{"title":"Berbamine targets the FKBP12-rapamycin-binding (FRB) domain of the mTOR complex to promote microglial autophagy and ameliorate neuroinflammation in Alzheimer’s disease","authors":"Pingyuan Ge , Siqi Guo , Pingping Wang , Peng Zhou , Zhishu Tang , Nianyun Yang , Rui Guo , Qingqing Xiao , Xin Chai , Qichun Zhang , Huaxu Zhu","doi":"10.1016/j.phymed.2025.156771","DOIUrl":"10.1016/j.phymed.2025.156771","url":null,"abstract":"<div><h3>Background</h3><div>Berbamine (BBM), a natural bisbenzylisoquinoline alkaloid, has demonstrated promising effects in ameliorating pathological process and inflammation response in central neuronal system (CNS). Alzheimer’s disease (AD), primarily characterized by amyloid-beta (Aβ)-containing extra-cellular plaques and abnormal “autophagy-brake regulation” of neuroinflammation, currently lacks of effective therapeutic options. Therapeutics of BBM on AD is indeed intriguing, and the potential targets and mechanisms are vague yet.</div></div><div><h3>Purpose</h3><div>This study is designed to elucidate the therapeutic potential of BBM on AD, focusing particularly on its ability to enhance autophagy, induce microglial M2 polarization, and to uncover the underlying molecular mechanisms and implicated targets.</div></div><div><h3>Methods</h3><div>The therapeutic efficacy of BBM was systematically investigated in APP/PS1 mice, with a focus on its potential to enhance autophagy, induce M2 polarization in microglia, and facilitate the clearance of Aβ plaques. Cognitive function was rigorously assessed through a series of behavioral tests, including the Morris Water Maze and Object Location Task. Immunofluorescence was employed to visualize the spatial distribution of inflammatory cytokines and autophagic markers within the brain parenchyma. Quantitative measurements of these cytokines were obtained using enzyme-linked immunosorbent assay (ELISA). Western blotting was utilized to analyze protein profiles associated with autophagy and microglial phenotypes. Additionally, chemo-proteomics and molecular docking techniques were applied to identify the key molecular targets of BBM.</div></div><div><h3>Results</h3><div>BBM treatment significantly ameliorated cognitive dysfunction and reduced Aβ plaque deposition in APP/PS1 transgenic mice. Notably, BBM promoted microglial polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, accompanied by attenuation of neuroinflammation. Mechanistically, BBM exerted its effects through inhibition of mTOR signaling via direct interaction with the FKBP12-rapamycin-binding domain, thereby restoring autophagic flux and facilitating M2 microglial polarization. The mTOR activator MHY1485 abrogated the beneficial effects of BBM, highlighting the pivotal role of mTOR inhibition in its mechanism of action.</div></div><div><h3>Conclusions</h3><div>BBM promotes M2 microglial polarization and restores autophagic flux in AD by inhibiting mTOR signaling, representing a novel dual-modulatory mechanism for AD intervention. These findings highlight BBM’s ability to target mTOR and intersecting pathways, offering a promising disease-modifying therapeutic approach for AD and other neurodegenerative disorders.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"142 ","pages":"Article 156771"},"PeriodicalIF":6.7,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143868391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PhytomedicinePub Date : 2025-04-16DOI: 10.1016/j.phymed.2025.156775
Hanrui Ji , Zhizhi Dong , Yanan Yang , Wenqiang Cui , Jingbo Han , Yibin Hu , Haonan Chen , Chongxuan Qiao , Qingxiao Li , He Li , Shengxian Wu
{"title":"Neixiao-ruanmai decoction No 2 improves carotid atherosclerosis by modulating gut microbiota and inhibiting TLR4/NF-κB pathway activation","authors":"Hanrui Ji , Zhizhi Dong , Yanan Yang , Wenqiang Cui , Jingbo Han , Yibin Hu , Haonan Chen , Chongxuan Qiao , Qingxiao Li , He Li , Shengxian Wu","doi":"10.1016/j.phymed.2025.156775","DOIUrl":"10.1016/j.phymed.2025.156775","url":null,"abstract":"<div><h3>Background</h3><div>Carotid atherosclerosis(CAs) plaques are challenging to reverse. Neixiao-Ruanmai Decoction No 2(NXRMT No 2), a Traditional Chinese Medicine (TCM) decoction, has shown potential in treating CAs. However, while preliminary clinical trials have confirmed the efficacy of NXRMT No 2 in improving CAs, the comparative effectiveness of long-term versus short-term treatment courses remains unclear, and the underlying mechanisms of this decoction are not yet fully understood.</div></div><div><h3>Methods</h3><div>We conducted clinical trials, animal studies, 16S rRNA sequencing, metabolomics and fecal microbiota transplantation.</div></div><div><h3>Result</h3><div>Clinical research results indicate that NXRMT No 2(24 weeks of treatment) reduced total plaque area by 22.02%, maximum plaque thickness by 7.91%, and maximum plaque area by 21.29%. NXRMT No 2 improves patients’serum inflammatory levels, with a 24-week treatment course demonstrated superior efficacy compared to the 12-week treatment. Animal experiments demonstrated that NXRMT No 2 improved CAs progression, modulated the gut microbiota, inhibited the intestinal Toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) pathway and activated the expression of intestinal tight junction proteins.</div></div><div><h3>Conclusion</h3><div>NXRMT No 2 significantly attenuates CAs progression, with its primary mechanism likely related to modulating the gut microbiota to counteract the TLR4/NF-κB pathway and protect the intestinal barrier. This study provides evidence-based support for the use of NXRMT No 2 in treating CAs, offers guidance on optimal treatment duration for patients, and contributes to the development of traditional Chinese medicine formulations that improve CAs by modulating the gut microbiota—a significant advance in the prevention and treatment of CAs.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"142 ","pages":"Article 156775"},"PeriodicalIF":6.7,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143868326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PhytomedicinePub Date : 2025-04-16DOI: 10.1016/j.phymed.2025.156769
Lin Li , Huiqin Hu , Weifeng Jiang, Shihui Mao, Zheng Yang, Ting Lan, Xiaowei Hu, Yan Fang, Lanxi Xu, Jiadong Xu, Yan Yang, Weiru Jiang, Lisheng Chu
{"title":"Artemisinin alleviates ischemic stroke injury and promotes neurogenesis through PPARγ-mediated M2 polarization of microglia","authors":"Lin Li , Huiqin Hu , Weifeng Jiang, Shihui Mao, Zheng Yang, Ting Lan, Xiaowei Hu, Yan Fang, Lanxi Xu, Jiadong Xu, Yan Yang, Weiru Jiang, Lisheng Chu","doi":"10.1016/j.phymed.2025.156769","DOIUrl":"10.1016/j.phymed.2025.156769","url":null,"abstract":"<div><h3>Background</h3><div>Ischemic stroke (IS) remains a challenge in clinical treatment due to limited therapeutic options. While artemisinin (ART), an antimalarial drug, shields against acute IS via anti-inflammatory, antioxidant, and anti-apoptotic properties, the long-term benefits and specific underlying mechanisms have not been fully elucidated. Here, we investigate whether ART ameliorates IS injury and promotes neurogenesis by activating the peroxisome proliferator-activated receptor γ (PPARγ)-dependent M2 microglial polarization.</div></div><div><h3>Methods</h3><div>The experimental models included transient middle cerebral artery occlusion/reperfusion (MCAO/R) in rats and oxygen-glucose deprivation/reoxygenation (OGD/R) in primary microglial cultures to simulate IS. The therapeutic effects of ART were evaluated by neurological functions and infarct volume. PPARγ inhibitor T0070907 (T007) was intraperitoneally injected 24 h following MCAO/R at a dose of 2 mg/kg in vivo and a concentration of 10 μM for 30 min before OGD in vitro. We utilized real-time quantitative polymerase chain reaction (RT-qPCR) along with Western blot analyses to detect the microglia markers and PPARγ. The proliferation and differentiation of neural stem cells (NSCs) both in vivo and in vitro were assessed via immunofluorescence labeling. The neurogenic potential of ART-treated microglia was investigated by conditioned medium. The levels of brain-derived growth factor (BDNF) and insulin-like growth factor-1 (IGF-1) in microglia were measured by immunofluorescence staining and enzyme-linked immunosorbent assay (ELISA).</div></div><div><h3>Results</h3><div>ART treatment significantly alleviated short- and long-term neurological deficits and reduced cerebral infarct volume in rats with IS. Experiments conducted both in vivo and in vitro experiments illustrated that ART directed microglia away from the pro-inflammatory M1 state towards the anti-inflammatory M2 state, enhanced neurogenesis, and upregulated the expression of PPARγ, BDNF, and IGF-1. In addition, the conditioned medium from ART-exposed microglia stimulated the proliferation and neuronal differentiation of primary NSCs. However, these positive effects were effectively counteracted by the use of PPARγ inhibitor T0070907 (T007).</div></div><div><h3>Conclusion</h3><div>Our findings demonstrate that ART ameliorates IS injury and promotes neurogenesis mainly through PPARγ-mediated microglia M2 polarization. Therefore, ART can be considered a potential therapeutic drug for IS.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"142 ","pages":"Article 156769"},"PeriodicalIF":6.7,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143868322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PhytomedicinePub Date : 2025-04-15DOI: 10.1016/j.phymed.2025.156772
Yi Chen , Hongming Huang , Yuelian Luo , Haoyang Wu , Wenting Deng , Xin Min , Huilin Lao , Hao Xiong
{"title":"Senolytic treatment alleviates cochlear senescence and delays age-related hearing loss in C57BL/6J mice","authors":"Yi Chen , Hongming Huang , Yuelian Luo , Haoyang Wu , Wenting Deng , Xin Min , Huilin Lao , Hao Xiong","doi":"10.1016/j.phymed.2025.156772","DOIUrl":"10.1016/j.phymed.2025.156772","url":null,"abstract":"<div><h3>Background</h3><div>Age-related hearing loss (ARHL) is a prevalent sensory deficit that significantly affects quality of life in older individuals. Cellular senescence contributes to various age-related degenerative disorders. However, its effect on ARHL remains unclear.</div></div><div><h3>Purpose</h3><div>The aim of this study was to explore the therapeutic potential of senolytics in attenuating cochlear senescence and delaying the progression of ARHL.</div></div><div><h3>Methods</h3><div>The senolytic drugs dasatinib and quercetin (D + Q) were used to target senescent cells at different stages of ARHL in C57BL/6J mice. The impact of D + Q treatment on ARHL progression and cochlear degeneration was also assessed. Additionally, the protective effects of D + Q treatment were evaluated in HEI-OC1 auditory cells and cochlear explants. Transcriptomic analysis was conducted on cochlear explants subjected to different treatments.</div></div><div><h3>Results</h3><div>D + Q treatment at an early stage of ARHL significantly delayed ARHL progression and alleviated cochlear degeneration in male and female C57BL/6J mice. Treatment of mice with normal hearing also mitigated age-related hair cell loss. In HEI-OC1 auditory cells, D + Q treatment exerted protective effects by alleviating the senescence-associated secretory phenotype (SASP). Transcriptomic analysis of cochlear explants revealed that downregulation of inflammatory cytokines and chemokines was involved in the beneficial effects of D + Q treatment against cellular senescence. Mechanistically, D + Q treatment alleviated hair cell senescence via binding to NF-κB and inhibiting its activity.</div></div><div><h3>Conclusion</h3><div>Senolytics may offer a novel therapeutic strategy for attenuating cochlear senescence and slowing the progression of ARHL.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"142 ","pages":"Article 156772"},"PeriodicalIF":6.7,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143848695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PhytomedicinePub Date : 2025-04-14DOI: 10.1016/j.phymed.2025.156731
Qing Kong , Suqing Liu , Shan He , Zhuyu Luo , Rui Lei , Ruilong Wang , Xiao Liu , Jinfeng Wu
{"title":"Celastrol enhanced CD8+T cell immunity in melanoma by targeting SHP2 and upregulating MHC-I","authors":"Qing Kong , Suqing Liu , Shan He , Zhuyu Luo , Rui Lei , Ruilong Wang , Xiao Liu , Jinfeng Wu","doi":"10.1016/j.phymed.2025.156731","DOIUrl":"10.1016/j.phymed.2025.156731","url":null,"abstract":"<div><h3>Background</h3><div>Celastrol (CEL) has demonstrated promising anti-cancer properties, yet its specific mechanisms against melanoma remain insufficient. This study investigated the CEL's anti-tumor effects and determined its potential mechanisms in the regulation of MHC-I expression in melanoma. In addition, we also tested its efficacy in sensitizing immune checkpoint inhibitors (ICIs) to melanoma.</div></div><div><h3>Methods</h3><div>CEL's anti-tumor activity was evaluated in B16F10 melanoma-bearing C57BL/6 mice across five groups (control, CEL 0.5 mg/kg, CEL 1 mg/kg, CEL 2 mg/kg, and ICIs), the tumor volume, histopathology, and body weight were assessed. Mechanistic insights were obtained through network pharmacology and RNA sequencing in B16F10 cells. Differential gene and pathway analysis were validated using qRT-PCR, Western blotting, and flow cytometry. CD8+<em>T</em> cell activation and cytotoxicity were analyzed in co-culture with CEL-pretreated B16F10 cells using flow cytometry and ELISA. CEL's interaction with potential targets was determined by molecular docking, surface plasmon resonance (SPR), and siRNA. The synergistic effect of CEL combined with ICIs was confirmed in B16F10-bearing C57BL/6 mice, and tumor-infiltrating T cells were assessed by flow cytometry across four groups (control, CEL, ICIs, CEL+ICIs).</div></div><div><h3>Results</h3><div>CEL exhibited a significant anti-tumor effect in B16F10 melanoma-bearing mice. Mechanistically, CEL-pretreated B16F10 cells notably enhanced CD8+<em>T</em> cell activation and promoted IFNγ and TNFα secretion, leading to B16F10 cell death. CEL upregulated MHC-I expression through activation of the JAK/STAT1 pathway in B16F10 cells. The binding assay revealed that CEL interacted with SHP2, with an affinity of 37.93 μM. When SHP2 was silenced in B16F10 cells by siRNA, CEL failed to induce MHC-I upregulation. Moreover, CEL combined with ICIs produced superior antitumor efficacy compared to ICIs alone, which was accompanied by increased CD8+<em>T</em> cell infiltration in melanoma.</div></div><div><h3>Conclusion</h3><div>CEL enhanced CD8+<em>T</em> cell immunity by upregulating MHC-I expression in melanoma cells, these effects were at least partially through targeting SHP2 and activating JAK/STAT1 pathway. CEL might be a novel sensitizer for ICIs in melanoma.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"142 ","pages":"Article 156731"},"PeriodicalIF":6.7,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143868324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PhytomedicinePub Date : 2025-04-14DOI: 10.1016/j.phymed.2025.156765
Liyu Lin , Daoqi Shen , Yiqi Su , Zhen Zhang , Jinbo Yu , Chenqi Xu , Kunming Pan , Yaqiong Wang , Lin Zhang , Shi Jin , Nana Song , Xiaoqiang Ding , Jie Teng , Xialian Xu
{"title":"Magnesium Lithospermate B Protects Against Ischemic AKI-to-CKD progression via regulating the KLF5/CDK1/Cyclin B1 pathway","authors":"Liyu Lin , Daoqi Shen , Yiqi Su , Zhen Zhang , Jinbo Yu , Chenqi Xu , Kunming Pan , Yaqiong Wang , Lin Zhang , Shi Jin , Nana Song , Xiaoqiang Ding , Jie Teng , Xialian Xu","doi":"10.1016/j.phymed.2025.156765","DOIUrl":"10.1016/j.phymed.2025.156765","url":null,"abstract":"<div><h3>Background</h3><div>Ischemia-reperfusion injury (IRI) is the primary cause of acute kidney injury (AKI), which can result in chronic kidney disease (CKD) with renal fibrosis. Magnesium lithospermate B (Mlb), a bioactive compound produced from <em>Salvia miltiorrhiza Bunge</em>, exerts nephroprotective effects against AKI. However, the significance of Mlb in the evolution of IRI-induced AKI in patients with CKD remains unclear. Notably, the specific mechanisms underlying the putative antifibrotic activities of Mlb during this progression remain to be fully elucidated.</div></div><div><h3>Purpose</h3><div>This study sought to explore the therapeutic benefits of Mlb in AKI-to-CKD progression and uncover the potential mechanisms, with a special interest in its effects on renal fibrosis and cell cycle regulation.</div></div><div><h3>Study design and methods</h3><div>Unilateral ischemia/reperfusion (UIR)-induced mouse AKI-to-CKD progression (in vivo) and HK-2 cells with TGF-β-induced fibrosis model (in vitro) were used in the study. The beneficial effects of Mlb on renal fibrosis and cell cycle-related signaling pathways were investigated using histological analysis, molecular assays, network pharmacology, and RNA sequencing.</div></div><div><h3>Results</h3><div>Mlb treatment significantly reduced renal dysfunction, inflammation, apoptosis, and the G2/M phase cell cycle stalling in mice 14 days post-UIR-induced AKI, subsequently improving renal fibrosis. Mechanistically, Mlb promotes the activity of the CDK1/Cyclin B1 signaling pathway, thereby alleviating the G2/M phase cell cycle stalling. Network pharmacology and RNA sequencing analyses identified the KLF5/CDK1/Cyclin B1 signaling pathway as a potential target of the antifibrotic effects of Mlb, which was further verified in both in vivo and in vitro experiments. The KLF5 inhibitor ML264 attenuated the protective effects of Mlb by reducing CDK1/Cyclin B1 expression and reinstating the G2/M phase cell cycle stalling, highlighting the critical role of this pathway in Mlb-mediated renal protection.</div></div><div><h3>Conclusions</h3><div>Mlb decreases renal fibrosis by inhibiting the G2/M phase cell cycle stalling via the KLF5/CDK1/Cyclin B1 signaling pathway during AKI-to-CKD progression. Our findings offer new insight into the therapeutic potential of Mlb in preventing CKD progression following AKI and identify a previously unrecognized mechanism involving the KLF5/CDK1/Cyclin B1 pathway.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"142 ","pages":"Article 156765"},"PeriodicalIF":6.7,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143851657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PhytomedicinePub Date : 2025-04-14DOI: 10.1016/j.phymed.2025.156748
Qianqian Yao , Rui Wang , Hailin Wang , Ding Yuan , Chengfu Yuan
{"title":"Total saponins from Panax japonicus alleviate insulin resistance via exosomal miR204/Elovl6-mediated adipocyte–macrophage crosstalk","authors":"Qianqian Yao , Rui Wang , Hailin Wang , Ding Yuan , Chengfu Yuan","doi":"10.1016/j.phymed.2025.156748","DOIUrl":"10.1016/j.phymed.2025.156748","url":null,"abstract":"<div><h3>Background</h3><div>Insulin resistance (IR) is a key factor in the development of type 2 diabetes, and M2-like macrophages are important in maintaining normal glucose homeostasis. Our previous research has demonstrated that the total saponins from <em>Panax japonicus</em> (TSPJ) reduce IR in adipocytes and promote the M2 polarization of macrophages, but the molecular mechanism is unclear.</div></div><div><h3>Purpose</h3><div>In the study, we aimed to elucidate whether TSPJ mitigate IR by enhancing the intercellular communication between adipocytes and macrophages and describe how the exosomes from bone marrow-derived macrophages (BMDMs) modulate the insulin sensitivity of adipocytes via miR204.</div></div><div><h3>Methods</h3><div>We used both <em>in vitro</em> and <em>in vivo</em> models to study the effects of TSPJ on IR, with a particular emphasis on the exosomes from M2-type BMDMs. Furthermore, we investigated the mechanisms by which exosomal miR204 and its downstream target <em>Elovl6</em> influence IR in an obese mouse model, as well as in adipocytes with double inhibition of miR204 and <em>Elovl6</em>.</div></div><div><h3>Results</h3><div>In the animal model, TSPJ significantly increased miR204 expression in BMDMs-derived exosomes and decreased the level of <em>Elovl6</em> in adipocytes. However, when the C75BL/6 mice had miR204 ablation, TSPJ became less capable of enhancing insulin sensitivity, and the expressions of <em>Irs1, Insr</em>, and <em>Slc2a4</em> in the adipose tissue decreased. In the cell model where the macrophages carried miR204 ablation and the adipocytes had <em>Elovl6</em> knockdown, the expressions of IR-related genes increased in the adipocytes.</div></div><div><h3>Conclusions</h3><div>TSPJ mitigated IR through adipocyte–BMDM crosstalk mediated by exosomes via the miR204/<em>Elovl6</em> pathway.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"142 ","pages":"Article 156748"},"PeriodicalIF":6.7,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143850250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PhytomedicinePub Date : 2025-04-14DOI: 10.1016/j.phymed.2025.156764
Xuan Wan , Pengchao Xu , Xing Zhou , Jiangyuan Liu , Yiwen Yang , Chaoyi Liang , Jinglei Wang , Weixiang Wang , Fengjiao Xu , Xiaoming Wan , Jian Kang , Peijian Tong , Hanting Xia
{"title":"Qi-Gu capsule alleviates osteoporosis by inhibiting mesenchymal stem cell senescence via the HIF-1α/AMPK axis","authors":"Xuan Wan , Pengchao Xu , Xing Zhou , Jiangyuan Liu , Yiwen Yang , Chaoyi Liang , Jinglei Wang , Weixiang Wang , Fengjiao Xu , Xiaoming Wan , Jian Kang , Peijian Tong , Hanting Xia","doi":"10.1016/j.phymed.2025.156764","DOIUrl":"10.1016/j.phymed.2025.156764","url":null,"abstract":"<div><h3>Background</h3><div>Osteoporosis (OP) represents a systemic disease causing reduced bone mass and fragility fractures. Qigu Capsule (QGC), a traditional Chinese medicine, shows potential in alleviating human OP, but its precise mechanisms remain unclear, limiting clinical application.</div></div><div><h3>Methods</h3><div>The bioactive components of QGC were analyzed using high-performance liquid chromatography (HPLC). An ovariectomy (OVX)-provoked OP rat model was established to evaluate QGC's effects on bone mass, trabecular architecture, and mechanical strength using micro-CT, histological staining, and biomechanical testing. RNA-seq analysis of human OP-derived mesenchymal stem cell (MSC) samples was performed to identify oxidative stress (OxS)- and senescence-associated gene changes. OxS-induced MSC senescence was modeled <em>in vitro</em> using H₂O₂, and QGC's effects on MSC proliferation, migration, and osteogenic differentiation were assessed. Network pharmacology (NP) was deployed to predict the key mechanisms behind the QGC treatment of OP. Further mechanistic studies utilized pharmacological inhibitors and siRNA-mediated gene knockdown to confirm the involvement of critical signaling pathways.</div></div><div><h3>Results</h3><div>HPLC-MS analysis identified 505 unique bioactive compounds in QGC. <em>In vivo</em>, QGC significantly improved BMD, enhanced trabecular microarchitecture, and restored mechanical properties in OVX rats. ELISA, histological, and immunohistochemical analyses confirmed that QGC primarily enhanced osteoblast activity. RNA-seq analysis of GEO datasets revealed upregulation of senescence and OxS markers (P53, CDKN1A, and INOS) in human OP-derived MSCs. Both <em>in vivo</em> and <em>in vitro</em> QGC alleviated OxS-induced MSC senescence, reduced reactive oxygen species (ROS) levels, suppressed senescence and OxS marker, and promoted MSC proliferation, migration, and osteogenic differentiation. Moreover, NP predicted HIF-1α signaling as critical in QGC's regulation of MSC function during OP. Mechanistic studies demonstrated that QGC activated the HIF-1α/AMPK axis, and inhibition of either HIF-1α or AMPK abolished its therapeutic effects.</div></div><div><h3>Conclusion</h3><div>QGC mitigates OxS-induced MSC senescence and promotes osteogenesis through the HIF-1α/AMPK axis, highlighting its mechanistic basis in treating OP. These findings show QGC's potential as a therapeutic agent, not only by promoting osteogenesis but also by complementing or serving as an alternative to current OP treatments, offering valuable prospects for enhanced clinical management.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"142 ","pages":"Article 156764"},"PeriodicalIF":6.7,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143848696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PhytomedicinePub Date : 2025-04-14DOI: 10.1016/j.phymed.2025.156742
Fengting Yin , Ping Li , Chang Liu , Ying Zheng , Guangli Yan , Mengmeng Wang , Yuhang Wang , Xiangmei Chen , Xiaotong Yan , Jinwei Han , Hui Sun , Shihan Guan , Xijun Wang
{"title":"Spatially resolved multi-omics reveals the renal cortex-metabolic reprogramming of Shenhua Tablet for intervention on IgA nephropathy","authors":"Fengting Yin , Ping Li , Chang Liu , Ying Zheng , Guangli Yan , Mengmeng Wang , Yuhang Wang , Xiangmei Chen , Xiaotong Yan , Jinwei Han , Hui Sun , Shihan Guan , Xijun Wang","doi":"10.1016/j.phymed.2025.156742","DOIUrl":"10.1016/j.phymed.2025.156742","url":null,"abstract":"<div><h3>Background</h3><div>Shenhua tablet (SHT) is a clinically used Chinese patent medicine, which has garnered attention for its effectiveness in treating IgA nephropathy (IgAN). Nevertheless, early researches lacked anatomical and metabolic data, hindering a comprehensive understanding of the therapeutic mechanisms of SHT in spatial contexts.</div></div><div><h3>Purpose</h3><div>We aimed to explore the molecular mechanism of SHT intervention in IgAN by utilizing spatial multi-omics strategies.</div></div><div><h3>Study design</h3><div>We injected Thy-1 into tail vein to induce IgAN rat model and administer SHT. Classical pharmacological parameters were used to evaluate the efficacy of SHT. The distribution of active components of SHT and their regulation for metabolites and upstream genes in the cortex were examined to determine the intervention mechanism of SHT.</div></div><div><h3>Methods</h3><div>After establishing the animal models and administering SHT treatment, Kidney injury were assessed using biochemical indexes and histopathology. Classical and spatial metabolomics were employed to detect metabolites in serum and kidney. Spatial transcriptomics was used to detect mRNA levels in renal sections adjacent to the spatial metabolomics. In addition, mass-spectrometry-imaging and cell experiments were used to explore and verify the active components of SHT.</div></div><div><h3>Results</h3><div>SHT reduced inflammation and mesangial cell proliferation, and reversed kidney damage. Mechanically, in renal tubules, SHT regulated glutathione metabolism by reversing the expression of Gclc and Gpx3. It was further found that Pck1 and G6pc1 were increased to inhibit glycolysis. In glomeruli, SHT downregulated Oat and Odc1 and reduced spermidine and l-proline levels to inhibit mesangial cell proliferation. Finally, formononetin, calycosin and curzerenone were identified as the main active components of SHT and showed their distribution in the cortex.</div></div><div><h3>Conclusions</h3><div>SHT ameliorated renal injury by regulating glutathione metabolism, glycolysis, and l-proline metabolism, providing a more comprehensive insight into the molecular mechanisms of SHT intervention in IgAN in a spatial context, and offering new perspectives for the treatment of IgAN.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"141 ","pages":"Article 156742"},"PeriodicalIF":6.7,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143828766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PhytomedicinePub Date : 2025-04-13DOI: 10.1016/j.phymed.2025.156768
Sha Long , Lu Wang , Qi Zeng , Yaoyao Li , Jiangtao Su , Yuxin Chen , Gao Zhou
{"title":"Exochorda racemosa attenuates DSS-induced colitis in C57BL/6 J mice by regulating inflammatory factors, reducing oxidative stress, and modulating intestinal flora","authors":"Sha Long , Lu Wang , Qi Zeng , Yaoyao Li , Jiangtao Su , Yuxin Chen , Gao Zhou","doi":"10.1016/j.phymed.2025.156768","DOIUrl":"10.1016/j.phymed.2025.156768","url":null,"abstract":"<div><h3>Background</h3><div>Exochorda racemosa is a member of the genus Exochorda in the Rosaceae family. Its tender leaves and buds are favored as a unique wild vegetable by people in central China.</div></div><div><h3>Purpose</h3><div>This study systematically evaluated the pharmacological safety and anti-inflammatory efficacy of <em>E. racemosa</em> extracts, with concurrent identification and characterization of their primary bioactive components.</div></div><div><h3>Methods</h3><div>The chemical composition of <em>E. racemosa</em> extract (ERE) was analyzed using HPLC and LC-MS techniques. The safety and <em>in vivo</em> anti-inflammatory effects of ERE were evaluated using the maximum tolerated dose (MTD) in ICR mice and a dextran sodium sulfate-induced ulcerative colitis model in C57BL/6 J mice.</div></div><div><h3>Results</h3><div>HPLC and LC-MS analyses revealed that ERE contained abundant flavonoid active ingredients. MTD study confirmed that ERE exhibited good safety. The symptoms of persistent weight loss, DAI, and shortened colon length in UC mice were suppressed by ERE. Pathological damage in colon tissues was attenuated by ERE, with a considerable reduction in histopathological scores and a substantial increase in the number of goblet cells. The levels of IL-6, IL-1β, and TNF-α in serum were significantly decreased following ERE treatment. Moreover, nitric oxide (NO) levels and myeloperoxidase (MPO) activity in colon tissues decreased, whereas glutathione (GSH) levels and superoxide dismutase (SOD) activity in colon tissues increased after ERE treatment. Furthermore, ERE could regulate the intestinal microbial composition and maintain intestinal flora homeostasis, thereby inhibiting inflammatory responses.</div></div><div><h3>Conclusion</h3><div>ERE exhibited a favorable safety profile and alleviated UC through multiple mechanisms. It is expected to serve as a promising low-toxicity natural product for adjuvant treatment in UC.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"142 ","pages":"Article 156768"},"PeriodicalIF":6.7,"publicationDate":"2025-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143838213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}