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Karasu N, Kuzucu M, Mat OC, Gul M, Yay A, Dundar M. Protective effect of deinoxanthin in sorafenib-induced nephrotoxicity in rats with the hepatocellular carcinoma model. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:5969-5988. [PMID: 39625488 DOI: 10.1007/s00210-024-03633-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 11/13/2024] [Indexed: 04/11/2025]
Abstract
Sorafenib is a synthetic compound and an orally administered multichines inhibitor that targets growth signaling and angiogenesis. It is widely recognized as the standard of care for advanced hepatocellular carcinoma (HCC) but has toxic side effects. Deinoxanthin, purified from the radioresistant bacterium Deinococcus radiodurans, has strong antioxidant characteristics. In this study, the protective effect of deinoxanthin against sorafenib-induced nephrotoxicity was investigated in a rat model of hepatocellular carcinoma. In this regard, the expressions of DDAH1, KIM1, and INOS genes were examined, histopathological and immunohistochemical analyses were performed, and various parameters such as SOD, MDA, GST, CAT, TAS, and TOS were tested biochemically. BUN and creatinine levels were measured in renal tissues. RT-qPCR, Western blot, and ELISA methods were used for all these analyses. As a result, the analyses show that deinoxanthin, which has a high antioxidant capacity, reduces kidney injury and can be used as a protective agent. The primary objective of this study is to evaluate the potential of deinoxanthin as a protective agent against the nephrotoxic side effects of sorafenib in HCC. Our study identified the potential synergistic effects of sorafenib and deinoxanthin on nephrotoxicity in rats with hepatocellular carcinoma.
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Affiliation(s)
- Nilgun Karasu
- Faculty of Medicine, Department of Medical Genetics, Erciyes University, Kayseri, Turkey
- Faculty of Medicine, Department of Medical Genetics, Uskudar University, Istanbul, Turkey
| | - Mehmet Kuzucu
- Faculty of Arts and Sciences, Department of Biology, Erzincan Binali Yıldırım University, Erzincan, Turkey
| | - Ozge Cengiz Mat
- Faculty of Medicine, Department of Histology and Embryology, Erciyes University, Kayseri, Turkey
| | - Mustafa Gul
- Faculty of Medicine, Department of Physiology, Ataturk University, Erzurum, Turkey
| | - Arzu Yay
- Faculty of Medicine, Department of Histology and Embryology, Erciyes University, Kayseri, Turkey
| | - Munis Dundar
- Faculty of Medicine, Department of Medical Genetics, Erciyes University, Kayseri, Turkey.
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Zhang C, Yuan M, Rong W, Du H, Li X, Ji T, Li J, Dai B, Ma Z, Qi H, Zhang N, Yang J, Duan X, Bi Y. Synergistic effects of Lianhuaqingwen in combination with Oseltamivir and Baloxavir against seasonal influenza virus: In vitro and in vivo assessment. JOURNAL OF ETHNOPHARMACOLOGY 2025; 338:119091. [PMID: 39528119 DOI: 10.1016/j.jep.2024.119091] [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: 09/16/2024] [Revised: 11/06/2024] [Accepted: 11/08/2024] [Indexed: 11/16/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Lianhuaqingwen (LH), a traditional Chinese medicine, presents a broad-spectrum antiviral effect and has been widely used to treat influenza. Given the potential rise of drug-resistant influenza viruses, it is necessary to develop new antiviral drugs and explore combination therapies involving LH in tandem with existing antivirals such as Oseltamivir acid (Osel) or Baloxavir (Bal). These multidrug combinations could help effectively control the seasonal influenza epidemics and reduce the disease burden. AIM OF THE STUDY This study aimed to evaluate the antiviral effects of LH, alone and in combination with Osel or Bal, against human seasonal influenza viruses in vitro and in vivo models. MATERIALS AND METHODS The antiviral efficacy of LH alone and LH in combination with Osel/Bal against seasonal influenza A viruses (IAVs) (H1N1 and H3N2 subtypes) and influenza B viruses (IBVs) (BV- and BY-lineages) was assessed in vitro using MDCK cells. The median effective concentration (EC50) was determined, and the drug synergies were analyzed. Additionally, the antiviral activity of LH monotherapy and LH + Osel/Bal combination therapy were evaluated in vivo using an H1N1-infected BABL/c mouse model by monitoring changes in body weight, survival rate, lung viral titer, pathological damage, and inflammatory reaction. RESULTS In vitro, LH alone and in combination with Osel/Bal exhibited antiviral activity against both IAVs and IBVs. The addition of LH to Osel/Bal improved the therapeutic efficacy compared to Osel/Bal alone. In vivo, LH monotherapy reduced body weight loss and increased the survival rates of H1N1-infected mice. LH in combination with Osel/Bal resulted in lower virus titers, more effective relief of pathological damage, and comparable low expression of inflammatory factors in the lungs of H1N1-infected mice compared to the use of Osel/Bal alone. Transcriptomic analysis of the lungs revealed that LH + Osel/Bal significantly increased the expression of genes associated with antiviral and anti-inflammatory effects. CONCLUSIONS This study evaluated the antiviral effects of LH monotherapy and combination therapy with Osel/Bal against human seasonal influenza viruses in vitro and in vivo models. The results suggest that combining LH with Osel or Bal could enhance the antiviral efficiency for influenza viruses compared to the monotherapy using any of these three drugs.
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Affiliation(s)
- Cheng Zhang
- College of Life Science and Technology, Xinjiang University, Urumchi, 830046, China; CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Center for Influenza Research and Early-warning (CASCIRE), CAS-TWAS Center of Excellence for Emerging Infectious Diseases (CEEID), Chinese Academy of Sciences, Beijing, 100101, China
| | - Manhua Yuan
- CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Center for Influenza Research and Early-warning (CASCIRE), CAS-TWAS Center of Excellence for Emerging Infectious Diseases (CEEID), Chinese Academy of Sciences, Beijing, 100101, China
| | - Wenwan Rong
- CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Center for Influenza Research and Early-warning (CASCIRE), CAS-TWAS Center of Excellence for Emerging Infectious Diseases (CEEID), Chinese Academy of Sciences, Beijing, 100101, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Han Du
- College of Life Science and Technology, Xinjiang University, Urumchi, 830046, China
| | - Xuanxuan Li
- College of Life Science and Technology, Xinjiang University, Urumchi, 830046, China
| | - Tiannan Ji
- Department of Emergency, Department of Radiotherapy, The Fifth Medical Center of PLA General Hospital, Beijing, 100071, China
| | - Jianxiong Li
- Department of Emergency, Department of Radiotherapy, The Fifth Medical Center of PLA General Hospital, Beijing, 100071, China
| | - Bo Dai
- Department of Pharmacy, Air Force Medical Center, PLA, Beijing, 100142, China
| | - Zhenghai Ma
- College of Life Science and Technology, Xinjiang University, Urumchi, 830046, China
| | - Hui Qi
- Hebei Academy of Integrated Traditional Chinese and Western Medicine, National Key Laboratory for Innovation and Transformation of Luobing Theory, Shijiazhuang, 050035, China
| | - Ning Zhang
- CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Center for Influenza Research and Early-warning (CASCIRE), CAS-TWAS Center of Excellence for Emerging Infectious Diseases (CEEID), Chinese Academy of Sciences, Beijing, 100101, China
| | - Jing Yang
- CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Center for Influenza Research and Early-warning (CASCIRE), CAS-TWAS Center of Excellence for Emerging Infectious Diseases (CEEID), Chinese Academy of Sciences, Beijing, 100101, China
| | - Xuefeng Duan
- CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Center for Influenza Research and Early-warning (CASCIRE), CAS-TWAS Center of Excellence for Emerging Infectious Diseases (CEEID), Chinese Academy of Sciences, Beijing, 100101, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yuhai Bi
- CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Center for Influenza Research and Early-warning (CASCIRE), CAS-TWAS Center of Excellence for Emerging Infectious Diseases (CEEID), Chinese Academy of Sciences, Beijing, 100101, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
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Wang M, Yang F, Kong J, Zong Y, Li Q, Shao B, Wang J. Traditional Chinese medicine enhances the effectiveness of immune checkpoint inhibitors in tumor treatment: A mechanism discussion. JOURNAL OF ETHNOPHARMACOLOGY 2025; 338:118955. [PMID: 39427737 DOI: 10.1016/j.jep.2024.118955] [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: 06/25/2024] [Revised: 10/08/2024] [Accepted: 10/15/2024] [Indexed: 10/22/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Immune checkpoint inhibitors (ICIs) have altered the landscape of tumor immunotherapy, offering novel therapeutic approaches alongside surgery, chemotherapy, and radiotherapy and significantly improving survival benefits. However, their clinical efficacy is limited in some patients, and their use may cause immune-related adverse events (irAEs). Integrating traditional Chinese medicine (TCM) with ICIs has demonstrated the potential to boost sensitization and reduce toxicity. Clinical trials and experimental explorations have confirmed that TCM and its active components synergistically enhance the effectiveness of ICIs. AIMS This narrative review summarizes the TCM practices that enhance the clinical efficacy and reduce irAEs of ICIs. This paper also summarizes the mechanism of experimental studies on the synergies of Chinese herbal decoctions, Chinese herbal preparation, and Chinese herbal active ingredients. Most of the studies on TCM combined with ICIs are basic experiments. We discussed the mechanism of TCM enhanced ICIs to provide reference for the research and development of TCM adjuvant immunotherapy. METHODS We conducted a literature search using PubMed and Chinese National Knowledge Infrastructure databases, with a focus on herbal decoction, Chinese medicine preparations, and active ingredients that boost the effectiveness of ICIs and reduce irAEs. The search keywords were "ICIs and traditional Chinese medicine", "PD-1 and traditional Chinese medicine", "PD-L1 and traditional Chinese medicine", "CTLA-4 and traditional Chinese medicine", "IDO1 and traditional Chinese medicine", "Tim-3 and traditional Chinese medicine", "TIGIT and traditional Chinese medicine", "irAEs and traditional Chinese medicine". The search period was from May 2014 to May 2024. Articles involving the use of TCM or its components in combination with ICIs and investigating the underlying mechanisms were screened. Finally, 30 Chinese medicines used in combination with ICIs were obtained to explore the mechanism. In the part of immune checkpoint molecules other than PD-1, there were few studies on the combined application of TCM, so studies involving the regulation of immune checkpoint molecules by TCM were included. RESULTS TCM has been shown to boost the effectiveness of ICIs and reduce irAEs. Researchers indicate that TCM and its active components can work synergistically with ICIs by regulating immune checkpoints PD-1, PD-L1, CTLA-4, and IDO1, regulating intestinal flora, improving tumor microenvironment and more. CONCLUSIONS Combining TCM with ICIs can play a better anti-tumor role, but larger samples and high-quality clinical trials are necessary to confirm this. Many Chinese medicines and their ingredients have been shown to sensitize ICIs in experimental studies, which provides a rich choice for the subsequent development of ICI enhancers.
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Affiliation(s)
- Manting Wang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China; National Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Fan Yang
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Shandong, 250014, China; First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Shandong, 250014, China; National Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Jingwei Kong
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, 100007, China; National Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Yuhan Zong
- The Second School of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China; National Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Qin Li
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
| | - Bin Shao
- Department of Breast Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, 100142, China.
| | - Ji Wang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China; National Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
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Zhang Z, Zhou X, Xia L, Li N, Xu S, Dong X, Zhu L, Huang M, Wan G. Wenshen Xiaozheng Tang alleviates fibrosis in endometriosis by regulating differentiation and paracrine signaling of endometrium-derived mesenchymal stem cells. JOURNAL OF ETHNOPHARMACOLOGY 2025; 336:118724. [PMID: 39181283 DOI: 10.1016/j.jep.2024.118724] [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: 08/19/2024] [Accepted: 08/21/2024] [Indexed: 08/27/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Wenshen Xiaozheng Tang (WXT), a traditional Chinese medicine (TCM) decoction, is effective for treating endometriosis. However, the effect of WXT on endometrium-derived mesenchymal stem cells (eMSCs) which play a key role in the fibrogenesis of endometriosis requires further elucidation. AIMS OF THE STUDY The aim of this study was to clarify the potential mechanism of WXT in improving fibrosis in endometriosis by investigating the regulation of WXT on differentiation and paracrine of eMSCs. MATERIALS AND METHODS The nude mice with endometriosis were randomly divided into model group, WXT group and mifepristone group. After 21 days of treatment, the lesion volume was calculated. Fibrosis in the lesions was evaluated by Masson staining and expression of fibrotic proteins. The differentiation of eMSCs in vivo was explored using a fate-tracking experiment. To further clarify the regulation of WXT on eMSCs, primary eMSCs from the ectopic lesions of endometriosis patients were isolated and characterized. The effect of WXT on the proliferation and differentiation of ectopic eMSCs was examined. To evaluate the role of WXT on the paracrine activity of ectopic eMSCs, the conditioned medium (CM) from ectopic eMSCs pretreated with WXT was collected and applied to treat ectopic endometrial stromal cells (ESCs), after which the expression of fibrotic proteins in ectopic ESCs was assessed. In addition, transcriptome sequencing was used to investigate the regulatory mechanism of WXT on ectopic eMSCs, and western blot and ELISA were employed to determine the key mediator. RESULTS WXT impeded the growth of ectopic lesions in nude mice with endometriosis and reduced collagen deposition and the expression of fibrotic proteins fibronectin, collagen I, α-SMA and CTGF in the endometriotic lesions. The fate-tracking experiment showed that WXT prevented human eMSCs from differentiating into myofibroblasts in the nude mice. We successfully isolated eMSCs from the lesions of patients with endometriosis and demonstrated that WXT suppressed proliferation and myofibroblast differentiation of ectopic eMSCs. Moreover, the expression of α-SMA, collagen I, fibronectin and CTGF in ectopic ESCs was significantly down-regulated by the CM of ectopic MSCs pretreated with WXT. Combining the results of RNA sequencing, western blot and ELISA, we found that WXT not only reduced thrombospondin 4 expression in ectopic eMSCs, but also decreased thrombospondin 4 secretion from ectopic eMSCs. Thrombospondin 4 concentration-dependently upregulated the expression of collagen I, fibronectin, α-SMA and CTGF in ectopic ESCs, indicating that thrombospondin 4 was a key mediator of WXT in inhibiting the fibrotic process in endometriosis. CONCLUSION WXT improved fibrosis in endometriosis by regulating differentiation and paracrine signaling of eMSCs. Thrombospondin 4, whose release from ectopic eMSCs is inhibited by WXT, may be a potential target for the treatment of endometriosis.
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Affiliation(s)
- Zhenzhen Zhang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, Jiangsu, China; Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, Jiangsu, China.
| | - Xue Zhou
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, Jiangsu, China; Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, Jiangsu, China.
| | - Lu Xia
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, Jiangsu, China; Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, Jiangsu, China.
| | - Nan Li
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, Jiangsu, China; Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, Jiangsu, China.
| | - Shihan Xu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, Jiangsu, China; Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, Jiangsu, China.
| | - Xiaohong Dong
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, Jiangsu, China; Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, Jiangsu, China.
| | - Li Zhu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, Jiangsu, China; Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, Jiangsu, China.
| | - Meihua Huang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, Jiangsu, China; Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, Jiangsu, China.
| | - Guiping Wan
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, Jiangsu, China; Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, Jiangsu, China.
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Liu Y, Li Y, Chen L, Zha W, Zhang J, Wang K, Hao C, Gan J. Construction of an Oxidative Stress Risk Model to Analyze the Correlation Between Liver Cancer and Tumor Immunity. Curr Cancer Drug Targets 2025; 25:49-63. [PMID: 38375834 DOI: 10.2174/0115680096284532231220061048] [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: 09/27/2023] [Revised: 11/11/2023] [Accepted: 11/17/2023] [Indexed: 02/21/2024]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) remains one of the most lethal cancers globally. Despite advancements in immunotherapy, the prognosis for patients with HCC continues to be poor. As oxidative stress plays a significant role in the onset and progression of various diseases, including metabolism-related HCC, comprehending its mechanism in HCC is critical for effective diagnosis and treatment. METHODS This study utilized the TCGA dataset and a collection of oxidative stress genes to identify the expression of oxidative stress-related genes in HCC and their association with overall survival using diverse bioinformatics methods. A novel prognostic risk model was developed, and the TCGA cohort was divided into high-risk and low-risk groups based on each tumor sample's risk score. Levels of immune cell infiltration and the expression of immune checkpoint-related genes in different risk subgroups were analyzed to investigate the potential link between tumor immunity and oxidative stress-related features. The expression of model genes in actual samples was validated through immunohistochemistry, and their mRNA and protein expression levels were measured in cell cultures. RESULTS Four oxidative stress-related genes (EZH2, ANKZF1, G6PD, and HMOX1) were identified and utilized to create a predictive risk model for HCC patient overall survival, which was subsequently validated in an independent cohort. A correlation was found between the expression of these prognostic genes and the infiltration of tumor immune cells. Elevated expression of EZH2, ANKZF1, G6PD, and HMOX1 was observed in both HCC tissues and cell lines. CONCLUSION The combined assessment of EZH2, ANKZF1, G6PD, and HMOX1 gene expression can serve as an oxidative stress risk model for assessing HCC prognosis. Furthermore, there is a correlation between the expression of these risk model genes and tumor immunity.
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Affiliation(s)
- Ying Liu
- Department of Infectious Disease, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yufeng Li
- Hebei Key Laboratory of Molecular Oncology, Tangshan People's Hospital, Tangshan, Hebei, 063001, China
- Institute of Cancer Research, Tangshan People's Hospital, Tangshan, China
| | - Li Chen
- Department of Infectious Disease, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Weina Zha
- Department of Endocrine, TangShan GongRen Hospital, Tangshan, China
| | - Jing Zhang
- Department of Hepatobiliary Medicine, Tangshan People's Hospital, Tangshan, China
| | - Kun Wang
- Department of Infectious Disease, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Chunhai Hao
- Department of Hepatobiliary Medicine, Tangshan People's Hospital, Tangshan, China
| | - Jianhe Gan
- Department of Infectious Disease, The First Affiliated Hospital of Soochow University, Suzhou, China
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Wang S, Ji F, Gao X, Li Z, Lv S, Zhang J, Luo J, Li D, Yan J, Zhang H, Fang K, Wu L, Li M. Tyrosine Kinase Inhibitor Lenvatinib Causes Cardiotoxicity by Inducing Endoplasmic Reticulum Stress and Apoptosis through Activating ATF6, IRE1α and PERK Signaling Pathways. Recent Pat Anticancer Drug Discov 2025; 20:168-184. [PMID: 38994620 DOI: 10.2174/0115748928265981231204044653] [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: 06/06/2023] [Revised: 10/14/2023] [Accepted: 10/18/2023] [Indexed: 07/13/2024]
Abstract
BACKGROUND Lenvatinib is a tyrosine kinase inhibitor that can improve progression-free survival in patients with thyroid cancer and hepatocellular carcinoma. However, it is limited by adverse cardiovascular events, including hypertension and cardiac dysfunction. Activation of endoplasmic reticulum stress is involved in cardiomyocyte apoptosis. OBJECTIVE This study aimed to confirm whether the cardiotoxicity of lenvatinib is associated with endoplasmic reticulum stress by targeting the activating transcription factor 6 (ATF6), inositol- requiring enzyme 1α (IRE1α) and protein kinase RNA-like ER kinase (PERK) signaling pathways. METHODS Male C57/BL6 mice were intragastric administration with 30 mg/kg/day lenvatinib. Electrocardiography (ECG) and echocardiography were used to detect arrhythmias and cardiac function. Neonatal rat cardiomyocytes were treated with lenvatinib for 48h. Cell counting kit (CCK8), 2´,7´-dichlorodihydrofluoresceine diacetate (H2DCFHDA), Hoechst 33258 and dihydrorhodamine 123 were respectively used for evaluating cell viability, the level of reactive oxygen species (ROS), nuclear morphological changes and mitochondrial membrane potential (MMP) level. RESULTS Lenvatinib remarkably decreased the posterior wall thickness of left ventricle during diastole and systole but caused little decrease to the left ventricular ejection fraction (LVEF, %). Furthermore, lenvatinib greatly prolonged the corrected QT interval (QTc) and altered the morphology of cardiomyocytes. No significant difference in fibrosis was found in mouse cardiac slices. Lenvatinib upregulates apoptosis-related protein expression. In addition, lenvatinib increased ERS-related proteins expression (GRP78, CHOP, and ATF6) and enhanced PERK phosphorylation. In neonatal rat cardiac myocytes, lenvatinib markedly decreased the viability of cardiomyocytes and induced apoptosis. Furthermore, ROS production increased and MMP decreased. Similar to the mice experiment, lenvatinib caused upregulation of apoptosis-related and ERS-related proteins and increased the phosphorylation levels of PERK and IRE1α. CONCLUSION Lenvatinib-induced cardiotoxicity is associated with ERS-induced apoptosis by targeting the ATF6, IRE1α, and PERK signaling pathways.
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Affiliation(s)
- Siqi Wang
- Key Laboratory of Medical Electrophysiology of Ministry of Education, Medical Electrophysiology Key Lab of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Fang Ji
- Key Laboratory of Medical Electrophysiology of Ministry of Education, Medical Electrophysiology Key Lab of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Xiaoli Gao
- Department of General Surgery (Breast Surgery), the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Zhiyi Li
- Key Laboratory of Medical Electrophysiology of Ministry of Education, Medical Electrophysiology Key Lab of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Si Lv
- Key Laboratory of Medical Electrophysiology of Ministry of Education, Medical Electrophysiology Key Lab of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Juan Zhang
- Key Laboratory of Medical Electrophysiology of Ministry of Education, Medical Electrophysiology Key Lab of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Jiarui Luo
- Key Laboratory of Medical Electrophysiology of Ministry of Education, Medical Electrophysiology Key Lab of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Dan Li
- Key Laboratory of Medical Electrophysiology of Ministry of Education, Medical Electrophysiology Key Lab of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Jie Yan
- Key Laboratory of Medical Electrophysiology of Ministry of Education, Medical Electrophysiology Key Lab of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Huayang Zhang
- Key Laboratory of Medical Electrophysiology of Ministry of Education, Medical Electrophysiology Key Lab of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Kaicheng Fang
- Key Laboratory of Medical Electrophysiology of Ministry of Education, Medical Electrophysiology Key Lab of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Lin Wu
- Key Laboratory of Medical Electrophysiology of Ministry of Education, Medical Electrophysiology Key Lab of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, 646000, China
- Department of Cardiology, Peking University First Hospital, Beijing, 100034, China
| | - Miaoling Li
- Key Laboratory of Medical Electrophysiology of Ministry of Education, Medical Electrophysiology Key Lab of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, 646000, China
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Zhang YJ, Wang XX, Zeng LJ, Ka-Yam LAM, Dai QY, Chen Y, Chen J, Guo Y, Cai Z. Rewiring the nexus between urban traffic pollution-derived polycyclic aromatic hydrocarbon exposure and DNA injury via urinary metabolomics. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2024; 363:125188. [PMID: 39486674 DOI: 10.1016/j.envpol.2024.125188] [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: 05/13/2024] [Revised: 09/23/2024] [Accepted: 10/22/2024] [Indexed: 11/04/2024]
Abstract
Urban road traffic environmental stress impacts outdoor population health, with oxidative damage serving as an early indicator of xenobiotic exposure. Polycyclic aromatic hydrocarbons (PAHs) as priority carcinogens pose significant public health burden, yet knowledge remains limited regarding the endogenous metabolic alternations associated with oxidative DNA injury. This cross-sectional study focused on the cohort consisting of 109 sanitation workers ("traffic exposure group") and 112 demographics-matched common residents ("controls") in South China. The goal was to elucidate the occurrence of internal exposure to nine hydroxyl PAHs, and the interrelations with oxidative DNA damage (indicated by 8-hydroxy-2'-deoxyguanosine, 8-OHdG) by linear mixed-effect regression model. T-test and orthogonal partial least squares discriminant analysis were used to determine differential metabolites in non-targeted metabolomics. Results revealed outdoor workers suffered from the heavier PAH exposure burden and exhibited a stronger dose-dependent correlation with 8-OHdG, evidenced by the higher regression coefficient (0.244, 95% CI: 0.154-0.334) than controls (0.203, 95% CI: 0.079-0.328). In total 42 differential endogenous metabolites witnessed significant expression under traffic emission scenario, mainly implicated in phenylalanine, tyrosine and tryptophan biosynthesis. The down-expressed uric acid was the unique metabolite that inversely correlated with the increased intake of ∑8PAH especially in cases. Partially attributed to the traffic-derived PAHs, the dysregulated amino acid, nicotinamide, purine, and steroid hormones metabolic pathways encompassing 11 metabolites were determined as underlying biomarkers in mediating DNA damage. Notably, our findings proposed uric acid may act as a potential antioxidant, as evidenced by the negative correlation with 8-OHdG. The study illustrates outcomes of metabolomics can collaboratively indicate DNA oxidative damage caused by PAHs linked to urban traffic exposure, which holds significant implications for future toxicological research.
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Affiliation(s)
- Ying-Jie Zhang
- State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong, 999077, China
| | - Xiao-Xiao Wang
- State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong, 999077, China
| | - Li-Juan Zeng
- School of Environment and Energy, South China University of Technology, Guangzhou, 510006, China
| | - L A M Ka-Yam
- State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong, 999077, China
| | - Qing-Yuan Dai
- State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong, 999077, China
| | - Yi Chen
- State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong, 999077, China
| | - Jian Chen
- State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong, 999077, China
| | - Ying Guo
- Guangdong Key Laboratory of Environmental Pollution and Health, School of Environment, Jinan University, Guangzhou, 510632, China.
| | - Zongwei Cai
- State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong, 999077, China.
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Bai Y, Liu F, Luo S, Wan Y, Zhang L, Wu X, Chen Q, Xie Y, Guo P. Experimental study on H 2O 2 activation of HSC-T6 and hepatic fibrosis in cholestatic mice by "Yajieshaba". JOURNAL OF ETHNOPHARMACOLOGY 2024; 335:118712. [PMID: 39173724 DOI: 10.1016/j.jep.2024.118712] [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: 06/05/2024] [Revised: 08/16/2024] [Accepted: 08/17/2024] [Indexed: 08/24/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Yajieshaba (YJSB), approved by the Yunnan Provincial Food and Drug Administration in 2008, are known for their anti-inflammatory, antiviral, and pro-apoptotic properties, effectively treating Hepatic fibrosis (HF). However, its mechanism of action remains unclear. AIM OF THE STUDY The objective of this investigation is to explore how YJSB influences the TGF-β1/Smad signaling pathway as a strategy for reducing HF. METHODS The establishment of a HF model in mice involved ligation of the common bile duct, followed by administration of YJSB. Body and liver weights were measured, and the liver index calculated. Serum levels of ALT, AST, ALP, TBA, and TBIL were assessed using colorimetric methods. Additionally, liver homogenates were analyzed for PIIINP, Col-IV, LN, HA, and Hyp, as well as TGF-β1 activity, using ELISA. Histological analyses of liver sections, stained with H&E, Ag, and Masson's trichrome, were performed to examine inflammation and the accumulation of collagen and reticular fibers. These studies aimed to elucidate the pharmacodynamic effects of YJSB on HF in mice with bile duct obstruction. The target pathways of YJSB were preliminarily identified through immunofluorescence detection of TGF-β1, P-Smad2L, P-Smad2C, P-Smad3L, P-Smad3C, and Smad4 proteins. In vitro experiments included the induction of hepatic stellate cell (HSC-T6) activation by H2O2. A cell injury model was established for HSC-T6, and the CCK-8 assay was used to determine the optimal YJSB concentration and treatment duration. After pirfenidone (PFD) administration, which inhibits the TGF-β1/Smad pathway, the effects of YJSB on HSC-T6 cell proliferation were observed. ELISA assays quantified Col-III, α-SMA, and Col-I in cell lysates to assess YJSB's impact on collagen synthesis in HSC-T6 cells. Western blot analysis was performed to assess the protein levels within the TGF-β1/Smad signaling cascade. RESULTS In the HF mouse model, administration of YJSB notably augmented the body weight and reduced the liver index. Concurrently, there was an elevation in serum concentrations of ALP, AST, ALT, TBA, and TBIL. Similarly, in the liver homogenates of HF mice, increases were observed in the levels of HA, PIIINP, Col-IV, LN, Hyp, and TGF-β1. Histological assessments using H&E, Ag, and Masson stains indicated a substantial diminution in liver tissue damage. Through immunofluorescence analysis, it was discerned that YJSB modulated the expression of TGF-β1, P-Smad2L, P-Smad2C, and P-Smad3L downwards, while elevating P-Smad3C and Smad4 protein expressions. Additional investigations revealed a significant reduction in α-SMA, Col-I, and Col-III levels in cell culture fluids, suggesting a decrease in collagen synthesis and a protective role against cellular damage. Western blot analyses demonstrated that the TGF-β1/Smad pathway inhibitor, PFD, acted in synergy with YJSB, enhancing its regulatory effects on this pathway, decreasing levels of TGF-β1, P-Smad2L, P-Smad2C, P-Smad3L, and promoting the expression of P-Smad3C. CONCLUSIONS YJSB demonstrates a pharmacodynamic effect against HF, enhancing liver functionality and effectively mitigating the damage associated with bile duct obstruction. The proposed action mechanism of YJSB involves modulation of the TGF-β1/Smad signaling pathway. Research indicates that YJSB might play a role in suppressing the movement, programmed cell death, and activation of HSC-T6, potentially decelerating the advancement of hepatic fibrosis.
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Affiliation(s)
- Yuanmei Bai
- College of Ethnic Medicine, Yunnan University of Chinese Medicine, Yunnan, Kunming, 650500, China
| | - Feifan Liu
- College of Ethnic Medicine, Yunnan University of Chinese Medicine, Yunnan, Kunming, 650500, China
| | - Shifang Luo
- College of Ethnic Medicine, Yunnan University of Chinese Medicine, Yunnan, Kunming, 650500, China
| | - Yan Wan
- College of Ethnic Medicine, Yunnan University of Chinese Medicine, Yunnan, Kunming, 650500, China
| | - Linao Zhang
- College of Chinese Medicine, Yunnan University of Chinese Medicine, Yunnan, Kunming, 650500, China
| | - Xue Wu
- College of Chinese Medicine, Yunnan University of Chinese Medicine, Yunnan, Kunming, 650500, China
| | - Qinghua Chen
- College of Ethnic Medicine, Yunnan University of Chinese Medicine, Yunnan, Kunming, 650500, China.
| | - Yuhuan Xie
- College of Basic Medical Sciences, Yunnan University of Chinese Medicine, Yunnan, Kunming, 650500, China.
| | - Peixin Guo
- College of Ethnic Medicine, Yunnan University of Chinese Medicine, Yunnan, Kunming, 650500, China.
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9
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Song L, Wang D, Zhai Y, Zhang X, Zhang Y, Yu Y, Sun L, Zhou K. Aqueous extract of Epimedium sagittatum (Sieb. et Zucc.) Maxim. induces liver injury in mice via pyroptosis. JOURNAL OF ETHNOPHARMACOLOGY 2024; 329:118164. [PMID: 38593963 DOI: 10.1016/j.jep.2024.118164] [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: 12/25/2023] [Revised: 04/04/2024] [Accepted: 04/06/2024] [Indexed: 04/11/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Epimedium sagittatum (Sieb. et Zucc.) Maxim. has been used traditionally in Asia. It can dispel wind and cold, tonify the kidney, and strengthen bones and tendons. However, adverse effects of E. sagittatum have been reported, and the underlying mechanisms remain unclear. AIM OF THE STUDY This study aimed to investigate liver injury caused by an aqueous extract of E. sagittatum in Institute of Cancer Research (ICR) mice and explore its potential mechanisms. MATERIALS AND METHODS Dried E. sagittatum leaves were decocted in water to prepare aqueous extracts for ultra-high performance liquid chromatography analysis. Mice were administered an aqueous extract of E. sagittatum equivalent to either 3 g raw E. sagittatum/kg or 10 g raw E. sagittatum/kg once daily via intragastric injection for three months. The liver weights and levels of the serum biochemical parameters including alanine transaminase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), total bilirubin (TBIL), and alkaline phosphatase were measured. Hematoxylin-eosin staining was performed for histopathology. Apoptosis was detected using the TUNEL apoptosis assay kit. IL-1β was detected using ELISA kits. Proteomics was used to identify the differentially expressed proteins. Western blot analysis was performed to determine the levels of proteins significantly affected by the aqueous extract of E. sagittatum. RESULTS E. sagittatum treatment increased the liver weights and liver coefficients, and ALT and AST levels significantly increased (p < 0.05). A high dose of E. sagittatum significantly increased LDH and TBIL levels (p < 0.05). Ruptured cell membranes and multiple sites of inflammatory cell infiltration were also observed. No evidence of apoptosis was observed. IL-1β levels were significantly increased (p < 0.05). The expressions of PIK3R1, p-MAP2K4, p-Jun N-terminal kinase (JNK)/JNK, p-c-Jun, VDAC2, Bax, and CYC were upregulated, whereas that of Bcl-2 was inhibited by E. sagittatum. The expression of cleaved caspase-1 was significantly increased; however, its effects on GSDMD and GSDMD-N were significantly decreased. The expression levels of cleaved caspase-3 and its effector proteins GSDME and GSDME-N significantly increased. CONCLUSIONS Our results suggest that the aqueous extract of E. sagittatum induces liver injury in ICR mice after three months of intragastric injection via inflammatory pyroptosis.
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Affiliation(s)
- Lei Song
- Center of Drug Safety Evaluation, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China; State Key Laboratory of Component-based Chinese Medicine, Tianjin, 301617, China
| | - Dongyu Wang
- Center of Drug Safety Evaluation, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Yuxia Zhai
- Center of Drug Safety Evaluation, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Xiaoying Zhang
- Center of Drug Safety Evaluation, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Yue Zhang
- Center of Drug Safety Evaluation, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China; State Key Laboratory of Component-based Chinese Medicine, Tianjin, 301617, China
| | - Yingli Yu
- Center of Drug Safety Evaluation, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China; State Key Laboratory of Component-based Chinese Medicine, Tianjin, 301617, China
| | - Likang Sun
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Kun Zhou
- Center of Drug Safety Evaluation, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China; State Key Laboratory of Component-based Chinese Medicine, Tianjin, 301617, China.
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Zhang W, Dong J, Wu Y, Liang X, Suo L, Wang L. Integrated Bioinformatic Analysis Reveals the Oncogenic, Survival, and Prognostic Characteristics of TPX2 in Hepatocellular Carcinoma. Biochem Genet 2024:10.1007/s10528-024-10840-3. [PMID: 38833082 DOI: 10.1007/s10528-024-10840-3] [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: 12/16/2023] [Accepted: 05/13/2024] [Indexed: 06/06/2024]
Abstract
Targeting protein for Xenopus kinesin-like protein 2 (TPX2), a well-known mitotic protein, has been linked to carcinogenesis in several cancers. This study investigated the role of TPX2 in hepatocellular carcinoma (HCC) from various aspects using bioinformatic analyses. TPX2 expression and its prognostic value in pan-cancers were analyzed using SangerBox. TPX2 expression and its association with prognosis, immune infiltration, tumor mutations, and signaling pathways in HCC were analyzed using UALCAN, BoxKaplan-Meier Plotter, GEPIA, Human Protein Atlas, TIMER 2.0, and SangerBox. Genes co-expressed with TPX2 in HCC were analyzed using the HCCDB database, followed by functional enrichment using SangerBox. Clinical predictive models were established based on TPX2 and its co-expressed genes using the ACLBI database. TPX2 expression significantly increased in pan-cancers and was associated with survival in nearly half of the cancer types. High TPX2 expression has been linked to poor survival outcomes in patients with HCC. TPX2 expression was positively correlated with abundant infiltration of immune cells (including B cells, CD4 + /CD8 + T cells, macrophages, neutrophils, and dendritic cells), TP53 mutation, and carcinogenesis-related pathways, such as the PI3K/AKT/mTOR pathway, cellular response to hypoxia, and tumor proliferation signature. Nineteen genes were found to be co-expressed with TPX2 in HCC, and these genes showed close positive correlations and were mainly implicated in cell cycle-related functions. A prognostic model established using TPX2 and its expressed genes could stratify HCC patients into high- and low-risk groups, with a significantly shorter survival time in high-risk groups. The prognostic model performed well in predicting 1-, 3-, and 5-year survival of patients with HCC, with areas under the curve of 0.801, 0.725, and 0.711, respectively. TPX2 functions as an oncogene in HCC, and its high expression is detrimental to the survival of patients with HCC. Thus, TPX2 may be a prognostic biomarker and potential therapeutic target for HCC.
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Affiliation(s)
- Weibin Zhang
- Department of Hepatobiliary Surgery, The Second Hospital of Dalian Medical University, Dalian, China
| | - Jia Dong
- Department of Radiology, Jinzhou Maternity and Infant Hospital, Jinzhou, China
| | - Yunfei Wu
- Department of General Surgery, Jinzhou Central Hospital, Jinzhou, China
| | - Xiangnan Liang
- Department of Hepatobiliary Surgery, The Second Hospital of Dalian Medical University, Dalian, China
| | - Lida Suo
- Department of Hepatobiliary Surgery, The Second Hospital of Dalian Medical University, Dalian, China
| | - Liming Wang
- Department of Hepatobiliary Surgery, The Second Hospital of Dalian Medical University, Dalian, China.
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11
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Mokhtarian R, Rajabi S, Zahedian S, Jafarinejad-Farsangi S, Hadizadeh M, Sadeghinejad M. The effect of saffron and its extracts on the treatment of breast cancer: A narrative review. ANNALES PHARMACEUTIQUES FRANÇAISES 2024; 82:629-640. [PMID: 38367937 DOI: 10.1016/j.pharma.2024.02.011] [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] [Received: 10/01/2023] [Revised: 02/11/2024] [Accepted: 02/12/2024] [Indexed: 02/19/2024]
Abstract
Breast cancer (BC) is the most prevalent malignancy in women and the second most common disease worldwide, affecting approximately one million individuals annually. Despite the efficacy of conventional chemotherapy, medication resistance and adverse effects limit its effectiveness, leading researchers to explore alternative treatments, including herbal remedies. Saffron, a well-known spice derived from the Crocus sativus L. plant, has shown potential as a BC treatment. The active components of saffron exhibit anti-cancer properties by inducing apoptosis, inhibiting cell division, and modulating signaling pathways implicated in cancer development, such as PI3K/AKT, NF-κB, and MAPK. Clinical findings suggest that saffron can alleviate chemotherapy-induced symptoms, reduce serum tumor marker levels, and enhance quality of life. Preliminary clinical trials are investigating the safety and efficacy of saffron in treating BC, with recent evidence indicating that recommended doses of saffron supplementation are well-tolerated and safe. This review provides an overview of the anti-tumor effects of saffron and its unique chemical composition in BC. However, further research and clinical studies are imperative to fully comprehend the potential of saffron in adjuvant therapy for BC patients.
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Affiliation(s)
- Roya Mokhtarian
- Division of Cellular and Molecular Biology, Department of Biology, NourDanesh Institute of Higher Education, Meymeh, Isfahan, Iran
| | - Soodeh Rajabi
- Student Research Committee, Kerman University of Medical Sciences, Kerman, Iran
| | - Setareh Zahedian
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Saeideh Jafarinejad-Farsangi
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran.
| | - Morteza Hadizadeh
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Masoumeh Sadeghinejad
- Department of Kinesiology and Applied Physiology, College of Health Sciences, University of Delaware, Newark, DE, United States
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12
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Xu F, Zhang H, Chen J, Zhan J, Liu P, Liu W, Qi S, Mu Y. Recent progress on the application of compound formulas of traditional Chinese medicine in clinical trials and basic research in vivo for chronic liver disease. JOURNAL OF ETHNOPHARMACOLOGY 2024; 321:117514. [PMID: 38042388 DOI: 10.1016/j.jep.2023.117514] [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: 09/19/2023] [Revised: 11/23/2023] [Accepted: 11/24/2023] [Indexed: 12/04/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Chronic liver diseases mainly include chronic viral liver disease, metabolic liver disease, cholestatic liver disease (CLD), autoimmune liver disease, and liver fibrosis or cirrhosis. Notably, the compound formulas of traditional Chinese medicine (TCM) is effective for chronic liver diseases in clinical trials and basic research in vivo, which provide evidence of chronic liver disease treatment with integrated TCM and traditional Western medicine. AIM OF THE REVIEW This paper aims to provide a comprehensive review of the compound formulas of TCM for treating different chronic liver diseases to elucidate the composition, main curative effects, and mechanisms of these formulas and research methods. MATERIALS AND METHODS Different keywords related to chronic liver diseases and keywords related to the compound formulas of TCM were used to search the literature. PubMed, Scopus, Web of Science, and CNKI were searched to screen out original articles about the compound formulas of TCM related to the treatment of chronic liver diseases, mainly including clinical trials and basic in vivo research related to Chinese patent drugs, classic prescriptions, proven prescriptions, and hospital preparations. We excluded review articles, meta-analysis articles, in vitro experiments, articles about TCM monomers, articles about single-medicine extracts, and articles with incomplete or uncertain description of prescription composition. Plant names were checked with MPNS (http://mpns.kew.org). RESULTS In this review, the clinical efficacy and mechanism of compound formulas of TCM were summarized for the treatment of chronic viral hepatitis, nonalcoholic fatty liver disease, CLD, and liver fibrosis or cirrhosis developed from these diseases and other chronic liver diseases. For each clinical trial and basic research in vivo, this review provides a detailed record of the specific composition of the compound formulas of TCM, type of clinical research, modeling method of animal experiments, grouping methods, medication administration, main efficacy, and mechanisms. CONCLUSION The general development process of chronic liver disease can be summarized as chronic hepatitis, liver fibrosis or cirrhosis, and hepatocellular carcinoma. The compound formulas of TCM have some applications in these stages of chronic liver diseases. Owing to the continuous progress of medical technology, the benefits of the compound formulas of TCM in the treatment of chronic liver diseases are constantly changing and developing.
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Affiliation(s)
- Feipeng Xu
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, China
| | - Hua Zhang
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, China
| | - Jiamei Chen
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, China
| | - Junyi Zhan
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, China
| | - Ping Liu
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, China; Institute of Interdisciplinary Complex Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Wei Liu
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, China; Department of pharmacy, The SATCM Third Grade Laboratory of Traditional Chinese Medicine Preparations, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Shenglan Qi
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, China; Department of pharmacy, The SATCM Third Grade Laboratory of Traditional Chinese Medicine Preparations, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Institute of Interdisciplinary Complex Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Yongping Mu
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, China.
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13
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Sumaiya S, Siddiqui A, Chaudhary SS, Aslam M, Ahmad S, Ansari MA. Isolation and characterization of bioactive components from hydroalcoholic extract of Cymbopogon jwarancusa (Jones) Schult. to evaluate its hepatoprotective activity. JOURNAL OF ETHNOPHARMACOLOGY 2024; 319:117185. [PMID: 37714225 DOI: 10.1016/j.jep.2023.117185] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 08/30/2023] [Accepted: 09/12/2023] [Indexed: 09/17/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Cymbopogon jwarancusa (Jones) Schult. (Family: Poacea/Gramineae) is being used to treat numerous ailments in traditional/folklore and indigenous system of medicine due to its antioxidant, anti-allergic, antiparasitic, analgesic, antipyretic and anticancer activities; however there is no documented evidence regarding its hepatoprotective efficacy. AIM This study was aimed to evaluate hepatoprotective activity of hydroalcoholic extract of Cymbopogon jwarancusa (HECJ) against paracetamol (PCM) induced liver damage in albino Wistar rats, and to identify the bioactive components present in the extract responsible for the said activity. MATERIALS AND METHODS Five groups of rats (n = 6) were orally treated with: 0.5% carboxymethyl cellulose (normal control), 50 mg/kg silymarin (reference standard), HECJ [515 mg/kg (low dose) and 720 mg/kg (high dose)] (test groups) for 7 days daily, followed by induction of hepato-toxicity using PCM (2 gm/kg) on 7th day (PCM control; reference standard; test groups). The blood samples to estimate the level of AST, ALT, ALP, total bilirubin and total protein; liver tissue homogenate for antioxidant markers (GSH, GST, GPx, and LPO) and liver section for histopathological analysis were collected. Isolation and characterization of phytochemicals from HECJ was done by preliminary screening, determination of phenolic, flavonoid and terpenoid content, and GC-MS analysis. RESULTS The animals pre-treated with HECJ dose-dependently and significantly alleviated the PCM-induced alterations in liver enzymes, plasma proteins, serum total bilirubin and antioxidant markers levels. The histopathological analysis suggest that PCM causes marked necrosis and lymphocyte infiltration, while preservation of the normal hepatic architecture was observed in groups pre-treated with, reference standard drug silymarin, and HECJ. Preliminary screening of the extract, determination of phenolic, flavonoid and terpenoid content, and GC-MS analysis revealed the presence of some important bioactive components such as phenolics, flavonoids, glycoside, tannins, steroids, fatty acids, sterols, esters, saponins, terpenes/terpenoids and essential oil which could be synergistically responsible for the plant's hepatoprotective effect. CONCLUSIONS This study concluded that C. jwarancusa could be taken as a beneficial natural product for its hepatoprotective efficacy; however, future line of work is required to establish its precise mechanism of action.
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Affiliation(s)
- Sajida Sumaiya
- Department of Ilmul Advia, School of Unani Medical Education and Research, Jamia Hamdard, New Delhi, 110062, India.
| | - Aisha Siddiqui
- Department of Ilmul Advia, School of Unani Medical Education and Research, Jamia Hamdard, New Delhi, 110062, India.
| | - Shahid Shah Chaudhary
- Department of Ilmul Saidla, School of Unani Medical Education and Research, Jamia Hamdard, New Delhi, 110062, India.
| | - Mohd Aslam
- Department of Ilmul Advia, School of Unani Medical Education and Research, Jamia Hamdard, New Delhi, 110062, India.
| | - Sayeed Ahmad
- Centre of Excellence in Unani Medicine, Department of Pharmacognosy & Phytochemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India.
| | - Mairaj Ahmed Ansari
- Department of Biotechnology, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, 110062, India.
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14
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Wang W, Chen S, Xu S, Liao G, Li W, Yang X, Li T, Zhang H, Huang H, Zhou Y, Pan H, Lin C. Jianpi Shengqing Huazhuo Formula improves abnormal glucose and lipid metabolism in obesity by regulating mitochondrial biogenesis. JOURNAL OF ETHNOPHARMACOLOGY 2024; 319:117102. [PMID: 37660955 DOI: 10.1016/j.jep.2023.117102] [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: 06/01/2023] [Revised: 08/13/2023] [Accepted: 08/28/2023] [Indexed: 09/05/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Jianpi Shengqing Huazhuo Formula (JSH) is a modified prescription based on traditional Chinese medicine theory and classic prescriptions (Buzhong Yiqi Decoction and Yuye Decoction). It has been found that JSH has a good effect on obese patients with early abnormal glucose and lipid metabolism. Therefore, this experiment was conducted to study its clinical efficacy and pharmacological effect. AIM OF THE STUDY To observe the clinical efficacy of JSH and explore the mechanism of the formula to improve glucose and lipid metabolism in obese rats. MATERIALS AND METHODS 1. CLINICAL OBSERVATION 10 overweight/obese patients with abnormal glucose and lipid metabolism were selected to observe the indicators of serum glucose, serum lipids and liver damage of the patients before and after treatment with JSH. 2. Animal experiments: Fifty Sprague-Dawley (SD) rats were randomly divided into control group, model group, Metformin group (120 mg/kg/day), JSH-L group (5 g/kg/day) and JSH-H group (20 g/kg/day), with 10 rats in each group. The obese SD rat model was produced by feeding 60% high-fat diet for 8 weeks, and the drug group was given prophylactic administration for 8 weeks. At the end of the experiment, body weight, abdominal fat, plasma glucose, plasma lipids, plasma alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were measured. The levels of interleukin-6 (IL-6), interleukin 1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α) in plasma were detected by Elisa, and the changes of malondialdehyde (MDA), glutathione (GSH) and catalase (CAT) in plasma and liver tissue were detected by kits. The pathological changes and lipid deposition in liver were observed by HE staining and oil red O staining, and the changes in the number of mitochondria in liver cells were observed by transmission electron microscopy. RT-qPCR and Western Blot (WB) were used to detect the mitochondrial regulation-related indicators PGC-1α, NRF1, TFAM, MFN2, DRP1 and apoptosis-related indicators Bcl-2, Bax, caspase 8 in liver tissue. RESULTS 1. CLINICAL OBSERVATION After one month administration, the patient's body weight, BMI, 2 h oral glucose tolerance test (2hOGTT), glycated hemoglobin (HbA1c), triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) decreased significantly, and the indicators of liver damage AST and ALT also decreased significantly. 2. Animal experiments: JSH can significantly reduce body weight and abdominal fat area, improve glucose and lipid metabolism, and also reduce plasma IL-6, IL-1β and TNF-α content in obese rats, and improve oxidative stress; HE staining and oil red O staining also showed that JSH can alleviate liver damage and lipid deposition in the liver. Further observations of liver cell ultrastructure showed that JSH can ameliorate the reduction of liver mitochondria caused by a high-fat diet and promote the expression of indicators of mitochondrial biogenesis related to PGC-1α, NRF1, and TFAM. Moreover, JSH could promote the expression of MFN2 and DRP1, decrease Bcl-2 and increase Bax in the liver. CONCLUSIONS 1. CLINICAL OBSERVATION JSH can reduce body weight, serum glucose, serum lipid, and liver injury in overweight/obese patients. 2. Animal experiments: JSH regulates PGC-1α/NRF1/TFAM signaling pathway promotes liver mitochondrial biogenesis, improves glucose and lipid metabolism in obese rats, and regulates mitochondrial dependent apoptosis indicators Bcl-2/Bax to reduce liver injury.
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Affiliation(s)
- Wenkai Wang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China; Pi-wei Institute, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.
| | - Shanshan Chen
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China; Pi-wei Institute, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.
| | - Shuting Xu
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China; Pi-wei Institute, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.
| | - Guangyi Liao
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China; Pi-wei Institute, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.
| | - Weihao Li
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China; Pi-wei Institute, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.
| | - Xiao Yang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China; Pi-wei Institute, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.
| | - Tingting Li
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China; Pi-wei Institute, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.
| | - Huifen Zhang
- Department of Endocrinology, Dongguan Hospital of Guangzhou University of Chinese Medicine, Dongguan Traditional Chinese Medicine Hospital, Dongguan, 523000, China.
| | - Huanhuan Huang
- Department of Endocrinology, Dongguan Hospital of Guangzhou University of Chinese Medicine, Dongguan Traditional Chinese Medicine Hospital, Dongguan, 523000, China.
| | - Yuqing Zhou
- Department of Endocrinology, Dongguan Hospital of Guangzhou University of Chinese Medicine, Dongguan Traditional Chinese Medicine Hospital, Dongguan, 523000, China.
| | - Huafeng Pan
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China; Pi-wei Institute, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.
| | - Chuanquan Lin
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China; Pi-wei Institute, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.
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Guo L, Bao W, Yang S, Liu Y, Lyu J, Wang T, Lu Y, Li H, Zhu H, Chen D. Rhei Radix et Rhizoma in Xuanbai-Chengqi decoction strengthens the intestinal barrier function and promotes lung barrier repair in preventing severe viral pneumonia induced by influenza A virus. JOURNAL OF ETHNOPHARMACOLOGY 2024; 319:117231. [PMID: 37783404 DOI: 10.1016/j.jep.2023.117231] [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: 07/30/2023] [Revised: 09/22/2023] [Accepted: 09/24/2023] [Indexed: 10/04/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Xuanbai-Chengqi decoction (XCD) is a traditional prescription for treating multiple organ injuries, which has been used to manage pneumonia caused by various pathogens. However, the effects of XCD on repairing pulmonary/intestinal barrier damage remain unclear, and there is a need to understand the compatibility mechanism of rhubarb. AIM OF THE STUDY This work aims to investigate the protective effect and mechanism of XCD on the pulmonary/intestinal barrier guided by the theory of "gut-lung concurrent treatment". Moreover, we elucidate the compatibility mechanism of rhubarb in XCD. MATERIALS AND METHODS An H1N1 virus-infected mouse model was adopted to investigate the reparative effects of XCD on the lung-intestinal barrier by assessing lung-intestinal permeability. Additionally, the characterization of type I alveolar epithelial cells (AT1) and type II alveolar epithelial cells (AT2) was performed to evaluate the damage to the alveolar epithelial barrier. The specific barrier-protective mechanisms of XCD were elucidated by detecting tight junction proteins and the epithelial cell repair factor IL-22. The role of rhubarb in XCD to pneumonia treatment was investigated through lung tissue transcriptome sequencing and flow cytometry. RESULTS XCD significantly improved lung tissue edema, inflammation, and alveolar epithelial barrier damage by regulating IL-6, IL-10, and IL-22, which, could further improve pulmonary barrier permeability when combined with the protection of alveolar epithelial cells (AT1 and AT2) as well as inhibition of H1N1 virus replication. Simultaneously, XCD significantly reduced intestinal inflammation and barrier damage by regulating IL-6, IL-1β, and tight junction protein levels (Claudin-1 and ZO-1), improving intestinal barrier permeability. The role of rhubarb in the treatment of pneumonia is clarified for the first time. In the progression of severe pneumonia, rhubarb can significantly protect the intestinal barrier, promote the repair of AT2 cells, and inhibit the accumulation of CD11b+Ly6Gvariable aberrant neutrophils by regulating the S100A8 protein. CONCLUSION In summary, our findings suggest that rhubarb in XCD plays a critical role in protecting intestinal barrier function and promoting lung barrier repair in preventing severe viral pneumonia caused by influenza A virus.
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Affiliation(s)
- Linfeng Guo
- Department of Natural Medicine, School of Pharmacy, Fudan University, 3728# Jinke Rd., Pudong District, Shanghai, 201203, PR China
| | - Weilian Bao
- Department of Natural Medicine, School of Pharmacy, Fudan University, 3728# Jinke Rd., Pudong District, Shanghai, 201203, PR China
| | - Shuiyuan Yang
- Department of Natural Medicine, School of Pharmacy, Fudan University, 3728# Jinke Rd., Pudong District, Shanghai, 201203, PR China
| | - Yang Liu
- Department of Natural Medicine, School of Pharmacy, Fudan University, 3728# Jinke Rd., Pudong District, Shanghai, 201203, PR China
| | - Jiaren Lyu
- Department of Natural Medicine, School of Pharmacy, Fudan University, 3728# Jinke Rd., Pudong District, Shanghai, 201203, PR China
| | - Ting Wang
- Department of Biological Medicines, Shanghai Engineering Research Center of ImmunoTherapeutics, School of Pharmacy, Fudan University, 3728# Jinke Rd., Pudong, District, Shanghai, 201203, PR China
| | - Yan Lu
- Department of Natural Medicine, School of Pharmacy, Fudan University, 3728# Jinke Rd., Pudong District, Shanghai, 201203, PR China
| | - Hong Li
- Department of Pharmacology, School of Pharmacy, Fudan University, 3728# Jinke Rd., Pudong, Shanghai, 201203, PR China
| | - Haiyan Zhu
- Department of Biological Medicines, Shanghai Engineering Research Center of ImmunoTherapeutics, School of Pharmacy, Fudan University, 3728# Jinke Rd., Pudong, District, Shanghai, 201203, PR China.
| | - Daofeng Chen
- Department of Natural Medicine, School of Pharmacy, Fudan University, 3728# Jinke Rd., Pudong District, Shanghai, 201203, PR China.
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Liu X, Zhang WM, Meng N, Lin LJ, Tang GD. LARP1 knockdown inhibits cultured gastric carcinoma cell cycle progression and metastatic behavior. Open Life Sci 2024; 19:20220806. [PMID: 38283117 PMCID: PMC10811526 DOI: 10.1515/biol-2022-0806] [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: 06/13/2023] [Revised: 11/07/2023] [Accepted: 11/14/2023] [Indexed: 01/30/2024] Open
Abstract
This study aimed to clarify the role of la-related protein 1 (LARP1) in cell cycle progression and metastatic behavior of cultured gastric carcinoma (GC) cells. To do that, LARP1 expression was detected in clinical GC tissues and cell lines using quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. The cell viability, apoptosis, cell cycle, migration, invasion, and cell growth were examined using a Cell Counting Kit-8, Annexin V-FITC staining, propidium iodide staining, Transwell migration and invasion assays, and colony formation assays after LARP1 knockdown. Phosphatidyl inositol 3-kinase (PI3K) and AKT1 mRNA and protein expression levels of PI3K, p-AKT1, AKT1, p-BAD, p-mTOR, and p21 in si-LARP1 transfected GC cells were determined using qRT-PCR and western blotting. Here, we've shown that LARP1 expression was upregulated in human GC tissues and KATO III cells. LARP1 knockdown inhibited GC cell proliferation, cell cycle progression, migration, invasion, and colony formation and promoted apoptosis. In si-LARP1-transfected KATO III cells, the mRNA expression levels of PI3K and AKT1, PI3K protein expression, and the p-AKT1/AKT1 ratio were significantly suppressed. p-mTOR and p-BAD were significantly decreased, whereas p21 was significantly increased in si-LARP1-transfected KATO III cells. In conclusion LARP1 knockdown induces apoptosis and inhibits cell cycle progression and metastatic behavior via PI3K/AKT1 signaling in GC cells.
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Affiliation(s)
- Xin Liu
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, No. 6, Shuangyong Road, Nanning, Guangxi 530021, P. R. China
- Department of Gastroenterology, Wuming Hospital Affiliated to Guangxi Medical University, Nanning, Guangxi, 530199, P. R. China
| | - Wei-Ming Zhang
- Department of Radiotherapy, Wuming Hospital Affiliated to Guangxi Medical University, Nanning, Guangxi, 530199, P. R. China
| | - Nuo Meng
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, No. 6, Shuangyong Road, Nanning, Guangxi 530021, P. R. China
| | - Lian-Jie Lin
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, No. 6, Shuangyong Road, Nanning, Guangxi 530021, P. R. China
| | - Guo-Du Tang
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, No. 6, Shuangyong Road, Nanning, Guangxi 530021, P. R. China
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Luo J, Chen QX, Li P, Yu H, Yu L, Lu JL, Yin HZ, Huang BJ, Zhang SJ. Lobelia chinensis Lour inhibits the progression of hepatocellular carcinoma via the regulation of the PTEN/AKT signaling pathway in vivo and in vitro. JOURNAL OF ETHNOPHARMACOLOGY 2024; 318:116886. [PMID: 37429502 DOI: 10.1016/j.jep.2023.116886] [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: 05/15/2023] [Revised: 07/05/2023] [Accepted: 07/07/2023] [Indexed: 07/12/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Lobelia chinensis Lour. (LCL) is a common herb used for clearing heat and detoxifying, and it has antitumor activity. Quercetin is one of its important components, which may play an important role in the treatment of hepatocellular carcinoma (HCC). AIM OF THE STUDY To study the active ingredients of LCL, their mechanism of action on HCC, and lay the foundations for the development of new drugs for the treatment of HCC. MATERIALS AND METHODS Network pharmacology was used to examine the probable active ingredients and mechanisms of action of LCL in HCC treatment. Based on an oral bioavailability of ≥30% and a drug-likeness index of ≥0.18, relevant compounds were selected from the Traditional Chinese Medicine Systems Pharmacology database and TCM Database@Taiwan. HCC-related targets were identified using gene cards and the Online Mendelian Inheritance in Man (OMIM) database. A Venn diagram was created to assess the relationship between the intersection of disease and medication targets by creating a protein-protein interaction network, and the hub targets were selected by topology. Gene Ontology enrichment analyses were performed using the DAVID tool. Finally, in vivo and in vitro experiments (qRT-PCR, western blotting, hematoxylin and eosin staining, transwell assays, scratch tests, and flow cytometry assays) verified that LCL demonstrated notable therapeutic effects on HCC. RESULTS In total, 16 bioactive LCL compounds met the screening criteria. The 30 most important LCL therapeutic target genes were identified. Of these, AKT1 and MAPK1 were the most important target genes, and the AKT signaling pathway was identified as the key pathway. Transwell and scratch assays showed that LCL prevented cell migration, and flow cytometry tests revealed that the LCL-treated group showed a considerably higher rate of apoptosis than the control group. LCL reduced tumor formation in mice in vivo, and Western blot analysis of tumor tissues treated with LCL indicated variations in PTEN, p-MAPK and p-AKT1 levels. The results show that LCL may inhibit the progression of HCC through the PTEN/AKT signaling pathway to achieve the goal of treating HCC. CONCLUSION LCL is a broad-spectrum anticancer agent. These findings reveal potential treatment targets and strategies for preventing the spread of cancer, which could aid in screening potential traditional Chinese medicine for anticancer and clarifying their mechanisms.
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Affiliation(s)
- Jin Luo
- The First Affiliated Hospital of Sun Yat-sen, Department of Traditional Chinese Medicine, Guangzhou, 510800, China; Shenzhen Children's Hospital, Futian District, Shenzhen, 518000, Guangdong, PR China
| | - Qiu-Xia Chen
- The First Affiliated Hospital of Sun Yat-sen, Department of Traditional Chinese Medicine, Guangzhou, 510800, China
| | - Pan Li
- Department of Radiotherapy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450003, China
| | - He Yu
- The First Affiliated Hospital of Sun Yat-sen, Department of Traditional Chinese Medicine, Guangzhou, 510800, China
| | - Ling Yu
- The First Affiliated Hospital of Sun Yat-sen, Department of Traditional Chinese Medicine, Guangzhou, 510800, China
| | - Jia-Li Lu
- Department of General Practice, Shenzhen Longgang Fourth People's Hospital, Shenzhen, 518100, China
| | - Hong-Zhi Yin
- Department of Pediatrics, Beijing University of Chinese Medicine Shenzhen Hospital (Longgang), Shenzhen, 518100, China
| | - Bi-Jun Huang
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Department of Experimental Research, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.
| | - Shi-Jun Zhang
- The First Affiliated Hospital of Sun Yat-sen, Department of Traditional Chinese Medicine, Guangzhou, 510800, China.
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Xu B, Liang J, Fu L, Wei J, Lin J. A Novel Oncogenic Role of Disulfidptosis-related Gene SLC7A11 in Anti-tumor Immunotherapy Response to Human Cancers. Curr Cancer Drug Targets 2024; 24:846-866. [PMID: 38303526 DOI: 10.2174/0115680096277818231229105732] [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: 08/17/2023] [Revised: 10/22/2023] [Accepted: 11/08/2023] [Indexed: 02/03/2024]
Abstract
BACKGROUND The protein Solute Carrier Family 7 Member 11 (SLC7A11) plays a pivotal role in cellular redox homeostasis by suppressing disulfidptosis, which restricts tumor growth. Yet, its relevance in prognosis, immunity, and cancer treatment efficacy is not well understood. METHODS We conducted a comprehensive analysis of the expression of SLC7A11 across 33 cancer types, employing datasets from public databases. Methods, such as Cox regression and survival analyses assessed its prognostic significance, while functional enrichment explored the biological processes tied to SLC7A11. The association between SLC7A11 expression, immune cell infiltration, and immune-related gene expression was also scrutinized. RESULTS Notably, SLC7A11 expression was more pronounced in cancerous compared to normal samples and correlated with higher tumor grades. Increased SLC7A11 expression was linked to poor outcomes, particularly in liver hepatocellular carcinoma (LIHC). This protein's expression also showcased significant relationships with diverse molecular and immune subtypes. Additionally, a prognostic nomogram was devised, integrating SLC7A11 expression and clinical variables. High SLC7A11 levels corresponded with cell growth and senescence pathways in various cancers and with lipid and cholesterol metabolism in LIHC. Furthermore, potential therapeutic compounds for LIHC with high SLC7A11 were identified. Real-time PCR (qPCR) and Western blot were conducted to explore the expression of SLC7A11 in tumor tissues and cancer cell lines. CONCLUSION In summation, this study emphasizes the prognostic and immunological importance of SLC7A11, spotlighting its potential as a therapeutic target in LIHC.
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Affiliation(s)
- Borui Xu
- Department of Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China
| | - Jiahua Liang
- Department of Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China
| | - Liangmin Fu
- Department of Urology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China
- Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China
| | - Jinhuan Wei
- Department of Urology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China
| | - Juan Lin
- Department of Pediatrics, Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510630, People's Republic of China
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19
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Xing Z, Jiang X, Wu Y, Yu Z. Targeted Mevalonate Pathway and Autophagy in Antitumor Immunotherapy. Curr Cancer Drug Targets 2024; 24:890-909. [PMID: 38275055 DOI: 10.2174/0115680096273730231206054104] [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: 08/17/2023] [Revised: 09/30/2023] [Accepted: 10/11/2023] [Indexed: 01/27/2024]
Abstract
Tumors of the digestive system are currently one of the leading causes of cancer-related death worldwide. Despite considerable progress in tumor immunotherapy, the prognosis for most patients remains poor. In the tumor microenvironment (TME), tumor cells attain immune escape through immune editing and acquire immune tolerance. The mevalonate pathway and autophagy play important roles in cancer biology, antitumor immunity, and regulation of the TME. In addition, there is metabolic crosstalk between the two pathways. However, their role in promoting immune tolerance in digestive system tumors has not previously been summarized. Therefore, this review focuses on the cancer biology of the mevalonate pathway and autophagy, the regulation of the TME, metabolic crosstalk between the pathways, and the evaluation of their efficacy as targeted inhibitors in clinical tumor immunotherapy.
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Affiliation(s)
- Zongrui Xing
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, 730000, Gansu, China
| | - Xiangyan Jiang
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, 730000, Gansu, China
- The Second School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, China
| | - Yuxia Wu
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, 730000, Gansu, China
- The Second School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, China
| | - Zeyuan Yu
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, 730000, Gansu, China
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20
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Zhang F, Wang B, Zhang W, Xu Y, Zhang C, Xue X. Transcription Factor MAZ Potentiates the Upregulated NEIL3-mediated Aerobic Glycolysis, thereby Promoting Angiogenesis in Hepatocellular Carcinoma. Curr Cancer Drug Targets 2024; 24:1235-1249. [PMID: 38347781 DOI: 10.2174/0115680096265896231226062212] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 11/06/2023] [Accepted: 11/17/2023] [Indexed: 09/25/2024]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is characterized by high vascularity and notable abnormality of blood vessels, where angiogenesis is a key process in tumorigenesis and metastasis. The main functions of Nei Like DNA Glycosylase 3 (NEIL3) include DNA alcoholization repair, immune response regulation, nervous system development and function, and DNA damage signal transduction. However, the underlying mechanism of high expression NEIL3 in the development and progression of HCC and whether the absence or silencing of NEIL3 inhibits the development of cancer remain unclear. Therefore, a deeper understanding of the mechanisms by which increased NEIL3 expression promotes cancer development is needed. METHODS Expression of NEIL3 and its upstream transcription factor MAZ in HCC tumor tissues was analyzed in bioinformatics efforts, while validation was done by qRT-PCR and western blot in HCC cell lines. The migration and tube formation capacity of HUVEC cells were analyzed by Transwell and tube formation assays. Glycolytic capacity was analyzed by extracellular acidification rate, glucose uptake, and lactate production levels. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter gene assays were utilized to investigate specific interactions between MAZ and NEIL3. RESULTS NEIL3 and MAZ were substantially upregulated in HCC tissues and cells. NEIL3 was involved in modulating the glycolysis pathway, suppression of which reversed the stimulative impact of NEIL3 overexpression on migration and angiogenesis in HUVEC cells. MAZ bound to the promoter of NEIL3 to facilitate NEIL3 transcription. Silencing MAZ reduced NEIL3 expression and suppressed the glycolysis pathway, HUVEC cell migration, and angiogenesis. CONCLUSION MAZ potentiated the upregulated NEIL3-mediated glycolysis pathway and HCC angiogenesis. This study provided a rationale for the MAZ/NEIL3/glycolysis pathway as a possible option for anti-angiogenesis therapy in HCC.
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Affiliation(s)
- Fabiao Zhang
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, 317000, China
| | - Binfeng Wang
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, 317000, China
| | - Wenlong Zhang
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, 317000, China
| | - Yongfu Xu
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, 317000, China
| | - Caiming Zhang
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, 317000, China
| | - Xiangyang Xue
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325035, China
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Prasher P, Fatima R, Sharma M, Tynybekov B, Alshahrani AM, Ateşşahin DA, Sharifi-Rad J, Calina D. Honokiol and its analogues as anticancer compounds: Current mechanistic insights and structure-activity relationship. Chem Biol Interact 2023; 386:110747. [PMID: 37816447 DOI: 10.1016/j.cbi.2023.110747] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 08/22/2023] [Accepted: 09/22/2023] [Indexed: 10/12/2023]
Abstract
Lignans are plant-derived polyphenolic compounds with a plethora of biological applications. Also, regarded as phytoestrogens, the lignans offer a variety of health benefits of which the anti-cancer effects are the most attractive. Honokiol is a lignan isolated from various parts of trees belonging to the genus Magnolia. The bioactivity of honokiol is attributed to its characteristic physical properties, which include small size and the presence of two phenolic groups that may interact with proteins in cell membranes via hydrophobic interactions, aromatic pi orbital co-valency, and hydrogen bonding. The hydrophobicity of honokiol enables its rapid dissolution in lipids and the crossing of physiological barriers, including the blood-brain barrier and cerebrospinal fluid. These factors contribute towards the high bioavailability of honokiol which further support its candidature in medicinal research. Therefore, the anticancer properties of honokiol are of particular interest as many of the contemporary anticancer drugs suffer from bioavailability drawbacks, which necessitates the identification and development of novel candidate molecules directed as anticancer chemotherapeutics. The antioncogenic profile of honokiol also arises from the regulation of various signalling pathways associated with oncogenesis, arresting of the cell cycle by regulation of cyclic proteins, upregulation of epithelial markers and downregulation of mesenchymal markers leading to the inhibition of epithelial-mesenchymal transition, and preventing the metastasis by restricting cell migration and invasion due to the downregulation of matrix-metalloproteinases. In this review, we discuss the anticancer properties of honokiol.
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Affiliation(s)
- Parteek Prasher
- Department of Chemistry, University of Petroleum & Energy Studies, Energy Acres, Dehradun, 248007, India.
| | - Rabab Fatima
- Department of Chemistry, University of Petroleum & Energy Studies, Energy Acres, Dehradun, 248007, India.
| | - Mousmee Sharma
- Department of Chemistry, Uttaranchal University, Arcadia Grant, Dehradun, 248007, India.
| | - Bekzat Tynybekov
- Al-Farabi Kazakh National University, Department of Biodiversity and Bioresources, Almaty, Kazakhstan.
| | - Asma M Alshahrani
- Department of Clinical Pharmacy, Faculty of Pharmacy, King Khalid University, Abha, Saudi Arabia.
| | - Dilek Arslan Ateşşahin
- Fırat University, Baskil Vocational School, Department of Plant and Animal Production, 23100, Elazıg, Turkey.
| | | | - Daniela Calina
- Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, 200349, Craiova, Romania.
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22
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Yu M, Li H, Wang B, Wu Z, Wu S, Jiang G, Wang H, Huang Y. Baicalein ameliorates polymyxin B-induced acute renal injury by inhibiting ferroptosis via regulation of SIRT1/p53 acetylation. Chem Biol Interact 2023; 382:110607. [PMID: 37354967 DOI: 10.1016/j.cbi.2023.110607] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 06/04/2023] [Accepted: 06/15/2023] [Indexed: 06/26/2023]
Abstract
The polypeptide antibiotic Polymyxin B (PMB) can cause acute kidney injury (AKI), we found that ferroptosis is one of the main mechanisms of renal injury caused by PMB. It was reported that baicalein can inhibit ferroptosis. Therefore, in this study we examined whether baicalein could attenuate PMB-induced renal injury by inhibiting ferroptosis. We confirmed that baicalein could reduce PMB-induced renal injury in vivo and in vitro studies. In the in vitro study, baicalein significantly increased the survival rate of human HK2 tubular epithelial cells. The results of HE staining and electron microscopy in mice also showed that baicalein reduced PMB-induced renal injury, and significantly decreased the levels of BUN and Scr. By detecting ferroptosis-related indicators, we found that pre-incubation of baicalein in HK2 cells down-regulated Fe2+ level, lipid peroxidation, MDA and HO-1 which had been increased by PMB. Furthermore, baicalein up-regulated the levels of SCL7A11, GPX4 and GSH that were decreased by PMB. Moreover, intraperitoneal injection of baicalein in the animal model down-regulated kidney iron level, PTGS2 and 4HNE, and increased the GSH level, which suggested that baicalein could inhibit PMB-induced ferroptosis. Finally, by detecting changes in levels of p53 and p53 K382 acetylation, baicalein was observed to decrease elevated p53 K382 acetylation after PMB treatment, further confirming that baicalein inhibits ferroptosis by reducing p53 K382 acetylation via upregulation of SIRT1 expression. In conclusion, these results suggest that baicalein decreases p53 acetylation level by elevating SIRT1, which can then inhibit PMB-induced ferroptosis and ultimately attenuates AKI.
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Affiliation(s)
- Meiling Yu
- Department of Pharmacy, The First Affiliated Hospital of Bengbu Medical College, 287 Changhuai Road, Bengbu, Anhui, 233004, PR China; Faculty of Pharmacy, Bengbu Medical College, 2600 Donghai Road, Bengbu, Anhui, 233003, PR China; Department of Pharmacy, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, PR China
| | - Hongyu Li
- Department of Pharmacy, The First Affiliated Hospital of Bengbu Medical College, 287 Changhuai Road, Bengbu, Anhui, 233004, PR China; Faculty of Pharmacy, Bengbu Medical College, 2600 Donghai Road, Bengbu, Anhui, 233003, PR China
| | - Boying Wang
- Department of Pharmacy, The First Affiliated Hospital of Bengbu Medical College, 287 Changhuai Road, Bengbu, Anhui, 233004, PR China; Faculty of Pharmacy, Bengbu Medical College, 2600 Donghai Road, Bengbu, Anhui, 233003, PR China
| | - Zhenxiang Wu
- Department of Critical Care Medicine, The First Affiliated Hospital of Bengbu Medical College, Anhui, Bengbu, 233004, PR China
| | - Sheng Wu
- Department of Pharmacy, The First Affiliated Hospital of Bengbu Medical College, 287 Changhuai Road, Bengbu, Anhui, 233004, PR China; Faculty of Pharmacy, Bengbu Medical College, 2600 Donghai Road, Bengbu, Anhui, 233003, PR China
| | - Guojun Jiang
- Faculty of Pharmacy, Bengbu Medical College, 2600 Donghai Road, Bengbu, Anhui, 233003, PR China
| | - Huaxue Wang
- Department of Critical Care Medicine, The First Affiliated Hospital of Bengbu Medical College, Anhui, Bengbu, 233004, PR China.
| | - Yingying Huang
- Department of Pharmacy, The First Affiliated Hospital of Bengbu Medical College, 287 Changhuai Road, Bengbu, Anhui, 233004, PR China; Faculty of Pharmacy, Bengbu Medical College, 2600 Donghai Road, Bengbu, Anhui, 233003, PR China.
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Markoska R, Stojković R, Filipović M, Jurin M, Špada V, Kavre Piltaver I, Pavelić K, Marković D, Kraljević Pavelić S. Study of zeolite clinoptilolite d-glucose adsorption properties in vitro and in vivo. Chem Biol Interact 2023; 382:110641. [PMID: 37482210 DOI: 10.1016/j.cbi.2023.110641] [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] [Received: 03/28/2023] [Revised: 07/06/2023] [Accepted: 07/17/2023] [Indexed: 07/25/2023]
Abstract
Beneficial effects of a natural zeolite clinoptilolite in vivo on mammals, including humans, have been empirically observed and documented in literature. The positive biological activities have been associated to its detoxifying and antioxidative properties, and its immunostimulative and adsorption properties. Herein, we present the in vitro and in vivo study of clinoptilolite zeolite materials adsorption properties for d-glucose. In particular, we present data on the interaction of d-glucose on the tested zeolites' surface obtained by scanning electron microscope (SEM) and Energy-dispersive X-ray spectroscopy (EDS) and quantification by ultra high-performance liquid chromatography (UHPLC). We also present results on the reduction of blood glucose levels in mice pre-treated with clinoptilolite in vivo upon feeding with d-glucose. In vivo results were in line with the in vitro adsorption and/or interaction properties of tested zeolite materials for d-glucose and were quantified by UHPLC as well (11.34% for TMAZ; 10.82% for PMA and 8.76% for PMAO2). In vivo experiments in mice showed that PMA zeolite reduces blood glucose levels upon 15 min for 13% (at p < 0.05) up to 19.11% upon 120 min (without statistical significance) in clinoptilolite pre-treated mice fed by addition of d-glucose. Due to lack of explicit mechanistic knowledge on zeolite clinoptilolite interactions or adsorption with sugars in vitro and in vivo, presented study provides novel insights into these aspects for researchers in the field. The presented data merit further investigations as the material clearly shows a potential in management of hyperglycemia, such as for example in obese people, people with diabetes and people with metabolic syndrome where it could help regulate blood glucose levels.
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Affiliation(s)
- Rumenka Markoska
- University of Rijeka, Department of Biotechnology, Radmile Matejčić 2, 51000 Rijeka, Croatia
| | - Ranko Stojković
- Rudjer Boskovic Institute, Division of Molecular Medicine, Laboratory for Chiral Technologies, Bijenička cesta 54, 10000 Zagreb, Croatia
| | - Marko Filipović
- Juraj Dobrila University of Pula, Zagrebacka 30, 52100 Pula, Croatia
| | - Mladenka Jurin
- Rudjer Boskovic Institute, Division of Organic Chemistry and Biochemistry, Laboratory for Chiral Technologies, Bijenička cesta 54, 10000 Zagreb, Croatia
| | - Vedrana Špada
- Istarsko Veleučilište - Università Istriana di scienze applicate, Riva 6, 52100 Pula, Croatia
| | - Ivna Kavre Piltaver
- University of Rijeka, Faculty of Physics and Centre for Micro- and Nanosciences and Technologies, Radmile Matejčić 2, 51000 Rijeka, Croatia
| | - Krešimir Pavelić
- Juraj Dobrila University of Pula, Zagrebacka 30, 52100 Pula, Croatia
| | - Dean Marković
- University of Rijeka, Department of Biotechnology, Radmile Matejčić 2, 51000 Rijeka, Croatia
| | - Sandra Kraljević Pavelić
- University of Rijeka, Faculty of Health Studies, Ulica Viktora Cara Emina 5, 51 000 Rijeka, Croatia.
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24
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Selvan TG, Gollapalli P, Kumar SHS, Ghate SD. Early diagnostic and prognostic biomarkers for gastric cancer: systems-level molecular basis of subsequent alterations in gastric mucosa from chronic atrophic gastritis to gastric cancer. J Genet Eng Biotechnol 2023; 21:86. [PMID: 37594635 PMCID: PMC10439097 DOI: 10.1186/s43141-023-00539-0] [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: 09/21/2022] [Accepted: 07/31/2023] [Indexed: 08/19/2023]
Abstract
PURPOSE It is important to comprehend how the molecular mechanisms shift when gastric cancer in its early stages (GC). We employed integrative bioinformatics approaches to locate various biological signalling pathways and molecular fingerprints to comprehend the pathophysiology of the GC. To facilitate the discovery of their possible biomarkers, a rapid diagnostic may be made, which leads to an improved diagnosis and improves the patient's prognosis. METHODS Through protein-protein interaction networks, functional differentially expressed genes (DEGs), and pathway enrichment studies, we examined the gene expression profiles of individuals with chronic atrophic gastritis and GC. RESULTS A total of 17 DEGs comprising 8 upregulated and 9 down-regulated genes were identified from the microarray dataset from biopsies with chronic atrophic gastritis and GC. These DEGs were primarily enriched for CDK regulation of DNA replication and mitotic M-M/G1 phase pathways, according to KEGG analysis (p > 0.05). We discovered two hub genes, MCM7 and CDC6, in the protein-protein interaction network we obtained for the 17 DEGs (expanded with increased maximum interaction with 110 nodes and 2103 edges). MCM7 was discovered to be up-regulated in GC tissues following confirmation using the GEPIA and Human Protein Atlas databases. CONCLUSION The elevated expression of MCM7 in both chronic atrophic gastritis and GC, as shown by our comprehensive investigation, suggests that this protein may serve as a promising biomarker for the early detection of GC.
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Affiliation(s)
- Tamizh G Selvan
- Central Research Laboratory, K S Hegde Medical Academy, Nitte (Deemed to Be University), Deralakatte, Mangalore, 575018, Karnataka, India
| | - Pavan Gollapalli
- Center for Bioinformatics, University Annexe, Nitte (Deemed to be University), Deralakatte, Mangalore, 575018, Karnataka, India.
| | - Santosh H S Kumar
- Department of Biotechnology, Jnana Sahyadri Campus, Kuvempu University, Shankaraghatta, 577451, Karnataka, India
| | - Sudeep D Ghate
- Center for Bioinformatics, University Annexe, Nitte (Deemed to be University), Deralakatte, Mangalore, 575018, Karnataka, India
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Kiseleva OI, Kurbatov IY, Arzumanian VA, Ilgisonis EV, Zakharov SV, Poverennaya EV. The Expectation and Reality of the HepG2 Core Metabolic Profile. Metabolites 2023; 13:908. [PMID: 37623852 PMCID: PMC10456947 DOI: 10.3390/metabo13080908] [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: 05/25/2023] [Revised: 07/29/2023] [Accepted: 08/01/2023] [Indexed: 08/26/2023] Open
Abstract
To represent the composition of small molecules circulating in HepG2 cells and the formation of the "core" of characteristic metabolites that often attract researchers' attention, we conducted a meta-analysis of 56 datasets obtained through metabolomic profiling via mass spectrometry and NMR. We highlighted the 288 most commonly studied compounds of diverse chemical nature and analyzed metabolic processes involving these small molecules. Building a complete map of the metabolome of a cell, which encompasses the diversity of possible impacts on it, is a severe challenge for the scientific community, which is faced not only with natural limitations of experimental technologies, but also with the absence of transparent and widely accepted standards for processing and presenting the obtained metabolomic data. Formulating our research design, we aimed to reveal metabolites crucial to the Hepg2 cell line, regardless of all chemical and/or physical impact factors. Unfortunately, the existing paradigm of data policy leads to a streetlight effect. When analyzing and reporting only target metabolites of interest, the community ignores the changes in the metabolomic landscape that hide many molecular secrets.
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Affiliation(s)
- Olga I. Kiseleva
- Institute of Biomedical Chemistry, Pogodinskaya Street, 10, 119121 Moscow, Russia (E.V.I.); (E.V.P.)
| | - Ilya Y. Kurbatov
- Institute of Biomedical Chemistry, Pogodinskaya Street, 10, 119121 Moscow, Russia (E.V.I.); (E.V.P.)
| | - Viktoriia A. Arzumanian
- Institute of Biomedical Chemistry, Pogodinskaya Street, 10, 119121 Moscow, Russia (E.V.I.); (E.V.P.)
| | - Ekaterina V. Ilgisonis
- Institute of Biomedical Chemistry, Pogodinskaya Street, 10, 119121 Moscow, Russia (E.V.I.); (E.V.P.)
| | - Svyatoslav V. Zakharov
- Chemistry Department, Lomonosov Moscow State University, Leninskie gory Street, 1/3, 119991 Moscow, Russia;
| | - Ekaterina V. Poverennaya
- Institute of Biomedical Chemistry, Pogodinskaya Street, 10, 119121 Moscow, Russia (E.V.I.); (E.V.P.)
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Liu D, Shi Y, Chen H, Nisar MA, Jabara N, Langwinski N, Mattson S, Nagaoka K, Bai X, Lu S, Huang CK. Molecular profiling reveals potential targets in cholangiocarcinoma. World J Gastroenterol 2023; 29:4053-4071. [PMID: 37476584 PMCID: PMC10354586 DOI: 10.3748/wjg.v29.i25.4053] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Revised: 02/16/2023] [Accepted: 05/23/2023] [Indexed: 06/28/2023] Open
Abstract
BACKGROUND Cholangiocarcinoma (CCA) is a devastating malignancy and has a very poor prognosis if tumors spread outside the liver. Understanding the molecular mechanisms underlying the CCA progression will likely yield therapeutic approaches toward treating this deadly disease. AIM To determine the molecular pathogenesis in CCA progression. METHODS In silico analysis, in vitro cell culture, CCA transgenic animals, histological, and molecular assays were adopted to determine the molecular pathogenesis. RESULTS The transcriptomic data of human CCA samples were retrieved from The Cancer Genome Atlas (TGCA, CHOL), European Bioinformatics Institute (EBI, GAD00001001076), and Gene Expression Omnibus (GEO, GSE107943) databases. Using Gene set enrichment analysis, the cell cycle and Notch related pathways were demonstrated to be significantly activated in CCA in TCGA and GEO datasets. We, through differentially expressed genes, found several cell cycle and notch associated genes were significantly up-regulated in cancer tissues when compared with the non-cancerous control samples. The associated genes, via quantitative real-time PCR and western blotting assays, were further examined in normal human cholangiocytes, CCA cell lines, mouse normal bile ducts, and mouse CCA tumors established by specifically depleting P53 and expressing KrasG12D mutation in the liver. Consistently, we validated that the cell cycle and Notch pathways are up-regulated in CCA cell lines and mouse CCA tumors. Interestingly, targeting cell cycle and notch pathways using small molecules also exhibited significant beneficial effects in controlling tumor malignancy. More importantly, we demonstrated that several cell cycle and Notch associated genes are significantly associated with poor overall survival and disease-free survival using the Log-Rank test. CONCLUSION In summary, our study comprehensively analyzed the gene expression pattern of CCA samples using publicly available datasets and identified the cell cycle and Notch pathways are potential therapeutic targets in this deadly disease.
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Affiliation(s)
- Dan Liu
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Yang Shi
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Hongze Chen
- Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112, United States
| | - Muhammad Azhar Nisar
- Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112, United States
| | - Nicholas Jabara
- Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112, United States
| | - Noah Langwinski
- Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112, United States
| | - Sophia Mattson
- Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112, United States
| | - Katsuya Nagaoka
- Department of Medicine, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI 02903, United States
| | - Xuewei Bai
- Department of Medicine, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI 02903, United States
| | - Shaolei Lu
- Department of Pathology, Alpert Medical School of Brown University, Providence, RI 02903, United States
| | - Chiung-Kuei Huang
- Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112, United States
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27
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Park Y, Kang D, Sinn DH, Kim H, Hong YS, Cho J, Gwak GY. Effect of lifestyle modification on hepatocellular carcinoma incidence and mortality among patients with chronic hepatitis B. World J Gastroenterol 2023; 29:3843-3854. [PMID: 37426323 PMCID: PMC10324530 DOI: 10.3748/wjg.v29.i24.3843] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 05/13/2023] [Accepted: 05/25/2023] [Indexed: 06/28/2023] Open
Abstract
BACKGROUND Research exploring the influence of healthier lifestyle modification (LSM) on the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB) is limited.
AIM To emulate a target trial to determine the effect of LSM on HCC incidence and mortality among patients with CHB by large-scale population-based observational data.
METHODS Among the patients with CHB enrolled in the Korean National Health Insurance Service between January 1, 2009, and December 31, 2017, those aged ≥ 20 years who drank alcohol, smoked cigarettes, and were sedentary were analyzed. Exposure included at least one LSM, including alcohol abstinence, smoking cessation, and regular exercise. The primary outcome was HCC development, and the secondary outcome was liver-related mortality. We used 2:1 propensity score matching to account for covariates.
RESULTS With 48766 patients in the LSM group and 103560 in the control group, the adjusted hazard ratio (HR) for incident HCC and liver-related mortality was 0.92 [95% confidence interval (CI): 0.87-0.96] and 0.92 (95%CI: 0.86-0.99) in the LSM group, respectively, compared with the control group. Among the LSM group, the adjusted HR (95%CI) for incident HCC was 0.84 (0.76-0.94), 0.87 (0.81-0.94), and 1.08 (1.00-1.16) for alcohol abstinence, smoking cessation, and regular exercise, respectively. The adjusted HR (95%CI) for liver-related mortality was 0.92 (0.80-1.06), 0.81 (0.72-0.91), and 1.15 (1.04-1.27) for alcohol abstinence, smoking cessation, and regular exercise, respectively.
CONCLUSION LSM lowered the risk of HCC and mortality in patients with CHB. Thus, active LSM, particularly alcohol abstinence and smoking cessation, should be encouraged in patients with CHB.
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Affiliation(s)
- Yewan Park
- Department of Internal Medicine, Kyung Hee University Hospital, Seoul 02447, South Korea
- Department of Digital Health, SAIHST, Sungkyunkwan University, Seoul 06355, South Korea
| | - Danbee Kang
- Department of Clinical Research Design and Evaluation, SAIHST, Sungkyunkwan University, Seoul 06355, South Korea
- Center for Clinical Epidemiology, Samsung Medical Center, Sungkyunkwan University, Seoul 06351, South Korea
| | - Dong Hyun Sinn
- Department of Digital Health, SAIHST, Sungkyunkwan University, Seoul 06355, South Korea
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea
| | - Hyunsoo Kim
- Center for Clinical Epidemiology, Samsung Medical Center, Sungkyunkwan University, Seoul 06351, South Korea
| | - Yun Soo Hong
- Departments of Epidemiology and Medicine, and Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Medical Institutions, Baltimore, MD 21287, United States
| | - Juhee Cho
- Department of Clinical Research Design and Evaluation, SAIHST, Sungkyunkwan University, Seoul 06355, South Korea
- Center for Clinical Epidemiology, Samsung Medical Center, Sungkyunkwan University, Seoul 06351, South Korea
- Departments of Epidemiology and Medicine, and Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Medical Institutions, Baltimore, MD 21287, United States
| | - Geum-Youn Gwak
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea
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28
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Fonseca TH, Von Rekowski CP, Araújo R, Oliveira MC, Justino G, Bento L, Calado CRC. The Impact of the Serum Extraction Protocol on Metabolomic Profiling Using UPLC-MS/MS and FTIR Spectroscopy. ACS OMEGA 2023; 8:20755-20766. [PMID: 37323376 PMCID: PMC10237515 DOI: 10.1021/acsomega.3c01370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 05/04/2023] [Indexed: 06/17/2023]
Abstract
Biofluid metabolomics is a very appealing tool to increase the knowledge associated with pathophysiological mechanisms leading to better and new therapies and biomarkers for disease diagnosis and prognosis. However, due to the complex process of metabolome analysis, including the metabolome isolation method and the platform used to analyze it, there are diverse factors that affect metabolomics output. In the present work, the impact of two protocols to extract the serum metabolome, one using methanol and another using a mixture of methanol, acetonitrile, and water, was evaluated. The metabolome was analyzed by ultraperformance liquid chromatography associated with tandem mass spectrometry (UPLC-MS/MS), based on reverse-phase and hydrophobic chromatographic separations, and Fourier transform infrared (FTIR) spectroscopy. The two extraction protocols of the metabolome were compared over the analytical platforms (UPLC-MS/MS and FTIR spectroscopy) concerning the number of features, the type of features, common features, and the reproducibility of extraction replicas and analytical replicas. The ability of the extraction protocols to predict the survivability of critically ill patients hospitalized at an intensive care unit was also evaluated. The FTIR spectroscopy platform was compared to the UPLC-MS/MS platform and, despite not identifying metabolites and consequently not contributing as much as UPLC-MS/MS in terms of information concerning metabolic information, it enabled the comparison of the two extraction protocols as well as the development of very good predictive models of patient's survivability, such as the UPLC-MS/MS platform. Furthermore, FTIR spectroscopy is based on much simpler procedures and is rapid, economic, and applicable in the high-throughput mode, i.e., enabling the simultaneous analysis of hundreds of samples in the microliter range in a couple of hours. Therefore, FTIR spectroscopy represents a very interesting complementary technique not only to optimize processes as the metabolome isolation but also for obtaining biomarkers such as those for disease prognosis.
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Affiliation(s)
- Tiago
A. H. Fonseca
- Instituto
Superior de Engenharia de Lisboa (ISEL), Instituto Politécnico de Lisboa, Rua Conselheiro Emídio Navarro 1, 1959-007 Lisboa, Portugal
| | - Cristiana P. Von Rekowski
- Instituto
Superior de Engenharia de Lisboa (ISEL), Instituto Politécnico de Lisboa, Rua Conselheiro Emídio Navarro 1, 1959-007 Lisboa, Portugal
| | - Rúben Araújo
- Instituto
Superior de Engenharia de Lisboa (ISEL), Instituto Politécnico de Lisboa, Rua Conselheiro Emídio Navarro 1, 1959-007 Lisboa, Portugal
| | - M. Conceição Oliveira
- Centro
de Química Estrutural, Institute of Molecular Sciences, Instituto
Superior Técnico, Universidade de
Lisboa, Av. Rovisco Pais, 1, 1049-001 Lisboa, Portugal
| | - Gonçalo
C. Justino
- Centro
de Química Estrutural, Institute of Molecular Sciences, Instituto
Superior Técnico, Universidade de
Lisboa, Av. Rovisco Pais, 1, 1049-001 Lisboa, Portugal
| | - Luís Bento
- Intensive
Care Department, Centro Hospitalar Universitário
de Lisboa Central (CHULC), Rua José António Serrano, 1150-199 Lisboa, Portugal
- Integrated
Pathophysiological Mechanisms, CHRC, NOVA Medical School, Faculdade
de Ciências Médicas, NMS, FCM, Universidade NOVA de Lisboa, Campo Mártires da Pátria, 130, 1169-056 Lisboa, Portugal
| | - Cecília R. C. Calado
- Instituto
Superior de Engenharia de Lisboa (ISEL), Instituto Politécnico de Lisboa, Rua Conselheiro Emídio Navarro 1, 1959-007 Lisboa, Portugal
- Centro
de Investigação em Modelação e Optimização
de Sistemas Multifuncionais (CIMOSM), Instituto Superior de Engenharia
de Lisboa (ISEL), Instituto Politécnico
de Lisboa, Rua Conselheiro
Emídio Navarro 1, 1959-007 Lisboa, Portugal
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Liang R, Sheng M, Li X, Jin J, Yi Y. Transcriptomic analysis reveals that the anti-PCOS effects of Zishen Qingre Lishi Huayu recipe may involve pathways and genes related to autophagy, steroidogenesis, oxidative stress, and inflammation in granulosa cells. JOURNAL OF ETHNOPHARMACOLOGY 2023; 314:116551. [PMID: 37121450 DOI: 10.1016/j.jep.2023.116551] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 04/12/2023] [Accepted: 04/24/2023] [Indexed: 05/17/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Zishen Qingre Lishi Huayu recipe (ZQLHR) is a Chinese medicine compound composed of nine herbs for the treatment of polycystic ovary syndrome (PCOS). It is used to nourish kidneys, clear heat, reduce dampness and dissipation blood stasis by promoting diuresis and blood circulation, dredging the meridians and harmonizing menstruation in the treatment of PCOS. Several clinical studies have shown that ZQLHR is effective in the treatment of PCOS, but the underlying mechanism remains unclear. AIM OF THE STUDY In this study, we researched on the effects and mechanism of action of ZQLHR during treatment of human granulosa cells (hGCs) obtained from PCOS patients in order to provide a scientific basis for the clinical application of ZQLHR in the treatment of PCOS, emphasize the importance of some genes that have been reported to play a role in the pathogenesis or therapeutic mechanisms of PCOS from the perspective of disease treatment, and identify some new genes and signaling pathways that may play an important role in the treatment of PCOS. MATERIALS AND METHODS KGN cells (a granulosa cell-like tumor cell line) were subjected to a cell counting kit-8 assay to explore the appropriate intervention concentration and duration of ZQLHR. Treated with or without ZQLHR (ZQLHR and control groups), the hGCs obtained from PCOS patients were sequenced using RNA sequencing, and the genes thus detected were further analyzed through Kyoto encyclopedia of genes and genomes enrichment analysis, gene set enrichment analysis, and individuation gene analysis. These genes were also compared with PCOS-related genes in other databases. To further verify the authenticity of the differentially expressed genes between the two groups, the expression of eight randomly selected vital genes and three proteins of interest was verified through real time quantitative polymerase chain reaction and Western blot experiment respectively. RESULTS The best intervention concentration and duration for ZQLHR to promote the proliferation of KGN cells were 0.2% and 48 h respectively in this experiment. Multiple signaling pathways and 55 focus differentially expressed genes, both related to autophagy, steroidogenesis, oxidative stress-related longevity, inflammation, and complications of PCOS, may play an important role in the therapeutic mechanism of action of ZQLHR. The expression of eight genes is consistent with the result of RNA sequencing, and the expression of three proteins of interest is the same as expected. CONCLUSIONS The promotion of hGCs proliferation upon treatment with ZQLHR may be a manifestation of ZQLHR in the treatment of PCOS patients. The positive effects of ZQLHR against PCOS may involve pathways and genes related to autophagy, steroidogenesis, oxidative stress-related longevity, and inflammation in hGCs. Some components of ZQLHR applied for the treatment of PCOS may also be effective for the treatment of some complications of PCOS.
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Affiliation(s)
- Ruining Liang
- Jiangxi University of Chinese Medicine, Nanchang, 330000, China; Department of Reproductive Medicine, Second Affiliated Hospital, Jiangxi University of Chinese Medicine, Nanchang, 330000, China; Institute of Obstetrics and Gynecology, Jiangxi University of Chinese Medicine, Nanchang, 330000, China.
| | - Mengzhen Sheng
- Jiangxi University of Chinese Medicine, Nanchang, 330000, China.
| | - Xin Li
- Jiangxi University of Chinese Medicine, Nanchang, 330000, China.
| | - Jing Jin
- Jiangxi University of Chinese Medicine, Nanchang, 330000, China.
| | - Yao Yi
- Jiangxi University of Chinese Medicine, Nanchang, 330000, China; Department of Reproductive Medicine, Second Affiliated Hospital, Jiangxi University of Chinese Medicine, Nanchang, 330000, China; Institute of Obstetrics and Gynecology, Jiangxi University of Chinese Medicine, Nanchang, 330000, China.
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Brockmueller A, Girisa S, Kunnumakkara AB, Shakibaei M. Resveratrol Modulates Chemosensitisation to 5-FU via β1-Integrin/HIF-1α Axis in CRC Tumor Microenvironment. Int J Mol Sci 2023; 24:ijms24054988. [PMID: 36902421 PMCID: PMC10003050 DOI: 10.3390/ijms24054988] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 02/26/2023] [Accepted: 03/02/2023] [Indexed: 03/08/2023] Open
Abstract
Frequent development of resistance to chemotherapeutic agents such as 5-flourouracil (5-FU) complicates the treatment of advanced colorectal cancer (CRC). Resveratrol is able to utilize β1-integrin receptors, strongly expressed in CRC cells, to transmit and exert anti-carcinogenic signals, but whether it can also utilize these receptors to overcome 5-FU chemoresistance in CRC cells has not yet been investigated. Effects of β1-integrin knockdown on anti-cancer capabilities of resveratrol and 5-FU were investigated in HCT-116 and 5-FU-resistant HCT-116R CRC tumor microenvironment (TME) with 3D-alginate as well as monolayer cultures. Resveratrol increased CRC cell sensitivity to 5-FU by reducing TME-promoted vitality, proliferation, colony formation, invasion tendency and mesenchymal phenotype including pro-migration pseudopodia. Furthermore, resveratrol impaired CRC cells in favor of more effective utilization of 5-FU by down-regulating TME-induced inflammation (NF-kB), vascularisation (VEGF, HIF-1α) and cancer stem cell production (CD44, CD133, ALDH1), while up-regulating apoptosis (caspase-3) that was previously inhibited by TME. These anti-cancer mechanisms of resveratrol were largely abolished by antisense oligonucleotides against β1-integrin (β1-ASO) in both CRC cell lines, indicating the particular importance of β1-integrin receptors for the 5-FU-chemosensitising effect of resveratrol. Lastly, co-immunoprecipitation tests showed that resveratrol targets and modulates the TME-associated β1-integrin/HIF-1α signaling axis in CRC cells. Our results suggest for the first time the utility of the β1-integrin/HIF-1α signaling axis related to chemosensitization and overcoming chemoresistance to 5-FU in CRC cells by resveratrol, underlining its potential supportive applications in CRC treatment.
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Affiliation(s)
- Aranka Brockmueller
- Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilians-University Munich, Pettenkoferstr. 11, D-80336 Munich, Germany
| | - Sosmitha Girisa
- Cancer Biology Laboratory and DBT-AIST International Centre for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati 781039, India
| | - Ajaikumar B. Kunnumakkara
- Cancer Biology Laboratory and DBT-AIST International Centre for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati 781039, India
| | - Mehdi Shakibaei
- Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilians-University Munich, Pettenkoferstr. 11, D-80336 Munich, Germany
- Correspondence: ; Tel.: +49-89-2180-72624
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31
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Yang D, Tan YM, Zhang Y, Song JK, Luo Y, Luo Y, Fei XY, Ru Y, Li B, Jiang JS, Kuai L. Sheng-ji Hua-yu ointment ameliorates cutaneous wound healing in diabetes via up-regulating CCN1. JOURNAL OF ETHNOPHARMACOLOGY 2023; 303:115954. [PMID: 36435409 DOI: 10.1016/j.jep.2022.115954] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 11/12/2022] [Accepted: 11/16/2022] [Indexed: 06/16/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Diabetic ulcers (DUs) are one of the most severe complications of diabetes, and efficacious therapeutic means are currently lacking. Sheng-ji Hua-yu (SJHY) ointment is a classical Chinese traditional prescription that can significantly attenuate DU defects, but the specific mechanism remains to be fully elucidated. AIM OF THE STUDY In order to verify the underlying mechanism of SJHY ointment in accelerating the closure of DUs. MATERIALS AND METHODS Modular pharmacology and molecular docking were utilized to predict the therapeutic targets of SJHY ointment against DUs. Male db/db diabetic mice and HaCaT cell models induced by methylglyoxal were used to validate the findings. RESULTS CCN1 was proven to be the core target of SJHY ointment involved in DUs treatment. CCN1 up-regulated by SJHY treatment (0.5 g/cm2/day) at the mRNA and protein levels was detected on Day9 after wounding. With CCN1 knockdown, accelerated cell proliferation, migration, and anti-inflammatory effect of SJHY treatment (10 mg/L) were reversed. CONCLUSIONS SJHY ointment ameliorates cutaneous wound healing by up-regulating CCN1.
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Affiliation(s)
- Dan Yang
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China.
| | - Yi-Mei Tan
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200443, China; Professional Technical Service Platform for Clinical Evaluation of Skin Health Related Products, Shanghai Science and Technology Commission, Shanghai, 200443, China; NMPA Key Laboratory for Monitoring and Evaluation of Cosmetics, Shanghai, 200443, China; Human Phenome Institute, Fudan University, Shanghai, 200433, China.
| | - Ying Zhang
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China.
| | - Jian-Kun Song
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200443, China.
| | - Yue Luo
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200443, China.
| | - Ying Luo
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China; Institute of Dermatology, Shanghai Academy of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Xiao-Ya Fei
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200443, China.
| | - Yi Ru
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China.
| | - Bin Li
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200443, China; Institute of Dermatology, Shanghai Academy of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Jing-Si Jiang
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200443, China.
| | - Le Kuai
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China.
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Ahmed SA, Sarma P, Barge SR, Swargiary D, Devi GS, Borah JC. Xanthosine, a purine glycoside mediates hepatic glucose homeostasis through inhibition of gluconeogenesis and activation of glycogenesis via regulating the AMPK/ FoxO1/AKT/GSK3β signaling cascade. Chem Biol Interact 2023; 371:110347. [PMID: 36627075 DOI: 10.1016/j.cbi.2023.110347] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 12/22/2022] [Accepted: 01/06/2023] [Indexed: 01/09/2023]
Abstract
Type 2 Diabetes Mellitus (T2DM) is characterized by hepatic insulin resistance, which results in increased glucose production and reduced glycogen storage in the liver. There is no previous study in the literature that has explored the role of Xanthosine in hepatic insulin resistance. Moreover, mechanistic explanation for the beneficial effects of Xanthosine in lowering glucose production in diabetes is yet to be determined. This study for the first time investigated the beneficial effects of Tribulus terrestris (TT) and its active constituent, Xanthosine on gluconeogenesis and glycogenesis in Free Fatty Acid (FFA)-induced CC1 hepatocytes and streptozotocin (STZ)-induced Wistar rats. Xanthosine enhanced glucose uptake and decreased glucose production through phosphorylation of AMP-activated protein kinase (AMPK) and forkhead box transcription factor O1 (FoxO1), and downregulation of two rate limiting enzymes of gluconeogenesis, phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) expression in FFA-induced CC1 cells. Xanthosine also prevented FFA-induced decreases in the phosphorylation of AKT/Protein kinase B, glycogen synthase kinase-3β (GSK3β), and increased glycogen synthase (GS) phosphorylation to increase the glycogen content in the hepatocytes. Moreover, in STZ-induced diabetic rats, oral administration of TT n-butanol fraction (TTBF) enriched with compound Xanthosine (10, 50 & 100 mg/kg body weight) improved insulin sensitivity, reduced fasting blood glucose levels, improved glucose homeostasis by reducing gluconeogenesis via AMPK/FoxO1-mediated PEPCK and G6Pase down-regulation and increasing glycogenesis via AKT/GSK3β-mediated GS activation. Overall, Xanthosine may be developed further for treating insulin resistance and hyperglycemia in T2DM.
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Affiliation(s)
- Semim Akhtar Ahmed
- Chemical Biology Laboratory 1, Life Sciences Division, Institute of Advanced Study in Science & Technology, Guwahati, 781035, Assam, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Pranamika Sarma
- Chemical Biology Laboratory 1, Life Sciences Division, Institute of Advanced Study in Science & Technology, Guwahati, 781035, Assam, India
| | - Sagar Ramrao Barge
- Chemical Biology Laboratory 1, Life Sciences Division, Institute of Advanced Study in Science & Technology, Guwahati, 781035, Assam, India
| | - Deepsikha Swargiary
- Chemical Biology Laboratory 1, Life Sciences Division, Institute of Advanced Study in Science & Technology, Guwahati, 781035, Assam, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Gurumayum Shalini Devi
- Chemical Biology Laboratory 1, Life Sciences Division, Institute of Advanced Study in Science & Technology, Guwahati, 781035, Assam, India
| | - Jagat C Borah
- Chemical Biology Laboratory 1, Life Sciences Division, Institute of Advanced Study in Science & Technology, Guwahati, 781035, Assam, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.
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Tang SC, Lu CT, Ko JL, Lin CH, Hsiao YP. Hydroxychloroquine repairs burn damage through the Wnt/β-catenin pathway. Chem Biol Interact 2023; 370:110309. [PMID: 36535310 DOI: 10.1016/j.cbi.2022.110309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 11/22/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022]
Affiliation(s)
- Sheau-Chung Tang
- Department of Nursing, National Taichung University of Science and Technology, Taichung, 40640, Taiwan
| | - Chun-Te Lu
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan; Institute of Medicine, School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Jiunn-Liang Ko
- Department of Medical Oncology and Chest Medicine, Chung Shan Medical University Hospital, Taichung, 402, Taiwan; Institute of Medicine, School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Cheng-Hui Lin
- Institute of Medicine, School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Yu-Ping Hsiao
- Department of Dermatology, Chung Shan Medical University Hospital, Taichung, Taiwan; Institute of Medicine, School of Medicine, Chung Shan Medical University, Taichung, Taiwan.
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Qi RB, Wu ZH. Association between COVID-19 and chronic liver disease: Mechanism, diagnosis, damage, and treatment. World J Virol 2023; 12:22-29. [PMID: 36743657 PMCID: PMC9896589 DOI: 10.5501/wjv.v12.i1.22] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 10/03/2022] [Accepted: 11/21/2022] [Indexed: 01/18/2023] Open
Abstract
As the outbreak evolves, our understanding of the consequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting coronavirus disease 2019 (COVID-19) on the liver has grown. In this review, we discussed the hepatotropic nature of SARS-CoV-2 and described the distribution of receptors for SARS-CoV-2 (e.g., angiotensin-converting enzyme 2) in the vascular endothelium and cholangiocytes of the liver. Also, we proposed mechanisms for possible viral entry that mediate liver injury, such as liver fibrosis. Due to SARS-CoV-2-induced liver damage, many COVID-19 patients develop liver dysfunction, mainly characterized by moderately elevated serum aminotransferase levels. Patients with chronic liver disease (CLD), such as cirrhosis, hepatocellular carcinoma, nonalcoholic fatty liver disease, and viral hepatitis, are also sensitive to SARS-CoV-2 infection. We discussed the longer disease duration and higher mortality following SARS-CoV-2 infection in CLD patients. Correspondingly, relevant risk factors and possible mechanisms were proposed, including cirrhosis-related immune dysfunction and liver deco-mpensation. Finally, we discussed the potential hepatotoxicity of COVID-19-related vaccines and drugs, which influence the treatment of CLD patients with SARS-CoV-2 infection. In addition, we suggested that COVID-19 vaccines in terms of immunogenicity, duration of protection, and long-term safety for CLD patients need to be further researched. The diagnosis and treatment for liver injury caused by COVID-19 were also analyzed in this review.
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Affiliation(s)
- Ruo-Bing Qi
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, Hubei Province, China
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, Hubei Province, China
| | - Zheng-Hao Wu
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, Hubei Province, China
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Moawad M, Nasr GM, Osman AS, Shaker ES. Curcumin nanocapsules effect in apoptotic processes, gene expression, and cell cycle on Hep-G2 cell lines. Int J Immunopathol Pharmacol 2023; 37:3946320231176396. [PMID: 37190979 DOI: 10.1177/03946320231176396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/17/2023] Open
Abstract
OBJECTIVES Curcumin has antioxidant and antiproliferative properties, and its therapeutic effect must be considered. Nanocurcumin capsules showed a potential increase against in vitro biological cancer. This study sought to determine how curcumin nanoparticles and nanocapsules affected the expression of p53, Bcl-2, Bax, and Bax in a liver cancer cell line (Hep-G2). Mechanisms of apoptosis were also examined in this cell line. METHODS This study used quantitative real-time polymerase chain reaction (qRT-PCR) to analyze the p53, Bcl-2, Bax, and Caspase-3 gene pathways and to evaluate the molecular mechanisms responsible for the efficacy of curcumin nanoparticles (CNPs) and curcumin nanocapsules (CNCs) against liver cell lines. Flow cytometry was used to check for signs of apoptosis and the cell cycle. RESULTS Curcumin nanocapsules produced by the ball milling process at 90 min significantly boosted the populations of apoptotic cells in a dose- and time-dependent manner. The mRNA expression analysis revealed that the proapoptotic Bax, Caspase-3, and the tumor suppressor gene p53 were upregulated throughout the process started by curcumin nanocapsules and decreased in the Bcl-2/Bax ratio. CONCLUSION This research provides a fresh understanding of the molecular mechanisms behind the liver cancer-fighting abilities of curcumin nanoparticles. Curcumin nanocapsules produced through a unique mechanical technique can be used as an anticancer agent.
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Affiliation(s)
- Mahmoud Moawad
- Department of Pathology, National Cancer Institute, Cairo Univ. Egypt
| | - Ghada M Nasr
- Genetic Engineering and Biotechnology Research Institute, Department of Molecular Diagnostics & therapeutics, University of Sadat City, Egypt
| | - Afaf S Osman
- Department of Medical Pharmacology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Emad S Shaker
- Department of Agricultural Biochemistry, Minia University, Egypt
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Cai Y, Zang GY, Huang Y, Sun Z, Zhang LL, Qian YJ, Yuan W, Wang ZQ. Advances in neovascularization after diabetic ischemia. World J Diabetes 2022; 13:926-939. [PMID: 36437864 PMCID: PMC9693741 DOI: 10.4239/wjd.v13.i11.926] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 09/09/2022] [Accepted: 11/02/2022] [Indexed: 11/11/2022] Open
Abstract
With the high incidence of diabetes around the world, ischemic complications cause a serious influence on people's production and living. Neovascularization plays a significant role in its development. Therefore, neovascularization after diabetic ischemia has aroused attention and has become a hot spot in recent years. Neovascularization is divided into angiogenesis represented by atherosclerosis and arteriogenesis characterized by coronary collateral circulation. When mononuclear macrophages successively migrate to the ischemia anoxic zone after ischemia or hypoxia, they induce the secretion of cytokines, such as vascular endothelial growth factor and hypoxia-inducible factor, activate signaling pathways such as classic Wnt and phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) pathways, trigger oxidative stress response, activate endothelial progenitor cells or enter the glycolysis or lactic acid process and promote the formation of new blood vessels, remodeling them into mature blood vessels and restoring blood supply. However, the hypoglycemic condition has different impacts on neovascularization. Consequently, this review aimed to introduce the mechanisms of neovascularization after diabetic ischemia, increase our un-derstanding of diabetic ischemic complications and their therapies and provide more treatment options for clinical practice and effectively relieve patients' pain. It is believed that in the near future, neovascularization will bring more benefits and hope to patients with diabetes.
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Affiliation(s)
- Yue Cai
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212000, Jiangsu Province, China
| | - Guang-Yao Zang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212000, Jiangsu Province, China
| | - Yan Huang
- Department of Ophthalmology, Affiliated Hospital of Jiangsu University, Zhenjiang 212000, Jiangsu Province, China
| | - Zhen Sun
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212000, Jiangsu Province, China
| | - Li-Li Zhang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212000, Jiangsu Province, China
| | - Yong-Jiang Qian
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212000, Jiangsu Province, China
| | - Wei Yuan
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212000, Jiangsu Province, China
| | - Zhong-Qun Wang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212000, Jiangsu Province, China
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Zhang X, You LY, Zhang ZY, Jiang DX, Qiu Y, Ruan YP, Mao ZJ. Integrating pharmacological evaluation and computational identification for deciphering the action mechanism of Yunpi-Huoxue-Sanjie formula alleviates diabetic cardiomyopathy. Front Pharmacol 2022; 13:957829. [PMID: 36147338 PMCID: PMC9487204 DOI: 10.3389/fphar.2022.957829] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 08/10/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Yunpi-Huoxue-Sanjie (YP-SJ) formula is a Chinese herbal formula with unique advantages for the treatment of diabetic cardiovascular complications, such as Diabetic cardiomyopathy (DCM). However, potential targets and molecular mechanisms remain unclear. Therefore, our research was designed to evaluate rat myocardial morphology, fat metabolism and oxidative stress to verify myocardial protective effect of YP-SJ formula in vivo. And then to explore and validate its probable mechanism through network pharmacology and experiments in vitro and in vivo. Methods: In this study, DCM rats were randomly divided into five groups: control group, model group, and three YP-SJ formula groups (low-dose, middle-dose, and high-dose groups). Experimental rats were treated with 6 g/kg/d, 12 g/kg/d and 24 g/kg/d YP-SJ formula by gavage for 10 weeks, respectively. Cardiac function of rats was measured by high-resolution small-animal imaging system. The cells were divided into control group, high glucose group, high glucose + control serum group, high glucose + dosed serum group, high glucose + NC-siRNA group, high glucose + siRNA-FoxO1 group. The extent of autophagy was measured by flow cytometry, immunofluorescence, and western blotting. Results: It was found that YP-SJ formula could effectively improve cardiac systolic function in DCM rats. We identified 46 major candidate YP-SJ formula targets that are closely related to the progression of DCM. Enrichment analysis revealed key targets of YP-SJ formula related to environmental information processing, organic systems, and the metabolic occurrence of reactive oxygen species. Meanwhile, we verified that YP-SJ formula can increase the expression of forkhead box protein O1 (FoxO1), autophagy-related protein 7 (Atg7), Beclin 1, and light chain 3 (LC3), and decrease the expression of phosphorylated FoxO1 in vitro and in vivo. The results showed that YP-SJ formula could activate the FoxO1 signaling pathway associated with DCM rats. Further experiments showed that YP-SJ formula could improve cardiac function by regulating autophagy. Conclusion: YP-SJ formula treats DCM by modulating targets that play a key role in autophagy, improving myocardial function through a multi-component, multi-level, multi-target, multi-pathway, and multi-mechanism approach.
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Affiliation(s)
- Xin Zhang
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
- Chinese Medicine Plant Essential Oil Zhejiang Engineering Research Center, Zhejiang, China
| | - Li-Yan You
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
- Chinese Medicine Plant Essential Oil Zhejiang Engineering Research Center, Zhejiang, China
| | - Ze-Yu Zhang
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Dong-Xiao Jiang
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
- Chinese Medicine Plant Essential Oil Zhejiang Engineering Research Center, Zhejiang, China
| | - Yu Qiu
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Ye-Ping Ruan
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
- Chinese Medicine Plant Essential Oil Zhejiang Engineering Research Center, Zhejiang, China
- *Correspondence: Zhu-Jun Mao, ; Ye-Ping Ruan,
| | - Zhu-Jun Mao
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
- Chinese Medicine Plant Essential Oil Zhejiang Engineering Research Center, Zhejiang, China
- *Correspondence: Zhu-Jun Mao, ; Ye-Ping Ruan,
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Huang JY, Lin YC, Chen HM, Lin JT, Kao SH. RETRACTED: Adenine Combined with Cisplatin Promotes Anticancer Activity against Hepatocellular Cancer Cells through AMPK-Mediated p53/p21 and p38 MAPK Cascades. Pharmaceuticals (Basel) 2022; 15:795. [PMID: 35890094 PMCID: PMC9322617 DOI: 10.3390/ph15070795] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 06/23/2022] [Accepted: 06/24/2022] [Indexed: 12/24/2022] Open
Abstract
Cisplatin has been widely used in cancer treatments. Recent evidence indicates that adenine has potential anticancer activities against various types of cancers. However, the effects of the combination of adenine and cisplatin on hepatocellular carcinoma (HCC) cells remain sketchy. Here, our objective was to elucidate the anticancer activity of adenine in combination with cisplatin in HCC cells and its mechanistic pathways. Cell viability and cell cycle progression were assessed by the SRB assay and flow cytometry, respectively. Apoptosis was demonstrated by PI/annexin V staining and flow cytometric analysis. Protein expression, signaling cascade, and mRNA expression were analyzed by Western blotting and quantitative RT-PCR, respectively. Our results showed that adenine jointly potentiated the inhibitory effects of cisplatin on the cell viability of SK-Hep1 and Huh7 cells. Further investigation showed that adenine combined with cisplatin induced higher S phase arrest and apoptosis in HCC cells. Mechanically, adenine induced AMPK activation, reduced mTOR phosphorylation, and increased p53 and p21 levels. The combination of adenine and cisplatin synergistically reduced Bcl-2 and increased PUMA, cleaved caspase-3, and PARP in HCC cells. Adenine also upregulated the mRNA expression of p53, p21, PUMA, and PARP, while knockdown of AMPK reduced the increased expression of these genes. Furthermore, adenine also induced the activation of p38 MAPK through AMPK signaling, and the inhibition of p38 MAPK reduced the apoptosis of HCC cells with exposure to adenine combined with cisplatin. Collectively, these findings reveal that the combination of adenine and cisplatin synergistically enhances apoptosis of HCC cells, which may be attributed to the AMPK-mediated p53/p21 and p38 MAPK cascades. It suggests that adenine may be a potential adjuvant for the treatment of HCC in combination with cisplatin.
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Affiliation(s)
- Jhen-Yu Huang
- Institute of Medicine, College of Medicine, Chung Shan Medical University, Taichung City 402306, Taiwan;
| | - You-Cian Lin
- Cardiovascular Division, Surgical Department, China Medical University Hospital, Taichung City 404332, Taiwan;
- School of Medicine, College of Medicine, China Medical University, Taichung City 404332, Taiwan
| | - Han-Min Chen
- Institute of Applied Science and Engineering, Catholic Fu Jen University, New Taipei 242048, Taiwan;
| | - Jiun-Tsai Lin
- Energenesis Biomedical Co., Ltd., Taipei 114694, Taiwan;
| | - Shao-Hsuan Kao
- Institute of Medicine, College of Medicine, Chung Shan Medical University, Taichung City 402306, Taiwan;
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung City 402306, Taiwan
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Salatino A, Mirabelli M, Chiefari E, Greco M, Di Vito A, Bonapace G, Brunetti FS, Crocerossa F, Epstein AL, Foti DP, Brunetti A. The anticancer effects of Metformin in the male germ tumor SEM-1 cell line are mediated by HMGA1. Front Endocrinol (Lausanne) 2022; 13:1051988. [PMID: 36506071 PMCID: PMC9727077 DOI: 10.3389/fendo.2022.1051988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Accepted: 11/09/2022] [Indexed: 11/24/2022] Open
Abstract
INTRODUCTION Germ cell tumors (GCTs) are the most common type of cancer in young men. These tumors usually originate from the testis, but they can occasionally develop from extragonadal sites probably due to primordial germ cells (PGCs) migration errors. Cisplatin-based chemotherapy is usually effective for male GCTs, but the risk of toxicity is high and new therapeutic strategies are needed. Although Metformin (Met) has been widely studied as a potential cancer treatment over the past decades, there is limited evidence to support its use in treating male GCTs. Additionally, the mechanism by which it acts on tumor cells is still not entirely understood. METHODS SEM-1 cells, a newly established human cell line of extragonadal origin, were treated with Met. Cell viability was studied by MTT assay, while cell migration and invasion were studied by the wound healing assay and the transwell assay, respectively. The effect of Met on 3D spheroid formation was determined by seeding SEM-1 cells in appropriate cell suspension culture conditions, and cell cycle was characterized by flow cytometry. Factors involved in PGCs migration and GCT invasion, such as IGFBP1, IGF1R, MMP-11 and c-Kit, together with cyclin D1 (a key regulator of cell cycle progression), and the upstream factor, HMGA1, were determined by immunoblots. RESULTS Treatment of SEM-1 cells with Met resulted in a potent and dose-dependent reduction of cell proliferation, as evidenced by decreased nuclear abundance of cyclin D1 and cell cycle arrest in G1 phase. Also, Met prevented the formation of 3D spheroids, and blocked cell migration and invasion by reducing the expression of IGFBP1, IGF1R and MMP-11. Both, IGFBP1 and MMP-11 are under control of HMGA1, a chromatin-associated protein that is involved in the regulation of important oncogenic, metabolic and embryological processes. Intriguingly, an early reduction in the nuclear abundance of HMGA1 occurred in SEM-1 cells treated with Met. CONCLUSIONS Our results document the antiproliferative and antimigratory effects of Met in SEM-1 cells, providing new insights into the potential treatments for male GCTs. The anticancer properties of Met in SEM-1 cells are likely related to its ability to interfere with HMGA1 and downstream targets, including cyclin D1, the IGFs system, and MMP-11.
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Affiliation(s)
- Alessandro Salatino
- Department of Health Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Maria Mirabelli
- Department of Health Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Eusebio Chiefari
- Department of Health Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Marta Greco
- Department of Health Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Anna Di Vito
- Department of Experimental and Clinical Medicine, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Giuseppe Bonapace
- Department of Medical and Surgical Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Francesco S. Brunetti
- Department of Health Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Fabio Crocerossa
- Department of Experimental and Clinical Medicine, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Alan L. Epstein
- Department of Pathology, USC Keck School of Medicine, Los Angeles, CA, United States
| | - Daniela P. Foti
- Department of Experimental and Clinical Medicine, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Antonio Brunetti
- Department of Health Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
- *Correspondence: Antonio Brunetti,
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