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Andani FM, Talebi-Garakani E, Ashabi G, Ganbarirad M, Hashemnia M, Sharifi M, Ghasemi M. Exercise-activated hepatic autophagy combined with silymarin is associated with suppression of apoptosis in rats subjected to dexamethasone induced- fatty liver damage. Mol Biol Rep 2024; 51:928. [PMID: 39172304 DOI: 10.1007/s11033-024-09844-4] [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: 04/17/2024] [Accepted: 08/06/2024] [Indexed: 08/23/2024]
Abstract
AIM There is a need for effective treatments for non-alcoholic fatty liver disease (NAFLD) that are economically inexpensive, and have few side effects. The present study aimed to investigate exercise training and silymarin on hepatocyte death factors in rats with liver damage. METHODS Forty-nine male Wistar rats were assigned to seven groups: sedentary control, fatty liver control (DEX), fatty liver + high-intensity interval training (HIIT), fatty liver + HIIT + silymarin (HIIT + SILY), fatty liver + continuous training (CT), fatty liver + CT + silymarin (CT + SILY), and fatty liver + silymarin (SILY). A subcutaneous injection of dexamethasone for 7 days was used to induce fatty liver in rats. Masson's trichrome and hematoxylin-eosin staining were done to evaluate hepatic injury. The hepatocyte apoptosis was determined by TUNEL assay. Real-Time PCR was conducted to evaluate the gene expressions of caspase-9, adenosine monophosphate-activated protein kinase (AMPKα1), mitofusin 2 (Mfn2), and damage-regulated autophagy modulator (DRAM). Liver tissue changes and serum levels of liver enzymes were also evaluated. RESULTS Liver apoptosis was decreased in the CT, HIIT, HIIT + SILY and CT + SILY groups compared to the DEX group. Both continuous and high-intensity training models produced beneficial alterations in liver morphology and hepatic injuries that were significant in exercise training + silymarin group. This impact was accompanied by increased AMPKα1 and DRAM gene expression and decreased caspase-9 and Mfn2 gene expression. Liver enzyme levels were high in the DEX group and treatment with silymarin significantly reduced it. CONCLUSION Silymarin supplementation combined with interval or continuous training substantially improves DEX-induced hepatic steatosis and hepatocyte injury mostly through suppressing liver apoptosis and upregulating autophagy, which may provide a novel perspective for NAFLD treatment.
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Affiliation(s)
- Fatemeh Mokhtari Andani
- Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Elahe Talebi-Garakani
- Department of Exercise Physiology, Faculty of Sports Sciences, University of Mazandaran, Mazandaran, Iran
| | - Ghorbangol Ashabi
- Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahtab Ganbarirad
- Gerash Cellular and Molecular Research Center, Gerash University of Medical Sciences, Gerash, Iran
| | - Mohammad Hashemnia
- Department of Pathobiology, Faculty of Veterinary Medicine, Razi University, Kermanshah, Iran
| | - Mohammadreza Sharifi
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Maedeh Ghasemi
- Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
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2
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Ghorbani N, Yaghubi R, Davoodi J, Pahlavan S. How does caspases regulation play role in cell decisions? apoptosis and beyond. Mol Cell Biochem 2024; 479:1599-1613. [PMID: 37976000 DOI: 10.1007/s11010-023-04870-5] [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: 06/14/2023] [Accepted: 10/05/2023] [Indexed: 11/19/2023]
Abstract
Caspases are a family of cysteine proteases, and the key factors behind the cellular events which occur during apoptosis and inflammation. However, increasing evidence shows the non-conventional pro-survival action of apoptotic caspases in crucial processes. These cellular events include cell proliferation, differentiation, and migration, which may appear in the form of metastasis, and chemotherapy resistance in cancerous situations. Therefore, there should be a precise and strict control of caspases activity, perhaps through maintaining the threshold below the required levels for apoptosis. Thus, understanding the regulators of caspase activities that render apoptotic caspases as non-apoptotic is of paramount importance both mechanistically and clinically. Furthermore, the functions of apoptotic caspases are affected by numerous post-translational modifications. In the present mini-review, we highlight the various mechanisms that directly impact caspases with respect to their anti- or non-apoptotic functions. In this regard, post-translational modifications (PTMs), isoforms, subcellular localization, transient activity, substrate availability, substrate selection, and interaction-mediated regulations are discussed.
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Affiliation(s)
- Negar Ghorbani
- Department of Biochemistry, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
| | - Roham Yaghubi
- Department of Biotechnology, College of Science, University of Tehran, Tehran, Iran
| | - Jamshid Davoodi
- Department of Biochemistry, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
| | - Sara Pahlavan
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
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3
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Ma Y, Li W, Yao Q, Liu Y, Yu J, Zang L, Wang S, Zhou L, Wen S, Luo Y, Li W, Niu X. Harmine ameliorates CCl 4-induced acute liver injury through suppression of autophagy and inflammation. Int Immunopharmacol 2024; 129:111538. [PMID: 38306830 DOI: 10.1016/j.intimp.2024.111538] [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: 10/20/2023] [Revised: 01/03/2024] [Accepted: 01/10/2024] [Indexed: 02/04/2024]
Abstract
CCl4-induced acute liver injury (ALI) is characterized by heightened autophagy, inflammation, and oxidative damage. Accumulating evidence suggests that harmine exerts beneficial effects in countering CCl4-induced ALI by mitigating inflammation and oxidative stress. However, the impact of autophagy on CCl4-induced ALI and the protective role of harmine remain unclear. This study aimed to investigate the potential protective effects of harmine against CCl4-induced ALI in mice by suppressing autophagy and inflammation. Male Kunming mice were orally administered harmine or bifendate for seven days. Subsequently, one hour after the final administration, the model group and treatment groups were intraperitoneally injected with CCl4 to induce ALI. The findings revealed that harmine significantly reduced the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in serum, and ameliorated the liver histopathological changes induced by CCl4. Furthermore, harmine diminished the levels of TNF-α and IL-6, restored the levels of glutathione (GSH) and superoxide dismutase (SOD), and suppressed the production of nitric oxide (NO) and malondialdehyde (MDA) in the liver. Mechanistically, harmine down-regulated LC3B II/I, p38 MAPK, TLR4, and NF-κB levels, while upregulating p62, Bcl-2, Beclin1, ULK1, and p-mTOR expression. In conclusion, harmine mitigated CCl4-induced ALI by inhibiting autophagy and inflammation through the p38 MAPK/mTOR autophagy pathway, the Bcl-2/Beclin1 pathway, and the TLR4/NF-κB pathway.
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Affiliation(s)
- Yajing Ma
- School of Pharmacy, Xi'an Jiaotong University, Xi'an, PR China
| | - Wenqi Li
- School of Chinese Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Qing Yao
- School of Pharmacy, Xi'an Jiaotong University, Xi'an, PR China
| | - Yang Liu
- School of Pharmacy, Xi'an Jiaotong University, Xi'an, PR China
| | - Jinjin Yu
- School of Pharmacy, Xi'an Jiaotong University, Xi'an, PR China
| | - Lulu Zang
- School of Pharmacy, Xi'an Jiaotong University, Xi'an, PR China
| | - Siqi Wang
- School of Pharmacy, Xi'an Jiaotong University, Xi'an, PR China
| | - Lili Zhou
- School of Pharmacy, Xi'an Jiaotong University, Xi'an, PR China
| | - Sha Wen
- School of Pharmacy, Xi'an Jiaotong University, Xi'an, PR China
| | - Yuzhi Luo
- School of Pharmacy, Xi'an Jiaotong University, Xi'an, PR China
| | - Weifeng Li
- School of Pharmacy, Xi'an Jiaotong University, Xi'an, PR China.
| | - Xiaofeng Niu
- School of Pharmacy, Xi'an Jiaotong University, Xi'an, PR China.
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4
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He S, Silva LD, Rutter GA, Lim GE. A high-throughput screening approach to discover potential colorectal cancer chemotherapeutics: Repurposing drugs to disrupt 14-3-3 protein-BAD interactions. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.12.14.571727. [PMID: 38168191 PMCID: PMC10760183 DOI: 10.1101/2023.12.14.571727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2024]
Abstract
Inducing apoptosis in different types of cancer cells is an effective therapeutic strategy. However, the success of existing chemotherapeutics can be compromised by tumor cell resistance and systemic off-target effects. Therefore, the discovery of pro-apoptotic compounds with minimal systemic side-effects is crucial. 14-3-3 proteins are molecular scaffolds that serve as important regulators of cell survival. Our previous study demonstrated that 14-3-3ζ can sequester BAD, a pro-apoptotic member of the BCL-2 protein family, in the cytoplasm and prevent its translocation to mitochondria to inhibit the induction of apoptosis. Despite being a critical mechanism of cell survival, it is unclear whether disrupting 14-3-3 protein:BAD interactions could be harnessed as a chemotherapeutic approach. Herein, we established a BRET-based high-throughput drug screening approach (Z'-score= 0.52) capable of identifying molecules that can disrupt 14-3-3ζ:BAD interactions. An FDA-approved drug library containing 1971 compounds was used for screening, and the capacity of identified hits to induce cell death was examined in NIH3T3-fibroblasts and colorectal cancer cell lines, HT-29 and Caco-2. Our in vitro results suggest that terfenadine, penfluridol, and lomitapide could be potentially repurposed for treating colorectal cancer. Moreover, our screening method demonstrates the feasibility of identifying pro-apoptotic agents that can be applied towards conditions where aberrant cell growth or function are key determinants of disease pathogenesis.
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Affiliation(s)
- Siyi He
- Department of Medicine, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada
- Cardiometabolic axis, Centre de Recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montréal, Québec, Canada
| | - Luis Delgadillo Silva
- Cardiometabolic axis, Centre de Recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montréal, Québec, Canada
| | - Guy A. Rutter
- Department of Medicine, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada
- Cardiometabolic axis, Centre de Recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montréal, Québec, Canada
- Department of Diabetes, Endocrinology and Medicine, Faculty of Medicine, Imperial College, London, UK
- LKC School of Medicine, Nanyang Technological College, Singapore, Republic of Singapore
| | - Gareth E. Lim
- Department of Medicine, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada
- Cardiometabolic axis, Centre de Recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montréal, Québec, Canada
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Zhao X, Yin F, Fu L, Ma Y, Ye L, Huang Y, Fan W, Gao W, Cai Y, Mou X. Garlic-derived exosome-like nanovesicles as a hepatoprotective agent alleviating acute liver failure by inhibiting CCR2/CCR5 signaling and inflammation. BIOMATERIALS ADVANCES 2023; 154:213592. [PMID: 37717364 DOI: 10.1016/j.bioadv.2023.213592] [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: 03/29/2023] [Revised: 07/27/2023] [Accepted: 08/15/2023] [Indexed: 09/19/2023]
Abstract
Acute liver failure (ALF) is a life-threatening clinical syndrome mostly induced by viral infections or drug abuse. As a novel therapeutic adjuvant or delivery vehicle, plant-derived exosome-like nanovesicles (PELNVs) have been extensively studied in recent years. This study aimed to develop garlic-derived exosome-like nanovesicles (GaELNVs) in order to ameliorate liver injury induced by LPS/D-GalN in mice, inhibit inflammatory eruption and reduce inflammatory cells infiltration. The results showed that treatment with GaELNVs improved liver pathology and reduced the levels of soluble inflammatory mediators IL-6, IL-1β and TNF-α in the serum of ALF mice. GaELNVs reversed the upregulation of Cleaved Caspase-9, Cleaved Caspase-3, p53 and Bax expression and decreased Bcl2 activation caused by D-GalN/LPS, and inhibited NF-κB p65 expression and translocation to the nucleus. Meanwhile, treatment with GaELNVs resulted significant reduction in NLRP3 activation and Caspase-1 maturation, as well as decrease in the release of the inflammatory mediator IL-18. Additionally, an upregulation of the expression of proteins related to energy metabolism and autophagy occurrence including Foxo3a, Sirt1, and LC3-II was detected in the liver. Oral administration of GaELNVs also led to significant alteration in the expression of F4/80 and CD11b in the liver. Furthermore, the detection of chemokines in mouse liver tissue revealed that GaELNVs exhibited minimal reduction in the expression of CCL2, CCL3, CCL5 and CCL8. The decreased expression of CCR2 and CCR5 in the liver suggests that GaELNVs have the ability to decrease the recruitment of monocytes from the circulation to the liver. A reduction in the infiltration of F4/80loCD11bhi monocyte-derived macrophages into the liver was also observed. This study provides novel evidence that GaELNVs can ameliorate inflammatory eruptions and hinder the migration of circulating monocytes to the liver, as well as decrease macrophage infiltration by inhibiting CCR2/CCR5 signaling. Consequently, GaELNVs hold promise as a novel therapeutic agent for clinical management of liver disease.
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Affiliation(s)
- Xin Zhao
- General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou 310014, China; College of Pharmacy, Hangzhou Medical College, Hangzhou 310059, China; Clinical Research Institute, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou 310014, China
| | - Fang Yin
- Shanghai Engineering Research Center of Human Intestinal Microflora Function Development, Shanghai Tenth People's Hospital, Shanghai 200072, China
| | - Luoqin Fu
- Clinical Research Institute, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou 310014, China
| | - Yingyu Ma
- Clinical Research Institute, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou 310014, China
| | - Luyi Ye
- College of Pharmacy, Hangzhou Medical College, Hangzhou 310059, China
| | - Yilin Huang
- College of Pharmacy, Hangzhou Medical College, Hangzhou 310059, China
| | - Weijiao Fan
- Clinical Research Institute, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou 310014, China
| | - Wenxue Gao
- Clinical Research Unit, Shanghai Tenth People's Hospital, Shanghai 200072, China.
| | - Yu Cai
- General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou 310014, China; College of Pharmacy, Hangzhou Medical College, Hangzhou 310059, China; Clinical Research Institute, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou 310014, China.
| | - Xiaozhou Mou
- General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou 310014, China; College of Pharmacy, Hangzhou Medical College, Hangzhou 310059, China; Clinical Research Institute, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou 310014, China.
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Protective Effects of Sophorae tonkinensis Gagnep. (Fabaceae) Radix et Rhizoma Water Extract on Carbon Tetrachloride-Induced Acute Liver Injury. Molecules 2022; 27:molecules27248650. [PMID: 36557783 PMCID: PMC9780913 DOI: 10.3390/molecules27248650] [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: 11/16/2022] [Revised: 12/03/2022] [Accepted: 12/03/2022] [Indexed: 12/12/2022] Open
Abstract
Sophorae tonkinensis Radix et Rhizoma (STR) is a traditional Chinese herbal medicine. STR can reduce aminotransferase activity; however, the specific mechanism remains unclear. Here, we explored the potential therapeutic effects and hepatoprotective mechanism of STR on liver damage in mice. The chemical characteristics of the extract were characterized using ultra-high-performance liquid chromatography-tandem mass spectrometry fingerprinting, and its antioxidant capacity was verified using free radical scavenging tests. Forty-eight Kunming mice were randomly assigned into six groups. The model was made after the corresponding drug was given. The results showed that the STR water extract pretreatment significantly reduced serum aminotransferase and related liver function indicators compared with that in the model group. Furthermore, the STR water extract pretreatment significantly inhibited the apoptosis of liver cells, the level of liver high-mobility group box 1 (HMGB1), and inflammatory factors in hepatic tissue compared with that in the model group, and significantly downregulated the levels of toll-like receptor 4 (TLR4), Myeloid differentiation factor 88 (MyD88), and nuclear factor kappa B (NF-κB) compared with those in the model group. Overall, the STR water extract exerted a significant protective effect on CCL4-induced acute liver injury in this study, and the accurate active ingredients of the STR water extract will be explored in the near future.
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Procyanidin A1 alleviates DSS-induced ulcerative colitis via regulating AMPK/mTOR/p70S6K-mediated autophagy. J Physiol Biochem 2022; 78:213-227. [PMID: 35001346 DOI: 10.1007/s13105-021-00854-5] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 10/21/2021] [Indexed: 01/08/2023]
Abstract
Ulcerative colitis (UC) is a recurrent chronic inflammatory disease. The symptom of UC is mainly diarrhea including bloody stools. Increasing evidence has suggested that procyanidin A1 (PCA1) exerts an anti-inflammatory effect in several diseases. However, the role of PCA1 in UC is still a mystery. In our study, we explored the effect of PCA1 in dextran sulfate sodium (DSS)-induced UC mice and lipopolysaccharide (LPS)-stimulated HT-29 and IEC-6 cells. Then, cell proliferation, apoptosis, the production of proinflammatory cytokines, and autophagy-related markers were determined. Furthermore, the AMPK/mTOR/p70S6K signaling pathway was assayed by Western blot assay. In in vivo study, we found that PCA1 administration alleviated DSS-induced UC, as evidenced by reducing weight loss, clinical scores, colon weight/length ratio, histological damage, proinflammatory cytokines, and apoptosis. Moreover, we showed that the expression of Beclin-1 and LC3II/I ratio was increased, whereas the level of p62 was decreased after PCA1 treatment in vivo. Meanwhile, the reduced AMP/ATP ratio, enhanced expression of p-AMPK, and decreased p-p70S6K and p-mTOR levels indicate the activation of AMPK/mTOR/p70S6K signaling pathway. In in vitro study, PCA1 promoted cell proliferation and inhibited cell apoptosis in LPS-stimulated HT-29 and IEC-6 cells. Pro-inflammatory cytokines and autophagy-related factors exhibited the same trend as in in vivo results. Mechanically, PCA1 activated the AMPK/mTOR/p70S6K signaling pathway. The treatment with an AMPK inhibitor compound C significantly reversed the anti-inflammatory effect of PCA1 in LPS-stimulated cells. Taken together, these data indicated that PCA1 alleviated UC through induction of AMPK/mTOR/p70S6K-mediated autophagy.
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8
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Wang J, Cong S, Wu H, He Y, Liu X, Sun L, Zhao X, Zhang G. Identification and Analysis of Potential Autophagy-Related Biomarkers in Endometriosis by WGCNA. Front Mol Biosci 2021; 8:743012. [PMID: 34790699 PMCID: PMC8591037 DOI: 10.3389/fmolb.2021.743012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Accepted: 10/11/2021] [Indexed: 12/19/2022] Open
Abstract
Background: Endometriosis is a serious gynecological disorder characterized by debilitating pain, infertility and the establishment of innervated endometriosis lesions outside the uterus. Early detection and accurate diagnosis are pivotal in endometriosis. The work screened autophagy-related genes (ATGs) as potential biomarkers to reveal new molecular subgroups for the early diagnosis of endometriosis. Materials and Methods: The gene lists of ATGs from five databases were integrated. Then, weighted gene co-expression network analysis (WGCNA) was used to map the genes to the gene profile of endometriosis samples in GSE51981 to obtain functional modules. GO and KEGG analyses were performed on the ATGs from the key modules. Differentially expressed ATGs were identified by the limma R package and further validated in the external datasets of GSE7305 and GSE135485. The DESeq2 R package was utilized to establish multifactorial network. Subsequently, one-way analysis of variance (ANOVA) was performed to identify new molecular subgroups. Real-time quantitative polymerase chain reaction (RT-qPCR) and Western blotting were used to confirm the differential expression of hub ATGs, and the receiver operating characteristic (ROC) curve analysis and Spearman correlation analysis were applied to assess the diagnostic value of hub ATGs in 40 clinical samples and human primary endometrial stromal cells (ESCs). Results: We screened 4 key modules and 12 hub ATGs and found the key genes to be strongly correlated with endometriosis. The pathways of ATGs were mainly enriched in autophagy, apoptosis, ubiquitin-protein ligase binding, and MAPK signaling pathway. The expression levels of EZH2 (Enhancer of Zeste homolog 2) and RND3 (also known as RhoE) had statistically significant changes with higher values in the endometriosis group compared with the controls, both in the tissue samples and primary ESCs. Besides, they also showed higher specificity and sensitivity by the receiver operating characteristic analysis and Spearman correlation analysis for the diagnosis of endometriosis. The TF-mRNA-miRNA-lncRNA multifactorial network was successfully constructed. Four new molecular subgroups were identified, and we preliminarily showed the ability of IQCG to independently differentiate subgroups. Conclusion: EZH2 and RND3 could be candidate biomarkers for endometriosis, which would contribute to the early diagnosis and intervention in endometriosis.
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Affiliation(s)
- Jing Wang
- Department of Gynecology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Shanshan Cong
- Department of Gynecology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Han Wu
- Department of Gynecology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yanan He
- Department of Gynecology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xiaoli Liu
- Department of Gynecology, The Red Cross Center Hospital of Harbin, Harbin, China
| | - Liyuan Sun
- Department of Gynecology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xibo Zhao
- Department of Gynecology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Guangmei Zhang
- Department of Gynecology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
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Molnár T, Pallagi P, Tél B, Király R, Csoma E, Jenei V, Varga Z, Gogolák P, Odile Hueber A, Máté Z, Erdélyi F, Szabó G, Pettkó-Szandtner A, Bácsi A, Virág L, Maléth J, Koncz G. Caspase-9 acts as a regulator of necroptotic cell death. FEBS J 2021; 288:6476-6491. [PMID: 33899329 DOI: 10.1111/febs.15898] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 03/04/2021] [Indexed: 01/25/2023]
Abstract
Necroptosis is a regulated necrotic-like cell death modality which has come into the focus of attention since it is known to contribute to the pathogenesis of many inflammatory and degenerative diseases as well as to tumor regulation. Based on current data, necroptosis serves as a backup mechanism when death receptor-induced apoptosis is inhibited or absent. However, the necroptotic role of the proteins involved in mitochondrial apoptosis has not been investigated. Here, we demonstrated that the stimulation of several death and pattern recognition receptors induced necroptosis under caspase-compromised conditions in wild-type, but not in caspase-9-negative human Jurkat and murine MEF cells. Cerulein-induced pancreatitis was significantly reduced in mice with acinar cell-restricted caspase-9 gene knockout. The absence of caspase-9 led to impaired association of receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and RIPK3 and resulted in decreased phosphorylation of RIP kinases, but the overexpression of RIPK1 or RIPK3 rescued the effect of caspase-9 deficiency. Inhibition of either Aurora kinase A (AURKA) or its known substrate, glycogen synthase kinase 3β (GSK3ß) restored necroptosis sensitivity of caspase-9-deficient cells, indicating an interplay between caspase-9 and AURKA-mediated pathways to regulate necroptosis. Our findings suggest that caspase-9 acts as a newly identified regulator of necroptosis, and thus, caspase-9 provides a promising therapeutic target to manipulate the immunological outcome of cell death.
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Affiliation(s)
- Tamás Molnár
- Department of Immunology, Faculty of Medicine, University of Debrecen, Hungary.,Doctoral School of Molecular Cellular and Immune Biology, University of Debrecen, Hungary
| | - Petra Pallagi
- First Department of Medicine, University of Szeged, Szeged, Hungary.,HAS-USZ Momentum Epithelial Cell Signalling and Secretion Research Group, University of Szeged, Szeged, Hungary
| | - Bálint Tél
- First Department of Medicine, University of Szeged, Szeged, Hungary.,HAS-USZ Momentum Epithelial Cell Signalling and Secretion Research Group, University of Szeged, Szeged, Hungary
| | - Róbert Király
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Hungary
| | - Eszter Csoma
- Department of Medical Microbiology, Faculty of Medicine, University of Debrecen, Hungary
| | - Viktória Jenei
- Department of Immunology, Faculty of Medicine, University of Debrecen, Hungary
| | - Zsófia Varga
- Department of Immunology, Faculty of Medicine, University of Debrecen, Hungary.,Doctoral School of Molecular Cellular and Immune Biology, University of Debrecen, Hungary
| | - Péter Gogolák
- Department of Immunology, Faculty of Medicine, University of Debrecen, Hungary
| | | | - Zoltán Máté
- Medical Gene Technology Unit, Institute of Experimental Medicine, Budapest, Hungary
| | - Ferenc Erdélyi
- Medical Gene Technology Unit, Institute of Experimental Medicine, Budapest, Hungary
| | - Gábor Szabó
- Medical Gene Technology Unit, Institute of Experimental Medicine, Budapest, Hungary
| | | | - Attila Bácsi
- Department of Immunology, Faculty of Medicine, University of Debrecen, Hungary
| | - László Virág
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Hungary
| | - József Maléth
- First Department of Medicine, University of Szeged, Szeged, Hungary.,HAS-USZ Momentum Epithelial Cell Signalling and Secretion Research Group, University of Szeged, Szeged, Hungary
| | - Gábor Koncz
- Department of Immunology, Faculty of Medicine, University of Debrecen, Hungary
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10
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Chang SN, Kim SH, Dey DK, Park SM, Nasif O, Bajpai VK, Kang SC, Lee J, Park JG. 5-O-Demethylnobiletin Alleviates CCl 4-Induced Acute Liver Injury by Equilibrating ROS-Mediated Apoptosis and Autophagy Induction. Int J Mol Sci 2021; 22:ijms22031083. [PMID: 33499185 PMCID: PMC7865239 DOI: 10.3390/ijms22031083] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 01/18/2021] [Accepted: 01/19/2021] [Indexed: 01/08/2023] Open
Abstract
Polymethoxyflavanoids (PMFs) have exhibited a vast array of therapeutic biological properties. 5-O-Demethylnobiletin (5-DN) is one such PMF having anti-inflammatory activity, yet its role in hepatoprotection has not been studied before. Results from in vitro study revealed that 5-DN did not exert a high level of cytotoxicity on HepG2 cells at 40 μM, and it was able to rescue HepG2 cell death induced by carbon tetrachloride (CCl4). Subsequently, we investigated acute liver injury on BALB/c mice induced by CCl4 through the intraperitoneal injection of 1 mL/kg CCl4 and co-administration of 5-DN at (1 and 2 mg/kg) by oral gavage for 15 days. The results illustrated that treatment with 5-DN attenuated CCl4-induced elevated serum aminotransferase (AST)/alanine aminotransferase (ALT) ratio and significantly ameliorated severe hepatic damage such as inflammation and fibrosis evidenced through lesser aberrations in the liver histology of 5-DN dose groups. Additionally, 5-DN efficiently counteracted and equilibrated the production of ROS accelerated by CCl4 and dramatically downregulated the expression of CYP2E1 vitally involved in converting CCl4 to toxic free radicals and also enhanced the antioxidant enzymes. 5-DN treatment also inhibited cell proliferation and inflammatory pathway abnormally regulated by CCl4 treatment. Furthermore, the apoptotic response induced by CCl4 treatment was remarkably reduced by enhanced Bcl-2 expression and noticeable reduction in Bax, Bid, cleaved caspase 3, caspase 9, and apaf-1 expression. 5-DN treatment also induced the conversion of LC3 and promoted the autophagic flux. Conclusively, 5-DN exhibited hepatoprotective effects in vitro and in vivo and prevented liver fibrosis induced by CCl4.
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Affiliation(s)
- Sukkum Ngullie Chang
- Department of Biotechnology, Daegu University, Gyeongsan 38453, Korea; (S.N.C.); (D.K.D.); (S.C.K.)
- Advanced Bio Convergence Center (ABCC), Pohang Technopark Foundation, Pohang 37668, Korea; (S.H.K.); (S.M.P.)
| | - Se Ho Kim
- Advanced Bio Convergence Center (ABCC), Pohang Technopark Foundation, Pohang 37668, Korea; (S.H.K.); (S.M.P.)
- School of Chemical Engineering, Yeungnam University, Gyeongsan 38541, Korea
| | - Debasish Kumar Dey
- Department of Biotechnology, Daegu University, Gyeongsan 38453, Korea; (S.N.C.); (D.K.D.); (S.C.K.)
| | - Seon Min Park
- Advanced Bio Convergence Center (ABCC), Pohang Technopark Foundation, Pohang 37668, Korea; (S.H.K.); (S.M.P.)
| | - Omaima Nasif
- Department of Physiology, College of Medicine, King Saud University (Medical City), King Khalid University Hospital, P.O. Box 2925, Riyadh 11461, Saudi Arabia;
| | - Vivek K. Bajpai
- Department of Energy and Materials Engineering, Dongguk University-Seoul, 30 Pildong-ro 1-gil, Seoul 04620, Korea
- Correspondence: (V.K.B.); (J.T.L.); (J.G.P.); Fax: +82-32-872-4046 (V.K.B.); +82-53-810-4631 (J.L.); +82-54-223-2780 (J.G.P.)
| | - Sun Chul Kang
- Department of Biotechnology, Daegu University, Gyeongsan 38453, Korea; (S.N.C.); (D.K.D.); (S.C.K.)
| | - Jintae Lee
- School of Chemical Engineering, Yeungnam University, Gyeongsan 38541, Korea
- Correspondence: (V.K.B.); (J.T.L.); (J.G.P.); Fax: +82-32-872-4046 (V.K.B.); +82-53-810-4631 (J.L.); +82-54-223-2780 (J.G.P.)
| | - Jae Gyu Park
- Advanced Bio Convergence Center (ABCC), Pohang Technopark Foundation, Pohang 37668, Korea; (S.H.K.); (S.M.P.)
- Correspondence: (V.K.B.); (J.T.L.); (J.G.P.); Fax: +82-32-872-4046 (V.K.B.); +82-53-810-4631 (J.L.); +82-54-223-2780 (J.G.P.)
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11
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Bala S, Calenda CD, Catalano D, Babuta M, Kodys K, Nasser IA, Vidal B, Szabo G. Deficiency of miR-208a Exacerbates CCl 4-Induced Acute Liver Injury in Mice by Activating Cell Death Pathways. Hepatol Commun 2020; 4:1487-1501. [PMID: 33024918 PMCID: PMC7527689 DOI: 10.1002/hep4.1540] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 04/28/2020] [Accepted: 04/29/2020] [Indexed: 12/17/2022] Open
Abstract
Acute liver injury (ALI) is associated with multiple cellular events such as necrosis, apoptosis, oxidative stress and inflammation, which can lead to liver failure. In this study, we demonstrate a new role of microRNA (miR)‐208a in ALI. ALI was induced in wild‐type (WT) and miR‐208a knockout (KO) mice by CCl4 administration. Increased alanine aminotransferase and decreased hepatic miR‐208a levels were found in WT mice after acute CCl4 treatment. Histopathological evaluations revealed increased necrosis and decreased inflammation in miR‐208a KO compared with WT mice after CCl4 treatment. CCl4 treatment induced a higher alanine aminotransferase elevation and increased numbers of circulating extracellular vesicles (exosomes and microvesicles) in miR‐208a KO compared with WT mice. We found increased CCl4‐induced nuclear factor kappa B activation and tumor necrosis factor‐α induction and decreased monocyte chemoattractant protein 1 levels in miR‐208a KO compared with WT mice. Terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick‐end labeling assay indicated aggravated hepatic apoptosis and necrosis in CCl4‐treated miR‐208a KO compared with WT mice. CCl4 treatment induced a greater increase in cleaved caspase‐8, p18, and caspase‐3 in miR‐208a KO compared with WT mice. p53 is involved in various cell death pathways, including necrosis and apoptosis. Our in silico analysis revealed p53 as a predicted miR‐208a target, and we found enhanced p53 and cyclophilin D protein expressions in miR‐208a KO mice after CCl4 treatment. Increased liver injury in miR‐208a KO mice was further associated with increased Bax (B cell lymphoma 2–associated X protein) and p21 expression. Our in vitro results indicated a role of miR‐208a in cell death. We found that CCl4‐induced cytotoxicity was partially rescued by miR‐208a overexpression in RAW macrophages. Altogether, our results revealed a role of miR‐208a in ALI in mice and suggest a role for miR‐208a in regulating cell death.
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Affiliation(s)
- Shashi Bala
- Department of Medicine Beth Israel Deaconess Medical Center Harvard Medical School Boston MA
| | - Charles D Calenda
- Department of Medicine Beth Israel Deaconess Medical Center Harvard Medical School Boston MA
| | - Donna Catalano
- Department of Medicine University of Massachusetts Medical School Worcester MA
| | - Mrigya Babuta
- Department of Medicine Beth Israel Deaconess Medical Center Harvard Medical School Boston MA
| | - Karen Kodys
- Department of Medicine University of Massachusetts Medical School Worcester MA
| | - Imad A Nasser
- Department of Medicine Beth Israel Deaconess Medical Center Harvard Medical School Boston MA
| | - Barbara Vidal
- Department of Medicine Beth Israel Deaconess Medical Center Harvard Medical School Boston MA
| | - Gyongyi Szabo
- Department of Medicine Beth Israel Deaconess Medical Center Harvard Medical School Boston MA
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12
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Hu C, Zhao L, Shen M, Wu Z, Li L. Autophagy regulation is an effective strategy to improve the prognosis of chemically induced acute liver injury based on experimental studies. J Cell Mol Med 2020; 24:8315-8325. [PMID: 32627386 PMCID: PMC7412417 DOI: 10.1111/jcmm.15565] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 05/25/2020] [Accepted: 06/16/2020] [Indexed: 12/12/2022] Open
Abstract
Acute liver injury (ALI) induced by chemicals in current experimental studies is characterized by inflammation, oxidative stress and necrosis, which can greatly influence the long-term outcome and lead to liver failure. In liver cells, different autophagy forms envelop cytoplasm components, including proteins, endoplasmic reticulum (ER), mitochondria and lipids, and they effectively participate in breaking down the cargo enclosed inside lysosomes to replenish cellular energy and contents. In general, autophagy serves as a cell survival mechanism in stressful microenvironments, but it also serves as a destructive mechanism that results in cell death in vitro and in vivo. In experimental animals, multiple chemicals are used to mimic ALI in patients to clarify the potential pathological mechanisms and develop effective strategies in the clinic. In this review, we summarize related publications about autophagy modulation to attenuate chemically induced ALI in vitro and in vivo. We also analysed the underlying mechanisms of autophagy regulators and genetic modifications to clarify how to control autophagy to protect against chemically induced ALI in animal models. We anticipate that selectively controlling the dual effects of hepatic autophagy will help to protect against ALI in various animals, but the detailed mechanisms and effects should be determined further in future studies. In this way, we are more confident that modulating autophagy in liver regeneration can improve the prognosis of ALI.
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Affiliation(s)
- Chenxia Hu
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious DiseasesState Key Laboratory for the Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouPR China
- National Clinical Research Center for Infectious DiseasesThe First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouPR China
| | - Lingfei Zhao
- Key Laboratory of Kidney Disease Prevention and Control TechnologyKidney Disease CenterInstitute of NephrologyFirst Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhouPR China
| | - Miaoda Shen
- Department of OrthopedicsThe First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouPR China
| | - Zhongwen Wu
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious DiseasesState Key Laboratory for the Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouPR China
- National Clinical Research Center for Infectious DiseasesThe First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouPR China
| | - Lanjuan Li
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious DiseasesState Key Laboratory for the Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouPR China
- National Clinical Research Center for Infectious DiseasesThe First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouPR China
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13
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Yang Y, Huang J, Li J, Yang H, Yin Y. The Effects of Lauric Acid on IPEC-J2 Cell Differentiation, Proliferation, and Death. Curr Mol Med 2020; 20:572-581. [PMID: 32003670 DOI: 10.2174/1566524020666200128155115] [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: 08/11/2019] [Revised: 12/02/2019] [Accepted: 12/06/2019] [Indexed: 11/22/2022]
Abstract
BACKGROUND Lauric acid (LA) has antimicrobial effects and the potential to replace antibiotics in feeds to prevent postweaning diarrhea and increase overall swine productivity. The effects of lauric acid on the intestinal epithelial cells remain unclear. METHODS AND RESULTS This study investigates the effects of LA on pig intestinal epithelial cell line (IPEC-J2) differentiation, proliferation, and death and explores its underlying mechanisms. It was found that 0.25-0.1 mM LA promoted IPEC-J2 cell differentiation. At 1 mM or higher concentrations, it induced IPEC-J2 cell viability decreases, lipid accumulation, cell proliferation inhibition, and cell apoptosis. The cell death induced did not depend on caspase pathways. The data demonstrated that LA induced the IPEC-J2 cell autophagy and impaired autophagy flux and autophagy plays a role in protecting against LA induced-cell death. p38 MAPK inhibitor SB202190 attenuated LA-reduced IPEC-J2 cell viability. This associated with an increase in autophagy level and a decrease in lipid accumulations and FABPI levels. CONCLUSION In summary, LA promoted the IPEC-J2 cell apoptosis depends on the p38 MAPK pathways and may involve autophagy and TG metabolism regulation.
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Affiliation(s)
- Yuan Yang
- Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Nutrition and Human Health Laboratory, School of Life Sciences, Hunan Normal University, Changsha City, Hunan 410081, China
| | - Jin Huang
- Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Nutrition and Human Health Laboratory, School of Life Sciences, Hunan Normal University, Changsha City, Hunan 410081, China
| | - Jianzhong Li
- Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Nutrition and Human Health Laboratory, School of Life Sciences, Hunan Normal University, Changsha City, Hunan 410081, China
| | - Huansheng Yang
- Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Nutrition and Human Health Laboratory, School of Life Sciences, Hunan Normal University, Changsha City, Hunan 410081, China
| | - Yulong Yin
- Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Nutrition and Human Health Laboratory, School of Life Sciences, Hunan Normal University, Changsha City, Hunan 410081, China
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14
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A Cell's Fate: An Overview of the Molecular Biology and Genetics of Apoptosis. Int J Mol Sci 2019; 20:ijms20174133. [PMID: 31450613 PMCID: PMC6747454 DOI: 10.3390/ijms20174133] [Citation(s) in RCA: 134] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 07/15/2019] [Accepted: 07/17/2019] [Indexed: 12/30/2022] Open
Abstract
Apoptosis is one of the main types of regulated cell death, a complex process that can be triggered by external or internal stimuli, which activate the extrinsic or the intrinsic pathway, respectively. Among various factors involved in apoptosis, several genes and their interactive networks are crucial regulators of the outcomes of each apoptotic phase. Furthermore, mitochondria are key players in determining the way by which cells will react to internal stress stimuli, thus being the main contributor of the intrinsic pathway, in addition to providing energy for the whole process. Other factors that have been reported as important players of this intricate molecular network are miRNAs, which regulate the genes involved in the apoptotic process. Imbalance in any of these mechanisms can lead to the development of several illnesses, hence, an overall understanding of these processes is essential for the comprehension of such situations. Although apoptosis has been widely studied, the current literature lacks an updated and more general overview on this subject. Therefore, here, we review and discuss the mechanisms of apoptosis, highlighting the roles of genes, miRNAs, and mitochondria involved in this type of cell death.
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15
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Gera M, Kim N, Ghosh M, Sharma N, Huynh DL, Chandimali N, Koh H, Zhang JJ, Kang TY, Park YH, Kwon T, Jeong DK. Synthesis and evaluation of the antiproliferative efficacy of BRM270 phytocomposite nanoparticles against human hepatoma cancer cell lines. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2019; 97:166-176. [PMID: 30678901 DOI: 10.1016/j.msec.2018.11.055] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 10/17/2018] [Accepted: 11/27/2018] [Indexed: 02/07/2023]
Abstract
BRM270 is the most leading phytochemical extract that possesses potent anticancer properties. A major challenge associated with this drug is its low bioavailability and thus requires high dosages for cancer treatment. Here, we report the novel nano-synthesis of phyto-composite, BRM270 for the first time by mechanical milling method with specific modifications for enhanced cytotoxicity against HepG2 human hepatoma cancer cells. Unlike free BRM270 and other phytomedicines, BRM270 nanoparticles (BRM270 NPs) are well-dispersed and small sized (23 to 70 nm) which is believed to greatly enhanced cellular uptake. Furthermore, the acidic tumor microenvironment attracts BRM270 NPs enhancing targeted therapy while leaving normal cells less affected. The comparative cytotoxicity analysis using MTT assay among the three treatment groups, such as free BRM270, BRM270 NPs, and doxorubicin demonstrated that BRM270 NPs induced greater cytotoxicity against HepG2 cells with an effective drug concentration of 12 μg/ml. From FACS analysis, we observed an apoptotic cell death of 44.4% at BRM270 NPs treated cells while only 12.5% found in the free BRM270 treated cells. Further, the comparative relative expression profiling of the candidate genes were showed significant (p < 0.05) down-regulation of IL6, BCL2, p53, and MMP9 in the BRM270 NPs treated cells, compared to the free BRM270 and doxorubicin. Indeed, the genes, CASPASE 9 and BAX have shown significant (p < 0.05) upregulation in cells treated with BRM270 NPs as compared to counter treatment groups. The investigation of the signal pathways and protein-protein network associations were also carried out to elucidate the functional insights underlying anti-cancer potential of BRM270 NPs in HepG2 cells. Taken together, our findings demonstrated that these uniquely engineered BRM270 NPs effectively enter into the cancer cells due to its acidic microenvironment thereby inducing apoptosis and regulate the cell-proliferation in-vitro at extremely low dosages.
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Affiliation(s)
- Meeta Gera
- Laboratory of Animal Genetic Engineering and Stem Cell Biology, Department of Animal Biotechnology, Jeju National University, Jeju, Jeju-Do 690-756, Republic of Korea
| | - Nameun Kim
- Laboratory of Animal Genetic Engineering and Stem Cell Biology, Department of Animal Biotechnology, Jeju National University, Jeju, Jeju-Do 690-756, Republic of Korea
| | - Mrinmoy Ghosh
- Department of Biotechnology, Division of Research and Development, Lovely Professional University, Punjab 144411, India
| | - Neelesh Sharma
- Division of Veterinary Medicine, Faculty of Veterinary Science and Animal Husbandry, Sher-e-Kashmir University of Agricultural Sciences and Technology of Jammu, R.S. Pura, Jammu 181102, India
| | - Do Luong Huynh
- Laboratory of Animal Genetic Engineering and Stem Cell Biology, Department of Animal Biotechnology, Jeju National University, Jeju, Jeju-Do 690-756, Republic of Korea
| | - Nisansala Chandimali
- Laboratory of Animal Genetic Engineering and Stem Cell Biology, Department of Animal Biotechnology, Jeju National University, Jeju, Jeju-Do 690-756, Republic of Korea
| | - Hyebin Koh
- Laboratory of Animal Genetic Engineering and Stem Cell Biology, Department of Animal Biotechnology, Jeju National University, Jeju, Jeju-Do 690-756, Republic of Korea
| | - Jiao Jiao Zhang
- Laboratory of Animal Genetic Engineering and Stem Cell Biology, Department of Animal Biotechnology, Jeju National University, Jeju, Jeju-Do 690-756, Republic of Korea
| | - Tae Yoon Kang
- Laboratory of Animal Genetic Engineering and Stem Cell Biology, Department of Animal Biotechnology, Jeju National University, Jeju, Jeju-Do 690-756, Republic of Korea
| | | | - Taeho Kwon
- Laboratory of Animal Genetic Engineering and Stem Cell Biology, Department of Animal Biotechnology, Jeju National University, Jeju, Jeju-Do 690-756, Republic of Korea
| | - Dong Kee Jeong
- Laboratory of Animal Genetic Engineering and Stem Cell Biology, Department of Animal Biotechnology, Jeju National University, Jeju, Jeju-Do 690-756, Republic of Korea.
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16
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Dai C, Xiao X, Li D, Tun S, Wang Y, Velkov T, Tang S. Chloroquine ameliorates carbon tetrachloride-induced acute liver injury in mice via the concomitant inhibition of inflammation and induction of apoptosis. Cell Death Dis 2018; 9:1164. [PMID: 30478280 PMCID: PMC6255886 DOI: 10.1038/s41419-018-1136-2] [Citation(s) in RCA: 116] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Revised: 10/08/2018] [Accepted: 10/10/2018] [Indexed: 02/07/2023]
Abstract
This is the first study to investigate the hepatoprotective effect of CQ on acute liver injury caused by carbon tetrachloride (CCl4) in a murine model and the underlying molecular mechanisms. Ninety-six mice were randomly divided into the control (n = 8), CQ (n = 8), CCl4 (n = 40), and CCl4 + CQ (n = 40) treatment groups. In the CCl4 group, mice were intraperitoneally (i.p) injected with 0.3% CCl4 (10 mL/kg, dissolved in olive oil); in the CCl4 + CQ group, mice were i.p injected with CQ at 50 mg/kg at 2, 24, and 48 h before CCl4 administration. The mice in the control and CQ groups were administered with an equal vehicle or CQ (50 mg/kg). Mice were killed at 2, 6, 12, 24, 48 h post CCl4 treatment and their livers were harvested for analysis. The results showed that CQ pre-treatment markedly inhibited CCl4-induced acute liver injury, which was evidenced by decreased serum transaminase, aspartate transaminase and lower histological scores of liver injury. CQ pretreatment downregulated the CCl4-induced hepatic tissue expression of high-mobility group box 1 (HMGB1) and the levels of serum HMGB1 as well as IL-6 and TNF-α. Furthermore, CQ pre-treatment inhibited autophagy, downregulated NF-kB expression, upregulated p53 expression, increased the ratio of Bax/Bcl-2, and increased the activation of caspase-3 in hepatic tissue. This is the first study to demonstrate that CQ ameliorates CCl4-induced acute liver injury via the inhibition of HMGB1-mediated inflammatory responses and the stimulation of pro-apoptotic pathways to modulate the apoptotic and inflammatory responses associated with progress of liver damage.
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Affiliation(s)
- Chongshan Dai
- College of Veterinary Medicine, China Agricultural University, No. 2 Yuanmingyuan West Road, Beijing, 100193, P. R. China
| | - Xilong Xiao
- College of Veterinary Medicine, China Agricultural University, No. 2 Yuanmingyuan West Road, Beijing, 100193, P. R. China
| | - Daowen Li
- College of Veterinary Medicine, China Agricultural University, No. 2 Yuanmingyuan West Road, Beijing, 100193, P. R. China
| | - Sun Tun
- College of Veterinary Medicine, China Agricultural University, No. 2 Yuanmingyuan West Road, Beijing, 100193, P. R. China
| | - Ying Wang
- College of Veterinary Medicine, China Agricultural University, No. 2 Yuanmingyuan West Road, Beijing, 100193, P. R. China
| | - Tony Velkov
- Department of Pharmacology & Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria, 3010, Australia. .,Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria, 3052, Australia.
| | - Shusheng Tang
- College of Veterinary Medicine, China Agricultural University, No. 2 Yuanmingyuan West Road, Beijing, 100193, P. R. China.
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Xu Y, Yang J, Li F, Lian G, Ouyang M. MiR-29a inhibited intestinal epithelial cells autophagy partly by decreasing ATG9A in ulcerative colitis. Anticancer Drugs 2018; 29:652-659. [PMID: 29916896 DOI: 10.1097/cad.0000000000000636] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Ulcerative colitis (UC), with high morbidity has become one of the fastest-growing severe illnesses in the world. Although MiR-29a is highly expressed in the tissues of UC patients, the mechanism of miR-29a involved in the specific pathogenesis of UC is not known. In this study, a GFP-light chain 3 (LC3) immunofluorescence assay was used to observe the formation of the autophagic spot; qRT-PCR and western blotting analyses were carried out to detect the expression of autophagy-related proteins, including BECN1, Autophagy-related gene (ATG)5, ATG16L, and transcription factor EB. The dual-fluorescence reporter assay was used to analyze the direct effect of miR-29a on ATG9A; experimental dextran sulfate sodium-induced colitis in mice was used to establish the UC model. Our studies showed that the overexpression of miR-29a not only suppressed the production of GFP-LC3 autophagy spots but also inhibited the level of LC3II/LC3I and upregulated the expression of P62 in HT29 and HCT116 cells. Moreover, the results showed that miR-29a directly targeted the 3'UTR region of ATG9A mRNA to suppress the activation of HT29 and HCT116 cells' autophagy. Also, overexpression of ATG9A rescued rapamycin-induced autophagy that was inhibited by overexpression of miR-29a. In addition, miR-29a also affected the expression of autophagy-related proteins (BECN1, ATG5, ATG16L1, and transcription factor EB). Notably, miR-29a was upregulated, whereas ATG9A was downregulated in the experimental dextran sulfate sodium-induced colitis in mice. In effect, this study showed that miR-29a inhibits rapamycin-induced intestinal epithelial cells' autophagy partly by decreasing ATG9A in UC. These findings may provide new insights that may help control the inflammation in UC.
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Affiliation(s)
| | - Junwen Yang
- Gastroenterology Department, Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Fujun Li
- Gastroenterology Department, Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Guanghui Lian
- Gastroenterology Department, Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Miao Ouyang
- Gastroenterology Department, Xiangya Hospital, Central South University, Changsha, People's Republic of China
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Liu YM, Ma JH, Zeng QL, Lv J, Xie XH, Pan YJ, Yu ZJ. MiR-19a Affects Hepatocyte Autophagy via Regulating lncRNA NBR2 and AMPK/PPARα in D-GalN/Lipopolysaccharide-Stimulated Hepatocytes. J Cell Biochem 2017; 119:358-365. [PMID: 28586153 DOI: 10.1002/jcb.26188] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2017] [Accepted: 06/05/2017] [Indexed: 12/14/2022]
Abstract
This study aims to evaluate the potential involvement and regulatory mechanism of miR-19a in hepatocytes autophagy of acute liver failure (ALF). The in vitro hepatocytes injury model of primary hepatocyte and hepatocytes line HL-7702 was established by D-galactosamine (D-GalN) and lipopolysaccharide (LPS) co-treatment. Relative expression level of miR-19a and NBR2 was determined by qRT-PCR. Protein expression of AMPK/PPARα and autophagy-related gene was determined by Western blot. In hepatic tissue of 20 ALF patients and D-GalN/LPS-stimulated hepatocytes, miR-19a was upregulated and NBR2 was downregulated. D-GalN/LPS stimulation caused the inactivation of AMPK/PPARα signaling and the decrease of autophagy-related LC3-II/LC3-I ratio and beclin-1 expression in hepatocytes. The expression of both AMPK/PPARα and NBR2 were negatively controlled by miR-19a overexpression or knockdown. Moreover, both NBR2 and PPARα were targeted regulated by miR-19a according to luciferase reporter assay. In D-GalN/LPS-stimulated hepatocytes, AMPK activation promoted PPARα expression. AMPK inactivation inhibited the pro-autophagy effect of miR-19a and caused the decrease of LC3-II/LC3-I ratio and beclin-1 expression. PPARα activation abrogated the anti-autophagy effect of miR-19a mimic and caused the increase of LC3-II/LC3-I ratio and beclin-1 expression. NBR2 knockdown reversed the anti-autophagy impact of miR-19a inhibitor and caused the decrease of LC3-II/LC3-I ratio and beclin-1 expression. In summary, our data suggested that miR-19a negatively controlled the autophagy of hepatocytes attenuated in D-GalN/LPS-stimulated hepatocytes via regulating NBR2 and AMPK/PPARα signaling. J. Cell. Biochem. 119: 358-365, 2018. © 2017 Wiley Periodicals, Inc.
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Affiliation(s)
- Yan-Min Liu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jin-Hui Ma
- National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qing-Lei Zeng
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jun Lv
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xu-Hua Xie
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ya-Jie Pan
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zu-Jiang Yu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Iida T, Onodera K, Nakase H. Role of autophagy in the pathogenesis of inflammatory bowel disease. World J Gastroenterol 2017; 23:1944-1953. [PMID: 28373760 PMCID: PMC5360635 DOI: 10.3748/wjg.v23.i11.1944] [Citation(s) in RCA: 109] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Revised: 02/07/2017] [Accepted: 03/02/2017] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) results from a complex series of interactions between susceptibility genes, the environment, and the immune system. Recently, some studies provided strong evidence that the process of autophagy affects several aspects of mucosal immune responses. Autophagy is a cellular stress response that plays key roles in physiological processes, such as innate and adaptive immunity, adaptation to starvation, degradation of aberrant proteins or organelles, antimicrobial defense, and protein secretion. Dysfunctional autophagy is recognized as a contributing factor in many chronic inflammatory diseases, including IBD. Autophagy plays multiple roles in IBD pathogenesis by altering processes that include intracellular bacterial killing, antimicrobial peptide secretion by Paneth cells, goblet cell function, proinflammatory cytokine production by macrophages, antigen presentation by dendritic cells, and the endoplasmic reticulum stress response in enterocytes. Recent studies have identified susceptibility genes involved in autophagy, such as NOD2, ATG16L1, and IRGM, and active research is ongoing all over the world. The aim of this review is a systematic appraisal of the current literature to provide a better understanding of the role of autophagy in the pathogenesis of IBD. Understanding these mechanisms will bring about new strategies for the treatment and prevention of IBD.
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