Phytomedicine最新文献

{"title":"Exploring the mechanism of Ling-Gui-Zhu-Gan decoction in metabolic cardiomyopathy via inhibiting ferroptosis.","authors":"Chuan-Zhi Zhao, Hui-Min Ding, Zi-Qing Hu, Lan Zhou, Yong-Qin Du, Peng Zhou, Liang Wang","doi":"10.1016/j.phymed.2024.156234","DOIUrl":"10.1016/j.phymed.2024.156234","url":null,"abstract":"<p><strong>Objective: </strong>This study was to investigate the mechanism of Ling-Gui-Zhu-Gan decoction (LGZGD) in regulating lipid metabolism and thus inhibiting ferroptosis.</p><p><strong>Methods: </strong>UPLC for the determination of the main chemical composition of LGZGD. A HF-induced rat model of metabolic cardiomyopathy was established. Echocardiography was used to detect cardiac function. Serum lipid levels, myocardial injury markers, and lipid peroxidation levels were detected. Pathological changes were detected. Lipid deposition was assessed by oil red O, and the mitochondrial ultrastructure was observed by electron microscopy. Mechanistically, PLIN5, CD36, ATGL, GPX4, ACSL4, FPN1, DRP1, MFF, FIS1, and OPA1 expressions were examined. After PA-induced H9c2 cells established, apoptosis, myocardial injury markers, and lipid peroxidation levels were detected and lipid deposition levels were assessed. The expressions of PLIN5, CD36, ATGL, GPX4, ACSL4 and FPN1 were detected. H9c2 cardiomyocytes with transient knockdown of PLIN5 and overexpression of PLIN5 were constructed and treated with drug administration and modeling, and the apoptosis level was detected by flow cytometry, the levels of lipid peroxidation and ROS were detected by fluorescence, and the protein and gene expressions of ACSL4 and GPX4 were detected. Results The main active components of LGZGD were liquiritin, isoliquiritin, cinnamic acid, cinnamaldehyde, glycyrrhizic acid, and atractylenolide III. LGZGD significantly improved cardiac dysfunction, lowered lipid level and lipid deposition, reduced CK, NT-proBNP and MDA levels, restored SOD levels, and improved inflammatory cell infiltration as well as collagen fiber deposition. LGZGD decreased the expression of PLIN5, CD36, ACSL4, and increased the expression of ATGL, GPX4, and FPN1. LGZGD also decreased the gene expression of DRP1, MFF, FIS1, and increased OPA1 expression. LGZGD significantly ameliorated PA-induced apoptosis, decreased lipid deposition, lowered lipid peroxidation levels and CK level, decreased PLIN5, CD36, and ACSL4 expressions, and increased ATGL, GPX4, and FPN1 expressions. LGZGD reversed cardiomyocyte injury aggravated by transient knockdown of PLIN5, decreased apoptosis levels, lipid peroxidation levels, ROS levels, and ACSL4 expressions, and increased GPX4 expression. LGZGD enhanced cardiomyocyte protection after overexpression of PLIN5, reduced apoptosis levels, lipid peroxidation level and ROS level, decreased ACSL4 expression, and increased GPX4 expression.</p><p><strong>Conclusion: </strong>PLIN5 interferes with lipid peroxidation, regulates mitochondrial function, and inhibits HF-induced ferroptosis in cardiomyocytes. LGZGD ameliorates impairment of cardiac structural function in model rats through PLIN5-mediated ferroptosis pathway, and has the effect of preventing metabolic cardiomyopathy.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"135 ","pages":"156234"},"PeriodicalIF":6.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639576","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}

{"title":"Phytosesquiterpene lactones deregulate mitochondrial activity and phenotypes associated with triple-negative breast cancer metastasis.","authors":"Yu-Ting Cheng, Dao-Ming Chang, Yi-Chung Tung, Pei-Wen Hsiao, Kyoko Nakagawa-Goto, Lie-Fen Shyur","doi":"10.1016/j.phymed.2024.156226","DOIUrl":"10.1016/j.phymed.2024.156226","url":null,"abstract":"<p><strong>Background: </strong>Triple-negative breast cancer (TNBC) recurrence and metastasis are the major causes of failure in TNBC therapy. The difficulties in treating TNBCs may be because of increased cancer cell plasticity that involves the fine-tuning of cellular redox homeostasis, mitochondrial bioenergetics, metabolic characteristics, and the development of cancer stem cells (CSCs).</p><p><strong>Purpose: </strong>To investigate the effects and the underlying mechanisms of the phytosesquiterpene lactone deoxyelephantopin (DET) and its semi-synthesized derivative (DETD-35) in suppressing different phenotypic TNBC cell populations that contribute to tumor metastasis.</p><p><strong>Methods: </strong>A timelapse microfluidic-based system was established to analyze the effects of DETD-35 and DET on cell migration behavior in an oxygen gradient. Seahorse real-time cell metabolic analyzer and gas chromatography/quadrupole-time-of-flight mass spectrometry (GC/Q-TOF MS) were utilized to analyze the effects of the compounds on mitochondrial bioenergetics in TNBC cells. A miRNA knockout technique and miRNA sponges were employed to evaluate the miR-4284 involvement in the anti-TNBC cell effect of either compound.</p><p><strong>Results: </strong>DETD-35 and DET attenuated TNBC cell migration toward hypoxic regions under a 2-19 % oxygen gradient in a timelapse microfluidic-based system. DETD-35 and DET also suppressed CSC-like phenotypes, including the expression of Sox2, Oct4, and CD44 in TNBC cells under hypoxic conditions. DETD-35 and DET affected mitochondrial basal respiration, ATP production, proton leak, and primary metabolism, including glycolysis, the TCA cycle, and amino acid metabolism in the lung-metastatic TNBC cells. Furthermore, the expression of mitophagy markers PARKIN, BNIP3, PINK1, LC3-II, and apoptotic markers Bax, cleaved caspase 7, and cleaved PARP in hypoxic and lung-metastatic TNBC cells was also regulated by treatment with either compound. In miR-4284 knockout cells or miR-4284 inhibitor co-treated TNBC cells, DET- and DETD-35-induced over-expression of mitophagic and apoptotic markers was partially reversed, indicating miR-4284 involved with the compounds caused programmed cell death.</p><p><strong>Conclusion: </strong>This study demonstrated the novel activities of DETD-35 and DET in suppressing CSC-like phenotypes and metastatic TNBC cells through the de-regulation of mitochondrial bioenergetics.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"135 ","pages":"156226"},"PeriodicalIF":6.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142688661","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}

{"title":"Eriocalyxin B ameliorated experimental autoimmune prostatitis via modulation of macrophage polarization through gut microbiota-mediated vitamin D₃ alteration.","authors":"Zi-Qiang Yu, He-Xi Du, Shan Gao, Chao-Zhao Liang","doi":"10.1016/j.phymed.2024.156191","DOIUrl":"10.1016/j.phymed.2024.156191","url":null,"abstract":"<p><strong>Background: </strong>Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a often heterogeneous condition in urology. Accumulating evidence suggests that the autoimmune response against prostate antigens is related to CP/CPPS. The gut microbiota may be a possible cause of a number of autoimmune diseases. Eriocalyxin B (EriB) is used as an anti-inflammatory treatment for autoimmune disorders. The underlying mechanism of fecal metabolome involved in CP/CPPS treatment by EriB remains unclear.</p><p><strong>Methods: </strong>The experimental autoimmune prostatitis (EAP) mouse model was generated by subcutaneous immunization. Macrophages, inflammatory cytokines, intestinal microbiota, and fecal metabolome of the mice were analyzed. The alteration of the fecal metabolome was investigated in detail in EriB-treated EAP mice and confirmed by in vitro experiments.</p><p><strong>Results: </strong>EriB ameliorated significantly decreased prostate inflammation in EAP mice and promoted macrophage phenotype polarizing from M1 to M2. The gut microbiome was altered, and intestinal barrier damage was improved by EriB treatment. Furthermore, the enrichment of vitamin digestion and absorption pathways in the fecal metabolome revealed that vitamin D₃ was altered by EriB. In vitro experiments confirmed that macrophage polarization from M1 to M2 was promoted by vitamin D₃. Finally, fecal transplantation from EriB-treated mice markedly reduced inflammatory indicators and the macrophage M1/M2 ratio in pseudogerm-free EAP mice. In our study, the immune state of macrophage regulated by gut microbiota-mediated vitamin D3 alteration was first time revealed in EAP treatment.</p><p><strong>Conclusions: </strong>EriB ameliorated in mice with EAP, the gut microbiota mediates vitamin D₃ alterations to modulate macrophage phenotype polarizing from M1 to M2.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"135 ","pages":"156191"},"PeriodicalIF":6.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142606113","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}

{"title":"Ginsenoside compound K alleviates brain aging by inhibiting ferroptosis through modulation of the ASK1-MKK7-JNK signaling pathway.","authors":"Xiaojun Yan, Xue Bai, Guanghui Sun, Zhiguang Duan, Rongzhan Fu, Wen Zeng, Chenhui Zhu, Daidi Fan","doi":"10.1016/j.phymed.2024.156239","DOIUrl":"10.1016/j.phymed.2024.156239","url":null,"abstract":"<p><strong>Background: </strong>Aging of the brain is a major contributor to the onset and progression of neurodegenerative diseases. Conventional treatments for these diseases are often limited by significant side effects and a lack of efficacy in halting disease progression. Ginsenoside compound K (CK), a bioactive secondary metabolite derived from ginseng, has shown promise because of its potent antioxidant properties.</p><p><strong>Purpose: </strong>This study aimed to elucidate the molecular mechanisms underlying the impact of CK on brain senescence, with a particular focus on its role in modulating oxidative stress and related signaling pathways.</p><p><strong>Methods: </strong>We employed a d-galactose (D-gal)-induced PC-12 senescent cell model and a mouse brain aging model to explore the antioxidant properties of CK in the context of brain aging. The effects of CK on mitochondrial dysfunction associated with brain aging were assessed using immunofluorescence and western blotting techniques. The potential molecular mechanisms by CK influences brain aging were investigated using transcriptomic analysis and western blotting. Additionally, CK's regulatory effect on apoptosis signal-regulating kinase 1 (ASK1) was validated by molecular docking, microscale thermophoresis, and small interfering RNA transfection.</p><p><strong>Results: </strong>Our findings demonstrate that CK effectively alleviates cognitive decline associated with brain aging. CK reduces the number of senescent cells, alleviates neuronal damage, and enhances the activity of key antioxidant enzymes, including catalase, superoxide dismutase, and glutathione peroxidase. Additionally, CK restores mitochondrial function and upregulated the expression of solute carrier family 7 member 11 and glutathione peroxidase 4, thereby inhibiting ferroptosis. Furthermore, CK targets ASK1 and suppresses the hyperphosphorylation of MAPK kinase 7 (MKK7) and c-Jun N-terminal kinase (JNK). This suppression promotes the nuclear accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2), effectively reducing ferroptosis and oxidative damage linked to brain aging.</p><p><strong>Conclusion: </strong>In summary, our research demonstrates that CK effectively delays brain aging by inhibiting the ASK1-MKK7-JNK signaling pathway, enhancing nuclear Nrf2 expression, and suppressing the ferroptosis response. These findings highlight CK as a promising therapeutic agent for slowing brain aging and alleviating neurodegenerative diseases.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"135 ","pages":"156239"},"PeriodicalIF":6.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639577","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}

{"title":"Berberine modulates microglial polarization by activating TYROBP in Alzheimer's disease.","authors":"Yu Yang, Jiwen Wu, Luping Jia, Shicheng Feng, Zihan Qi, Hao Yu, Yili Wu, Shuai Wang","doi":"10.1016/j.phymed.2024.156237","DOIUrl":"10.1016/j.phymed.2024.156237","url":null,"abstract":"<p><strong>Background: </strong>Characterized by β-amyloid (Aβ) plaques, neurofibrillary tangles, and aberrant neuroinflammation in the brain, Alzheimer's disease (AD) is the most common neurodegenerative disease. Microglial polarization is a subtle mechanism which maintains immunological homeostasis and has emerged as a putative therapeutic to combat AD. Berberine (BBR) is a natural alkaloid compound with multiple pharmacological effects, and has shown considerable therapeutic potential against inflammatory disorders. However, BBR functions and underlying mechanisms in neuroinflammation remain unclear.</p><p><strong>Purpose: </strong>To examine BBR pharmacological effects and mechanisms in neuroinflammation with a view to treating AD.</p><p><strong>Methods: </strong>BBR effects on cognitive performance in 5 × FAD mice were assessed using open field, Y-maze, and Morris Water Maze (MWM) tests. Neuroinflammation-related markers and Aβ pathology were examined in brain sections from mice. Transcriptomic analyses of hippocampus tissues were also conducted. Microglial BV2 cells were also used to verify potential BBR mechanisms in neuroinflammation and microglial polarization.</p><p><strong>Results: </strong>BBR improved cognitive performance, reduced amyloid pathology, and alleviated aberrant neuroinflammation in an AD mouse model. BBR induced microglial polarization to an M2-like phenotype, which was manifested by lowered and elevated proinflammatory and anti-inflammatory cytokine production, respectively, improved microglial uptake and Aβ clearance. Mechanistically, BBR directly interacted with TYROBP and promoted its activation by stabilizing TYROBP oligomerization. TYROBP knockdown aggravated M1-like polarization and pro-inflammatory gene expression in microglial cells in the presence of lipopolysaccharide (LPS)+Aβ, while blocked microglial M2-like polarization benefited from BBR administration.</p><p><strong>Conclusions: </strong>BBR modulated neuroinflammation by regulating microglial polarization via TYROBP activation. Our study provided new insight into BBR pharmacological actions in regulating microglial homeostasis and combating AD.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"135 ","pages":"156237"},"PeriodicalIF":6.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142682467","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}

{"title":"Benzoylmesaconine mitigates NLRP3 inflammasome-related diseases by reducing intracellular K⁺ efflux and disrupting NLRP3 inflammasome assembly.","authors":"Zhongyun Zhang, Chen Wu, Zilu Bao, Zhaoxiang Ren, Min Zou, Shuhui Lei, Kaiqun Liu, Xukun Deng, Shijin Yin, Zhaohua Shi, Liqin Zhang, Zhou Lan, Lvyi Chen","doi":"10.1016/j.phymed.2024.156154","DOIUrl":"10.1016/j.phymed.2024.156154","url":null,"abstract":"<p><strong>Background: </strong>Benzoylmesaconine (BMA), a major alkaloid derived from the traditional Chinese medicine Aconitum carmichaeli Debx, exhibits potent anti-inflammatory properties. However, the precise mechanism underlying its action remains unclear.</p><p><strong>Purpose: </strong>This study aimed to investigate the inhibitory mechanism of BMA on the NLRP3 inflammasome and assess its therapeutic efficacy in NLRP3-related metabolic diseases.</p><p><strong>Methods: </strong>A classic NLRP3 inflammasome-activated bone marrow-derived macrophage (BMDM) model was established to evaluate BMA's effects on NLRP3 upstream and downstream protein expression, as well as pyroptosis. Two distinct animal disease models, MSU-induced gouty arthritis and DSS-induced colitis, were utilized to validate BMA's anti-inflammatory activity in vivo.</p><p><strong>Results: </strong>In vitro findings revealed that BMA can suppress NLRP3 inflammasome activation by inhibiting interleukin-1β (IL-1β) secretion and GSDMD-N protein expression. This mechanism involved blocking intracellular K⁺ efflux and interfering with the formation of NLRP3 inflammasomes. In vivo studies demonstrated that BMA significantly alleviated inflammatory symptoms in MSU-induced acute gout and DSS-induced colitis models.</p><p><strong>Conclusion: </strong>These findings suggest that BMA effectively inhibits the activation of the NLRP3 signaling pathway through dual mechanisms: reducing intracellular K⁺ efflux and disrupting NLRP3 inflammasome assembly. This multifaceted action highlights the therapeutic potential of BMA for NLRP3-related diseases.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"135 ","pages":"156154"},"PeriodicalIF":6.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142506461","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}

{"title":"Acacetin alleviates rheumatoid arthritis by targeting HSP90 ATPase domain to promote COX-2 degradation.","authors":"Wenshuang Wang, Shanshan Zhai, Wen Yang, He Gao, Nianwei Chang, Man Zhang, Yuanyuan Hou, Gang Bai","doi":"10.1016/j.phymed.2024.156171","DOIUrl":"10.1016/j.phymed.2024.156171","url":null,"abstract":"<p><strong>Background: </strong>Inflammation plays a significant role in initiating and sustaining rheumatoid arthritis (RA). Acacetin, a natural flavonoid compound, exhibits excellent anti-inflammatory effects specifically for RA. However, its relevant targets and molecular mechanisms remain to be elucidated.</p><p><strong>Purpose: </strong>This study aims to investigate the mechanism of acacetin in the therapeutic efficacy of acacetin in RA and search for new therapeutic options for RA treatment.</p><p><strong>Methods: </strong>A collagen-induced RA mouse model was established to evaluate the therapeutic effect of acacetin. Acacetin functional probes were synthesized to capture potential target proteins in RAW264.7 cells. Various small molecule-protein interaction methods were conducted to verify the binding of acacetin to target protein. Molecular docking and site directed mutagenesis tests were performed to analyze the specific binding sites. Co-immunoprecipitation, immunofluorescence assay and western blot were engineered to explore the effect of acacetin on COX-2 degradation by targeting HSP90.</p><p><strong>Results: </strong>Acacetin specifically binds to the ATP domain of HSP90, to facilitate the dissociation between HSP90 and COX-2, inducing the ubiquitin-degradation of COX-2 in macrophages. Acacetin suppressed the production of pro-inflammatory cytokines, as well as inflammatory related pathways, exerting excellent anti-inflammatory effects in RA.</p><p><strong>Conclusions: </strong>This research proved that acacetin, a novel HSP90 ATPase inhibitor, inhibits the functional folding of the client protein COX-2, promoting its ubiquitin degradation for anti-inflammation. Targeting HSP90 is a viable strategy to inhibit inflammation, affording a distinct way to managing joint inflammation and pains associated with RA.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"135 ","pages":"156171"},"PeriodicalIF":6.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569423","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}

{"title":"An automatic LC-MS/MS data analysis workflow for herbal compound annotation with AutoAnnotatoR: A case study of ten botanical origins of Fritillaria species.","authors":"Ya-Ling An, Jia-Yuan Li, Wen-Long Wei, Yun Li, Jian-Qing Zhang, Chang-Liang Yao, Qi-Rui Bi, Shu Wang, Zhong-da Zeng, De-An Guo","doi":"10.1016/j.phymed.2024.156193","DOIUrl":"10.1016/j.phymed.2024.156193","url":null,"abstract":"<p><strong>Background: </strong>Despite the widespread implementation of analytical hardware capable of recording large-scale datasets for botanical natural products, the data processing procedures for compound annotation remain a bothersome obstacle that demand a tremendous amount of time and expert knowledge.</p><p><strong>Methods: </strong>Herein, an automatic LC-MS/MS data analysis workflow with AutoAnnotatoR was introduced for the compound annotation of plant derived natural products, which has the merits of great efficiency, high accuracy, saving time and simplified process. This procedure enabled automatic matching of MS² data with characteristic fragment ions, as well as MS¹ data with compound libraries, which improves the accuracy of structural elucidation. Notably, the optimization of collision energy for each target ion was successfully performed for the first time, facilitating the acquisition of comprehensive fragmentation information.</p><p><strong>Results: </strong>The automatic analysis workflow with AutoAnnotatoR was successfully applied for the annotation of alkaloids from 10 botanical origins of Fritillaria species. Consequently, a total of 2684 chemical constituents were tentatively characterized, with 23 components being unambiguously validated by reference standards and 2434 being probable novel chemicals.</p><p><strong>Conclusion: </strong>The entire data analysis procedure takes only a few hours, vastly improving analysis speed while assuring high accuracy. This method provides a powerful tool for the rapid and precise annotation of complex natural products. The workflow is publicly accessible on Github as an open-source R package called AutoAnnotatoR (https://github.com/anyaling2022/AutoAnnotatoR).</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"135 ","pages":"156193"},"PeriodicalIF":6.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142606022","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}

{"title":"Inhibition of colorectal cancer aggressiveness by Oleanolic acid through Nur77 degradation.","authors":"Shan Deng, Yuping Liu, Xiyu Liu, Jialin Yu, Yan Chen, Jiege Huo","doi":"10.1016/j.phymed.2024.156192","DOIUrl":"10.1016/j.phymed.2024.156192","url":null,"abstract":"<p><strong>Background: </strong>Colorectal cancer (CRC) is the second primary malignancy in China with tough treatment challenge. Although Oleanolic acid (OA) protects against various cancers, its mechanisms in CRC are not well defined. Our previously study showed that Nur77 has CRC promoting effect. Thus, we investigated the roles of OA as Nur77 ligand and the regulatory effects on Nur77 degradation in CRC progression.</p><p><strong>Methods: </strong>The proliferative and metastatic phenotypes of OA was examined by CCK-8, EdU, organoid culture, would healing and transwell assays, respectively. Epithelial-mesenchymal transition (EMT) properties were assessed by Western blotting (WB). The interaction between OA and Nur77 was monitored by molecular docking and Molecular Dynamics stimulation (MD). Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene set enrichment analysis (GSEA) were employed to screen the downstream regulatory pathways. The half-time and proteasome degradation of Nur77 were treated with cycloheximide (CHX) and MG132. Co-immunoprecipitation (Co-IP) and ubiquitination assays were employed to detect direct association between Nur77 and PPARγ. Rescued experiments were performed by Nur77 agonist Cytosporone B (Csn-B) treatment. The findings were verified in xenograft and in situ models.</p><p><strong>Results: </strong>For the first time, we found the effect of OA on ubiquitination degradation. OA inhibited CRC cell survival and EMT phenotypes by suppressing Nur77. Mechanistically, OA directly bind to Nur77 and facilitated the ubiquitin degradation of Nur77. During this process, PPARγ acted as the ubiquitination activator via interacting with Nur77. Rescued experiments revealed that OA-induced inhibition was recovered by replenishing Nur77. In both subcutaneous and orthotopic CRC models, OA exhibited significant anti-tumor effect together with Nur77 inhibition.</p><p><strong>Conclusion: </strong>We revealed a new regulatory effect of OA in CRC tumorigenesis via PPARγ-mediated Nur77 ubiquitin degradation.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"135 ","pages":"156192"},"PeriodicalIF":6.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142626310","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}

{"title":"Cellular and molecular mechanisms elicited by natural products, including dietary supplements, against neurological disorders.","authors":"Rajeev K Singla, Rohit Sharma, Bairong Shen","doi":"10.1016/j.phymed.2024.156236","DOIUrl":"10.1016/j.phymed.2024.156236","url":null,"abstract":"","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"135 ","pages":"156236"},"PeriodicalIF":6.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142644408","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}