, which have limitations such as side effects, single targets, and slow onset of action. Unlike synthetic medications, phytochemicals offer the benefits of a multi-target and multi-pathway mode of treatment for depression. In this literature review, we describe the pharmacological actions, experimental models, and clinical trials of the antidepressant effects of various phytochemicals. Additionally, we summarize the potential mechanisms by which these phytochemicals prevent depression, including regulating neurotransmitters and their receptors, the HPA axis, inflammatory responses, managing oxidative stress, neuroplasticity, and the gut microbiome. Phytochemicals exert therapeutic effects through multiple pathways and targets, making traditional Chinese medicine (TCM) a promising adjunctive antidepressant for the prevention, alleviation, and treatment of depression. Therefore, this review aims to provide robust evidence for subsequent research into developing phytochemical resources as effective antidepressant agents.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107566"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142922480","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.2025.107593
Yuxi Zhou , Shiqian Huang , Tianhao Zhang , Daling Deng , Li Huang , Xiangdong Chen
General anesthesia is administered to millions of individuals each year, however, the precise mechanism by which it induces unconsciousness remains unclear. While some theories suggest that anesthesia shares similarities with natural sleep, targeting sleep-promoting areas and inhibiting arousal nuclei, recent research indicates a more complex process. Emerging evidence highlights the critical role of corticothalamocortical circuits, which are involved in higher cognitive functions, in controlling arousal states and modulating transitions between different conscious states during anesthesia. The administration of general anesthetics disrupts connectivity within these circuits, resulting in a reversible state of unconsciousness. This review elucidates how anesthetics impair corticothalamocortical interactions, thereby affecting the flow of information across various cortical layers and disrupting higher-order cognitive functions while preserving basic sensory processing. Additionally, the role of the prefrontal cortex in regulating arousal through both top-down and bottom-up pathways was examined. These findings highlight the intricate interplay between the cortical and subcortical networks in maintaining and restoring consciousness under anesthesia, offering potential therapeutic targets for enhancing anesthesia management.
{"title":"Deciphering consciousness: The role of corticothalamocortical interactions in general anesthesia","authors":"Yuxi Zhou , Shiqian Huang , Tianhao Zhang , Daling Deng , Li Huang , Xiangdong Chen","doi":"10.1016/j.phrs.2025.107593","DOIUrl":"10.1016/j.phrs.2025.107593","url":null,"abstract":"<div><div>General anesthesia is administered to millions of individuals each year, however, the precise mechanism by which it induces unconsciousness remains unclear. While some theories suggest that anesthesia shares similarities with natural sleep, targeting sleep-promoting areas and inhibiting arousal nuclei, recent research indicates a more complex process. Emerging evidence highlights the critical role of corticothalamocortical circuits, which are involved in higher cognitive functions, in controlling arousal states and modulating transitions between different conscious states during anesthesia. The administration of general anesthetics disrupts connectivity within these circuits, resulting in a reversible state of unconsciousness. This review elucidates how anesthetics impair corticothalamocortical interactions, thereby affecting the flow of information across various cortical layers and disrupting higher-order cognitive functions while preserving basic sensory processing. Additionally, the role of the prefrontal cortex in regulating arousal through both top-down and bottom-up pathways was examined. These findings highlight the intricate interplay between the cortical and subcortical networks in maintaining and restoring consciousness under anesthesia, offering potential therapeutic targets for enhancing anesthesia management.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107593"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142952901","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}
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