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Xu DJ, Wang GT, Zhong Q. Extracellular matrix gene set and microRNA network in intestinal ischemia-reperfusion injury: Insights from RNA sequencing for diagnosis and therapy. World J Gastrointest Surg 2025; 17:100034. [DOI: 10.4240/wjgs.v17.i2.100034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 11/26/2024] [Accepted: 12/06/2024] [Indexed: 01/22/2025] Open
Abstract
Intestinal ischemia-reperfusion injury (IIRI) is a complex and severe pathophysiological process characterized by oxidative stress, inflammation, and apoptosis. In recent years, the critical roles of extracellular matrix (ECM) genes and microRNAs (miRNAs) in IIRI have garnered widespread attention. This review aims to systematically summarize the diagnostic and therapeutic potential of ECM gene sets and miRNA regulatory networks in IIRI. First, we review the molecular mechanisms of IIRI, focusing on the dual role of the ECM in tissue injury and repair processes. The expression changes and functions of ECM components such as collagen, elastin, and matrix metalloproteinases during IIRI progression are deeply analyzed. Second, we systematically summarize the regulatory roles of miRNAs in IIRI, particularly the mechanisms and functions of miRNAs such as miR-125b and miR-200a in regulating inflammation, apoptosis, and ECM remodeling. Additionally, this review discusses potential diagnostic biomarkers and treatment strategies based on ECM genes and miRNAs. We extensively evaluate the prospects of miRNA-targeted therapy and ECM component modulation in preventing and treating IIRI, emphasizing the clinical translational potential of these emerging therapies. In conclusion, the diagnostic and therapeutic potential of ECM gene sets and miRNA regulatory networks in IIRI provides new directions for further research, necessitating additional clinical and basic studies to validate and expand these findings for improving clinical outcomes in IIRI patients.
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Affiliation(s)
- Dao-Jian Xu
- Department of Emergency Medicine, Taizhou Municipal Hospital, Taizhou 318000, Zhejiang Province, China
| | - Guo-Tao Wang
- Department of Emergency Medicine, Taizhou Municipal Hospital, Taizhou 318000, Zhejiang Province, China
| | - Qiang Zhong
- Department of Emergency Medicine, Taizhou Municipal Hospital, Taizhou 318000, Zhejiang Province, China
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Shan H, Wang Z, Chen Y, Ma TF, Zhang J, Zhang J, Cheng Z, Jia L. Etomidate Inhibits Hepatic Ischemia-Reperfusion Injury Depending on the Activation of Nrf2-HO-1 Signaling Pathway. DNA Cell Biol 2025; 44:13-24. [PMID: 39470379 DOI: 10.1089/dna.2024.0125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/30/2024] Open
Abstract
Hepatic ischemia-reperfusion (I/R) injury (HIRI) is recognized as a local aseptic inflammatory response driven by innate immunity and is considered a leading cause of early organ dysfunction and failure following liver transplantation. Etomidate (Eto), an anesthetic drug known for its ability to inhibit inflammatory response and apoptosis, was the focus of our investigation. In this study, we conducted hepatic I/R surgery in vivo on C57 mice, analyzing liver damage through histopathology. Additionally, primary hepatocytes isolated from mice were cultured and subjected to hypoxia/reoxygenation (H/R) insult in vitro, with cell activity assessed using the CCK8 assay and immunofluorescence staining employed to analyze liver inflammatory cell infiltration and apoptosis. Results showed that Eto effectively inhibited liver injury, inflammatory response, and apoptosis induced by HIRI surgery, with the greatest effect observed at an Eto concentration of 10 mg/kg. Furthermore, Eto also showed the ability to inhibit H/R-induced cell damage, inflammatory activation, and apoptosis in primary hepatocytes. Further mechanistic studies revealed that Eto could promote the activation of the Nrf2-HO-1 signaling pathway, and the protective effect of Eto on HIRI was nullified when the Nrf2 inhibitor ML385 was utilized. This study highlights the potential of Eto to protect against HIRI by promoting the Nrf2-HO-1 signaling axis.
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Affiliation(s)
- Huajing Shan
- Department of Cardiology, Huanggang Central Hospital, Huanggang, China
| | - Zhifang Wang
- Department of Nephrology, Huanggang Central Hospital, Huanggang, China
| | - Yun Chen
- Clinical Trial Centers, Huanggang Central Hospital, Huanggang, China
| | - Teng-Fei Ma
- Clinical Trial Centers, Huanggang Central Hospital, Huanggang, China
- Huanggang Institute of Translational Medicine, Huanggang, China
| | - Jianqing Zhang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Jinpeng Zhang
- Department of Critical Care Medicine, Huanggang Central Hospital, Huanggang, China
| | - Zhonghua Cheng
- Department of Orthopedics, Huanggang Central Hospital, Huanggang, China
| | - Liping Jia
- Respiratory and Critical Care Medicine, Huanggang Central Hospital, Huanggang, China
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Wang A, Yang J, Deng J, Wang K, Chen G, Lin D. Kaempferol promotes flap survival by inhibiting ferroptosis and inflammation through network pharmacology and in vivo experiments. Wound Repair Regen 2025; 33:e13250. [PMID: 39719508 DOI: 10.1111/wrr.13250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Revised: 11/22/2024] [Accepted: 12/11/2024] [Indexed: 12/26/2024]
Abstract
Skin flap transplantation is a primary method for wound repair; however, postoperative skin flap necrosis remains a significant challenge. Kaempferol, a flavonol abundant in various foods, exhibits diverse pharmacological effects. This study investigated the potential targets of kaempferol for treating skin flap ischemia-reperfusion (I/R) injury through network pharmacology and molecular docking, followed by in vivo validation. Using SwissTargetPredict, PubChem, SymMap V2, and GeneCards databases, 174 potential target proteins of kaempferol were identified. KEGG and GO enrichment analyses, performed using R software, indicated that kaempferol promotes skin flap survival by modulating ferroptosis, TNF-α, and NF-κB signalling pathways. Molecular docking demonstrated stable binding between kaempferol and key proteins, including SIRT1 and NRF2. In vivo, a McFarlane skin flap model was established in Sprague-Dawley rats. Kaempferol treatment improved flap survival, enhanced perfusion areas and distal arteriole visualisation, and increased blood flow in the flap. Furthermore, kaempferol reduced neutrophil infiltration, alleviated oxidative stress, improved mitochondrial morphology and function, and inhibited the release of proinflammatory cytokines. Western blot and immunofluorescence analyses confirmed that kaempferol inhibited ferroptosis and inflammation while promoting flap survival. Mechanistically, kaempferol was found to activate SIRT1-mediated HMGB1/TLR4/NF-κB and NRF2/SLC7A11/GPX4 pathways, thereby promoting skin flap survival and mitigating I/R injury.
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Affiliation(s)
- An Wang
- Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Medicine, Wenzhou Medical University, Wenzhou, China
| | - Jialong Yang
- Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Medicine, Wenzhou Medical University, Wenzhou, China
| | - Jiapeng Deng
- Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Medicine, Wenzhou Medical University, Wenzhou, China
| | - Kaitao Wang
- Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Medicine, Wenzhou Medical University, Wenzhou, China
| | - Guodong Chen
- Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Medicine, Wenzhou Medical University, Wenzhou, China
| | - Dingsheng Lin
- Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Medicine, Wenzhou Medical University, Wenzhou, China
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Liu J, Luo R, Zhang Y, Li X. Current status and perspective on molecular targets and therapeutic intervention strategy in hepatic ischemia-reperfusion injury. Clin Mol Hepatol 2024; 30:585-619. [PMID: 38946464 PMCID: PMC11540405 DOI: 10.3350/cmh.2024.0222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 06/25/2024] [Accepted: 06/26/2024] [Indexed: 07/02/2024] Open
Abstract
Hepatic ischemia‒reperfusion injury (HIRI) is a common and inevitable complication of hepatic trauma, liver resection, or liver transplantation. It contributes to postoperative organ failure or tissue rejection, eventually affecting patient prognosis and overall survival. The pathological mechanism of HIRI is highly complex and has not yet been fully elucidated. The proposed underlying mechanisms include mitochondrial damage, oxidative stress imbalance, abnormal cell death, immune cell hyperactivation, intracellular inflammatory disorders and other complex events. In addition to serious clinical limitations, available antagonistic drugs and specific treatment regimens are still lacking. Therefore, there is an urgent need to not only clarify the exact etiology of HIRI but also reveal the possible reactions and bottlenecks of existing drugs, helping to reduce morbidity and shorten hospitalizations. We analyzed the possible underlying mechanism of HIRI, discussed various outcomes among different animal models and explored neglected potential therapeutic strategies for HIRI treatment. By thoroughly reviewing and analyzing the literature on HIRI, we gained a comprehensive understanding of the current research status in related fields and identified valuable references for future clinical and scientific investigations.
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Affiliation(s)
- Jia Liu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Ranyi Luo
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Yinhao Zhang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaojiaoyang Li
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
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Zhang S, Zhang S, Bai X, Wang Y, Liu Y, Liu W. Thonningianin A ameliorated renal interstitial fibrosis in diabetic nephropathy mice by modulating gut microbiota dysbiosis and repressing inflammation. Front Pharmacol 2024; 15:1389654. [PMID: 39193336 PMCID: PMC11347433 DOI: 10.3389/fphar.2024.1389654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Accepted: 07/25/2024] [Indexed: 08/29/2024] Open
Abstract
Objectives This study was conducted to examine the potential health benefits of thonningianin A (TA) on renal injury and interstitial fibrosis in diabetic nephropathy (DN) mice. Methods In this study, a DN mice model was established using male C57BL/6 mice injected with streptozotocin (STZ, 50 mg/kg) intraperitoneally and treated with TA for 12 weeks. Firstly, the therapeutic and anti-fibrotic effects of TA on DN were evaluated. Secondly, the effect of TA on renal inflammation was evaluated and Western blot was used to detect the changes of NLRP3/ASC/Caspase-1 pathway-related protein expressions in kidney. Furthermore, the effect of TA on impairments in the intestinal mucosa barrier was evaluated and the changes of lipopolysaccharide (LPS) levels in feces and serum were detected by ELISA. Finally, 16S rRNA sequencing was used to detect alteration of gut microbiota diversity and abundance in mice after TA treatment. Results The results showed that TA markedly mitigated blood glucose (Glu), decreased 24-h urinary total protein (24hUTP), improved renal dysfunction and kidney index (KI) in DN mice. Furthermore, TA significantly alleviated renal injury and interstitial fibrosis, repressing renal inflammation. Western blot results showed that the NLRP3/ASC/Caspase-1 signaling pathway-related proteins decreased after TA treatment. In addition, TA also ameliorated impairments in the intestinal mucosa barrier and restored the expressions of intestinal tight junction proteins (Claudin-1, Occludin and ZO-1). Subsequently, it reduced LPS levels of DN mice in fecal and serum. Furthermore, 16S rRNA high-throughput sequencing showed that TA modulated gut microbiota dysbiosis and decreased the abundance of Gram-negative bacteria (Proteobacteria and Escherichia-Shigella). Conclusion This study suggested that TA might exert a beneficial effect on renal interstitial fibrosis in DN mice by modulating gut microbiota dysbiosis, ameliorating impairments in the intestinal mucosa barrier, reducing the production and release of LPS, inhibiting the activation of NLRP3/ASC/Caspase-1 signaling pathway, and repressing renal inflammatory.
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Affiliation(s)
- Shujiao Zhang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Key Laboratory of Chinese Internal Medicine of Ministry of Education, Beijing Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Shuaixing Zhang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Key Laboratory of Chinese Internal Medicine of Ministry of Education, Beijing Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Xuehui Bai
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Key Laboratory of Chinese Internal Medicine of Ministry of Education, Beijing Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Yaoxian Wang
- Henan University of Chinese Medicine, Zhengzhou, China
| | - Yuning Liu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Key Laboratory of Chinese Internal Medicine of Ministry of Education, Beijing Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Renal Research Institution of Beijing University of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Weijing Liu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Key Laboratory of Chinese Internal Medicine of Ministry of Education, Beijing Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Renal Research Institution of Beijing University of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
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Jiang X, Cui X, Nie R, You H, Tang Z, Liu W. Network pharmacology-based analysis on the key mechanisms of Yiguanjian acting on chronic hepatitis. Heliyon 2024; 10:e29977. [PMID: 38756592 PMCID: PMC11096846 DOI: 10.1016/j.heliyon.2024.e29977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 04/17/2024] [Accepted: 04/18/2024] [Indexed: 05/18/2024] Open
Abstract
Chronic hepatitis (CH) encompasses a prevalent array of liver conditions that significantly contribute to global morbidity and mortality. Yiguanjian (YGJ) is a classical traditional Chinese medicine with a long history of medicinal as a treatment for CH. Although it has been reported that YGJ can reduce liver inflammation, the intricate mechanism requires further elucidation. We used network pharmacology approaches in this work, such as gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and network-based analysis of protein-protein interactions (PPIs), to clarify the pharmacological constituents, potential therapeutic targets, and YGJ signaling pathways associated with CH. Employing the random walk restart (RWR) algorithm, we identified GNAS, GNB1, CYP2E1, SFTPC, F2, MAPK3, PLG, SRC, HDAC1, and STAT3 as pivotal targets within the PPI network of YGJ-CH. YGJ attenuated liver inflammation and inhibited GNAS/STAT3 signaling in vivo. In vitro, we overexpressed the GNAS gene further to verify the critical role of GNAS in YGJ treatment. Our findings highlight GNAS/STAT3 as a promising therapeutic target for CH, providing a basis and direction for future investigations.
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Affiliation(s)
- Xiaodan Jiang
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Xinyi Cui
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Ruifang Nie
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Hongjie You
- School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Zuoqing Tang
- School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Wenlan Liu
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
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Shen C, Luo Z, Ma S, Yu C, Lai T, Tang S, Zhang H, Zhang J, Xu W, Xu J. Microbe-Derived Antioxidants Protect IPEC-1 Cells from H 2O 2-Induced Oxidative Stress, Inflammation and Tight Junction Protein Disruption via Activating the Nrf2 Pathway to Inhibit the ROS/NLRP3/IL-1β Signaling Pathway. Antioxidants (Basel) 2024; 13:533. [PMID: 38790638 PMCID: PMC11117695 DOI: 10.3390/antiox13050533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 04/15/2024] [Accepted: 04/16/2024] [Indexed: 05/26/2024] Open
Abstract
Oxidative stress can induce inflammation and tight junction disruption in enterocytes. The initiation of inflammation is thought to commence with the activation of the ROS/NLRP3/IL-1β signaling pathway, marking a crucial starting point in the process. In our previous studies, we found that microbe-derived antioxidants (MAs) showed significant potential in enhancing both antioxidant capabilities and anti-inflammatory effects. The main aim of this research was to investigate the ability of MAs to protect cells from oxidative stress caused by H2O2, to reduce inflammatory responses, and to maintain the integrity of tight junction proteins by modulating the ROS/NLRP3/IL-1β signaling pathway. IPEC-1 cells (1 × 104 cells/well) were initially exposed to 100 mg/L of MAs for 12 h, after which they were subjected to 1 mM H2O2 treatment for 1 h. We utilized small interfering RNA (siRNA) to inhibit the expression of NLRP3 and Nrf2. Inflammatory factors such as IL-1β and antioxidant enzyme activity levels were detected by ELISA. Oxidative stress marker ROS was examined by fluorescence analysis. The NLRP3/IL-1β signaling pathway, Nrf2/HO-1 signaling pathway and tight junction proteins (ZO-1 and Occludin) were detected by RT-qPCR or Western blotting. In our research, it was observed that MA treatment effectively suppressed the notable increase in H2O2-induced inflammatory markers (TNF-α, IL-1β, and IL-18), decreased ROS accumulation, mitigated the expression of NLRP3, ASC, and caspase-1, and promoted the expression of ZO-1 and Occludin. After silencing the NLRP3 gene with siRNA, the protective influence of MAs was observed to be linked with the NLRP3 inflammasome. Additional investigations demonstrated that the treatment with MAs triggered the activation of Nrf2, facilitating its translocation into the nucleus. This process resulted in a notable upregulation of Nrf2, NQO1, and HO-1 expression, along with the initiation of the Nrf2-HO-1 signaling pathway. Consequently, there was an enhancement in the activities of antioxidant enzymes like SOD, GSH-Px, and CAT, which effectively mitigated the accumulation of ROS, thereby ameliorating the oxidative stress state. The antioxidant effectiveness of MAs was additionally heightened in the presence of SFN, an activator of Nrf2. The antioxidant and anti-inflammatory functions of MAs and their role in regulating intestinal epithelial tight junction protein disruption were significantly affected after siRNA knockdown of the Nrf2 gene. These findings suggest that MAs have the potential to reduce H2O2-triggered oxidative stress, inflammation, and disruption of intestinal epithelial tight junction proteins in IPEC-1 cells. This reduction is achieved by blocking the ROS/NLRP3/IL-1β signaling pathway through the activation of the Nrf2 pathway.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Jianxiong Xu
- Shanghai Key Laboratory of Veterinary Biotechnology/Shanghai Collaborative Innovation Center of Agri-Seeds, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200240, China; (C.S.); (Z.L.); (S.M.); (T.L.); (S.T.); (H.Z.); (J.Z.); (W.X.)
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Lv C, Cheng T, Zhang B, Sun K, Lu K. Triptolide protects against podocyte injury in diabetic nephropathy by activating the Nrf2/HO-1 pathway and inhibiting the NLRP3 inflammasome pathway. Ren Fail 2023; 45:2165103. [PMID: 36938748 PMCID: PMC10035962 DOI: 10.1080/0886022x.2023.2165103] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/21/2023] Open
Abstract
Objectives: Diabetic nephropathy (DN) is the most common microvascular complication of diabetes mellitus. This study investigated the mechanism of triptolide (TP) in podocyte injury in DN.Methods: DN mouse models were established by feeding with a high-fat diet and injecting with streptozocin and MPC5 podocyte injury models were induced by high-glucose (HG), followed by TP treatment. Fasting blood glucose and renal function indicators, such as 24 h urine albumin (UAlb), serum creatinine (SCr), blood urea nitrogen (BUN), and kidney/body weight ratio of mice were examined. H&E and TUNEL staining were performed for evaluating pathological changes and apoptosis in renal tissue. The podocyte markers, reactive oxygen species (ROS), oxidative stress (OS), serum inflammatory cytokines, nuclear factor-erythroid 2-related factor 2 (Nrf2) pathway-related proteins, and pyroptosis were detected by Western blotting and corresponding kits. MPC5 cell viability and pyroptosis were evaluated by MTT and Hoechst 33342/PI double-fluorescence staining. Nrf2 inhibitor ML385 was used to verify the regulation of TP on Nrf2.Results: TP improved renal function and histopathological injury of DN mice, alleviated podocytes injury, reduced OS and ROS by activating the Nrf2/heme oxygenase-1 (HO-1) pathway, and weakened pyroptosis by inhibiting the nod-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome pathway. In vitro experiments further verified the inhibition of TP on OS and pyroptosis by mediating the Nrf2/HO-1 and NLRP3 inflammasome pathways. Inhibition of Nrf2 reversed the protective effect of TP on MPC5 cells.Conclusions: Overall, TP alleviated podocyte injury in DN by inhibiting OS and pyroptosis via Nrf2/ROS/NLRP3 axis.
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Affiliation(s)
- Chenlei Lv
- Department of Nephrology, The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Tianyang Cheng
- Department of Nephrology, The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Bingbing Zhang
- College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Ke Sun
- Department of Nephrology, The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Keda Lu
- Department of Nephrology, The Third Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
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Ma X, Pan B, Wang L, Feng Z, Peng C. Network pharmacology and molecular docking elucidate potential mechanisms of Eucommia ulmoides in hepatic ischemia-reperfusion injury. Sci Rep 2023; 13:20716. [PMID: 38001230 PMCID: PMC10673959 DOI: 10.1038/s41598-023-47918-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Accepted: 11/20/2023] [Indexed: 11/26/2023] Open
Abstract
Eucommia ulmoides (EU) and its diverse extracts have demonstrated antioxidative, anti-inflammatory, and cytoprotective properties against hepatic ischemia-reperfusion injury (HIRI). However, the primary constituents of EU and their putative mechanisms remain elusive. This study aims to explore the potential mechanisms of EU in the prevention and treatment of HIRI by employing network pharmacology and molecular docking methodologies. The main components and corresponding protein targets of EU were searched in the literature and TCMSP, and the compound target network was constructed by Cytoscape 3.9.1. Liver ischemia-reperfusion injury targets were searched in OMIM and GeneCards databases. The intersection points of compound targets and disease targets were obtained, and the overlapping targets were imported into the STRING database to construct the PPI network. We further analyzed the targets for GO and KEGG enrichment. Finally, molecular docking studies were performed on the core targets and active compounds. The component-target network unveiled a total of 26 efficacious bioactive compounds corresponding to 207 target proteins. Notably, the top-ranking compounds based on degree centrality were quercetin, β-sitosterol, and gallic acid. Within the PPI network, the highest degree centrality encompassed RELA, AKT1, TP53. GO and KEGG enrichment analysis elucidated that EU in HIRI primarily engaged in positive regulation of gene expression, positive transcriptional regulation via RNA polymerase II promoter, negative modulation of apoptotic processes, positive regulation of transcription from DNA templates, and drug responsiveness, among other biological processes. Key pathways included cancer pathways, RAGE signaling pathway, lipid metabolism, atherosclerosis, TNF signaling pathway, PI3K-Akt signaling pathway, and apoptotic pathways. Molecular docking analysis revealed robust affinities between quercetin, β-sitosterol, gallic acid, and RELA, AKT1, TP53, respectively. This study reveals EU exhibits substantial potential in mitigating and treating HIRI through multifaceted targeting and involvement in intricate signaling pathways.
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Affiliation(s)
- Xuan Ma
- Department of General Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, Guizhou, China
| | - Bochen Pan
- Department of Biochemistry and Molecular Biology, Zunyi Medical University, Zunyi, 563000, Guizhou, China
| | - Liusong Wang
- Department of General Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, Guizhou, China
| | - Zanjie Feng
- Clinical Medical Research Center, The affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
| | - Cijun Peng
- Department of Hepatobiliary Surgery, The affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
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10
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Hu J, Xie H, Lin N, Yang Y. Penthorum chinense Pursh improves type 2 diabetes mellitus via modulating gut microbiota in db/db mice. BMC Complement Med Ther 2023; 23:314. [PMID: 37689643 PMCID: PMC10492416 DOI: 10.1186/s12906-023-04136-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Accepted: 08/22/2023] [Indexed: 09/11/2023] Open
Abstract
Penthorum chinense Pursh (P. chinense) has been traditionally used as hepatoprotective food and medicine for hundreds of years due to its significant antioxidant and anti-inflammatory activities. However, the efficacy and mechanisms of action of P. chinense in type 2 diabetes mellitus were not fully understood. In this study, we found that P. chinense extract (PCP) supplementation resulted in reduced body weight and hyperglycemia, improved pancreatic tissue injury and insulin sensitivity, and decreased inflammatory cytokines expression in spontaneously diabetic db/db mice. 16S rRNA gene sequencing of fecal samples showed that PCP administration decreased the abundance of Firmicutes and increased the proportion of Bacteroidetes at the phylum level. Moreover, Muribaculum, Barnesiella, Prevotella, and Mucinivorans were enriched, with Desulfovibrio and Lactobacillus lowered at the genus level in db/db mice with PCP supplementation. These results suggested that PCP may ameliorate hyperglycemia, insulin resistance, and inflammation by remodeling the gut microbiota in db/db mice.
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Affiliation(s)
- Jilei Hu
- Clinical Nutrition, The General Hospital of Western Theater Command, Chengdu, 610083, P. R. China
- School of Public Health, Southwest Medical University, Luzhou, 646000, P. R. China
| | - Huibo Xie
- School of Public Health, Southwest Medical University, Luzhou, 646000, P. R. China
| | - Ning Lin
- Clinical Nutrition, The General Hospital of Western Theater Command, Chengdu, 610083, P. R. China.
| | - Yan Yang
- School of Public Health, Southwest Medical University, Luzhou, 646000, P. R. China.
- Environmental health effects and risk assessment Key Laboratory of Luzhou, School of Public Health, Southwest Medical University, Luzhou, 646000, P. R. China.
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11
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Lu Q, Hu Y, Nabi F, Li Z, Janyaro H, Zhu W, Liu J. Effect of Penthorum Chinense Pursh Compound on AFB1-Induced Immune Imbalance via JAK/STAT Signaling Pathway in Spleen of Broiler Chicken. Vet Sci 2023; 10:521. [PMID: 37624308 PMCID: PMC10459701 DOI: 10.3390/vetsci10080521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 07/18/2023] [Accepted: 08/10/2023] [Indexed: 08/26/2023] Open
Abstract
Aflatoxin B1(AFB1) is the main secondary metabolite produced by Aspergillus flavus, which is highly toxic, carcinogenic, mutagenic and teratogenic. It can induce immune imbalance in animals or humans. Penthorum chinense Pursh (PCP) is a traditional herbal plant that has been used as a hepatoprotective drug with a long history in China. Based on the theory of traditional Chinese Medicine, we prepared Penthorum chinense Pursh Compound (PCPC) by combining four herbal medicines: 5 g Penthorum chinense Pursh, 5 g Radix bupleuri, 1 g Artemisia capillaris Thunb and 1 g Radix glycyrrhizae. The role of the Penthorum chinense Pursh Compound (PCPC) in preventing AFB1-induced immune imbalance in broiler chickens was studied. A total of 180 broiler chickens were equally distributed in six groups: controls, AFB1, YCHD and high-, medium- and low-dose PCPC treatment groups. After 28 days, broilers were anesthetized, and serum spleen and thymus samples were collected for analysis. Results show that AFB1 significantly increased and decreased the relative organ weight of the spleen and thymus, respectively. Pathological section of hematoxylin/eosin (H&E) stained spleen sections showed that AFB1 resulted in splenic tissue damage. Both the serum levels of Immunoglobulin A (IgA) and Immunoglobulin G (IgG) were suppressed in the AFB1 group. IL-6 was elevated in the AFB1 group. The balance between pro-inflammatory cytokines (IFN-γ and IL-2) and anti-inflammatory cytokine (IL-4) was disturbed by AFB1. The apoptosis-related protein and JAK/STAT pathway-related gene expression indicated that AFB1-induced apoptosis via JAK/STAT pathway. PCPC has proven its immunoprotective effects by preventing AFB1-induced immune imbalance. PCPC can be applied as a novel immune-modulating medicine in broiler chickens. It can be applied as a novel immune modulator in veterinary clinical practice.
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Affiliation(s)
- Qin Lu
- Immunology Research Center of Medical Research Institute, Southwest University, Chongqing 402460, China;
| | - Yu Hu
- College of Veterinary Medicine, Southwest University, Chongqing 402460, China; (Y.H.); (F.N.); (Z.L.)
- Wanzhou District Livestock Industry Development Center, Chongqing 404020, China
| | - Fazul Nabi
- College of Veterinary Medicine, Southwest University, Chongqing 402460, China; (Y.H.); (F.N.); (Z.L.)
| | - Zhenzhen Li
- College of Veterinary Medicine, Southwest University, Chongqing 402460, China; (Y.H.); (F.N.); (Z.L.)
- College of Animal Science and Technology, Chongqing Three Gorges Vocational College, Chongqing 404155, China
| | - Habibullah Janyaro
- Department of Veterinary Surgery, Shaheed Benazir Bhutto University of Veterinary and Animal Science, Sakrand 67210, Pakistan;
| | - Wenyan Zhu
- College of Pharmacy, Chongqing Medical University, Chongqing 400016, China
- Chongqing Engineering Research Center of Pharmaceutical Sciences, Chongqing Medical and Pharmaceutical College, Chongqing 401331, China
| | - Juan Liu
- Immunology Research Center of Medical Research Institute, Southwest University, Chongqing 402460, China;
- College of Veterinary Medicine, Southwest University, Chongqing 402460, China; (Y.H.); (F.N.); (Z.L.)
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An Updated Review on Efficiency of Penthorum chinense Pursh in Traditional Uses, Toxicology, and Clinical Trials. BIOMED RESEARCH INTERNATIONAL 2023; 2023:4254051. [PMID: 36852294 PMCID: PMC9966574 DOI: 10.1155/2023/4254051] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 01/02/2023] [Accepted: 01/06/2023] [Indexed: 02/20/2023]
Abstract
Traditional Chinese medicines (TCM) play an important role in the control and treatment of several animal diseases. Penthorum chinense Pursh (PCP) is a famous plant for its use in traditional medication practice and therapeutic effects in numerous pathological conditions. In China, PCP is utilized for both food and medication due to numerous bioactivities. PCP is widely administered in prevention and treatment of traumatic injury, edema, and liver diseases with functions of reducing swelling, support diuresis, blood stasis, and mitigation symptoms of excessive alcohol intake. Recently, PCP highlighted for research trials in various fields including pharmacology, pharmacognosy, cosmeceuticals, nutraceuticals, and pharmaceuticals due to medicinal significance with less toxicity and an effective ethnomedicine in veterinary practice. PCP contains diverse important ingredients such as flavonoids, organic acids, coumarins, lignans, polyphenols, and sterols that are important bioactive constituents of PCP exerting the therapeutic benefits and organ-protecting effects. In veterinary, PCP extract, compound, and phytochemicals/biomolecules significantly reversed the liver and kidney injuries, via antioxidation, oxidative stress, apoptosis, mitochondrial signaling pathways, and related genes. PCP water extract and compounds also proved in animal and humans' clinical trial for their hepatoprotective, antiaging, nephroprotective, anti-inflammatory, antidiabetic, antibacterial, antiapoptotic, immune regulation, and antioxidative stress pathways. This updated review spotlighted the current information on efficiency and application of PCP by compiling and reviewing recent publications on animal research. In addition, this review discussed the toxicology, traditional use, comparative, and clinical application of PCP in veterinary practices to authenticate and find out new perspectives on the research and development of this herbal medicine.
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Zhao X, Zhou M, Deng Y, Guo C, Liao L, He L, Peng C, Li Y. Functional Teas from Penthorum chinense Pursh Alleviates Ethanol-Induced Hepatic Oxidative Stress and Autophagy Impairment in Zebrafish via Modulating the AMPK/p62/Nrf2/mTOR Signaling Axis. PLANT FOODS FOR HUMAN NUTRITION (DORDRECHT, NETHERLANDS) 2022; 77:514-520. [PMID: 36103040 DOI: 10.1007/s11130-022-01010-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 08/22/2022] [Indexed: 06/15/2023]
Abstract
Penthorum chinense Pursh (PCP), a medicinal and edible plant, is widely used in many clinical liver diseases. Oxidative stress and autophagy impairment play crucial roles in the pathophysiology of alcoholic liver disease (ALD). Therefore, the aim of this study was to elucidate the mechanism of PCP in attenuating ethanol-induced liver injury. The liver-specific transgenic zebrafish larvae (lfabp: EGFP) at three days post-fertilization (3 dpf) were treated with different concentrations of PCP (100, 50 and 25 μg/mL) for 48 h, after soaked in a 350 mM ethanol for 32 h. Whole-mount oil red O, H&E staining and biochemical kits were used to detect fatty liver function and fat accumulation, western blot (WB) and immunofluorescence were used to determine proteins expression, and RT-qPCR was used to further verify the related gene expression. PCP restored zebrafish liver function. Additionally, PCP (as dose-dependent) blocked the expression of cytochrome P450 2E1 (CYP2E1), the production of intracellular reactive oxygen species (ROS) and alleviated liver fat accumulation and oxidative damage. PCP exerted its hepatoprotective function by downregulating the expression of kelch-like ECH-associated protein 1 (Keap1), up-regulating the expression of nucleus factor-E2-related factor 2 (Nrf2) (transferring to the nucleus), and attenuating systemic oxidative stress. Furthermore, PCP reduced the expression of sequestosome 1 (p62/SQSTM1, p62), Atg13, and Beclin 1, up-regulating autophagy signaling pathway. Taken together, the molecular evidence that PCP protected the ethanol-induced hepatic oxidative stress and autophagy impairment through activating AMPK/p62/Nrf2/mTOR signaling axis.
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Affiliation(s)
- Xingtao Zhao
- State Key Laboratory of Southwestern Chinese Medicine Resources, Ministry of Education, Chengdu, 611137, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Sichuan Province, 1166 Liutai Avenue, Wenjiang District, Chengdu, 611137, China
| | - Mengting Zhou
- State Key Laboratory of Southwestern Chinese Medicine Resources, Ministry of Education, Chengdu, 611137, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Sichuan Province, 1166 Liutai Avenue, Wenjiang District, Chengdu, 611137, China
| | - Ying Deng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Ministry of Education, Chengdu, 611137, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Sichuan Province, 1166 Liutai Avenue, Wenjiang District, Chengdu, 611137, China
| | - Chaocheng Guo
- State Key Laboratory of Southwestern Chinese Medicine Resources, Ministry of Education, Chengdu, 611137, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Sichuan Province, 1166 Liutai Avenue, Wenjiang District, Chengdu, 611137, China
| | - Li Liao
- State Key Laboratory of Southwestern Chinese Medicine Resources, Ministry of Education, Chengdu, 611137, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Sichuan Province, 1166 Liutai Avenue, Wenjiang District, Chengdu, 611137, China
| | - Linfeng He
- State Key Laboratory of Southwestern Chinese Medicine Resources, Ministry of Education, Chengdu, 611137, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Sichuan Province, 1166 Liutai Avenue, Wenjiang District, Chengdu, 611137, China
| | - Cheng Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Ministry of Education, Chengdu, 611137, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Sichuan Province, 1166 Liutai Avenue, Wenjiang District, Chengdu, 611137, China
| | - Yunxia Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, Ministry of Education, Chengdu, 611137, China.
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Sichuan Province, 1166 Liutai Avenue, Wenjiang District, Chengdu, 611137, China.
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Liu DL, Liu SJ, Hu SQ, Chen YC, Guo J. Probing the Potential Mechanism of Quercetin and Kaempferol against Heat Stress-Induced Sertoli Cell Injury: Through Integrating Network Pharmacology and Experimental Validation. Int J Mol Sci 2022; 23:ijms231911163. [PMID: 36232461 PMCID: PMC9570440 DOI: 10.3390/ijms231911163] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 09/18/2022] [Accepted: 09/19/2022] [Indexed: 11/16/2022] Open
Abstract
Quercetin and kaempferol are flavonoids widely present in fruits, vegetables, and medicinal plants. They have attracted much attention due to their antioxidant, anti-inflammatory, anticancer, antibacterial, and neuroprotective properties. As the guarantee cells in direct contact with germ cells, Sertoli cells exert the role of support, nutrition, and protection in spermatogenesis. In the current study, network pharmacology was used to explore the targets and signaling pathways of quercetin and kaempferol in treating spermatogenic disorders. In vitro experiments were integrated to verify the results of quercetin and kaempferol against heat stress-induced Sertoli cell injury. The online platform was used to analyze the GO biological pathway and KEGG pathway. The results of the network pharmacology showed that quercetin and kaempferol intervention in spermatogenesis disorders were mostly targeting the oxidative response to oxidative stress, the ROS metabolic process and the NFκB pathway. The results of the cell experiment showed that Quercetin and kaempferol can prevent the decline of cell viability induced by heat stress, reduce the expression levels of HSP70 and ROS in Sertoli cells, reduce p-NF-κB-p65 and p-IκB levels, up-regulate the expression of occludin, vimentin and F-actin in Sertoli cells, and protect cell structure. Our research is the first to demonstrate that quercetin and kaempferol may exert effects in resisting the injury of cell viability and structure under heat stress.
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