|
1
|
Okasha H, Nasr SM, Hafiz E, Samir S. Investigating the anticancer effect of purified rCec-B peptide in a DEN murine model: Insights into tumorigenesis prevention, bioavailability, and molecular mechanisms. Arch Biochem Biophys 2025; 770:110468. [PMID: 40383465 DOI: 10.1016/j.abb.2025.110468] [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: 01/11/2025] [Revised: 04/25/2025] [Accepted: 05/13/2025] [Indexed: 05/20/2025]
Abstract
BACKGROUND Anticancer peptides (ACPs) are considered cancer therapeutic candidates through decreasing tumor cell proliferation, migration, and angiogenesis. OBJECTIVES Determine the therapeutic potential of purified recombinant cecropin-B (rCec-B) peptide in vivo on HCC murine model and its effect, particularly on the activation of apoptotic pathways. METHODS Intact mass analysis of rCec-B was confirmed using mass spectrometry, molecular docking on epidermal growth factor receptor (EGFR) apoptosis was studied, and an in vivo acute toxicity study, followed by establishing the HCC model using diethylnitrosamine (DEN) was performed. Biochemical, molecular, and immunohistochemical parameters were detected in serum and liver samples. RESULTS A molecular docking study on EGFR showed a predicted binding model of rCec-B as a ligand with a high binding affinity equal to -50.167 kcal/mol. The peptide showed remarkable safety in the studied high doses. The liver of the HCC untreated model had a distorted lobular pattern with minimal to mild nuclear atypia. In HCC treated with rCec-B, liver sections had periportal inflammation, hydropic degeneration with focal cholestasis, and apoptotic hepatocellular bodies. Molecular detection and immunohistochemical analysis showed an upregulation of the oncogenic marker, Bcl-2, and a downregulation of apoptotic markers (FAS, FAS-L, Cas-8, BAX, and BID) in the untreated DEN group. Treated groups had a significant increase in all the detected apoptotic markers. CONCLUSION This study sheds light on the potential rCec-B's role in suppressing HCC progression. Hence, this peptide could be considered a promising therapeutic drug alone or in combination with other drugs to alleviate HCC treatment.
Collapse
Affiliation(s)
- Hend Okasha
- Biochemistry and Molecular Biology Department, Theodor Bilharz Research Institute, Warrak El-Hadar, Imbaba, 12411, Giza, Egypt.
| | - Sami Mohamed Nasr
- Biochemistry and Molecular Biology Department, Theodor Bilharz Research Institute, Warrak El-Hadar, Imbaba, 12411, Giza, Egypt; School of Biotechnology, Badr University in Cairo, Cairo, Badr City, 11829, Egypt.
| | - Ehab Hafiz
- Electron Microscopy Department, Theodor Bilharz Research Institute, Warrak El-Hadar, Imbaba, 12411, Giza, Egypt.
| | - Safia Samir
- Biochemistry and Molecular Biology Department, Theodor Bilharz Research Institute, Warrak El-Hadar, Imbaba, 12411, Giza, Egypt.
| |
Collapse
|
|
2
|
Zhao Q, Dong G, Zhang X, Gao X, Li H, Guo Z, Gong L, Yang H. Unraveling the mechanism of core prescription in primary liver cancer: integrative analysis through data mining, network pharmacology, and molecular simulation. In Silico Pharmacol 2025; 13:63. [PMID: 40255256 PMCID: PMC12003234 DOI: 10.1007/s40203-025-00352-2] [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: 12/11/2024] [Accepted: 03/31/2025] [Indexed: 04/22/2025] Open
Abstract
This study aims to identify core Traditional Chinese Medicine compound prescriptions (TCM CPs) for Primary Liver Cancer (PLC) and their underlying mechanisms. A comprehensive search was conducted using China National Knowledge Infrastructure (CNKI) and the Chinese Medical Code V5.0, identifying 151 TCM CPs. Medication frequency and association rules were analyzed with TCMICS V3.0, while active compounds were identified via TCMSP and TCMIP V2.0. Targets were predicted using Swiss Target Prediction, and disease targets from DisGeNET, OMIM, and GeneCards were cross-referenced. A protein-protein interaction (PPI) network was constructed, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis using DAVID. In the process of studying active compounds, an orthogonal experiment was carried out on the extraction process of relevant herbs. The results of the orthogonal experiment and range analysis showed that for the extraction rate of the extract and the content of paeoniflorin, the decoction cycles had the most significant impact, followed by soaking time and water volume. The optimal extraction conditions were determined as soaking time of 30 min, water volume of tenfold, and 3 decoction cycles. Under these conditions, the extract yield reached 42.49%, and the paeoniflorin content was 73.60 mg/25.02 g crude herb (equivalent to 2.94 mg/g). ANOVA analysis further confirmed the significance of these factors. The results revealed 109 common targets between TCM component targets and disease targets, with key targets including STAT3, SRC, AKT1, HRAS, and PIK3CA. Molecular docking showed strong binding affinities of paeoniflorin and 3,5,6,7-tetramethoxy-2-(3,4,5-trimethoxyphenyl) chromone to PLC targets, with ADME predictions favoring paeoniflorin. Furthermore, Molecular Dynamics (MD) simulations revealed that paeoniflorin maintains stable binding to the target proteins, demonstrating promising conformational stability. The CCK-8 assay demonstrated that the core TCM CP exerted a dose-dependent inhibitory effect on HepG2 cells. After 24 h of intervention, the IC50 values of paeoniflorin and the TCM CP on HepG2 cells were 17.58 μg/mL and 120.5 μg/mL, respectively, which confirmed their anti-proliferative activity against PLC. This study identifies key active compounds and investigates their roles in modulating the Ras/Raf/MEK/ERK, AKT/NF-κB, and JAK-STAT signaling pathways, offering valuable insights into the therapeutic potential of TCM for PLC treatment. Supplementary Information The online version contains supplementary material available at 10.1007/s40203-025-00352-2.
Collapse
Affiliation(s)
- Qingsi Zhao
- Yanjing Medical College, Capital Medical University, Beijing, 101300 China
| | - Gaoyue Dong
- Yanjing Medical College, Capital Medical University, Beijing, 101300 China
| | - Xinyue Zhang
- Yanjing Medical College, Capital Medical University, Beijing, 101300 China
| | - Xing Gao
- Yanjing Medical College, Capital Medical University, Beijing, 101300 China
| | - Hongyu Li
- Yanjing Medical College, Capital Medical University, Beijing, 101300 China
| | - Zhongyuan Guo
- College of Medicine, Henan University of Chinese Medicine, Zhengzhou, 450046 Henan China
- Institue of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700 China
| | - Leilei Gong
- Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, 100026 China
| | - Hong Yang
- Yanjing Medical College, Capital Medical University, Beijing, 101300 China
| |
Collapse
|
|
3
|
Gao W, Wang M, Xu W, Ma R, Wang X, Sun T, Li P, Li F, He Y, Xie X, Pang X, Zhou Y, Pang G. Modified weiling decoction inhibited excessive autophagy via AKT/mTOR/ULK1 pathway to alleviate T2DM: Integrating network pharmacology and experimental validation. JOURNAL OF ETHNOPHARMACOLOGY 2025; 347:119753. [PMID: 40194640 DOI: 10.1016/j.jep.2025.119753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Revised: 04/03/2025] [Accepted: 04/04/2025] [Indexed: 04/09/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Weiling Decoction is a traditional Chinese herbal formula that has the function of removing dampness and transforming turbidity, and it is widely used in the treatment of metabolic diseases. The hypoglycemic and antihyperlipidemic effects of Modified Weiling Decoction (MWLD) have been clinically verified in patients with type 2 diabetes mellitus (T2DM), however, the molecular mechanism remains unclear. AIM OF THE STUDY To explore the hypoglycemic mechanism of MWLD based on integrative network pharmacology and experimental validation in vivo and in vitro. MATERIALS AND METHODS The overlap between T2DM-related genes and target genes of MWLD were deemed to the potential targets of MWLD in alleviating T2DM. Protein-protein interaction analysis was performed to find the core targets from above-mentioned potential targets, and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and Gene Ontology (GO) analysis were carried out to gain the key pathways involved in the T2DM improvement by MWLD. T2DM mice and palmitic acid-induced HepG2 cells were employed to validate the mechanism of MWLD predicated by network pharmacology. RESULTS A total of 292 target genes from 113 bioactive compounds in MWLD were identified, among of which 42 genes were recognized as core genes of MWLD in ameliorating T2DM. KEGG analysis showed that the therapeutic effect of MWLD on T2DM may be associated with insulin resistance (IR), islet β cell dysfunction, AKT, and MAPK. We found that MWLD significantly reduced fasting blood glucose and improved oral glucose tolerance in T2DM mice. Meanwhile, MWLD activated the AKT/GSK3β pathway to increase liver glycogen production and improve glucose metabolism in T2DM mice. MWLD activated the AKT/mTOR/ULK1 signaling pathway and reversed the increase of autophagy associated proteins (LC3II, Beclin1, Cathepsin B, and LAMP2) in the liver of T2DM mice. Similar results were also confirmed palmitic acid-induced HepG2 cells, an in vitro model for IR. Conversely, AKT inhibitor MK2206 neutralized the effects of MWLD on autophagy and glucose uptake, which was consistent with these results that the main active components of MWLD show strong affinity with AKT1 analyzed by molecular docking. CONCLUSION Both in vivo and in vitro experiments showed that MWLD inhibited excessive autophagy through the AKT/mTOR/ULK1 pathway to improve hepatic IR, and stimulate liver glycogen production through AKT/GSK3β pathway.
Collapse
Affiliation(s)
- Weiping Gao
- The Zhongzhou Laboratory for Integrative Biology, School of Pharmacy, Henan University, Kaifeng, 475004, China
| | - Mengwei Wang
- The Zhongzhou Laboratory for Integrative Biology, School of Pharmacy, Henan University, Kaifeng, 475004, China
| | - Wangjun Xu
- The Zhongzhou Laboratory for Integrative Biology, School of Pharmacy, Henan University, Kaifeng, 475004, China
| | - Ruichen Ma
- The Zhongzhou Laboratory for Integrative Biology, School of Pharmacy, Henan University, Kaifeng, 475004, China; Kaifeng Traditional Chinese Medicine Hospital, Kaifeng, 475000, China
| | - Xian Wang
- The Zhongzhou Laboratory for Integrative Biology, School of Pharmacy, Henan University, Kaifeng, 475004, China
| | - Taimeng Sun
- The Zhongzhou Laboratory for Integrative Biology, School of Pharmacy, Henan University, Kaifeng, 475004, China; Kaifeng Traditional Chinese Medicine Hospital, Kaifeng, 475000, China
| | - Penghui Li
- Kaifeng Traditional Chinese Medicine Hospital, Kaifeng, 475000, China
| | - Fangxu Li
- Kaifeng Traditional Chinese Medicine Hospital, Kaifeng, 475000, China
| | - Yangyang He
- The Zhongzhou Laboratory for Integrative Biology, School of Pharmacy, Henan University, Kaifeng, 475004, China
| | - Xinmei Xie
- The Zhongzhou Laboratory for Integrative Biology, School of Pharmacy, Henan University, Kaifeng, 475004, China
| | - Xiaobin Pang
- The Zhongzhou Laboratory for Integrative Biology, School of Pharmacy, Henan University, Kaifeng, 475004, China
| | - Yunfeng Zhou
- The Zhongzhou Laboratory for Integrative Biology, School of Pharmacy, Henan University, Kaifeng, 475004, China.
| | - Guoming Pang
- Kaifeng Traditional Chinese Medicine Hospital, Kaifeng, 475000, China.
| |
Collapse
|
|
4
|
Yang R, Fu X, Wang Z, Xue P, Wu L, Tan X, Peng W, Li K, Gao W, Zeng P. Unlocking the potential of Traditional Chinese Medicine (TCM): Shipi Xiaoji formula (SPXJF) as a novel ferroptosis inducer in hepatocellular carcinoma. JOURNAL OF ETHNOPHARMACOLOGY 2025; 340:119236. [PMID: 39674355 DOI: 10.1016/j.jep.2024.119236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 11/07/2024] [Accepted: 12/09/2024] [Indexed: 12/16/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Hepatocellular Carcinoma (HCC) is a major health concern with limited treatment options. Traditional Chinese Medicine (TCM) offers potential therapeutic approaches for HCC, and SPXJF, a TCM formula, has shown promise in clinical observations for prolonging the survival of liver cancer patients. AIM OF THE STUDY To investigate the anti-tumor effects of SPXJF on HCC cells and explore its potential mechanism, focusing on ferroptosis induction. MATERIALS AND METHODS LC/Q-TOF-MS was used for compound identification. Cell viability assays, EdU proliferation assay, colony formation assay, wound healing assay, Transwell assay, and Western-blotting were conducted to evaluate the effects of SPXJF on HCC cell proliferation, migration, and invasion. Bioinformatics analysis and RT-PCR were employed to identify potential ferroptosis-related genes and validate the results. Ferroptosis induction was investigated using ferroptosis inhibitors, ROS and lipid peroxidation detection, and TEM. In vivo experiments using a subcutaneous xenograft tumor model confirmed the anti-tumor effects of SPXJF and its ability to induce ferroptosis in HCC. RESULTS SPXJF effectively inhibited the proliferation, migration, and invasion of HCC cells in vitro. The mechanism of action was found to be related to the induction of ferroptosis, as evidenced by increased intracellular Fe2+ and ROS levels, decreased GSH levels, altered mitochondrial morphology, and upregulation of ferroptosis-inducing proteins ACSL4 and LPCAT3, along with downregulation of ferroptosis-inhibiting proteins xCT and GPX4. Bioinformatics analysis and RT-PCR further identified GSTZ1, CDC25A, AURKA, NOX4, and CAPG as potential ferroptosis-related genes regulated by SPXJF. In vivo experiments confirmed the anti-tumor effects of SPXJF and its ability to induce ferroptosis in HCC. CONCLUSIONS SPXJF exerts anti-tumor effects on HCC cells by inducing ferroptosis, and its mechanism of action involves the regulation of ferroptosis-related genes and proteins. This study provides a theoretical basis for the clinical treatment of HCC and the development of new anti-cancer drugs, offering a valuable contribution to the field of ethnopharmacology.
Collapse
MESH Headings
- Ferroptosis/drug effects
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/metabolism
- Humans
- Liver Neoplasms/drug therapy
- Liver Neoplasms/pathology
- Liver Neoplasms/metabolism
- Animals
- Drugs, Chinese Herbal/pharmacology
- Drugs, Chinese Herbal/therapeutic use
- Cell Proliferation/drug effects
- Mice
- Mice, Nude
- Cell Line, Tumor
- Cell Movement/drug effects
- Mice, Inbred BALB C
- Medicine, Chinese Traditional
- Xenograft Model Antitumor Assays
- Antineoplastic Agents, Phytogenic/pharmacology
- Male
- Reactive Oxygen Species/metabolism
- Cell Survival/drug effects
Collapse
Affiliation(s)
- Renyi Yang
- Hunan Provincial Hospital of Integrated Traditional Chinese and Western, Cancer Research Institute of Hunan Academy of Traditional Chinese Medicine, Hunan Academy of Chinese Medicine, Hunan, 410006, China; School of Integrated Chinese and Western Medicine, Key Laboratory of Hunan Provincial for Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Hunan, 410208, China
| | - Xinying Fu
- School of Integrated Chinese and Western Medicine, Key Laboratory of Hunan Provincial for Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Hunan, 410208, China
| | - Zhibing Wang
- School of Integrated Chinese and Western Medicine, Key Laboratory of Hunan Provincial for Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Hunan, 410208, China
| | - Peisen Xue
- School of Integrated Chinese and Western Medicine, Key Laboratory of Hunan Provincial for Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Hunan, 410208, China
| | - Ling Wu
- School of Integrated Chinese and Western Medicine, Key Laboratory of Hunan Provincial for Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Hunan, 410208, China
| | - Xiaoning Tan
- Hunan Provincial Hospital of Integrated Traditional Chinese and Western, Cancer Research Institute of Hunan Academy of Traditional Chinese Medicine, Hunan Academy of Chinese Medicine, Hunan, 410006, China
| | - Wei Peng
- Hunan Provincial Hospital of Integrated Traditional Chinese and Western, Cancer Research Institute of Hunan Academy of Traditional Chinese Medicine, Hunan Academy of Chinese Medicine, Hunan, 410006, China
| | - Kexiong Li
- Hunan Provincial Hospital of Integrated Traditional Chinese and Western, Cancer Research Institute of Hunan Academy of Traditional Chinese Medicine, Hunan Academy of Chinese Medicine, Hunan, 410006, China.
| | - Wenhui Gao
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Hunan, 410208, China.
| | - Puhua Zeng
- Hunan Provincial Hospital of Integrated Traditional Chinese and Western, Cancer Research Institute of Hunan Academy of Traditional Chinese Medicine, Hunan Academy of Chinese Medicine, Hunan, 410006, China.
| |
Collapse
|
|
5
|
Wei X, Chang QY, Liu Y, Hua HN, Liu YN, Tang ZH, Mu LQ. Influence of Wild and Cultivated Environments on the Antioxidant and Medicinal Components of Rhodiola sachalinensis A. Boriss. PLANTS (BASEL, SWITZERLAND) 2024; 13:3544. [PMID: 39771241 PMCID: PMC11680074 DOI: 10.3390/plants13243544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 12/16/2024] [Accepted: 12/18/2024] [Indexed: 01/11/2025]
Abstract
Rhodiola sachalinensis A. Boriss., recognized for its significant medicinal potential, is increasingly threatened by overharvesting in wild habitats. This study aims to elucidate the phytochemical and pharmacological distinctions between wild and cultivated R. sachalinensis to support sustainable cultivation practices. Utilizing UPLC and GC-MS, we conducted a comprehensive analysis of primary metabolites (e.g., soluble sugars, amino acids) and secondary metabolites (e.g., phenolic compounds, flavonoids) in both root and aboveground tissues from wild and cultivated sources. Results revealed that habitat plays a critical role in metabolite composition, with wild R. sachalinensis roots showing notably higher antioxidant properties and concentrations of key secondary metabolites, including epigallocatechin, which are linked to the plant's medicinal efficacy. Conversely, cultivated plants demonstrated elevated levels of primary metabolites, reflecting adaptation to nutrient-rich, soil-based growth environments. These findings underscore the pharmacological importance of environmental factors in optimizing R. sachalinensis for medicinal use and highlight essential considerations for its sustainable cultivation strategies.
Collapse
Affiliation(s)
- Xin Wei
- School of Forestry, Northeast Forestry University, Harbin 150040, China; (X.W.); (Q.-Y.C.); (H.-N.H.); (Y.-N.L.)
| | - Qiu-Yang Chang
- School of Forestry, Northeast Forestry University, Harbin 150040, China; (X.W.); (Q.-Y.C.); (H.-N.H.); (Y.-N.L.)
| | - Yang Liu
- Engineering Research Center of Agricultural Microbiology Technology, Ministry of Education, Heilongjiang University, Harbin 150500, China;
| | - He-Nian Hua
- School of Forestry, Northeast Forestry University, Harbin 150040, China; (X.W.); (Q.-Y.C.); (H.-N.H.); (Y.-N.L.)
| | - Ya-Nan Liu
- School of Forestry, Northeast Forestry University, Harbin 150040, China; (X.W.); (Q.-Y.C.); (H.-N.H.); (Y.-N.L.)
| | - Zhong-Hua Tang
- College of Chemistry, Chemical Engineering and Resource Utilization, Northeast Forestry University, Harbin 150040, China;
| | - Li-Qiang Mu
- School of Forestry, Northeast Forestry University, Harbin 150040, China; (X.W.); (Q.-Y.C.); (H.-N.H.); (Y.-N.L.)
| |
Collapse
|
|
6
|
Wu H, Xu J, Zhao W, Lv W, Feng Z, Heng L. Genetic and Functional Changes in Mitochondria in the Pituitary Adenoma: The Pathogenesis and Its Therapy. Antioxidants (Basel) 2024; 13:1514. [PMID: 39765842 PMCID: PMC11727349 DOI: 10.3390/antiox13121514] [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: 10/17/2024] [Revised: 11/26/2024] [Accepted: 12/10/2024] [Indexed: 01/03/2025] Open
Abstract
Pituitary adenoma is a common neoplasm of the pituitary gland. Although most pituitary adenomas are benign, they can pose significant challenges in terms of their consequences and prognosis due to their tendency to invade surrounding tissues and their effects on hormone secretion. The management of pituitary adenomas typically involves surgery, medical therapy, and radiotherapy, each of which has its own limitations. Mitochondria play a crucial role in tumor development and progression by regulating various metabolic processes and signaling pathways within tumor cells and the tumor microenvironment. Multiple studies have indicated that mitochondrial dysfunction is implicated in human pituitary adenomas. Furthermore, several compounds with therapeutic effects on pituitary adenomas have been reported to target mitochondrial function. In this review, we summarize recent studies that highlight the involvement of mitochondrial homeostasis imbalance in the biology of pituitary adenomas. We conclude that mitochondria may represent a promising therapeutic target for the treatment of pituitary adenomas.
Collapse
Affiliation(s)
- Hansen Wu
- Frontier Institute of Science and Technology, Xi’an Jiaotong University, Xi’an 710049, China; (H.W.); (W.Z.)
| | - Jie Xu
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an 710049, China; (J.X.); (W.L.)
| | - Wenxuan Zhao
- Frontier Institute of Science and Technology, Xi’an Jiaotong University, Xi’an 710049, China; (H.W.); (W.Z.)
| | - Weiqiang Lv
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an 710049, China; (J.X.); (W.L.)
| | - Zhihui Feng
- Frontier Institute of Science and Technology, Xi’an Jiaotong University, Xi’an 710049, China; (H.W.); (W.Z.)
- School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao 266071, China
| | - Lijun Heng
- Department of Neurosurgery, Tangdu Hospital, Air Force Medical University, Xi’an 710038, China
| |
Collapse
|
|
7
|
Aslam S, Qasim M, Noor F, Shahid M, Ashfaq UA, Munir S, Al-Harthi HF, Mashraqi MM, Waqas U, Khurshid M. Potential Target Metabolites From Gut Microbiota Against Hepatocellular Carcinoma: A Network Pharmacology and Molecular Docking Study. Int J Microbiol 2024; 2024:4286228. [PMID: 39502516 PMCID: PMC11537736 DOI: 10.1155/2024/4286228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 10/16/2024] [Indexed: 11/08/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, posing significant challenges and economic burdens on healthcare systems. Gut microbiota metabolites have shown promise in cancer treatment, but the specific active metabolites and their key targets remain unclear. This study employed a network pharmacology-based approach to identify potent metabolites of gut microbiota and their key targets. Active metabolites produced by gut microbiota were retrieved using the database gutMGene, and targets associated with these metabolites were identified using the Swiss Target Prediction tool. HCC-related targets were obtained from the GeneCards database, and overlapping targets were selected through a Venn diagram tool. An integrated metabolites-target-pathway network was analyzed to identify active inhibitors against HCC, including p-cresol glucuronide, secoisolariciresinol, glycocholic acid, enterodiol, and citric acid. Molecular docking tests were performed to validate the findings and assess the binding affinity of the metabolites with their target proteins. The study identified AKT1, EGFR, ALB, and TNF genes as potential therapeutic targets against hepatic cancer. The metabolites, p-cresol glucuronide, secoisolariciresinol, glycocholic acid, enterodiol, and citric acid, exhibited significant binding affinity with their respective target proteins. The study also revealed multiple signaling pathways and biological processes associated with the metabolites, demonstrating their preventive effect against HCC. This research utilizes a network pharmacology-based approach to identify potent metabolites of gut microbiota and their key targets for the treatment of HCC. The findings were validated through molecular docking tests, providing a foundation for future studies on anti-HCC metabolites and their mechanisms of action. Furthermore, this study offers insights into the development of novel anti-HCC drugs utilizing gut microbiota metabolites.
Collapse
Affiliation(s)
- Sehar Aslam
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad, Faisalabad, Pakistan
| | - Muhammad Qasim
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad, Faisalabad, Pakistan
| | - Fatima Noor
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad, Faisalabad, Pakistan
- Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore, Pakistan
| | - Muhammad Shahid
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad, Faisalabad, Pakistan
| | - Usman Ali Ashfaq
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad, Faisalabad, Pakistan
| | - Samman Munir
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad, Faisalabad, Pakistan
| | - Helal F. Al-Harthi
- Biology Department, Turabah University College, Taif University, Taif 21995, Saudi Arabia
| | - Mutaib M. Mashraqi
- Department of Clinical Laboratory Sciences, College of Applied Medical Science, Najran University, Najran 61441, Saudi Arabia
| | - Umair Waqas
- College of Science and Engineering, Flinders University, Bedford Park, Adelaide, South Australia, Australia
| | - Mohsin Khurshid
- Institute of Microbiology, Government College University Faisalabad, Faisalabad, Pakistan
| |
Collapse
|
|
8
|
Yan X, Inta A, Yang X, Pandith H, Disayathanoowat T, Yang L. An Investigation of the Effect of the Traditional Naxi Herbal Formula Against Liver Cancer Through Network Pharmacology, Molecular Docking, and In Vitro Experiments. Pharmaceuticals (Basel) 2024; 17:1429. [PMID: 39598341 PMCID: PMC11597843 DOI: 10.3390/ph17111429] [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: 10/02/2024] [Revised: 10/22/2024] [Accepted: 10/23/2024] [Indexed: 11/29/2024] Open
Abstract
Background/Objectives: The formula Chong-Lou-Yao-Fang (CLYF) is an herbal medicinal formulation developed by the indigenous Naxi people for treating liver cancer. This study was to reveal the biological activity, potential targets, and molecular mechanisms of CLYF for cancer treatment. Methods: Network pharmacology, microarray data analysis, survival analysis, and molecular docking were employed to predict potential compounds, targets, and pathways for the treatment of liver cancer. In vitro experiments and Western blot validation were conducted to confirm these predictions. Results: 35 key compounds and 20 core targets were screened from CLYF, involving signaling pathways for PI3K-Akt, MAPK, hepatitis B and C, which were effective for liver cancer treatment. Microarray data analysis and survival analysis indicated that EGFR and TP53 serve as promising biomarkers for diagnosis and prognosis in liver cancer. Molecular docking revealed stable binding between EGFR, TP53, and AKT1 with active ingredients. Cell experiments confirmed that CLYF-A suppressed cell proliferation, induced apoptosis, and caused cell cycle arrest in HepG2 cells, which were associated with a loss of mitochondrial membrane potential. Compared to the control group, the relative protein expression levels of EGFR and AKT1 significantly decreased following treatment with CLYF-A, while TP53 levels increased significantly. Conclusions: Verification of the anticancer activity of CLYF and its potential mechanisms may have important implications for anticancer therapies. Our results may provide a scientific basis for the clinical use of CLYF for cancer treatment and have important implications for developing pharmaceutical preparations, which also need more pharmacological experiments, clinical experiments, and in vivo experiments.
Collapse
Affiliation(s)
- Xiuxiang Yan
- Key Laboratory of Economic Plants and Biotechnology, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China; (X.Y.); (X.Y.)
- Department of Biology, Faculty of Science, Chiang Mai University, 239 Huay Kaew Road, Chiang Mai 50200, Thailand; (A.I.); (H.P.)
| | - Angkhana Inta
- Department of Biology, Faculty of Science, Chiang Mai University, 239 Huay Kaew Road, Chiang Mai 50200, Thailand; (A.I.); (H.P.)
| | - Xuefei Yang
- Key Laboratory of Economic Plants and Biotechnology, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China; (X.Y.); (X.Y.)
- Yunnan International Joint Laboratory of Southeast Asia Biodiversity Conservation, Menglun 666303, China
- Southeast Asia Biodiversity Research Institute, Chinese Academy of Sciences, Yezin, Nay Pyi Taw 05282, Myanmar
| | - Hataichanok Pandith
- Department of Biology, Faculty of Science, Chiang Mai University, 239 Huay Kaew Road, Chiang Mai 50200, Thailand; (A.I.); (H.P.)
| | - Terd Disayathanoowat
- Department of Biology, Faculty of Science, Chiang Mai University, 239 Huay Kaew Road, Chiang Mai 50200, Thailand; (A.I.); (H.P.)
| | - Lixin Yang
- Key Laboratory of Economic Plants and Biotechnology, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China; (X.Y.); (X.Y.)
- Yunnan International Joint Laboratory of Southeast Asia Biodiversity Conservation, Menglun 666303, China
- Southeast Asia Biodiversity Research Institute, Chinese Academy of Sciences, Yezin, Nay Pyi Taw 05282, Myanmar
| |
Collapse
|
|
9
|
Chen Y, Chen X, Zhang J, Zhang X, Wang D, Lu N, Wang C, Yue Y, Yuan Y. Network pharmacology and experimental evidence: ERK/CREB/BDNF signaling pathway is involved in the antidepressive roles of Kaiyu Zhishen decoction. JOURNAL OF ETHNOPHARMACOLOGY 2024; 329:118098. [PMID: 38582152 DOI: 10.1016/j.jep.2024.118098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 03/17/2024] [Accepted: 03/21/2024] [Indexed: 04/08/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Major Depressive Disorder (MDD) emerges as a complex psychosomatic condition, notable for its considerable suicidality and mortality rates. Increasing evidence suggests the efficacy of Chinese herbal medicine in mitigating depression symptoms and offsetting the adverse effects associated with conventional Western therapeutics. Notably, clinical trials have revealed the adjunctive antidepressant potential of Kaiyu Zhishen Decoction (KZD) alongside Western medication. However, the standalone antidepressant efficacy of KZD and its underlying mechanisms merit in-depth investigation. AIM OF THE STUDY This research aims to elucidate the impact of KZD on MDD and delineate its mechanistic pathways through integrated network pharmacological assessments and empirical in vitro and in vivo analyses. MATERIALS AND METHODS To ascertain the optimal antidepressant dosage and mechanism of KZD, a Chronic Unpredictable Mild Stress (CUMS)-induced depression model in mice was established to evaluate depressive behaviors. High-Performance Liquid Chromatography (HPLC) and network pharmacological approaches were employed to predict KZD's antidepressant mechanisms. Subsequently, hippocampal samples were subjected to 4D-DIA proteomic sequencing and validated through Western blot, immunofluorescence, Nissl staining, and pathway antagonist applications. Additionally, cortisol-stimulated PC12 cells were utilized to simulate neuronal damage, analyzing protein and mRNA levels of MAPK-related signals and cell proliferation markers. RESULTS The integration of network pharmacology and HPLC identified kaempferol and quercetin as KZD's principal active compounds for MDD treatment. Proteomic and network pharmacological KEGG pathway analyses indicated the MAPK signaling pathway as a critical regulatory mechanism for KZD's therapeutic effect on MDD. KZD was observed to mitigate CUMS-induced upregulation of p-ERK/ERK, CREB, and BDNF protein expressions in hippocampal cells by attenuating oxidative stress, thereby ameliorating neuronal damage and exerting antidepressant effects. The administration of PD98059 counteracted KZD's improvements in depression-like behaviors and downregulated p-ERK/ERK and BDNF protein expressions in the hippocampus. CONCLUSIONS This investigation corroborates KZD's pivotal, dose-dependent role in antidepressant activity. Both in vivo and in vitro experiments demonstrate KZD's capacity to modulate the ERK-CREB-BDNF signaling pathway by diminishing ROS expression induced by oxidative stress, enhancing neuronal repair, and thus, manifesting antidepressant properties. Accordingly, KZD represents a promising herbal candidate for further antidepressant research.
Collapse
Affiliation(s)
- Ying Chen
- Department of Psychosomatics and Psychiatry, ZhongDa Hospital, School of Medicine, Southeast University, Nanjing, China; Institute of Psychosomatics, Medical School of Southeast University, Nanjing, Jiangsu, 210009, China
| | - Xiangxu Chen
- Department of Orthopaedics, ZhongDa Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Jialin Zhang
- Department of Psychosomatics and Psychiatry, ZhongDa Hospital, School of Medicine, Southeast University, Nanjing, China; Institute of Psychosomatics, Medical School of Southeast University, Nanjing, Jiangsu, 210009, China
| | - Xuejun Zhang
- Department of Orthopaedics, ZhongDa Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Dan Wang
- Department of Psychosomatics and Psychiatry, ZhongDa Hospital, School of Medicine, Southeast University, Nanjing, China; Institute of Psychosomatics, Medical School of Southeast University, Nanjing, Jiangsu, 210009, China
| | - Na Lu
- Department of Psychosomatics and Psychiatry, ZhongDa Hospital, School of Medicine, Southeast University, Nanjing, China; Institute of Psychosomatics, Medical School of Southeast University, Nanjing, Jiangsu, 210009, China
| | - Changsong Wang
- Department of Internal Medicine of Chinese Medicine, ZhongDa Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Yingying Yue
- Department of Psychosomatics and Psychiatry, ZhongDa Hospital, School of Medicine, Southeast University, Nanjing, China; Institute of Psychosomatics, Medical School of Southeast University, Nanjing, Jiangsu, 210009, China.
| | - Yonggui Yuan
- Department of Psychosomatics and Psychiatry, ZhongDa Hospital, School of Medicine, Southeast University, Nanjing, China; Institute of Psychosomatics, Medical School of Southeast University, Nanjing, Jiangsu, 210009, China.
| |
Collapse
|
|
10
|
Jian HY, Liang ZC, Wen H, Zhang Z, Zeng PH. Shi-pi-xiao-ji formula suppresses hepatocellular carcinoma by reducing cellular stiffness through upregulation of acetyl-coA acetyltransferase 1. World J Gastrointest Oncol 2024; 16:2727-2741. [PMID: 38994152 PMCID: PMC11236261 DOI: 10.4251/wjgo.v16.i6.2727] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2024] [Revised: 03/14/2024] [Accepted: 04/23/2024] [Indexed: 06/14/2024] Open
Abstract
BACKGROUND Previous studies have shown that the Shi-pi-xiao-ji (SPXJ) herbal decoction formula is effective in suppressing hepatocellular carcinoma (HCC), but the underlying mechanisms are not known. Therefore, this study investigated whether the antitumor effects of the SPXJ formula in treating HCC were mediated by acetyl-coA acetyltransferase 1 (ACAT1)-regulated cellular stiffness. Through a series of experiments, we concluded that SPXJ inhibits the progression of HCC by upregulating the expression level of ACAT1, lowering the level of cholesterol in the cell membrane, and altering the cellular stiffness, which provides a new idea for the research of traditional Chinese medicine against HCC. AIM To investigate the anti-tumor effects of the SPXJ formula on the malignant progression of HCC. METHODS HCC cells were cultured in vitro with SPXJ-containing serum prepared by injecting SPXJ formula into wild-type mice. The apoptotic rate and proliferative, invasive, and migratory abilities of control and SPXJ-treated HCC cells were compared. Atomic force microscopy was used to determine the cell surface morphology and the Young's modulus values of the control and SPXJ-treated HCC cells. Plasma membrane cholesterol levels in HCC cells were detected using the Amplex Red cholesterol detection kit. ACAT1 protein levels were estimated using western blotting. RESULTS Compared with the vehicle group, SPXJ serum considerably reduced proliferation of HCC cells, increased stiffness and apoptosis of HCC cells, inhibited migration and invasion of HCC cells, decreased plasma membrane cholesterol levels, and upregulated ACAT1 protein levels. However, treatment of HCC cells with the water-soluble cholesterol promoted proliferation, migration, and invasion of HCC cells as well as decreased cell stiffness and plasma membrane cholesterol levels, but did not alter the apoptotic rate and ACAT1 protein expression levels compared with the vehicle control. CONCLUSION SPXJ formula inhibited proliferation, invasion, and migration of HCC cells by decreasing plasma membrane cholesterol levels and altering cellular stiffness through upregulation of ACAT1 protein expression.
Collapse
Affiliation(s)
- Hui-Ying Jian
- Graduate School, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Zi-Cheng Liang
- Graduate School, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Huan Wen
- Hunan Provincial Hospital of Integrated Traditional Chinese and Western, Cancer Research Institute of Hunan Academy of Traditional Chinese Medicine, Hunan Academy of Chinese Medicine, Changsha 410006, Hunan Province, China
| | - Zhen Zhang
- Hunan Provincial Hospital of Integrated Traditional Chinese and Western, Cancer Research Institute of Hunan Academy of Traditional Chinese Medicine, Hunan Academy of Chinese Medicine, Changsha 410006, Hunan Province, China
| | - Pu-Hua Zeng
- Hunan Provincial Hospital of Integrated Traditional Chinese and Western, Cancer Research Institute of Hunan Academy of Traditional Chinese Medicine, Hunan Academy of Chinese Medicine, Changsha 410006, Hunan Province, China
| |
Collapse
|
|
11
|
Jian HY, Liang ZC, Wen H, Zhang Z, Zeng PH. Shi-pi-xiao-ji formula suppresses hepatocellular carcinoma by reducing cellular stiffness through upregulation of acetyl-coA acetyltransferase 1. World J Gastrointest Oncol 2024; 16:2715-2729. [DOI: 10.4251/wjgo.v16.i6.2715] [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: 01/01/2024] [Revised: 03/14/2024] [Accepted: 04/23/2024] [Indexed: 06/13/2024] Open
Abstract
BACKGROUND Previous studies have shown that the Shi-pi-xiao-ji (SPXJ) herbal decoction formula is effective in suppressing hepatocellular carcinoma (HCC), but the underlying mechanisms are not known. Therefore, this study investigated whether the antitumor effects of the SPXJ formula in treating HCC were mediated by acetyl-coA acetyltransferase 1 (ACAT1)-regulated cellular stiffness. Through a series of experiments, we concluded that SPXJ inhibits the progression of HCC by upregulating the expression level of ACAT1, lowering the level of cholesterol in the cell membrane, and altering the cellular stiffness, which provides a new idea for the research of traditional Chinese medicine against HCC.
AIM To investigate the anti-tumor effects of the SPXJ formula on the malignant progression of HCC.
METHODS HCC cells were cultured in vitro with SPXJ-containing serum prepared by injecting SPXJ formula into wild-type mice. The apoptotic rate and proliferative, invasive, and migratory abilities of control and SPXJ-treated HCC cells were compared. Atomic force microscopy was used to determine the cell surface morphology and the Young’s modulus values of the control and SPXJ-treated HCC cells. Plasma membrane cholesterol levels in HCC cells were detected using the Amplex Red cholesterol detection kit. ACAT1 protein levels were estimated using western blotting.
RESULTS Compared with the vehicle group, SPXJ serum considerably reduced proliferation of HCC cells, increased stiffness and apoptosis of HCC cells, inhibited migration and invasion of HCC cells, decreased plasma membrane cholesterol levels, and upregulated ACAT1 protein levels. However, treatment of HCC cells with the water-soluble cholesterol promoted proliferation, migration, and invasion of HCC cells as well as decreased cell stiffness and plasma membrane cholesterol levels, but did not alter the apoptotic rate and ACAT1 protein expression levels compared with the vehicle control.
CONCLUSION SPXJ formula inhibited proliferation, invasion, and migration of HCC cells by decreasing plasma membrane cholesterol levels and altering cellular stiffness through upregulation of ACAT1 protein expression.
Collapse
Affiliation(s)
- Hui-Ying Jian
- Graduate School, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Zi-Cheng Liang
- Graduate School, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Huan Wen
- Hunan Provincial Hospital of Integrated Traditional Chinese and Western, Cancer Research Institute of Hunan Academy of Traditional Chinese Medicine, Hunan Academy of Chinese Medicine, Changsha 410006, Hunan Province, China
| | - Zhen Zhang
- Hunan Provincial Hospital of Integrated Traditional Chinese and Western, Cancer Research Institute of Hunan Academy of Traditional Chinese Medicine, Hunan Academy of Chinese Medicine, Changsha 410006, Hunan Province, China
| | - Pu-Hua Zeng
- Hunan Provincial Hospital of Integrated Traditional Chinese and Western, Cancer Research Institute of Hunan Academy of Traditional Chinese Medicine, Hunan Academy of Chinese Medicine, Changsha 410006, Hunan Province, China
| |
Collapse
|
|
12
|
Yang R, Gao W, Wang Z, Jian H, Peng L, Yu X, Xue P, Peng W, Li K, Zeng P. Polyphyllin I induced ferroptosis to suppress the progression of hepatocellular carcinoma through activation of the mitochondrial dysfunction via Nrf2/HO-1/GPX4 axis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 122:155135. [PMID: 37856990 DOI: 10.1016/j.phymed.2023.155135] [Citation(s) in RCA: 79] [Impact Index Per Article: 79.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 09/14/2023] [Accepted: 09/29/2023] [Indexed: 10/21/2023]
Abstract
BACKGROUND Ferroptosis is an emerging iron-dependent programmed cell death mode characterized by lipid peroxidation and iron accumulation, closely associated with Hepatocellular Carcinoma (HCC) progression. Although the impact of Polyphyllin I (PPI), a prominent bioactive constituent derived from Paris polyphylla, on diverse malignancies has been established, the specific role and potential mechanistic pathways through which PPI modulates ferroptosis in HCC remain elusive. PURPOSE This study aimed to elucidate the anti-cancer properties and potential mechanisms of PPI in inducing ferroptosis and triggering mitochondrial injury in HCC. METHODS Cell viability was assessed using CCK-8 assays. EdU proliferation and colony formation assays were employed to evaluate cell proliferation. A wound-healing assay was performed to assess cell migration. Transwell assay was utilized to evaluate cell invasion. Ferroptosis was evaluated through the utilization of a FerroOrange fluorescent probe, malondialdehyde (MDA) and reduced glutathione (GSH) assay kits, DCFH-DA fluorescent probe, western blotting, and transmission electron microscopy (TEM) analysis. Molecular docking, immunofluorescence, and western blotting were employed to predict and validate the binding and interaction of PPI with Nrf2, HO-1, xCT, and GPX4. Mitochondrial structure and membrane potential changes were evaluated using JC-1 and Mito Tracker Green fluorescent probes. A nude mice xenograft model was constructed to determine the inhibitory effects and the levels of ferroptosis of PPI on HCC through hematoxylin and eosin (H&E), Prussian blue reaction, immunofluorescence staining, immunohistochemistry, and western blotting analysis, in vivo. RESULTS PPI exhibited dose-dependent inhibitory effects on the proliferation, invasion, and metastasis of HCC cells mediated by increasing reactive oxygen species (ROS) and MDA levels, promoting Fe2+ accumulation, depleting GSH, and suppressing the expression of xCT and GPX4, thereby inducing ferroptosis in HCC. The induction of ferroptosis by PPI was associated with the binding of PPI to Nrf2, HO-1, and GPX4 proteins, modulating the Nrf2/HO-1/GPX4 antioxidant axis. PPI also induced mitochondrial structural damage and decreased mitochondrial membrane potential (MMP). Inhibition of ferroptosis by ferrostatin-1 (Fer-1) mitigated the mitochondrial disruption induced by PPI. In vivo, PPI inhibited Nrf2/HO-1/GPX4 axis-induced ferroptosis, impeding HCC growth similar to the effects of sorafenib. CONCLUSION These results demonstrated that PPI intervention can suppress the proliferation, invasion, and metastasis of HCC cells by enhancing mitochondrial disruption and inducing ferroptosis via the Nrf2/HO-1/GPX4 axis. Consequently, our research advances the frontiers of pharmacodynamics and deepens our comprehension of the intricate mechanisms underpinning PPI. Furthermore, it has yielded an innovative treatment stratagem rooted in the tenets of Traditional Chinese Medicine (TCM), thereby furnishing a novel therapeutic avenue for addressing HCC.
Collapse
Affiliation(s)
- Renyi Yang
- Hunan Provincial Hospital of Integrated Traditional Chinese and Western, Cancer Research Institute of Hunan Academy of Traditional Chinese Medicine, Hunan Academy of Chinese Medicine, Hunan, 410006, China
| | - Wenhui Gao
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Hunan, 410208, China
| | - Zhibing Wang
- School of Integrated Chinese and Western Medicine, Key Laboratory of Hunan Provincial for Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Hunan, 410208, China
| | - Huiying Jian
- Hunan Provincial Hospital of Integrated Traditional Chinese and Western, Cancer Research Institute of Hunan Academy of Traditional Chinese Medicine, Hunan Academy of Chinese Medicine, Hunan, 410006, China
| | - Lian Peng
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Hunan, 410208, China
| | - Xiaopeng Yu
- Hunan Provincial Hospital of Integrated Traditional Chinese and Western, Cancer Research Institute of Hunan Academy of Traditional Chinese Medicine, Hunan Academy of Chinese Medicine, Hunan, 410006, China
| | - Peisen Xue
- Hunan Provincial Hospital of Integrated Traditional Chinese and Western, Cancer Research Institute of Hunan Academy of Traditional Chinese Medicine, Hunan Academy of Chinese Medicine, Hunan, 410006, China
| | - Wei Peng
- Hunan Provincial Hospital of Integrated Traditional Chinese and Western, Cancer Research Institute of Hunan Academy of Traditional Chinese Medicine, Hunan Academy of Chinese Medicine, Hunan, 410006, China.
| | - Kexiong Li
- Hunan Provincial Hospital of Integrated Traditional Chinese and Western, Cancer Research Institute of Hunan Academy of Traditional Chinese Medicine, Hunan Academy of Chinese Medicine, Hunan, 410006, China.
| | - Puhua Zeng
- Hunan Provincial Hospital of Integrated Traditional Chinese and Western, Cancer Research Institute of Hunan Academy of Traditional Chinese Medicine, Hunan Academy of Chinese Medicine, Hunan, 410006, China.
| |
Collapse
|
|
13
|
Mir WR, Bhat BA, Kumar A, Dhiman R, Alkhanani M, Almilaibary A, Dar MY, Ganie SA, Mir MA. Network pharmacology combined with molecular docking and in vitro verification reveals the therapeutic potential of Delphinium roylei munz constituents on breast carcinoma. Front Pharmacol 2023; 14:1135898. [PMID: 37724182 PMCID: PMC10505441 DOI: 10.3389/fphar.2023.1135898] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Accepted: 08/09/2023] [Indexed: 09/20/2023] Open
Abstract
Delphinium roylei Munz is an indigenous medicinal plant to India where its activity against cancer has not been previously investigated, and its specific interactions of bioactive compounds with vulnerable breast cancer drug targets remain largely unknown. Therefore, in the current study, we aimed to evaluate the anti-breast cancer activity of different extracts of D. roylei against breast cancer and deciphering the molecular mechanism by Network Pharmacology combined with Molecular Docking and in vitro verification. The experimental plant was extracted with various organic solvents according to their polarity index. Phytocompounds were identified by High resolution-liquid chromatography-mass spectrometry (HR-LC/MS) technique, and SwissADME programme evaluated their physicochemical properties. Next, target(s) associated with the obtained bioactives or breast cancer-related targets were retrieved by public databases, and the Venn diagram selected the overlapping targets. The networks between overlapping targets and bioactive were visualized, constructed, and analyzed by STRING programme and Cytoscape software. Finally, we implemented a molecular docking test (MDT) using AutoDock Vina to explore key target(s) and compound(s). HR-LC/MS detected hundreds of phytocompounds, and few were accepted by Lipinski's rules after virtual screening and therefore classified as drug-like compounds (DLCs). A total of 464 potential target genes were attained for the nine quantitative phytocompounds and using Gene Cards, OMIM and DisGeNET platforms, 12063 disease targets linked to breast cancer were retrieved. With Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment, a total of 20 signalling pathways were manifested, and a hub signalling pathway (PI3K-Akt signalling pathway), a key target (Akt1), and a key compound (8-Hydroxycoumarin) were selected among the 20 signalling pathways via molecular docking studies. The molecular docking investigation revealed that among the nine phytoconstituents, 8-hydroxycoumarin showed the best binding energy (-9.2 kcal/mol) with the Akt1 breast cancer target. 8-hydroxycoumarin followed all the ADME property prediction using SwissADME, and 100 nanoseconds (ns) MD simulations of 8-hydroxycoumarin complexes with Akt1 were found to be stable. Furthermore, D. roylei extracts also showed significant antioxidant and anticancer activity through in vitro studies. Our findings indicated for the first time that D. roylei extracts could be used in the treatment of BC.
Collapse
Affiliation(s)
- Wajahat Rashid Mir
- Department of Bio-Resources, School of Biological Sciences, University of Kashmir, Srinagar, Jammu and Kashmir, India
| | - Basharat Ahmad Bhat
- Department of Bio-Resources, School of Biological Sciences, University of Kashmir, Srinagar, Jammu and Kashmir, India
| | - Ashish Kumar
- Department of Life Science, National Institute of Technology, Rourkela, Odisha, India
| | - Rohan Dhiman
- Department of Life Science, National Institute of Technology, Rourkela, Odisha, India
| | - Mustfa Alkhanani
- Department of Family and Community Medicine, Faculty of Medicine, Al Baha University, Al Bahah, Saudi Arabia
| | - Abdullah Almilaibary
- Department of Biology, College of Science, Hafr Al Batin University of Hafr Al-Batin, Hafar Al Batin, Saudi Arabia
| | - Mohd Younis Dar
- Regional Research Institute of Unani Medicine (RRIUM), University of Kashmir, Srinagar, Jammu and Kashmir, India
| | - Showkat Ahmad Ganie
- Department of Clinical Biochemistry, School of Biological Sciences, University of Kashmir, Srinagar, Jammu and Kashmir, India
| | - Manzoor Ahmad Mir
- Department of Bio-Resources, School of Biological Sciences, University of Kashmir, Srinagar, Jammu and Kashmir, India
| |
Collapse
|
|
14
|
Sadaqat M, Qasim M, Tahir Ul Qamar M, Masoud MS, Ashfaq UA, Noor F, Fatima K, Allemailem KS, Alrumaihi F, Almatroudi A. Advanced network pharmacology study reveals multi-pathway and multi-gene regulatory molecular mechanism of Bacopa monnieri in liver cancer based on data mining, molecular modeling, and microarray data analysis. Comput Biol Med 2023; 161:107059. [PMID: 37244150 DOI: 10.1016/j.compbiomed.2023.107059] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 05/05/2023] [Accepted: 05/20/2023] [Indexed: 05/29/2023]
Abstract
Liver cancer is a malignant tumor that grows on the surface or inside the liver. The leading cause is a viral infection with hepatitis B or C virus. Natural products and their structural analogues have historically made a major contribution to pharmacotherapy, especially for cancer. A list of studies evidences the therapeutic efficacy of Bacopa monnieri against liver cancer, but the precise molecular mechanism is yet to be discovered. This study combines data mining, network pharmacology, and molecular docking analysis to potentially revolutionize liver cancer treatment by identifying effective phytochemicals. Initially, the information on active constituents of B. monnieri and target genes of both liver cancer and B. monnieri were retrieved from literature as well as from publicly available databases. Based on the matching results between B. monnieri potential targets and liver cancer targets, the protein-protein interaction (PPI) network was constructed using the STRING database and imported into Cytoscape for screening of hub genes based on their degree of connectivity. Later, the interactions network between compounds and overlapping genes was constructed using Cytoscape software to analyze the network pharmacological prospective effects of B. monnieri on liver cancer. Gene Ontology (GO) and KEGG pathway analysis of hub genes revealed that these genes are involved in the cancer-related pathway. Lastly, the expression level of core targets was analyzed using microarray data (GSE39791, GSE76427, GSE22058, GSE87630, and GSE112790). Further, the GEPIA server and PyRx software were used for survival and molecular docking analysis, respectively. In summary, we proposed that quercetin, luteolin, apigenin, catechin, epicatechin, stigmasterol, beta-sitosterol, celastrol, and betulic acid inhibit tumor growth by affecting tumor protein 53 (TP53), interleukin 6 (IL6), RAC-alpha serine/threonine protein kinases 1 (AKT1), caspase-3 (CASP3), tumor necrosis factor (TNF), jun proto-oncogene (JUN), heat shot protein 90 AA1 (HSP90AA1), vascular endothelial growth factor A (VEGFA), epidermal growth factor receptor (EGFR), and SRC proto-oncogene (SRC). Through, microarray data analysis, the expression level of JUN and IL6 were found to be upregulated while the expression level of HSP90AA1 was found to be downregulated. Kaplan-Meier survival analysis indicated that HSP90AA1 and JUN are promising candidate genes that can serve as diagnostic and prognostic biomarkers for liver cancer. Moreover, the molecular docking and molecular dynamic simulation of 60ns well complemented the binding affinity of the compound and revealed strong stability of predicted compounds at the docked site. Calculation of binding free energies using MMPBSA and MMGBSA validated the strong binding affinity between the compound and binding pockets of HSP90AA1 and JUN. Despite that, in vivo and in vitro studies are mandatory to unveil pharmacokinetics and biosafety profiles to completely track the candidature status of B. monnieri in liver cancer.
Collapse
Affiliation(s)
- Muhammad Sadaqat
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad (GCUF), Faisalabad, 38000, Pakistan.
| | - Muhammad Qasim
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad (GCUF), Faisalabad, 38000, Pakistan.
| | - Muhammad Tahir Ul Qamar
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad (GCUF), Faisalabad, 38000, Pakistan.
| | - Muhammad Shareef Masoud
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad (GCUF), Faisalabad, 38000, Pakistan.
| | - Usman Ali Ashfaq
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad (GCUF), Faisalabad, 38000, Pakistan.
| | - Fatima Noor
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad (GCUF), Faisalabad, 38000, Pakistan.
| | - Kinza Fatima
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad (GCUF), Faisalabad, 38000, Pakistan.
| | - Khaled S Allemailem
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, 51452, Saudi Arabia.
| | - Faris Alrumaihi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, 51452, Saudi Arabia.
| | - Ahmad Almatroudi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, 51452, Saudi Arabia.
| |
Collapse
|
|
15
|
Molecular docking and in vitro experiments verified that kaempferol induced apoptosis and inhibited human HepG2 cell proliferation by targeting BAX, CDK1, and JUN. Mol Cell Biochem 2022; 478:767-780. [PMID: 36083512 DOI: 10.1007/s11010-022-04546-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 08/12/2022] [Indexed: 10/14/2022]
Abstract
Hepatocellular carcinoma, as a common liver cirrhosis complication, has become the sixth most common cancer worldwide, and its increasing incidence has resulted in considerable medical and economic burdens. As a natural polyphenolic compound, kaempferol has exhibits a wide range of antitumor activities against multiple cancer targets. In this study, the Autodock software was used for molecular docking to simulate the interaction process between kaempferol and HCC targets and the PyMOL software was used for visualization. Proliferation of kaempferol HepG2 cells under the effect of kaempferol was detected using Cell Counting Kit-8 (CCK-8) assay, and the apoptosis rate of HepG2 cells was detected using flow cytometry. The expressions of proteins BAX, CDK1, and JUN protein expressions were detected by Western blot. Molecular docking found that the kaempferol ligand has 3 rotatable bonds, 6 nonpolar hydrogen atoms, and 12 aromatic carbon atoms, and can form complexes with the kaempferol targets P53, BAX, AR, CDK1, and JUN through electrostatic energy. GO (Gene Ontology) enrichment analysis suggests that kaempferol regulates the biological function of hepatocellular carcinoma cells and is related to apoptosis. Cell Counting Kit-8 assay suggested that Kaempferol can significantly inhibited HepG2 cell proliferation, and the inhibition rate increased with the increase in drug concentration and incubation time. Moreover, kaempferol can promoted HepG2 cell apoptosis in a dose-dependent manner. This compound upregulated BAX and JUN expression and downregulated CDK1 expression. Thus, Kaempferol can promote HepG2 cell apoptosis, and the regulatory mechanism may be related to the regulation of the expression levels of the apoptosis-related proteins BAX, CDK1, and JUN.
Collapse
|
|
16
|
Xie J, Chen R, Wang Q, Mao H. Exploration and validation of Taraxacum mongolicum anti-cancer effect. Comput Biol Med 2022; 148:105819. [PMID: 35810695 DOI: 10.1016/j.compbiomed.2022.105819] [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: 04/01/2022] [Revised: 06/28/2022] [Accepted: 07/03/2022] [Indexed: 11/03/2022]
Abstract
Taraxacum mongolicum gained a lot of concern and was applied in 93 formulas in China due to its fame as a traditional Chinese medicine. The earliest recorded application of Taraxacum mongolicum was traced back to the Han dynasty. Generations of doctors boosted the usage and enriched the pharmacological mechanism. Clinical application of the Taraxacum mongolicum is flourishing as it treats multiple diseases. This study aims to explore the anti-cancer effect, retrieve the active ingredients and screen the key targets of Taraxacum mongolicum in cancer therapy. We collected and evaluated 10 key active compounds to investigate the anti-cancer effect via 69 significant targets and a variety of biological processes and pathways. Gene Ontology (GO) enrichment analysis uncovered targets associated with protein phosphorylation, cell proliferation and apoptotic processes via regulation of kinases, ATP and enzyme binding activities. Half of the top 20 enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were directly involved in cancer. Based on standard selection criteria, seven hub targets were obtained. These targets functioned through distinct patterns and pathways in realizing the anti-cancer effect. Molecular docking was conducted to validate the potential combination between compounds and hub targets to explore the pharmacological mechanism of key compounds in Taraxacum mongolicum against cancer. In summary, our findings indicate that the famous and widely used Chinese herb, Taraxacum mongolicum, shows good anti-cancer effect through its active compounds, targeted genes, and multiple involved biological processes. The results may provide a theoretical basis for subsequent experimental validation and drug development of Taraxacum mongolicum extract against cancer.
Collapse
Affiliation(s)
- Jumin Xie
- Hubei Key Laboratory of Renal Disease Occurrence and Intervention, Medical School, Hubei Polytechnic University, Huangshi, Hubei, 435003, PR China
| | - Ruxi Chen
- Hubei Key Laboratory of Renal Disease Occurrence and Intervention, Medical School, Hubei Polytechnic University, Huangshi, Hubei, 435003, PR China
| | - Qingzhi Wang
- Medical College of YiChun University, Xuefu Road No 576, Yichun, Jiangxi, 336000, PR China.
| | - Hui Mao
- Department of Dermatology, Huangshi Central Hospital, Huangshi, Hubei, 435000, PR China.
| |
Collapse
|
|
17
|
Huoxue Qianyang Qutan Recipe Protects against Early Renal Damage Induced by Obesity-Related Hypertension via the SIRT1/NF- κB/IL-6 Pathway: Integrating Network Pharmacology and Experimental Validation-Based Strategy. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:9599090. [PMID: 35668772 PMCID: PMC9166942 DOI: 10.1155/2022/9599090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Accepted: 05/13/2022] [Indexed: 11/28/2022]
Abstract
Obesity is recognized as not only a major contributing factor to cardiovascular diseases but also an independent risk factor for end-stage renal disease. Previous studies have found that Huoxue Qianyang Qutan Recipe (HQQR) could reduce urinary microalbumin in patients with obesity-related hypertension (OBH). However, the renal protective activity of HQQR in OBH and its molecular targets involved remains ambiguous. In this work, we investigate the mechanism of HQQR against OBH-induced early renal damage using integrating network pharmacology and experimental validation-based strategy. First, via network pharmacology, IL-6 is identified as one of the key targets of HQQR against early renal damage in hypertension, and inhibition of inflammation is a crucial process. Second, in in vivo experiments, HQQR can lower blood pressure, lose weight, and restore metabolic abnormalities in OBH rats, which could be associated with the effects on protecting early renal damage. Finally, in the mechanism, HQQR increases SIRT1 mRNA and protein expression consistent with reduction of NF-κB acetylation and suppressed the p65-mediated inflammatory signaling pathway. As a result, HQQR robustly inhibits OBH-induced renal inflammation by reducing IL-6 mRNA and protein levels in the renal tissue and the release of IL-6 in serum of OBH rats. This study aims to provide a multimethod (network pharmacology-animal experiment) and multilevel (component-target-pathway) strategy for the prevention and treatment of OBH-induced target organ damage by traditional Chinese medicine.
Collapse
|
|
18
|
Batool S, Javed MR, Aslam S, Noor F, Javed HMF, Seemab R, Rehman A, Aslam MF, Paray BA, Gulnaz A. Network Pharmacology and Bioinformatics Approach Reveals the Multi-Target Pharmacological Mechanism of Fumaria indica in the Treatment of Liver Cancer. Pharmaceuticals (Basel) 2022; 15:ph15060654. [PMID: 35745580 PMCID: PMC9229061 DOI: 10.3390/ph15060654] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 05/04/2022] [Accepted: 05/16/2022] [Indexed: 12/13/2022] Open
Abstract
Liver cancer (LC), a frequently occurring cancer, has become the fourth leading cause of cancer mortality. The small number of reported data and diverse spectra of pathophysiological mechanisms of liver cancer make it a challenging task and a serious economic burden in health care management. Fumaria indica is a herbaceous annual plant used in various regions of Asia to treat a variety of ailments, including liver cancer. Several in vitro investigations have revealed the effectiveness of F. indica in the treatment of liver cancer; however, the exact molecular mechanism is still unrevealed. In this study, the network pharmacology technique was utilized to characterize the mechanism of F. indica on liver cancer. Furthermore, we analyzed the active ingredient-target-pathway network and uncovered that Fumaridine, Lastourvilline, N-feruloyl tyramine, and Cryptopine conclusively contributed to the development of liver cancer by affecting the MTOR, MAPK3, PIK3R1, and EGFR gene. Afterward, molecular docking was used to verify the effective activity of the active ingredients against the prospective targets. The results of molecular docking predicted that several key targets of liver cancer (along with MTOR, EGFR, MAPK3, and PIK3R1) bind stably with the corresponding active ingredient of F. indica. We concluded through network pharmacology methods that multiple biological processes and signaling pathways involved in F. indica exerted a preventing effect in the treatment of liver cancer. The molecular docking results also provide us with sound direction for further experiments. In the framework of this study, network pharmacology integrated with docking analysis revealed that F. indica exerted a promising preventive effect on liver cancer by acting on liver cancer-associated signaling pathways. This enables us to understand the biological mechanism of the anti liver cancer activity of F. indica.
Collapse
Affiliation(s)
- Sara Batool
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad (GCUF), Allama Iqbal Road, Faisalabad 38000, Pakistan; (S.B.); (F.N.); (R.S.); (A.R.)
| | - Muhammad Rizwan Javed
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad (GCUF), Allama Iqbal Road, Faisalabad 38000, Pakistan; (S.B.); (F.N.); (R.S.); (A.R.)
- Correspondence: (M.R.J.); (S.A.); Tel.: +92-(0)301-6012931 (M.R.J.); +92-(0)312-1759482 (S.A.)
| | - Sidra Aslam
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad (GCUF), Allama Iqbal Road, Faisalabad 38000, Pakistan; (S.B.); (F.N.); (R.S.); (A.R.)
- Correspondence: (M.R.J.); (S.A.); Tel.: +92-(0)301-6012931 (M.R.J.); +92-(0)312-1759482 (S.A.)
| | - Fatima Noor
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad (GCUF), Allama Iqbal Road, Faisalabad 38000, Pakistan; (S.B.); (F.N.); (R.S.); (A.R.)
| | | | - Riffat Seemab
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad (GCUF), Allama Iqbal Road, Faisalabad 38000, Pakistan; (S.B.); (F.N.); (R.S.); (A.R.)
| | - Abdur Rehman
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad (GCUF), Allama Iqbal Road, Faisalabad 38000, Pakistan; (S.B.); (F.N.); (R.S.); (A.R.)
| | - Muhammad Farhan Aslam
- School of Biological Sciences, University of Edinburgh, Edinburgh P.O. Box EH9 3FF, UK;
| | - Bilal Ahamad Paray
- Department of Zoology, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia;
| | - Aneela Gulnaz
- College of Pharmacy, Woosuk University, Wanju-gun 55338, Korea;
| |
Collapse
|
|
19
|
Wu J, Wang Z, Xu S, Fu Y, Gao Y, Wu Z, Yu Y, Yuan Y, Zhou L, Li P. Analysis of the role and mechanism of EGCG in septic cardiomyopathy based on network pharmacology. PeerJ 2022; 10:e12994. [PMID: 35287352 PMCID: PMC8917800 DOI: 10.7717/peerj.12994] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 02/02/2022] [Indexed: 01/11/2023] Open
Abstract
Background Septic cardiomyopathy (SC) is a common complication of sepsis that leads to an increase in mortality. The pathogenesis of septic cardiomyopathy is unclear, and there is currently no effective treatment. EGCG (epigallocatechin gallate) is a polyphenol that has anti-inflammatory, antiapoptotic, and antioxidative stress effects. However, the role of EGCG in septic cardiomyopathy is unknown. Methods Network pharmacology was used to predict the potential targets and molecular mechanisms of EGCG in the treatment of septic cardiomyopathy, including the construction and analysis of protein-protein interaction (PPI) network, gene ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and molecular docking. The mouse model of septic cardiomyopathy was established after intraperitoneal injection of LPS (lipopolysaccharide). The myocardial protective effect of EGCG on septic mice is observed by cardiac ultrasound and HE staining. RT-PCR is used to verify the expression level of the EGCG target in the septic cardiomyopathy mouse model. Results A total of 128 anti-SC potential targets of EGCGareselected for analysis. The GO enrichment analysis and KEGG pathway analysis results indicated that the anti-SC targets of EGCG mainly participate in inflammatory and apoptosis processes. Molecular docking results suggest that EGCG has a high affinity for the crystal structure of six targets (IL-6 (interleukin-6), TNF (tumor necrosis factor), Caspase3, MAPK3 (Mitogen-activated protein kinase 3), AKT1, and VEGFA (vascular endothelial growth factor)), and the experimental verification result showed levated expression of these 6 hub targets in the LPS group, but there is an obvious decrease in expression in the LPS + EGCG group. The functional and morphological changes found by echocardiography and HE staining show that EGCG can effectively improve the cardiac function that is reduced by LPS. Conclusion Our results reveal that EGCG may be a potentially effective drug to improve septic cardiomyopathy. The potential mechanism by which EGCG improves myocardial injury in septic cardiomyopathy is through anti-inflammatory and anti-apoptotic effects. The anti-inflammatory and anti-apoptotic effects of EGCG occur not only through direct binding to six target proteins (IL-6,TNF-α, Caspase3, MAPK3, AKT1, and VEGFA) but also by reducing their expression.
Collapse
Affiliation(s)
- Ji Wu
- Department of Cardiovascular, The Second Affiliated Hospital of Nanchang University, Nan Chang, China
| | - Zhenhua Wang
- Department of Cardiovascular, The Second Affiliated Hospital of Nanchang University, Nan Chang, China
| | - Shanling Xu
- Department of Cardiovascular, Medicine, Fuzhou First People’s Hospital, Fu Zhou, China
| | - Yang Fu
- Department of Cardiovascular, The Second Affiliated Hospital of Nanchang University, Nan Chang, China
| | - Yi Gao
- Department of Cardiovascular, The Second Affiliated Hospital of Nanchang University, Nan Chang, China
| | - Zuxiang Wu
- Department of Cardiovascular, The Second Affiliated Hospital of Nanchang University, Nan Chang, China
| | - Yun Yu
- Department of Cardiovascular, The Second Affiliated Hospital of Nanchang University, Nan Chang, China
| | - Yougen Yuan
- Department of Cardiovascular, The Three Affiliated Hospital of Nanchang University, Nan Chang, China
| | - Lin Zhou
- Department of Cardiovascular, The Three Affiliated Hospital of Nanchang University, Nan Chang, China
| | - Ping Li
- Department of Cardiovascular, The Second Affiliated Hospital of Nanchang University, Nan Chang, China
| |
Collapse
|
|
20
|
Guo B, Zhao C, Zhang C, Xiao Y, Yan G, Liu L, Pan H. Elucidation of the anti-inflammatory mechanism of Er Miao San by integrative approach of network pharmacology and experimental verification. Pharmacol Res 2022; 175:106000. [PMID: 34838694 DOI: 10.1016/j.phrs.2021.106000] [Citation(s) in RCA: 75] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Revised: 11/21/2021] [Accepted: 11/22/2021] [Indexed: 01/10/2023]
Abstract
Traditional Chinese medicine (TCM) has been long time used in China and gains ever-increasing worldwide acceptance. Er Miao San (EMS), a TCM formula, has been extensively used to treat inflammatory diseases, while its bioactive components and therapeutic mechanisms remain unclear. In this study, we conducted an integrative approach of network pharmacology and experimental study to elucidate the underlying mechanisms of EMS in treating human rheumatoid arthritis (RA) and other inflammatory conditions. Quercetin, wogonin and rutaecarpine were probably the main active compounds of EMS in RA treatment as they affected the most RA-related targets, and TNF-α, IL-6 and IL-1β were considered to be the core target proteins. The main compounds in EMS bound to these core proteins, which was further confirmed by molecular docking and bio-layer interferometry (BLI) analysis. Moreover, the potential molecular mechanisms of EMS predicted from network pharmacology analysis, were validated in vivo and in vitro experiments. EMS was found to inhibit the production of NO, TNF-α and IL-6 in lipopolysaccharide (LPS)-stimulated RAW264.7 cells; reduce xylene-induced mouse ear edema; and decrease the incidence of carrageenan-induced rat paw edema. The carrageenan-induced up-regulation of TNF-α, IL-6 and IL-1β mRNA expression in rat paws was down-regulated by EMS, consistent with the network pharmacology results. This study provides evidence that EMS plays a critical role in anti-inflammation via suppressing inflammatory cytokines, indicating that EMS is a candidate herbal drug for further investigation in treating inflammatory and arthritic conditions.
Collapse
Affiliation(s)
- Bin Guo
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macao 999078, China; Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Macau University of Science and Technology, Macao 999078, China; Guizhou University of Traditional Chinese Medicine, Guiyang 550025, China
| | - CaiPing Zhao
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macao 999078, China
| | - Chuanhai Zhang
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macao 999078, China; Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Macau University of Science and Technology, Macao 999078, China
| | - Yao Xiao
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macao 999078, China; Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Macau University of Science and Technology, Macao 999078, China
| | - Guangli Yan
- National Chinmedomics Research Center, Sino-America Chinmedomics Technology Collaboration Center, National TCM Key Laboratory of Serum Pharmacochemistry, Heilongjiang University of Chinese Medicine, Harbin 150006, China
| | - Liang Liu
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macao 999078, China; Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou 510000, China.
| | - Hudan Pan
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macao 999078, China; Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Macau University of Science and Technology, Macao 999078, China; Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou 510000, China.
| |
Collapse
|
|
21
|
Chemical Constituents and Pharmacological Activities of Steroid Saponins Isolated from Rhizoma Paridis. J CHEM-NY 2021. [DOI: 10.1155/2021/1442906] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Rhizoma Paridis, the rhizome of liliaceous plants Paris polyphylla, is one of the most commonly used herbal drugs in China. Phytochemical and pharmacological studies have shown that steroid saponins were the major effective ingredients of Rhizoma Paridis to exert antitumor, anti-inflammatory, hemostasis, and antifibrosis functions. In this review, we discussed the chemical structures of steroid saponins and their related biological activity and mechanisms in cellular and animal models, aiming to provide a reference for future comprehensive exploitation and development of saponins.
Collapse
|
|
22
|
Yu S, Gao W, Zeng P, Chen C, Liu Z, Zhang Z, Liu J. Exploring the effect of Polyphyllin I on hepatitis B virus-related liver cancer through network pharmacology and in vitro experiments. Comb Chem High Throughput Screen 2021; 25:934-944. [PMID: 34397325 DOI: 10.2174/1386207324666210816141436] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 06/12/2021] [Accepted: 06/15/2021] [Indexed: 11/22/2022]
Abstract
AIM AND OBJECTIVE To investigate the effect of Polyphyllin I (PPI) on HBV-related liver cancer through network pharmacology and in vitro experiments, and to explore its mechanism of action. MATERIALS AND METHODS Use bioinformatics software to predict the active ingredient target of PPI and the disease target of liver cancer, and perform active ingredient-disease target analysis. The results of network pharmacology through molecular docking and in vitro experiments can be further verified. The HepG2 receptor cells (HepG2. 2. 15) were transfected with HBV plasmid for observation, with the human liver cancer HepG2 being used as the control. RESULTS Bioinformatics analysis found that PPI had totally 161 protein targets, and the predicted target and liver cancer targets were combined to obtain 13 intersection targets. The results of molecular docking demonstrated that PPI had good affinity with STAT3, PTP1B, IL2, and BCL2L1. The results of the in vitro experiments indicated that the PPI inhibited cell proliferation and metastasis in a concentration-dependent manner (P<0.01). Compared with the vehicle group, the PPI group of 1.5, 3, and 6 μmol/L can promote the apoptosis of liver cancer to different degrees (P<0.01). CONCLUSION The present study revealed the mechanism of PPI against liver cancer through network pharmacology and in vitro experiments. Its mechanism of action is related to the inhibition of PPI on the proliferation of HBV-related liver cancer through promoting the apoptosis of liver cancer cells. Additionally, in vitro experiments have also verified that PPI can promote the apoptosis of HepG2 and HepG2.2.15 cells.
Collapse
Affiliation(s)
- Shuxian Yu
- School of Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Wenhui Gao
- School of Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Puhua Zeng
- Affiliated Hospital of Hunan Academy of Traditional Chinese Medicine, Changsha 410006, China
| | - Chenglong Chen
- School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Zhuo Liu
- Affiliated Hospital of Hunan Academy of Traditional Chinese Medicine, Changsha 410006, China
| | - Zhen Zhang
- School of Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Jiyong Liu
- School of Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, China
| |
Collapse
|
|
23
|
Network Pharmacology/Metabolomics-Based Validation of AMPK and PI3K/AKT Signaling Pathway as a Central Role of Shengqi Fuzheng Injection Regulation of Mitochondrial Dysfunction in Cancer-Related Fatigue. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:5556212. [PMID: 34326918 PMCID: PMC8302405 DOI: 10.1155/2021/5556212] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 05/06/2021] [Accepted: 06/12/2021] [Indexed: 12/17/2022]
Abstract
Chinese herbal medicines have multiple targets and properties, and their use in multidisciplinary cancer therapies has consequently received increasing attention. Here, we have investigated the possible active ingredients associated with cancer-related fatigue (CRF) in the Shengqi Fuzheng Injection (SFI). In vitro cell models were used to measure the regulation effects of SFI on CRF. Metabolomic analysis was used to identify the potential genes and pathways in C2C12 mouse myoblasts treated with SFI, and the interaction of compounds and CRF targets was predicted using network pharmacology and molecular docking analyses. The putative pathways were further verified using immuno-blotting assays. The results showed that SFI significantly inhibited muscle cell apoptosis and increased the mitochondrial membrane potential of muscle cells. The network pharmacology analysis results identified 36 candidate compounds, and 244 potential targets were yielded by SFI, and they shared 10 key targets associated with cancer-related fatigue. According to the enrichment analysis and experimental validation, SFI might ameliorate muscle cell mitochondrial function by activating AMPK and inhibiting the PI3K/Akt signaling pathways, and the expression changes of mitochondrial metabolic enzymes MnSOD and apoptosis-associated proteins Bax and Bcl-2 were also triggered. The functions and mechanisms of SFI in anticancer-related fatigue were found here to be at least partly due to the targeting of the AMPK and PI3K/Akt signaling pathways, and this has highlighted new potential applications for network pharmacology when researching Chinese Medicines.
Collapse
|