JOURNAL OF ETHNOPHARMACOLOGY
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2025
·
IF 5.4
Siyuan Liu,Jincheng Lv,Peng Peng,Xianshu Song,Pengyu Dai,Fangle Liu,Yufeng Yao,Chenchen Zhu,Chaozhan Lin
Ethnopharmacological relevance Recurrent or persistent respiratory tract infection may progress to chronic pneumonia or other debilitating sequelae in the absence of appropriate therapeutic interventions, seriously compromising the patients' quality of life. LianZhiXiaoYan Formula (LZXYF), a Chinese prescription composed of Chinese medical herbs Andrographis herba (ChuanXinLian) and Radix helicteris (ShanZhiMa), possesses efficiency of clearing heat and detoxifying, and shown a good therapeutic effect on respiratory infectious diseases, but its mechanism of action is not clear. Aim of the study Aim to evaluate the therapeutic efficacy of LZXYF in treatment of CP and investigate its molecular and physiological mechanisms. Materials and methods The therapeutic effects of LZXYF on CP was evaluated in an LPS-induced murine model by assessing the pulmonary function, lung histopathology, and biochemical indicators. To explore the mechanism of LZXYF, the lung metabolomics and the components of LZXYF distributed in lung were analyzed by UHPLC-Q-TOF-MS/MS. The impact of LZXYF on SIRT3-SDH-SCUNR1 pathway was investigated using RT-qPCR and Western blot, and the interaction between LZXYF and SIRT3 was verified via CETSA. LPS-induced LLC cell and succinate-induced RAW264.7 cell were employed to investigate the effect and mechanism of LZXYF on metabolic reprogramming and inflammation regulation, with selective inhibition of SIRT3 and SUCNR1, respectively. Results LZXYF treatment improved pulmonary function as demonstrated by increased Tidal volume, enhanced Minute ventilation, elevated Peak expiratory flow rate, and reduced Timed inspiration ( P < 0.05). Moreover, histopathological analysis revealed that LZXYF treatment attenuated emphysema and airway remodeling, concomitant with reduced the levels of TGF-β and HYP ( P < 0.01). Metabolomics demonstrated that LZXYF treatment restored 38 dysregulated metabolites in CP mice, primarily involving tryptophan, histidine, lysine and arginine metabolic pathways. Correlation analysis of 16 lung-distributed components and the 38 differential metabolites further indicated that LZXYF alleviated CP through SIRT3 signaling pathway mediated metabolic reprogramming. We further demonstrated that LZXYF could up-regulate SIRT3 to enhance the activities of SDH ( P < 0.01), a metabolic enzyme in TCA cycle, thereby regulating metabolic reprogramming and inhibiting the activation of SUCNR1 to prevent succinate-induced inflammation responses ( P < 0.01). Furthermore, we elucidated that the active components of LZXYF exerted ameliorated effects by up-regulating SIRT3 expression in LPS or 3-TYP induced LLC cell metabolic reprogramming, which revealed SIRT3 as a critical molecular target for LZXYF to improve metabolic reprogramming and suppress inflammatory responses induced by succinate. Conclusion LXZYF could ameliorate CP through up-regulating SIRT3, which enhances TCA cycle and suppresses succinate-mediated inflammation. This study provides new insight into the therapeutic potential of LZXYF for CP treatment.
研究领域:
呼吸病学
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中药药理学
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代谢生物学
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炎症免疫学
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分子药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2021
·
IF 4.932
Yonglan Ruan,Jinying Ling,Fan Ye,Nuo Cheng,Fei Wu,Zongxiang Tang,Xiaolan Cheng,Hongquan Liu
Background Treatment of chronic inflammatory pain remains a major goal in the clinic. It is thus of prime importance to characterize inherent pathophysiological pathways to design new therapeutic strategies and analgesics for pain management. Paeoniflorin (PF), a monoterpenoid glycoside from Paeonia lactiflora Pallas plants, possesses promising anti-nociceptive property. However, therapeutic effect and underlying mechanism of action of PF on inflammatory pain have not yet been fully elucidated. In this study, we aim to investigate the analgesic effect further and clarify its mechanism of action of PF on complete freund’s adjuvant (CFA)-evoked inflammatory pain. Methods Twenty-four male mice were divided into 3 groups: sham, CFA, and CFA + PF groups (n = 8/group). Mice were treated with normal saline or PF (30 mg/kg) for 11 days. Footpad swelling (n = 8/group), mechanical (n = 8/group) and thermal hypersensitivity (n = 8/group) were measured to evaluate the analgesic effect of PF on CFA-injected mice. At the end of the animal experiment, blood and L4-L6 dorsal root ganglion neurons were collected to assess the therapeutic effect of PF on CFA-induced inflammatory pain. Next, hematoxylin and eosin, quantitative realtime PCR, ELISA, capsaicin and dimethyl succinate induced pain test (n = 8/group), motor coordination test (n = 8/group), tail flicking test (n = 8/group), pyruvate and succinate dehydrogenase assay (n = 6/group), immunohistochemical staining, were performed to clarify the action mechanism of PF on CFA-evoked inflammatory pain. Besides, the effect of PF on TRPV1 was evaluated by whole-cell patch clamp recording on primary neurons (n = 7). Finally, molecular docking further performed to evaluate the binding ability of PF to TRPV1. Results PF significantly relieved inflammatory pain ( P < 0.001 ) and paw edema ( P < 0.001 ) on a complete Freund adjuvant (CFA)-induced peripheral inflammatory pain model. Furthermore, PF inhibited neutrophil infiltration ( P < 0.01 ), IL-1β increase ( P < 0.01 ), and pain-related peptide substance P release ( P < 0.001 ). Intriguingly, CFA-induced succinate aggregation was notably reversed by PF via modulating pyruvate and SDH activity ( P < 0.01 ). In addition, PF dampened the high expression of subsequent succinate receptor SUCNR1 ( P < 0.01 ), HIF-1α ( P < 0.05 ), as well as the activation of NLPR3 inflammasome ( P < 0.05 ) and TRPV1 ( P < 0.05 ). More importantly, both capsaicin and dimethyl succinate supplementation obviously counteracted the pain-relieving effect of PF and TRPV1 ( P < 0.01 or P < 0.001 ). Conclusion Our findings suggest that PF can significantly relieve CFA-induced paw swelling, as well as mechanical and thermal hyperalgesia. PF alleviated inflammatory pain partly through inhibiting the activation of TRPV1 and succinate/SUCNR1-HIF-1α/NLPR3 pathway. Furthermore, we found that PF exerted its analgesic effect without affecting motor coordination and pain-related cold ion-channels. In summary, this study may provide valuable evidence for the potential application of PF as therapeutic strategy for inflammatory pain treatment.
研究领域:
药理学
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疼痛管理
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神经科学
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炎症
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2024
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IF 6.7
Wenjia CHEN,Chu ZHANG,Mingzhu XU,Tao LI,Xin LI,Peihao LI,Xun GONG,Yang QU,Chunling ZHOU,Xia MAO,Na LIN,Wei LIU,Quan JIANG,Haiyu XU,Yanqiong ZHANG
Background : Specific treatment for rheumatoid arthritis (RA) is still an unmet need. Yu-Xue-Bi (YXB) capsule effectively treats RA with blood stasis syndrome (BS). However, its mechanism remains unclear. Purpose : Exploring and elucidating the therapeutic effect and pharmacological mechanism of YXB capsule in treating RA. Methods : This study identified differentially expressed genes (DEGs) in patients with RA and BS compared to healthy controls using clinical transcriptomics data. Clinical symptoms of RA and BS, and the related genes were collected from the SoFDA and HPO databases. Candidate bioactive constituents in YXB were identified via UPLC-QTOF/MS and evaluated using ADMET rules. Putative targets were predicted, and a network linking disease-related DEGs and drug targets was constructed. Key targets were screened utilizing random walk-with-restart (RWR) algorithms and verified through experiments using rat models of collagen-induced arthritis with BS (CIA-BS model) in vivo . Results : We found 1220 DEGs along with 976 clinical symptom-related genes, as RA with BS-related genes. Chemical profiling identified 193 YXB constituents, with 98 meeting optimal ADMET criteria. We predicted 459 putative targets for these constituents. Network calculations screened 209 key targets, 129 RA with BS-related genes and 92 YXB targets involved in immune inflammation, blood stagnation, and hyperalgesia imbalance. Notably, the SUCNR1/HIF-1α/TRPV1 axis was enriched by YXB targets against RA with BS. Experimentally, YXB inhibited inflamed joint deterioration, including synovial inflammation, cartilage damage and bone erosion, relieving mechanical and cold allodynia hyperglasia. It reversed hemorrheology and vascular function in CIA-BS rats, restoring SDHB and eNOS expression, preventing SDHA, SUCNR1 and HIF-1α activation, reducing SUCN, TNF-1α and IL-1β production, and TRPV1 and TRPA1 expression. Conclusion : Our data support YXB's therapeutic effects on aggressive RA-BS by modulating the SUCNR1/HIF-1α/TRPV1 axis.
研究领域:
药理学
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分子生物学
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风湿病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
·
2024
·Vol. 327
·期 1
·C1
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IF 5
Yangyang Wang,Zhiming Xiu,Kuo Qu,Liying Wang,Huiyan Wang,Yongli Yu
Download figureDownload PowerPoint The purpose of this study is to investigate the previously unknown connection that succinate has with neutrophils in the setting of adjuvant-mediated immunological enhancement. It has been discovered that succinates stimulate the recruitment of neutrophils in immunization sites, which in turn induces the expression of what is known as neutrophil-derived B cell-activating factor (BAFF). Further amplification of vaccine-induced antibody responses is provided via the succinate receptor 1-interferon regulatory factor 5 (SUCNR1-IRF5)-BAFF signaling pathway, which provides insights into a unique mechanism for immunological enhancement. NEW & NOTEWORTHY This study explores the role of succinate as a vaccine adjuvant, revealing its capacity to enhance neutrophil recruitment at immunization sites, which boosts B cell activation through the succinate receptor 1-interferon regulatory factor 5-B cell-activating factor (SUCNR1-IRF5-BAFF) signaling pathway. Results demonstrate succinate’s potential to amplify vaccine-induced antibody responses, highlighting its significance in immunological enhancement and offering new insights into the adjuvant mechanisms of action, particularly in neutrophil-mediated immune responses.
研究领域:
免疫学
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疫苗学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Food & Function
·
2022
·Vol. 13
·期 21
·11070-11082
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IF 6.317
Xuan Li,Yuting Ren,Guowen Huang,Ruofan Zhang,Yanan Zhang,Weiyun Zhu,Kaifan Yu
Succinate is produced by both the host and microbiota with pleiotropic functions in the modulation of intestinal inflammation and metabolic homeostasis, but the mechanisms remain elusive. This study aimed to determine whether dietary succinate influences the intestinal inflammatory response and to analyze the possible mechanisms by which succinate regulates enterohepatic metabolism. Sixteen growing barrows were randomly assigned to two groups, fed with a basal diet that consisted of a typical commercial diet or fed with a basal diet supplemented with 1% sodium succinate. Our data showed that dietary succinate activated the expression of succinate receptor 1 (SUCNR1) and increased the concentrations of pro-inflammatory cytokines in the intestine. Dietary succinate inhibited the expression levels of the ileal Farnesol X receptor (FXR) and its target genes, promoted hepatic bile acid secretion, and altered the bile acid metabolic profile. Then, we demonstrated that the pro-inflammatory cytokines triggered by succinate disrupted the ability of bile acids to activate FXR and fibroblast growth factor 19. Furthermore, dietary succinate reduced the abundance of bile-salt hydrolase enriched bacteria in the ileum. Taken together, dietary succinate activated the pro-inflammatory response via SUCNR1 in the intestine, and the pro-inflammatory cytokines induced by succinate blocked the activation of FXR and its target genes and disturbed bile acid enterohepatic circulation.
研究领域:
营养学
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免疫学
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代谢学
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胃肠病学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF PROTEOME RESEARCH
·
2021
·
IF 4.466
Peng Ma,Zijing Wang,Yisa Wang,Biyu Hou,Jialin Sun,He Tian,Bowen Li,Guanghou Shui,Xiuying Yang,Xinyu Yang,Guifen Qiang,Chong Wee Liew,Guanhua Du
Once protein synthesis is excessive or misfolded protein becomes aggregated, which eventually overwhelms the capacity of the endoplasmic reticulum (ER), a state named ER stress would be reached. ER stress could affect many tissues, especially the liver, in which nonalcoholic fatty liver disease, liver steatosis, etc. have been reported relative. However, there is still a lack of systematic insight into ER stress in the liver, which can be obtained by integrating metabolomics and transcriptomics of the tissue. Here, tunicamycin was utilized to induce ER stress in C57BL/6N mice. Microarray and untargeted metabolomics were performed to identify the genes and metabolites significantly altered in liver tissues. Surprisingly, apart from the predictable unfolded protein response, liver lipid, arginine, and proline metabolisms were affirmed to be related to ER stress. Also, the ketone body metabolism changed most prominently in response to ER stress, with few studies backing. What is more, succinate receptor 1 (Sucnr1) may be a novel marker and therapeutical target of liver ER stress. In this study, the combination of the metabolome and transcriptome provided reliable information about liver pathological processes, including key relative pathways, potential markers, and targets involved in ER stress of the liver.
研究领域:
分子生物学
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生物化学
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系统生物学
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肝病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）