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Abbas-Hashemi SA, Yari Z, Hatami B, Anushiravani A, Kolahdoozan S, Zamanian A, Akbarzadeh N, Hekmatdoost A. Caffeine supplement, inflammation, and hepatic function in cirrhotic patients: A randomized, placebo- controlled, clinical trial. Heliyon 2025; 11:e41138. [PMID: 39758360 PMCID: PMC11699412 DOI: 10.1016/j.heliyon.2024.e41138] [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: 07/14/2024] [Revised: 12/08/2024] [Accepted: 12/10/2024] [Indexed: 01/07/2025] Open
Abstract
Aim We investigated the possibility of caffeine supplementation for managing the inflammation, and hepatic function in cirrhotic patients. Methods In this randomized, double-blind, placebo-controlled trial, fifty patients with cirrhosis were randomly assigned to receive either caffeine supplement (400 mg), or placebo for eight weeks. Results The results indicated a significant decrease in AST, platelets (P = 0.002), and PTT (P < 0.001), in the caffeine group compared to the placebo group. Also, caffeine supplementation resulted in a significant reduction in inflammatory biomarkers compared to placebo (p < 0.05). A significant improvement in liver indices including AST to platelet ratio index (APRI), (P < 0.001). Fibrosis 4 score (P < 0.001), and MELD score (P = 0.034)., was observed after 8 weeks caffeine supplementation. Conclusion The results of the present study indicated that daily supplementation of 400 mg caffeine in cirrhotic patients can significantly improve liver fibrosis and reduce inflammatory factors.The trial was registered at the Iranian Registry of Clinical Trials (Registration ID: IRCT20100524004010N34).
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Affiliation(s)
- Seyed Ali Abbas-Hashemi
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Zahra Yari
- Department of Nutrition Research, National Nutrition and Food Technology Research Institute and Faculty of Nutrition Sciences and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Behzad Hatami
- Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Amir Anushiravani
- Digestive Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Shadi Kolahdoozan
- Digestive Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Zamanian
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Nadia Akbarzadeh
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Azita Hekmatdoost
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Science, Tehran, Iran
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Guo Y, Zheng Z, Zhang G, Zhong J, Fan X, Li C, Zhu S, Cao R, Fu K. Berberine inhibits LPS-induced epithelial-mesenchymal transformation by activating the Nrf2 signalling pathway in bovine endometrial epithelial cells. Int Immunopharmacol 2024; 143:113346. [PMID: 39393271 DOI: 10.1016/j.intimp.2024.113346] [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: 06/25/2024] [Revised: 09/14/2024] [Accepted: 10/04/2024] [Indexed: 10/13/2024]
Abstract
BACKGROUND Gram-negative bacteria are the primary pathogens of endometritis in dairy cows. LPS, the primary pathogenic agent of gram-negative bacteria, triggers an ROS increase, ultimately causing epithelial-mesenchymal transformation (EMT). Its significance in endometritis pathogenesis in dairy cows cannot be overlooked. PURPOSE Our previous studies showed that berberine could activate the Nrf2 signalling pathway, but whether it can inhibit the effect of LPS-induced EMT is uncharacterized. METHODS This research examined how berberine protects bovine endometrial epithelial cells (BEECs) by treating them with the compound for 2 h before exposing them to LPS to induce injury. Subsequently, the levels of reactive oxygen species (ROS) and epithelial-mesenchymal transition (EMT) markers in BEECs were quantified using the DCFH-DA probe, RT-qPCR, and Western blotting techniques. RESULTS Our investigation revealed that the triggering of the Nrf2 signal transduction pathway can effectively prevent LPS-induced EMT by reducing ROS levels in BEECs. Additionally, we found that berberine inhibits LPS-induced EMT by activating Nrf2 to reduce ROS levels. CONCLUSION These results suggest that berberine reduces ROS levels by upregulating the Nrf2 pathway in BEECs stimulated with LPS.
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Affiliation(s)
- Yue Guo
- Institute of Animal Reproductive Physiology and Disease, College of Veterinary Medicine, Qingdao Agricultural University, Qingdao 266109, China
| | - Zhikang Zheng
- Institute of Animal Reproductive Physiology and Disease, College of Veterinary Medicine, Qingdao Agricultural University, Qingdao 266109, China
| | - Guoxing Zhang
- Institute of Animal Reproductive Physiology and Disease, College of Veterinary Medicine, Qingdao Agricultural University, Qingdao 266109, China
| | - Jiaxing Zhong
- Institute of Animal Reproductive Physiology and Disease, College of Veterinary Medicine, Qingdao Agricultural University, Qingdao 266109, China
| | - Xiucheng Fan
- Institute of Animal Reproductive Physiology and Disease, College of Veterinary Medicine, Qingdao Agricultural University, Qingdao 266109, China
| | - Chunying Li
- Institute of Animal Reproductive Physiology and Disease, College of Veterinary Medicine, Qingdao Agricultural University, Qingdao 266109, China
| | - Shiyong Zhu
- Institute of Animal Reproductive Physiology and Disease, College of Veterinary Medicine, Qingdao Agricultural University, Qingdao 266109, China
| | - Rongfeng Cao
- Institute of Animal Reproductive Physiology and Disease, College of Veterinary Medicine, Qingdao Agricultural University, Qingdao 266109, China.
| | - Kaiqiang Fu
- Institute of Animal Reproductive Physiology and Disease, College of Veterinary Medicine, Qingdao Agricultural University, Qingdao 266109, China.
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Zhou HY, Wang BQ, Chen MX, Wang YF, Jiang YF, Ma J. KDM4C represses liver fibrosis by regulating H3K9me3 methylation of ALKBH5 and m6A methylation of snail1 mRNA. J Dig Dis 2024; 25:298-309. [PMID: 38938016 DOI: 10.1111/1751-2980.13291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 05/22/2024] [Accepted: 05/24/2024] [Indexed: 06/29/2024]
Abstract
OBJECTIVE We aimed to disclose the molecular mechanism of snail1 in liver fibrosis. METHODS Carbon tetrachloride (CCl4) was used to induce a liver fibrosis model in mice whereby serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were evaluated, and liver pathological alternations were assessed. Rat hepatic stellate cells (HSC-T6) were irritated with transforming growth factor (TGF)-β1, followed by assessment of cell viability and migration. The levels of snail1, ALKBH5, and lysine specific demethylase 4C (KDM4C) were quantified by immunohistochemistry, western blot, or reverse transcription-quantitative polymerase chain reaction, in addition to α-smooth muscle actin (SMA), anti-collagen type I α1 (COL1A1), vimentin, and E-cadherin. Photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation and RNA stability were evaluated to determine the relationship between ALKBH5 and snail1. Changes in KDM4C-bound ALKBH5 promoter and enrichment of histone H3 lysine 9 trimethylation (H3K9me3) at the ALKBH5 promoter were determined using chromatin immunoprecipitation. RESULTS In fibrosis mice, snail1 was upregulated while ALKBH5 and KDM4C were downregulated. KDM4C overexpression reduced serum ALT and AST levels, liver injury, and α-SMA, COL1A1 and VIMENTIN expressions but increased E-cadherin expression. However, the aforementioned trends were reversed by concurrent overexpression of snail1. In HSC-T6 cells exposed to TGF-β1, ALKBH5 overexpression weakened cell viability and migration, downregulated α-SMA, COL1A1 and VIMENTIN, upregulated E-CADHERIN, and decreased m6A modification of snail1 and its mRNA stability. KDM4C increased ALKBH5 expression by lowering H3K9me3 level, but inhibited HSC-T6 cell activation by regulating the ALKBH5/snail1 axis. CONCLUSION KDM4C decreases H3K9me3 methylation to upregulate ALKBH5 and subsequently inhibits snail1, ultimately impeding liver fibrosis.
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Affiliation(s)
- Hua Ying Zhou
- Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Bing Qing Wang
- Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Meng Xuan Chen
- Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Yi Fan Wang
- Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Yong Fang Jiang
- Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Jing Ma
- Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China
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Song X, Kirtipal N, Lee S, Malý P, Bharadwaj S. Current therapeutic targets and multifaceted physiological impacts of caffeine. Phytother Res 2023; 37:5558-5598. [PMID: 37679309 DOI: 10.1002/ptr.8000] [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: 04/13/2023] [Revised: 08/04/2023] [Accepted: 08/17/2023] [Indexed: 09/09/2023]
Abstract
Caffeine, which shares consubstantial structural similarity with purine adenosine, has been demonstrated as a nonselective adenosine receptor antagonist for eliciting most of the biological functions at physiologically relevant dosages. Accumulating evidence supports caffeine's beneficial effects against different disorders, such as total cardiovascular diseases and type 2 diabetes. Conversely, paradoxical effects are also linked to caffeine ingestion in humans including hypertension-hypotension and tachycardia-bradycardia. These observations suggest the association of caffeine action with its ingested concentration and/or concurrent interaction with preferential molecular targets to direct explicit events in the human body. Thus, a coherent analysis of the functional targets of caffeine, relevant to normal physiology, and disease pathophysiology, is required to understand the pharmacology of caffeine. This review provides a broad overview of the experimentally validated targets of caffeine, particularly those of therapeutic interest, and the impacts of caffeine on organ-specific physiology and pathophysiology. Overall, the available empirical and epidemiological evidence supports the dose-dependent functional activities of caffeine and advocates for further studies to get insights into the caffeine-induced changes under specific conditions, such as asthma, DNA repair, and cancer, in view of its therapeutic applications.
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Affiliation(s)
- Xinjie Song
- Zhejiang Provincial Key Lab for Chemical and Biological Processing Technology of Farm Product, School of Biological and Chemical Engineering, Zhejiang University of Science and Technology, Hangzhou, China
| | - Nikhil Kirtipal
- School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea
| | - Sunjae Lee
- School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea
| | - Petr Malý
- Laboratory of Ligand Engineering, Institute of Biotechnology of the Czech Academy of Sciences v.v.i, BIOCEV Research Center, Vestec, Czech Republic
| | - Shiv Bharadwaj
- Laboratory of Ligand Engineering, Institute of Biotechnology of the Czech Academy of Sciences v.v.i, BIOCEV Research Center, Vestec, Czech Republic
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Dadaei Z, Bagherniya M, Sadeghi O, Khosravi A, Shirani S, Askari G. Dietary inflammatory index in relation to severe coronary artery disease in Iranian adults. Front Nutr 2023; 10:1226380. [PMID: 37841398 PMCID: PMC10570611 DOI: 10.3389/fnut.2023.1226380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Accepted: 09/11/2023] [Indexed: 10/17/2023] Open
Abstract
Background Limited findings are available on the relationship between dietary inflammation index (DII) and severe coronary artery disease (CAD). Considering the high prevalence of CAD and its complications, we examined the relationship between DII and CAD. Methods This cross-sectional study was conducted on 275 adults who underwent elective angiography. Severe coronary artery disease was measured by the gensini scoring system. DII was measured by a valid semi-quantitative 168-item food frequency questionnaire (FFQ). Blood samples were collected after 12 h of fasting to measure serum lipid profile and quantitative C-reactive protein (q-CRP) levels. Binary logistic regression was used to calculate the odds (OR) and 95% confidence interval (CI). Results People in the last tertile of the DII had a higher chance of suffering from severe coronary artery disease (OR: 3.71; 95% CI: 1.97-6.98), hypercholesterolemia (OR: 2.73; 95% CI: 5.03-1.48), reduced HDL-cholesterol levels (OR: 3.77; 95% CI: 9.34-1.52), and hypertension (OR: 1.93; 95% CI: 3.49-1.06) compared to people in the first tertile. After adjusting for confounding factors, the relationship remained significant. A direct and significant relationship was observed between the DII and increased q-CRP levels, which disappeared after adjusting for confounding factors in the adjusted model (OR: 2.02; 95% CI: 0.86-4.73). Conclusion This cross-sectional study showed a direct and linear relationship between following an anti-inflammatory diet and decreasing the chance of severe CAD. Therefore, it seems necessary to implement community-based educational programs to promote healthy nutrition in order to prevent CADs.
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Affiliation(s)
- Zahra Dadaei
- Nutrition and Food Security Research Center, Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran
- Student Research Committee, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohammad Bagherniya
- Nutrition and Food Security Research Center, Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Omid Sadeghi
- Nutrition and Food Security Research Center, Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Alireza Khosravi
- Department of Community of Cardiology, Isfahan Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Shahin Shirani
- Hypertension Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Gholamreza Askari
- Nutrition and Food Security Research Center, Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran
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Vargas-Pozada EE, Ramos-Tovar E, Acero-Hernández C, Cardoso-Lezama I, Galindo-Gómez S, Tsutsumi V, Muriel P. The antioxidant and anti-inflammatory activities of caffeine effectively attenuate nonalcoholic steatohepatitis and thioacetamide-induced hepatic injury in male rats. Can J Physiol Pharmacol 2023; 101:147-159. [PMID: 36744700 DOI: 10.1139/cjpp-2022-0303] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The antioxidant effect of caffeine, associated with its ability to upregulate the nuclear factor-E2-related factor-2 (Nrf2)-signaling pathway, was explored as a possible mechanism for the attenuation of liver damage. Nonalcoholic steatohepatitis (NASH) was induced in rats by the administration of a high-fat, high-sucrose, high-cholesterol diet (HFSCD) for 15 weeks. Liver damage was induced in rats by intraperitoneal administration of thioacetamide (TAA) for six weeks. Caffeine was administered orally at a daily dose of 50 mg/kg body weight during the period of NASH induction to evaluate its ability to prevent disease development. Meanwhile, rats received TAA for three weeks, after which 50 mg/kg caffeine was administered daily for three weeks with TAA to evaluate its capacity to interfere with the progression of hepatic injury. HFSCD administration induced hepatic steatosis, decreased Nrf2 levels, increased oxidative stress, induced the activation of nuclear factor-κB (NF-κB), and elevated proinflammatory cytokine levels, leading to hepatic damage. TAA administration produced similar effects, excluding steatosis. Caffeine increased Nrf2 levels; attenuated oxidative stress markers, including malondialdehyde and 4-hydroxynonenal; restored normal, reduced glutathione levels; and reduced NF-κB activation, inflammatory cytokine levels, and damage. Our findings suggest that caffeine may be useful in the treatment of human liver diseases.
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Affiliation(s)
- Eduardo E Vargas-Pozada
- Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Mexico City 14-740, Mexico
| | - Erika Ramos-Tovar
- Postgraduate Studies and Research Section, School of Higher Education in Medicine-IPN, Plan de San Luis y Díaz Mirón s/n, Casco de Santo Tomás, Mexico City 11340, Mexico
| | - Consuelo Acero-Hernández
- Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Mexico City 14-740, Mexico
| | - Irina Cardoso-Lezama
- Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Mexico City 14-740, Mexico
| | - Silvia Galindo-Gómez
- Department of Infectomics and Molecular Pathogenesis, Cinvestav-IPN, Mexico City 14-740, Mexico
| | - Víctor Tsutsumi
- Department of Infectomics and Molecular Pathogenesis, Cinvestav-IPN, Mexico City 14-740, Mexico
| | - Pablo Muriel
- Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Mexico City 14-740, Mexico
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Abstract
Liver fibrosis has a high incidence worldwide and is the common pathological basis of many chronic liver diseases. Liver fibrosis is caused by the excessive deposition of extracellular matrix and concomitant collagen accumulation in livers and can lead to the development of liver cirrhosis and even liver cancer. A large number of studies have provided evidence that liver fibrosis can be blocked or even reversed by appropriate medical interventions. However, the antifibrosis drugs with ideal clinical efficacy are still insufficient. The edible plant-derived natural compounds have been reported to exert effective antifibrotic effects with few side-effects, representing a kind of promising source for the treatment of liver fibrosis. In this article, we reviewed the current progress of the natural compounds derived from dietary plants in the treatment of liver fibrosis, including phenolic compounds (capsaicin, chlorogenic acid, curcumin, ellagic acid, epigallocatechin-3-gallate, resveratrol, sinapic acid, syringic acid, vanillic acid and vitamin E), flavonoid compounds (genistein, hesperidin, hesperetin, naringenin, naringin and quercetin), sulfur-containing compounds (S-allylcysteine, ergothioneine, lipoic acid and sulforaphane) and other compounds (betaine, caffeine, cucurbitacin B, lycopene, α-mangostin, γ-mangostin, ursolic acid, vitamin C and yangonin). The pharmacological effects and related mechanisms of these compounds in in-vivo and in-vitro models of liver fibrosis are focused.
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Combined Gamma Conglutin and Lupanine Treatment Exhibits In Vivo an Enhanced Antidiabetic Effect by Modulating the Liver Gene Expression Profile. Pharmaceuticals (Basel) 2023; 16:ph16010117. [PMID: 36678614 PMCID: PMC9867068 DOI: 10.3390/ph16010117] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 01/05/2023] [Accepted: 01/08/2023] [Indexed: 01/15/2023] Open
Abstract
Previous studies have individually shown the antidiabetic potential of gamma conglutin (Cγ) and lupanine from lupins. Until now, the influence of combining both compounds and the effective dose of the combination have not been assessed. Moreover, the resulting gene expression profile from this novel combination remains to be explored. Therefore, we aimed to evaluate different dose combinations of Cγ and lupanine by the oral glucose tolerance test (OGTT) to identify the higher antidiabetic effect on a T2D rat model. Later, we administered the selected dose combination during a week. Lastly, we evaluated biochemical parameters and liver gene expression profile using DNA microarrays and bioinformatic analysis. We found that the combination of 28 mg/kg BW Cγ + 20 mg/kg BW lupanine significantly reduced glycemia and lipid levels. Moreover, this treatment positively influenced the expression of Pdk4, G6pc, Foxo1, Foxo3, Ppargc1a, Serpine1, Myc, Slc37a4, Irs2, and Igfbp1 genes. The biological processes associated with these genes are oxidative stress, apoptosis regulation, and glucose and fatty-acid homeostasis. For the first time, we report the beneficial in vivo effect of the combination of two functional lupin compounds. Nevertheless, further studies are needed to investigate the pharmacokinetics and pharmacodynamics of the Cγ + lupanine combined treatment.
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Talpan D, Salla S, Seidelmann N, Walter P, Fuest M. Antifibrotic Effects of Caffeine, Curcumin and Pirfenidone in Primary Human Keratocytes. Int J Mol Sci 2023; 24:ijms24021461. [PMID: 36674976 PMCID: PMC9862324 DOI: 10.3390/ijms24021461] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 01/09/2023] [Accepted: 01/10/2023] [Indexed: 01/14/2023] Open
Abstract
We evaluated the small molecules (AFM) caffeine, curcumin and pirfenidone to find non-toxic concentrations reducing the transformation of activated human corneal stromal keratocytes (aCSK) to scar-inducing myofibroblasts (MYO-SF). CSK were isolated from 16 human corneas unsuitable for transplantation and expanded for three passages in control medium (0.5% FBS). Then, aCSK were exposed to concentrations of caffeine of 0−500 μM, curcumin of 0−200 μM, pirfenidone of 0−2.2 nM and the profibrotic cytokine TGF-β1 (10 ng/mL) for 48 h. Alterations in viability and gene expression were evaluated by cell viability staining (FDA/PI), real-time polymerase chain reaction (RT-PCR) and immunocytochemistry. We found that all AFMs reduced cell counts at high concentrations. The highest concentrations with no toxic effect were 100 µM of caffeine, 20 µM of curcumin and 1.1 nM of pirfenidone. The addition of TGF-β1 to the control medium effectively transformed aCSK into myofibroblasts (MYO-SF), indicated by a 10-fold increase in α-smooth muscle actin (SMA) expression, a 39% decrease in lumican (LUM) expression and a 98% decrease in ALDH3A1 expression (p < 0.001). The concentrations of 100 µM of caffeine, 20/50 µM of curcumin and 1.1 nM of pirfenidone each significantly reduced SMA expression under TGF-β1 stimulation (p ≤ 0.024). LUM and ALDH3A1 expression remained low under TGF-β1 stimulation, independently of AFM supplementation. Immunocytochemistry showed that 100 µM of caffeine, 20 µM of curcumin and 1.1 nM of pirfenidone reduce the conversion rate of aCSK to SMA+ MYO-SF. In conclusion, in aCSK, 100 µM of caffeine, 20 µM of curcumin and 1.1 nM of pirfenidone significantly reduced SMA expression and MYO-SF conversion under TGF-β1 stimulation, with no influence on cell counts. However, the AFMs were unable to protect aCSK from characteristic marker loss.
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Affiliation(s)
- Delia Talpan
- Department of Ophthalmology, RWTH Aachen University, 52074 Aachen, Germany
| | - Sabine Salla
- Department of Ophthalmology, RWTH Aachen University, 52074 Aachen, Germany
- Cornea Bank Aachen, RWTH Aachen University, 52074 Aachen, Germany
| | - Nina Seidelmann
- Department of Ophthalmology, RWTH Aachen University, 52074 Aachen, Germany
| | - Peter Walter
- Department of Ophthalmology, RWTH Aachen University, 52074 Aachen, Germany
- Cornea Bank Aachen, RWTH Aachen University, 52074 Aachen, Germany
| | - Matthias Fuest
- Department of Ophthalmology, RWTH Aachen University, 52074 Aachen, Germany
- Cornea Bank Aachen, RWTH Aachen University, 52074 Aachen, Germany
- Correspondence:
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Wei Y, Wang H, Zhang Y, Gu J, Zhang X, Gong X, Hao Z. Comprehensive Effect of Carbon Tetrachloride and Reversal of Gandankang Formula in Mice Liver: Involved in Oxidative Stress, Excessive Inflammation, and Intestinal Microflora. Antioxidants (Basel) 2022; 11:2234. [PMID: 36421420 PMCID: PMC9687142 DOI: 10.3390/antiox11112234] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 11/10/2022] [Accepted: 11/10/2022] [Indexed: 04/25/2025] Open
Abstract
To systematically evaluate the effect of Gandankang (GDK) aqueous extract in alleviating acute and chronic liver injury. Forty-one chemical compounds were identified by ultra-high performance liquid chromatography-linear trap quadrupole-orbitrap-tandem mass spectrometry (UHPLC-LTQ-Orbitrap-MS) from GDK. All dosages of GDK and Biphenyl diester (BD) improved CCl4-induced acute and chronic liver injury. GDK curbed liver fibrosis and blocked the NF-κB pathway to effectively inhibit the hepatic inflammatory response. Additionally, GDK treatment reduced the abundance of Phascolarctobacterium, Turicibacter, Clostridium_xlva, Atoprostipes, and Eubacterium, in comparison with those in the CCl4 mice and elevated the abundance of Megamonas and Clostridium_IV as evident from 16S rDNA sequencing. Correlation analysis showed that the abundance of Eubacterium and Phascolarctobacterium was positively correlated with inflammation, fibrosis, and oxidation indexes. This indicates that GDK ameliorates chronic liver injury by mitigating fibrosis and inflammation. Nrf2 pathway is the key target of GDK in inhibiting liver inflammation and ferroptosis. Eubacterium and Phascolarctobacterium played a vital role in attenuating liver fibrosis.
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Affiliation(s)
- Yuanyuan Wei
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
- Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, Beijing 100193, China
| | - Huiru Wang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
- Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, Beijing 100193, China
| | - Yannan Zhang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
- Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, Beijing 100193, China
| | - Jinhua Gu
- Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, Beijing 100193, China
- China Institute of Veterinary Drug Control, Beijing 100081, China
| | - Xiuying Zhang
- Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, Beijing 100193, China
- China Institute of Veterinary Drug Control, Beijing 100081, China
| | - Xuhao Gong
- Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, Beijing 100193, China
- China Institute of Veterinary Drug Control, Beijing 100081, China
| | - Zhihui Hao
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
- Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, Beijing 100193, China
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Duan Y, Li J, Qiu S, Ni S, Cao Y. TCF7/SNAI2/miR-4306 feedback loop promotes hypertrophy of ligamentum flavum. Lab Invest 2022; 20:468. [PMID: 36224570 PMCID: PMC9558422 DOI: 10.1186/s12967-022-03677-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 09/29/2022] [Indexed: 11/21/2022]
Abstract
Background Hypertrophy of ligamentum flavum (HLF) is the mainly cause of lumbar spinal stenosis (LSS), but the precise mechanism of HLF formation has not been fully elucidated. Emerging evidence indicates that transcription factor 7 (TCF7) is the key downstream functional molecule of Wnt/β-catenin signaling, which participated in regulating multiple biological processes. However, the role and underlying mechanism of TCF7 in HLF is still unclear. Methods We used mRNAs sequencing analysis of human LF and subsequent confirmation with RT-qPCR, western blot and immunohistochemistry to identified the TCF7 in HLF tissues and cells. Then effect of TCF7 on HLF progression was investigated both in vitro and in vivo. Mechanically, chromatin immunoprecipitation, dual-luciferase reporter assays, and rescue experiments were used to validate the regulation of TCF7/SNAI2/miR-4306 feedback loop. Results Our results identified for first time that the TCF7 expression was obviously elevated in HLF tissues and cells compared with control, and also found that TCF7 expression had significant positive correlation with LF thickness and fibrosis score. Notably, TCF7 inhibition suppressed the hyper-proliferation and fibrosis phenotype of HLF cells in vitro and ameliorated progression of HLF in mice in vivo, whereas TCF7 overexpression promoted hyper-proliferation and fibrosis phenotype of HLF cells in vitro. Our data further revealed that TCF7 interacted with SNAI2 promoter to transactivated the SNAI2 expression, thereby promoting hyper-proliferation and fibrosis phenotype of HLF cells in vitro. Furthermore, miR-4036 negatively regulated by SNAI2 could negatively feedback regulate TCF7 expression by directly binding to TCF7 mRNA 3’-UTR, thus inhibiting the hyper-proliferation and fibrosis phenotype of HLF cells in vitro. Conclusions Our study demonstrated that TCF7 inhibition could suppress HLF formation by modulating TCF7/SNAI2/miR-4306 feedback loop, which might be considered as a novel potential therapeutic target for HLF. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-022-03677-0.
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Affiliation(s)
- Yang Duan
- Department of Spine Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Jianjun Li
- Department of Spine Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Sujun Qiu
- Department of Spine Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Songjia Ni
- Department of Orthopaedic Trauma, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yanlin Cao
- Department of Spine Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
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Caffeine Inhibits NLRP3 Inflammasome Activation by Downregulating TLR4/MAPK/NF-κB Signaling Pathway in an Experimental NASH Model. Int J Mol Sci 2022; 23:ijms23179954. [PMID: 36077357 PMCID: PMC9456282 DOI: 10.3390/ijms23179954] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 08/26/2022] [Accepted: 08/29/2022] [Indexed: 12/13/2022] Open
Abstract
Caffeine elicits protective effects against liver diseases, such as NASH; however, its mechanism of action involving the pyrin domain-containing-3 (NLRP3) inflammasome signaling pathway remains to be elucidated. This study aimed to evaluate the effect of caffeine on the NLRP3 inflammasome signaling pathway in a rat model of NASH. NASH was induced by feeding rats a high-fat, -sucrose, and -cholesterol diet (HFSCD) for 15 weeks along with a weekly low dose (400 mg/kg, i.p.) of CCl4. Caffeine was administered at 50 mg/kg p.o. The effects of HFSCD+CCl4 and caffeine on the liver were evaluated using biochemical, ultrastructural, histological, and molecular biological approaches. The HFSCD+CCl4-treated rats showed fat accumulation in the liver, elevated levels of inflammatory mediators, NLRP3 inflammasome activation, antioxidant dysregulation, and liver fibrosis. Caffeine reduced necrosis, cholestasis, oxidative stress, and fibrosis. Caffeine exhibited anti-inflammatory effects by attenuating NLRP3 inflammasome activation. Moreover, caffeine prevented increases in toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB) protein levels and mitigated the phosphorylation of mitogen-activated protein kinase (MAPK). Importantly, caffeine prevented the activation of hepatic stellate cells. This study is the first to report that caffeine ameliorates NASH by inhibiting NLRP3 inflammasome activation through the suppression of the TLR4/MAPK/NF-κB signaling pathway.
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Guth I, Matos-Pardal C, Ferreira-Lima R, Loureiro-Rebouças R, Sobral A, Moraes-Marques C, Kubrusly L. Caffeine attenuates liver damage and improves neurologic signs in a rat model of hepatic encephalopathy. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO (ENGLISH EDITION) 2022; 87:159-169. [DOI: 10.1016/j.rgmxen.2022.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 11/24/2020] [Indexed: 02/07/2023] Open
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Vargas-Pozada EE, Ramos-Tovar E, Acero-Hernández C, Cardoso-Lezama I, Galindo-Gómez S, Tsutsumi V, Muriel P. Caffeine mitigates experimental nonalcoholic steatohepatitis and the progression of thioacetamide-induced liver fibrosis by blocking the MAPK and TGF-β/Smad3 signaling pathways. Ann Hepatol 2022; 27:100671. [PMID: 35065262 DOI: 10.1016/j.aohep.2022.100671] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 01/13/2022] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES Caffeine consumption is associated with beneficial effects on hepatic disorders. The objectives of this study were to evaluate the antifibrotic effects of caffeine on experimental nonalcoholic steatohepatitis (NASH) induced with a high-fat, high-sucrose, high-cholesterol diet (HFSCD), as well as to evaluate the ability of caffeine to prevent the progression of experimental liver fibrosis induced by the administration of thioacetamide (TAA) in rats and explore the mechanisms of action. METHODS NASH and fibrosis were induced in rats by the administration of an HFSCD for 15 weeks, and liver fibrosis was induced by intraperitoneal administration of 200 mg/kg TAA 3 times per week, for 6 weeks. Caffeine was administered at a dose of 50 mg/kg body weight. The effects of diet, TAA, and caffeine on fibrosis were evaluated by biochemical and histological examinations. The profibrotic pathways were analyzed by western blotting and immunohistochemistry. RESULTS Rats exhibited liver fibrosis after HFSCD feeding and the administration of TAA. Caffeine could reduce the hepatic level of collagen and the fibrotic area in the liver. Caffeine prevented the progression of liver fibrosis by decreasing transforming growth factor-beta (TGF-β), connective tissue growth factor (CTGF), and alpha-smooth muscle actin (α-SMA) expression and by inhibiting the activation of mitogen-activated protein kinases (MAPKs) and Smad3 phosphorylation. CONCLUSIONS Caffeine attenuates NASH and the progression of liver fibrosis due to its antifibrotic effects and modulating the MAPK and TGF-β pathways. Therefore, caffeine could be a suitable candidate for treating liver diseases associated with fibrosis.
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Affiliation(s)
- Eduardo E Vargas-Pozada
- Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Apartado 14-740 Mexico City, Mexico
| | - Erika Ramos-Tovar
- Postgraduate Studies and Research Section, School of Higher Education in Medicine-IPN, Apartado 11340 Plan de San Luis y Díaz Mirón s/n, Casco de Santo Tomás, Mexico City, Mexico
| | - Consuelo Acero-Hernández
- Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Apartado 14-740 Mexico City, Mexico
| | - Irina Cardoso-Lezama
- Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Apartado 14-740 Mexico City, Mexico
| | - Silvia Galindo-Gómez
- Department of Infectomics and Molecular Pathogenesis, Cinvestav-IPN, Apartado 14-740 Mexico City, Mexico
| | - Víctor Tsutsumi
- Department of Infectomics and Molecular Pathogenesis, Cinvestav-IPN, Apartado 14-740 Mexico City, Mexico
| | - Pablo Muriel
- Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Apartado 14-740 Mexico City, Mexico.
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Guth I, Matos-Pardal C, Ferreira-Lima R, Loureiro-Rebouças R, Sobral A, Moraes-Marques C, Kubrusly L. La cafeína atenúa daño hepático y mejora signos neurológicos en un modelo de encefalopatía hepática con ratas. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2022. [DOI: 10.1016/j.rgmx.2020.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Ubiquitin specific peptidase 1 promotes hepatic fibrosis through positive regulation of CXCL1 by deubiquitinating SNAIL. Dig Liver Dis 2022; 54:91-102. [PMID: 33926817 DOI: 10.1016/j.dld.2021.02.025] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 02/25/2021] [Accepted: 02/26/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Hepatic fibrosis is attributed to an imbalance of extracellular matrix production and lysis. Human hepatic stellate cells (HSCs) have been uncovered to converge through complex interactions with hepatocytes and immune cells, causing scarring in liver damage. AIMS We aimed to investigate the expression status of ubiquitin specific peptidase 1 (USP1) and its potential mechanisms on HSCs and hepatic fibrosis. METHODS Hepatic fibrosis animal and cell models were generated using mice with carbon tetrachloride (CCl4) treatment and HSCs LX-2 with TGF-β1 treatment. Relationships among USP1, SNAIL, and CXCL1 were identified via dual-luciferase reporter gene assay, co-immunoprecipitation, and chromatin immunoprecipitation. With gain- and loss-of-experiments, CCK-8 and flow cytometry assays were employed for cell proliferation and apoptosis. RESULTS USP1 upregulated SNAIL expression through deubiquitination to increase CXCL1 expression. USP1 downregulation decreased expressions of fibrosis-related genes, suppressed proliferation, and promoted apoptosis in TGF-β1-induced LX-2 cells, which were reversed by SNAIL overexpression. The pro-fibrosis role caused by SNAIL upregulation was abolished by CXCL1 reduction. Promotive function of USP1/SNAIL/CXCL1 axis in hepatic fibrosis was further confirmed in vivo. CONCLUSION These data supported siRNA-mediated silencing of USP1 improved hepatic fibrosis through inhibition of SNAIL and CXCL1, which yields a new therapeutic target for hepatic fibrosis treatment.
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Ebadi M, Ip S, Bhanji RA, Montano-Loza AJ. Effect of Coffee Consumption on Non-Alcoholic Fatty Liver Disease Incidence, Prevalence and Risk of Significant Liver Fibrosis: Systematic Review with Meta-Analysis of Observational Studies. Nutrients 2021; 13:nu13093042. [PMID: 34578919 PMCID: PMC8471033 DOI: 10.3390/nu13093042] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 08/25/2021] [Accepted: 08/27/2021] [Indexed: 02/08/2023] Open
Abstract
Background and aim: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Given the anti-fibrotic and antioxidant properties of coffee, this systematic review and meta-analysis aims to provide updated results on the impact of coffee consumption on NAFLD incidence, prevalence, and risk of significant liver fibrosis. Methods: We conducted a comprehensive search in MEDLINE (OvidSP) and Scopus from January 2010 through January 2021. Relative risks for the highest versus the lowest level of coffee consumption were pooled using random-effects models. Heterogeneity and publication bias were evaluated using the Higgins’ I2 statistic and Egger’s regression test, respectively. Results: Eleven articles consisting of two case-control studies, eight cross-sectional studies, and one prospective cohort study were included in the meta-analysis. Of those, three studies with 92,075 subjects were included in the analysis for NAFLD incidence, eight studies with 9558 subjects for NAFLD prevalence, and five with 4303 subjects were used for the analysis of liver fibrosis. There was no association between coffee consumption and NAFLD incidence (RR 0.88, 95% CI 0.63–1.25, p = 0.48) or NAFLD prevalence (RR 0.88, 95% CI 0.76–1.02, p = 0.09). The meta-analysis showed coffee consumption to be significantly associated with a 35% decreased odds of significant liver fibrosis (RR 0.65, 95% CI 0.54–0.78, p < 0.00001). There was no heterogeneity (I2 = 11%, p = 0.34) and no evidence of publication bias (p = 0.134). Conclusion: This meta-analysis supports the protective role of coffee consumption on significant liver fibrosis in patients with NAFLD. However, the threshold of coffee consumption to achieve hepatoprotective effects needs to be established in prospective trials.
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Affiliation(s)
- Maryam Ebadi
- Correspondence: (M.E.); (A.J.M.-L.); Tel.: +780-248-1892 (M.E. & A.J.M.-L.); Fax: +780-248-1895 (M.E. & A.J.M.-L.)
| | | | | | - Aldo J. Montano-Loza
- Correspondence: (M.E.); (A.J.M.-L.); Tel.: +780-248-1892 (M.E. & A.J.M.-L.); Fax: +780-248-1895 (M.E. & A.J.M.-L.)
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Kanlaya R, Subkod C, Nanthawuttiphan S, Thongboonkerd V. Caffeine prevents oxalate-induced epithelial-mesenchymal transition of renal tubular cells by its anti-oxidative property through activation of Nrf2 signaling and suppression of Snail1 transcription factor. Biomed Pharmacother 2021; 141:111870. [PMID: 34246192 DOI: 10.1016/j.biopha.2021.111870] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 06/12/2021] [Accepted: 06/28/2021] [Indexed: 01/14/2023] Open
Abstract
Caffeine is an active ingredient found in coffee and energy beverages. Its hepatoprotective effects against liver fibrosis are well-documented. Nonetheless, its renoprotective effects against renal fibrogenesis and epithelial-mesenchymal transition (EMT) processes remain unclear and under-investigated. In this study, the protective effects of caffeine against oxalate-induced EMT in renal tubular cells were evaluated by various assays to measure expression levels of epithelial and mesenchymal markers, cell migrating activity, level of oxidized proteins, and expression of Nrf2 and Snail1. Oxalate at sublethal dose significantly suppressed cell proliferation but increased cell elongation, spindle index and migration. Oxalate also decreased expression of epithelial markers (zonula occludens-1 (ZO-1) and E-cadherin) but increased expression of mesenchymal markers (fibronectin, vimentin and α-smooth muscle actin (α-SMA)). All of these EMT-inducing effects of oxalate could be prevented by pretreatment with caffeine. While oxalate increased oxidized proteins and Snail1 levels, it decreased Nrf2 expression. Caffeine could preserve all these molecules to their basal (control) levels. Finally, silencing of Nrf2 expression by small interfering RNA (siRNA) could abolish such protective effects of caffeine on oxalate-induced EMT. Our data indicate that the renoprotective effects of caffeine against oxalate-induced EMT is mediated, at least in part, by its anti-oxidative property through activation of Nrf2 signaling and suppression of Snail1 transcription factor.
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Affiliation(s)
- Rattiyaporn Kanlaya
- Medical Proteomics Unit, Office for Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Chonnicha Subkod
- Medical Proteomics Unit, Office for Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Supanan Nanthawuttiphan
- Medical Proteomics Unit, Office for Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Visith Thongboonkerd
- Medical Proteomics Unit, Office for Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
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El-Gendy ZA, El-Marasy SA, Ahmed RF, El-Batran SA, Abd El-Rahman SS, Ramadan A, Youssef SAH. Hepatoprotective effect of Saccharomyces Cervisciae Cell Wall Extract against thioacetamide-induced liver fibrosis in rats. Heliyon 2021; 7:e07159. [PMID: 34159266 PMCID: PMC8203708 DOI: 10.1016/j.heliyon.2021.e07159] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 11/04/2020] [Accepted: 05/25/2021] [Indexed: 12/28/2022] Open
Abstract
Fibrosis represents a common outcome of almost all chronic liver diseases and leads to an impairment of liver function that requires medical intervention. The current study aimed to evaluate the potential anti-fibrotic effect of Saccharomyces cervisciae cell wall extract (SCCWE) against thioacetamide (TAA)-induced liver fibrosis in rats (200mg/kg b.w. i.p. twice weekly for 6 weeks) using Ursodeoxycholic acid (UDCA) as a reference anti-fibrotic product. SCCWE at two doses (50 and 100 mg/kg) significantly ameliorated the rise in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamide transferase (GGT) activities, total bilirubin and direct bilirubin, increased total protein and albumin. SCCWE significantly reduced glutathione depletion (GSH), Nitric oxide (NOx) and malondialdehyde (MDA), thioredoxin (Trx) contents and elevated nuclear factor erythroid 2–related factor 2 (Nrf-2) content. Its anti-inflammatory effects were confirmed by observing a decrease in nuclear factor-κB (NF- κβ), interleukin-1b (IL-1β) and inducible nitric oxide synthase (iNOS) content. The anti-fibrotic effects of SCCWE were explored by assessing fibrosis related markers as it significantly reduced transform growth factor-β (TGF-β) and autotaxin (ATX) contents. Administration of SCCWE significantly decreased matrix metalloproteinase-3 and 9 (MMP-3 and -9). Furthermore, it also decreased alpha smooth muscle actin (α-SMA) and caspase-3 as assessed immunohistochemically those results were similar to that of the standard drug UDCA. This study shows that SCCWE protects against TAA-induced liver fibrosis in rats, through attenuating oxidative stress, and inflammation, ameliorating MMPs, combating apoptosis and thereby fibrotic biomarkers in addition to improving histopathological changes.
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Affiliation(s)
| | | | - Rania F Ahmed
- Department of Pharmacology, National Research Centre, Giza, Egypt
| | | | - Sahar S Abd El-Rahman
- Department of Pathology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
| | - A Ramadan
- Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
| | - S A H Youssef
- Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
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K P B, L L J, A L W, J B, N S, J R H, H H M H. Dietary inflammatory index and mortality in hemodialysis patients by path analysis approach (NUGE-HD study). Nutrition 2021; 89:111239. [PMID: 33930786 DOI: 10.1016/j.nut.2021.111239] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 02/28/2021] [Accepted: 03/04/2021] [Indexed: 02/07/2023]
Abstract
OBJECTIVE The aim of this study was to evaluate the interrelationships between dietary, nutritional, and inflammatory factors in predicting all-cause mortality among individuals in hemodialysis (HD) treatment. METHODS Participating in this study were 137 patients undergoing HD (58.4% men, 61.7 ± 15.4 y of age) from the NUtrition and GEnetics on HemoDialysis outcomes (NUGE-HD study) cohort. Sociodemographic, anthropometric, and clinical data were collected. Dietary inflammatory index scores were calculated from a quantitative food frequency questionnaire. Plasma C-reactive protein was used as an inflammatory marker. Data were analyzed by path analysis. RESULTS During the 2-y follow-up, 27 patients (19.7%) died. Compared with survivors, non-survivors were older (P = 0.01) and had lower body mass index (P = 0.04). In relation to direct (unmediated) associations, dietary inflammatory index (P = 0.049) and C-reactive protein (P = 0.016) were positively associated, whereas body mass index was negatively associated with mortality (P = 0.012). There were no indirect (mediated) associations of the variables evaluated with mortality. CONCLUSION More proinflammatory diet and systemic inflammation have a direct association with mortality among patients undergoing HD therapy. Additionally, more proinflammatory diet is associated with unhealthy dietary pattern.
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Affiliation(s)
- Balbino K P
- Department of Nutrition and Health, Universidade Federal de Viçosa, Viçosa, Minas Gerais, Brazil
| | - Juvanhol L L
- Department of Nutrition and Health, Universidade Federal de Viçosa, Viçosa, Minas Gerais, Brazil
| | - Wendling A L
- Department of Nutrition and Health, Universidade Federal de Viçosa, Viçosa, Minas Gerais, Brazil
| | - Bressan J
- Department of Nutrition and Health, Universidade Federal de Viçosa, Viçosa, Minas Gerais, Brazil
| | - Shivappa N
- Cancer Prevention and Control Program, University of South Carolina, Columbia, South Carolina, United States; Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina, United States; Department of Nutrition, Connecting Health Innovations LLC, Columbia, South Carolina, United States
| | - Hebert J R
- Cancer Prevention and Control Program, University of South Carolina, Columbia, South Carolina, United States; Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina, United States; Department of Nutrition, Connecting Health Innovations LLC, Columbia, South Carolina, United States
| | - Hermsdorff H H M
- Department of Nutrition and Health, Universidade Federal de Viçosa, Viçosa, Minas Gerais, Brazil.
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Nilnumkhum A, Kanlaya R, Yoodee S, Thongboonkerd V. Caffeine inhibits hypoxia-induced renal fibroblast activation by antioxidant mechanism. Cell Adh Migr 2020; 13:260-272. [PMID: 31271106 PMCID: PMC6650197 DOI: 10.1080/19336918.2019.1638691] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Caffeine has been demonstrated to possess anti-fibrotic activity against liver fibrosis. However, its role in renal fibrosis remained unclear. This study investigated the effects of caffeine on renal fibroblast activation induced by hypoxia (one of the inducers for renal fibrosis). BHK-21 fibroblasts were cultured under normoxia or hypoxia with or without caffeine treatment. Hypoxia increased levels of fibronectin, α-smooth muscle actin, actin stress fibers, intracellular reactive oxygen species (ROS), and oxidized proteins. However, caffeine successfully preserved all these activated fibroblast markers to their basal levels. Cellular catalase activity was dropped under hypoxic condition but could be reactivated by caffeine. Hif1a gene and stress-responsive Nrf2 signaling molecule were elevated/activated by hypoxia, but only Nrf2 could be partially recovered by caffeine. These data suggest that caffeine exhibits anti-fibrotic effect against hypoxia-induced renal fibroblast activation through its antioxidant property to eliminate intracellular ROS, at least in part, via downstream catalase and Nrf2 mechanisms.
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Affiliation(s)
- Angkhana Nilnumkhum
- a Medical Proteomics Unit, Office for Research and Development, Faculty of Medicine Siriraj Hospital , Mahidol University , Bangkok , Thailand
| | - Rattiyaporn Kanlaya
- a Medical Proteomics Unit, Office for Research and Development, Faculty of Medicine Siriraj Hospital , Mahidol University , Bangkok , Thailand
| | - Sunisa Yoodee
- a Medical Proteomics Unit, Office for Research and Development, Faculty of Medicine Siriraj Hospital , Mahidol University , Bangkok , Thailand
| | - Visith Thongboonkerd
- a Medical Proteomics Unit, Office for Research and Development, Faculty of Medicine Siriraj Hospital , Mahidol University , Bangkok , Thailand
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Lyu H, Wang H, Li L, Zhu J, Chen F, Chen Y, Liu C, Fu J, Yang B, Zhang Q, Xu Y, Pi J. Hepatocyte-specific deficiency of Nrf2 exacerbates carbon tetrachloride-induced liver fibrosis via aggravated hepatocyte injury and subsequent inflammatory and fibrogenic responses. Free Radic Biol Med 2020; 150:136-147. [PMID: 32112813 DOI: 10.1016/j.freeradbiomed.2020.02.015] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 02/10/2020] [Accepted: 02/19/2020] [Indexed: 12/21/2022]
Abstract
BACKGROUND Liver fibrosis, in which hepatocyte damage and inflammatory response play critical roles, is a physiological response to chronic or iterative liver injury and can progress to cirrhosis over time. Nuclear factor E2-related factor 2 (Nrf2) is a master transcription factor that regulates oxidative and xenobiotic stress responses as well as inflammation. METHOD To ascertain the cell-specific roles of Nrf2 in hepatocytes and myeloid lineage cells in the progression of liver fibrosis, mice lacking Nrf2 specifically in hepatocytes [Nrf2(L)-KO] and myeloid lineage cells [Nrf2(M)-KO] were generated to evaluate carbon tetrachloride (CCl4)-induced liver injury, subsequent inflammation and fibrosis. In addition, mouse primary hepatocytes were used to investigate the underlying mechanisms. RESULTS Nrf2-mediated antioxidant response in the liver is responsive to acute CCl4 exposure in mice. With repeated CCl4 administration, Nrf2(L)-KO, but not Nrf2(M)-KO, mice showed more severe liver fibrosis than Nrf2-LoxP control mice. In addition, in response to acute CCl4 exposure, Nrf2(L)-KO mice displayed aggravated liver injury, elevated lipid peroxidation and inflammatory response compared to control mice. In mouse primary hepatocytes, deficiency of Nrf2 resulted in more severe CCl4-induced lipid oxidation and inflammatory response. CONCLUSION Deficiency of Nrf2 in hepatocytes sensitizes the cells to CCl4-induced oxidative damage and inflammatory response, which are initiator and enhancer of subsequent hepatic inflammation and fibrosis. Thus, Nrf2 is a critical determinant of liver injury and fibrosis in response to CCl4, suggesting that Nrf2 might be a valuable target for the intervention.
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Affiliation(s)
- Hang Lyu
- School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, 110122, China
| | - Huihui Wang
- School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, 110122, China
| | - Lu Li
- School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, 110122, China
| | - Jiayu Zhu
- School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, 110122, China
| | - Feng Chen
- Department of Interventional Radiology, The First Affiliated Hospital of Shandong First Medical University, No. 16766 Jingshi Road, Lixia Area, Jinan, 250014, China
| | - Yannan Chen
- School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, 110122, China
| | - Cuijie Liu
- School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, 110122, China
| | - Jingqi Fu
- School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, 110122, China
| | - Bei Yang
- Department of Histology and Embryology, College of Basic Medical Science, China Medical University, China
| | - Qiang Zhang
- Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, 30322, USA
| | - Yuanyuan Xu
- School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, 110122, China.
| | - Jingbo Pi
- School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, 110122, China.
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Feng YL, Chen DQ, Vaziri ND, Guo Y, Zhao YY. Small molecule inhibitors of epithelial-mesenchymal transition for the treatment of cancer and fibrosis. Med Res Rev 2020; 40:54-78. [PMID: 31131921 DOI: 10.1002/med.21596] [Citation(s) in RCA: 101] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Revised: 03/20/2019] [Accepted: 04/26/2019] [Indexed: 02/07/2023]
Abstract
Tissue fibrosis and cancer both lead to high morbidity and mortality worldwide; thus, effective therapeutic strategies are urgently needed. Because drug resistance has been widely reported in fibrotic tissue and cancer, developing a strategy to discover novel targets for targeted drug intervention is necessary for the effective treatment of fibrosis and cancer. Although many factors lead to fibrosis and cancer, pathophysiological analysis has demonstrated that tissue fibrosis and cancer share a common process of epithelial-mesenchymal transition (EMT). EMT is associated with many mediators, including transcription factors (Snail, zinc-finger E-box-binding protein and signal transducer and activator of transcription 3), signaling pathways (transforming growth factor-β1, RAC-α serine/threonine-protein kinase, Wnt, nuclear factor-kappa B, peroxisome proliferator-activated receptor, Notch, and RAS), RNA-binding proteins (ESRP1 and ESRP2) and microRNAs. Therefore, drugs targeting EMT may be a promising therapy against both fibrosis and tumors. A large number of compounds that are synthesized or derived from natural products and their derivatives suppress the EMT by targeting these mediators in fibrosis and cancer. By targeting EMT, these compounds exhibited anticancer effects in multiple cancer types, and some of them also showed antifibrotic effects. Therefore, drugs targeting EMT not only have both antifibrotic and anticancer effects but also exert effective therapeutic effects on multiorgan fibrosis and cancer, which provides effective therapy against fibrosis and cancer. Taken together, the results highlighted in this review provide new concepts for discovering new antifibrotic and antitumor drugs.
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Affiliation(s)
- Ya-Long Feng
- School of Pharmacy, Faculty of Life Science & Medicine, Northwest University, Xi'an, Shaanxi, China
| | - Dan-Qian Chen
- School of Pharmacy, Faculty of Life Science & Medicine, Northwest University, Xi'an, Shaanxi, China
| | - Nosratola D Vaziri
- Department of Medicine, University of California Irvine, Irvine, California
| | - Yan Guo
- School of Pharmacy, Faculty of Life Science & Medicine, Northwest University, Xi'an, Shaanxi, China
- Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico
| | - Ying-Yong Zhao
- School of Pharmacy, Faculty of Life Science & Medicine, Northwest University, Xi'an, Shaanxi, China
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Effects of Ethyl Pyruvate on Bile Duct Ligation-Induced Liver Fibrosis by Regulating Nrf2 Pathway and Proinflammatory Cytokines in Rats. Gastroenterol Res Pract 2019; 2019:2969802. [PMID: 31933629 PMCID: PMC6942817 DOI: 10.1155/2019/2969802] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2019] [Revised: 05/02/2019] [Accepted: 05/19/2019] [Indexed: 12/14/2022] Open
Abstract
Aim The aim of this paper is to investigate the effects of ethyl pyruvate (EP) on experimental liver fibrosis induced by bile duct ligation (BDL) and explore the underlying molecular mechanisms. Material and Method Rats were randomly divided into three groups: the sham group, the BDL group, and the BDL+EP group. Liver fibrosis was induced by common bile duct ligation and was evaluated by serum biochemical parameter levels, Masson's trichrome staining, α-SMA expression, and collagen I deposition. The levels of Nrf2 signaling pathway-related antioxidant genes (Nrf2, SOD2, NQO1, and GSH-Px) in liver tissues were also measured. Meanwhile, the mRNA expression levels of HMGB1, IL-1β, TNF-α, and HSP27 were analyzed. In BDL-induced liver fibrosis rats, the successfully established model was confirmed by the significant increase of serum ALT and AST levels, the high liver fibrosis score, α-SMA expression, and collagen deposition. Results Compared with the BDL group, EP administration could diminish fibrosis level and substantially increase the expression of Nrf2 signaling pathway-related antioxidant genes. Furthermore, EP significantly suppressed the mRNA expression levels of HMGB1, IL-1β, TNF-α, and HSP27. Conclusions The results suggested that EP administration could effectively inhibit the liver fibrosis induced by BDL in rat, which may be associated with the enhanced activity of Nrf2 to mediate antioxidant enzyme system and downregulate the inflammatory genes.
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Shivappa N. Diet and Chronic Diseases: Is There a Mediating Effect of Inflammation? Nutrients 2019; 11:nu11071639. [PMID: 31323738 PMCID: PMC6683086 DOI: 10.3390/nu11071639] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Accepted: 07/17/2019] [Indexed: 12/27/2022] Open
Affiliation(s)
- Nitin Shivappa
- South Carolina Statewide Cancer Prevention and Control Program, University of South Carolina, Columbia, SC 29208, USA.
- Department of Epidemiology and Biostatistics, University of South Carolina, Columbia, SC 29208, USA.
- Connecting Health Innovations LLC, Columbia, SC 29201, USA.
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Genotoxic effect of caffeine in Yarrowia lipolytica cells deficient in DNA repair mechanisms. Arch Microbiol 2019; 201:991-998. [PMID: 31025056 DOI: 10.1007/s00203-019-01658-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Revised: 04/05/2019] [Accepted: 04/10/2019] [Indexed: 01/01/2023]
Abstract
Caffeine is a compound that can exert physiological-beneficial effects in the organism. Nevertheless, there are controversies about its protective-antioxidant and/or its negative genotoxic effect. To abound on the analysis of the possible genotoxic/antioxidant effect of caffeine, we used as research model the yeast Yarrowia lipolytica parental strain, and mutant strains (∆rad52 and ∆ku80), which are deficient in the DNA repair mechanisms. Caffeine (5 mM) showed a cytostatic effect on all strains, but after 72 h of incubation the parental and ∆ku80 strains were able to recover of this inhibitory effect on growth, whereas ∆rad52 was unable to recover. When cells were pre-incubated with caffeine and H2O2 or incubated with a mixture of both agents, a higher inhibitory effect on growth of mutant strains was observed and this effect was noticeably greater for the Δrad52 strain. The toxic effect of caffeine appears to be through a mechanism of DNA damage (genotoxic effect) that involves DSB generation since, in all tested conditions, the growth of Δrad52 strain (cells deficient in HR DNA repair mechanism) was more severely affected.
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Fang C, Cai X, Hayashi S, Hao S, Sakiyama H, Wang X, Yang Q, Akira S, Nishiguchi S, Fujiwara N, Tsutsui H, Sheng J. Caffeine-stimulated muscle IL-6 mediates alleviation of non-alcoholic fatty liver disease. Biochim Biophys Acta Mol Cell Biol Lipids 2019; 1864:271-280. [PMID: 30553055 DOI: 10.1016/j.bbalip.2018.12.003] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Revised: 11/20/2018] [Accepted: 12/10/2018] [Indexed: 02/05/2023]
Abstract
Caffeine intake is associated with a reduced risk developing non-alcoholic fatty liver disease (NAFLD), but the underlying molecular mechanisms remain to be fully elucidated. We report here that caffeine markedly improved high fat diet-induced NAFLD in mice resulting in a 10-fold increase in circulating IL-6 levels, leading to STAT3 activation in the liver. Interestingly, the expression of IL-6 mRNA was not increased in the liver, but increased substantially in the muscles of caffeine-treated mice. Caffeine was found to stimulate IL-6 production in cultured myotubes but not in hepatocytes, adipocytes, or macrophages. The inhibition of p38/MAPK abrogated caffeine-induced IL-6 production in muscle cells. Caffeine failed to improve NAFLD in IL-6 and hepatocyte-specific STAT3 knockout mice, indicating that the IL-6/STAT3 pathway is vital for the hepatoprotective effects of caffeine in NAFLD. The possibility that IL-6/STAT3-mediated hepatic autophagosome induction and hepatocytic oxygen consumption are involved in the anti-NAFLD effects of caffeine cannot be excluded, based on the findings presented here. Our results reveal that caffeine ameliorates NAFLD via crosstalk between muscle IL-6 production and liver STAT3 activation.
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Affiliation(s)
- Chongye Fang
- Key Laboratory of Pu-erh Tea Science, the Ministry of Education, Yunnan Agricultural University, Kunming 650201, China; Department of Pu-erh Tea and Medical Science, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan
| | - Xianbin Cai
- Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan; Department of Gastroenterology, First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Shuhei Hayashi
- Department of Pu-erh Tea and Medical Science, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan; Department of Microbiology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan.
| | - Shumei Hao
- Yunnan University, Kunming 650091, China
| | - Haruhiko Sakiyama
- Department of Biochemistry, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501, Japan
| | - Xuanjun Wang
- Key Laboratory of Pu-erh Tea Science, the Ministry of Education, Yunnan Agricultural University, Kunming 650201, China
| | - Qin Yang
- Department of Internal Medicine, Division of Endocrinology, University of California at Irvine, Irvine, CA 92697, USA
| | - Shizuo Akira
- Laboratory of Host Defense, World Premier International Research Center Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan; Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
| | - Shuhei Nishiguchi
- Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan
| | - Noriko Fujiwara
- Department of Biochemistry, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501, Japan
| | - Hiroko Tsutsui
- Key Laboratory of Pu-erh Tea Science, the Ministry of Education, Yunnan Agricultural University, Kunming 650201, China; Department of Microbiology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan
| | - Jun Sheng
- Key Laboratory of Pu-erh Tea Science, the Ministry of Education, Yunnan Agricultural University, Kunming 650201, China; State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Kunming, China; Pu'erh Tea Research Institute, Pu'erh, China.
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Thi Thanh Hai N, Thuy LTT, Shiota A, Kadono C, Daikoku A, Hoang DV, Dat NQ, Sato-Matsubara M, Yoshizato K, Kawada N. Selective overexpression of cytoglobin in stellate cells attenuates thioacetamide-induced liver fibrosis in mice. Sci Rep 2018; 8:17860. [PMID: 30552362 PMCID: PMC6294752 DOI: 10.1038/s41598-018-36215-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Accepted: 11/15/2018] [Indexed: 02/07/2023] Open
Abstract
Cytoglobin (CYGB), discovered in hepatic stellate cells (HSCs), is known to possess a radical scavenger function, but its pathophysiological roles remain unclear. Here, for the first time, we generated a new transgenic (TG) mouse line in which both Cygb and mCherry reporter gene expression were under the control of the native Cygb gene promoter. We demonstrated that the expression of Cygb-mCherry was related to endogenous Cygb in adult tissues by tracing mCherry fluorescence together with DNA, mRNA, and protein analyses. Administration of a single dose (50 mg/kg) of thioacetamide (TAA) in Cygb-TG mice resulted in lower levels of alanine transaminase and oxidative stress than those in WT mice. After 10 weeks of TAA administration, Cygb-TG livers exhibited reduced neutrophil accumulation, cytokine expression and fibrosis but high levels of quiescent HSCs. Primary HSCs isolated from Cygb-TG mice (HSCCygb-TG) exhibited significantly decreased mRNA levels of α-smooth muscle actin (αSMA), collagen 1α1, and transforming growth factor β-3 after 4 days in culture relative to WT cells. HSCsCygb-TG were resistant to H2O2-induced αSMA expression. Thus, cell-specific overexpression of Cygb attenuates HSC activation and protects mice against TAA-induced liver fibrosis presumably by maintaining HSC quiescence. Cygb is a potential new target for antifibrotic approaches.
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Affiliation(s)
- Nguyen Thi Thanh Hai
- Departments of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
- Department of Biochemistry, Hanoi Medical University, Hanoi, Vietnam
| | - Le Thi Thanh Thuy
- Departments of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | | | - Chiho Kadono
- Departments of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Atsuko Daikoku
- Departments of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Dinh Viet Hoang
- Departments of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Ninh Quoc Dat
- Departments of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Misako Sato-Matsubara
- Departments of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Katsutoshi Yoshizato
- Departments of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
- PhoenixBio Co. Ltd., Hiroshima, Japan
- Endowed Laboratory of Synthetic Biology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Norifumi Kawada
- Departments of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
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Eraky SM, El-Mesery M, El-Karef A, Eissa LA, El-Gayar AM. Silymarin and caffeine combination ameliorates experimentally-induced hepatic fibrosis through down-regulation of LPAR1 expression. Biomed Pharmacother 2018; 101:49-57. [PMID: 29477472 DOI: 10.1016/j.biopha.2018.02.064] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Revised: 02/14/2018] [Accepted: 02/15/2018] [Indexed: 01/08/2023] Open
Abstract
AIMS Lysophosphatidic acid is a lipid mediator that is supposed to be implicated in hepatic fibrosis. Silymarin and caffeine are natural compounds known for their anti-inflammatory and antioxidant effects. Our study aimed to explore the effect of silymarin, caffeine, and their combination on lysophosphatidic acid receptor 1 (LPAR1) pathway in thioacetamide (TAA)-induced hepatic fibrosis. MAIN METHODS Hepatic fibrosis was induced in male Sprague-Dawley rats by intraperitoneal injection of 200 mg/kg of TAA twice a week for 8 weeks. Silymarin (50 mg/kg), caffeine (50 mg/kg), and their combination (50 mg/kg silymarin + 50 mg/kg caffeine) were orally given to rats every day for 8 weeks along with TAA injection. Liver functions were measured. Histopathological examination of liver tissues was performed using hematoxylin and eosin and Masson's trichrome staining. mRNA expressions of LPAR1, transforming growth factor beta 1 (TGF-β1), connective tissue growth factor (CTGF), and alpha smooth muscle actin (α-SMA) were measured using RT-PCR. LPAR1 tissue expression was scored using immunohistochemistry. KEY FINDINGS Silymarin, caffeine, and their combination significantly improved liver function. They caused significant decrease in fibrosis and necro-inflammatory scores. Combination of silymain and caffeine caused a significant decrease in the necro-inflammatory score than the single treatment with silymarin or caffeine. In addition, silymarin, caffeine, and their combination significantly decreased hepatic LPAR1, TGF-β1, CTGF, and α-SMA gene expressions and LPAR1 tissue expression. SIGNIFICANCE Silymarin, caffeine, and their combination protect against liver fibrosis through down-regulation of LPAR1, TGF-β1, and CTGF.
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Affiliation(s)
- Salma M Eraky
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
| | - Mohamed El-Mesery
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Amro El-Karef
- Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Laila A Eissa
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
| | - Amal M El-Gayar
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
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Effects of Coffee Extracts with Different Roasting Degrees on Antioxidant and Anti-Inflammatory Systems in Mice. Nutrients 2018; 10:nu10030363. [PMID: 29547558 PMCID: PMC5872781 DOI: 10.3390/nu10030363] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Revised: 03/06/2018] [Accepted: 03/08/2018] [Indexed: 11/30/2022] Open
Abstract
Coffee roasting affects the taste, color, and aroma of coffee. The Maillard reaction, a major reaction during the roasting process, produces melanoidin, which affects the overall antioxidant capacity and anti-inflammatory effects of coffee. In this experiment, coffee roasting was divided into four degrees: Light, Medium, City, and French. To examine the in vivo antioxidant and anti-inflammatory effects of coffee extracts with different roasting degrees, we used 10-week-old male C57BL/6 mice. Mice were pre-treated with coffee extracts for 10 days by oral gavage (300 mg/Kg.B.W). After the last pre-treatment, lipopolysaccharide (LPS, 15 mg/Kg.B.W) was injected intraperitoneally for immune stimulation. Histopathological analysis showed that hepatic portal vein invasion and liver necrosis were severe in the LPS-treated group. However, these phenomena were greatly ameliorated when mice were pre-treated with Light- or Medium-roasted coffee extracts. Hepatic glutathione level was increased in the French group but decreased in the LPS-stimulated group. When mice were treated with LPS, mRNA expression level of tumor necrosis factor-alpha (TNF-α) was increased, whereas TNF-α expression was significantly reduced in the Light and Medium groups. Treatment with coffee extracts decreased the mRNA expression levels of interleukin 6 (IL-6) in mice stimulated by LPS, regardless of coffee roasting degrees. These effects decreased with the increasing coffee roasting degree. Results of luciferase reporter assay revealed that these effects of coffee extracts were transcriptionally regulated by the NF-κB pathway. Taken together, these results suggest that the roasting degree affects the antioxidant and anti-inflammatory effects of coffee extracts.
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Shivappa N, Godos J, Hébert JR, Wirth MD, Piuri G, Speciani AF, Grosso G. Dietary Inflammatory Index and Cardiovascular Risk and Mortality-A Meta-Analysis. Nutrients 2018; 10:nu10020200. [PMID: 29439509 PMCID: PMC5852776 DOI: 10.3390/nu10020200] [Citation(s) in RCA: 214] [Impact Index Per Article: 30.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Revised: 01/29/2018] [Accepted: 02/09/2018] [Indexed: 01/25/2023] Open
Abstract
Diet and chronic inflammation have been suggested to be risk factors in the development of cardiovascular disease (CVD) and related mortality. The possible link between the inflammatory potential of diet measured through the Dietary Inflammatory Index (DII®) and CVD has been investigated in several populations across the world. The aim of this study was to conduct a meta-analysis on studies exploring this association. Data from 14 studies were eligible, of which two were case-control, eleven were cohort, and one was cross-sectional. Results from the random-effects meta-analysis showed a positive association between increasing DII, indicating a pro-inflammatory diet, and CVD. Individuals in the highest versus the lowest (reference) DII category showed a 36% increased risk of CVD incidence and mortality, with moderate evidence of heterogeneity (relative risk (RR) = 1.36, 95% confidence interval (CI): 1.19, 1.57; heterogeneity index I2 = 69%, p < 0.001). When analyzed as a continuous variable, results showed an increased risk of CVD risk and mortality of 8% for each one-point increase in the DII score. Results remained unchanged when analyses were restricted to the prospective studies. Results of our meta-analysis support the importance of adopting a healthier anti-inflammatory diet for preventing CVD incidence and related mortality. In conclusion, a pro-inflammatory diet is associated with increased risk of CVD and CVD mortality. These results further substantiate the utility of DII as tool to characterize the inflammatory potential of diet and to predict CVD incidence and mortality.
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Affiliation(s)
- Nitin Shivappa
- Cancer Prevention and Control Program, University of South Carolina, Columbia, SC 29208, USA.
- Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA.
- Connecting Health Innovations, LLC, Columbia, SC 29201, USA.
| | - Justyna Godos
- NNEdPro Global Centre for Nutrition and Health, St John's Innovation Centre, Cambridge CB4 0WS, UK.
| | - James R Hébert
- Cancer Prevention and Control Program, University of South Carolina, Columbia, SC 29208, USA.
- Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA.
- Connecting Health Innovations, LLC, Columbia, SC 29201, USA.
| | - Michael D Wirth
- Cancer Prevention and Control Program, University of South Carolina, Columbia, SC 29208, USA.
- Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA.
- Connecting Health Innovations, LLC, Columbia, SC 29201, USA.
- College of Nursing, University of South Carolina, Columbia, SC 29208, USA.
| | - Gabriele Piuri
- Inflammation Society, 18 Woodlands Park, Bexley DA52EL, UK.
| | | | - Giuseppe Grosso
- NNEdPro Global Centre for Nutrition and Health, St John's Innovation Centre, Cambridge CB4 0WS, UK.
- Integrated Cancer Registry of Catania-Messina-Siracusa-Enna, Azienda Ospedaliera Universitaria Policlinico Vittorio Emanuele, 95123 Catania, Italy.
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Coffee Consumption and Risk of Biliary Tract Cancers and Liver Cancer: A Dose-Response Meta-Analysis of Prospective Cohort Studies. Nutrients 2017; 9:nu9090950. [PMID: 28846640 PMCID: PMC5622710 DOI: 10.3390/nu9090950] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Revised: 08/23/2017] [Accepted: 08/24/2017] [Indexed: 12/19/2022] Open
Abstract
Background: A meta-analysis was conducted to summarize the evidence from prospective cohort and case-control studies regarding the association between coffee intake and biliary tract cancer (BTC) and liver cancer risk. Methods: Eligible studies were identified by searches of PubMed and EMBASE databases from the earliest available online indexing year to March 2017. The dose–response relationship was assessed by a restricted cubic spline model and multivariate random-effect meta-regression. A stratified and subgroup analysis by smoking status and hepatitis was performed to identify potential confounding factors. Results: We identified five studies on BTC risk and 13 on liver cancer risk eligible for meta-analysis. A linear dose–response meta-analysis did not show a significant association between coffee consumption and BTC risk. However, there was evidence of inverse correlation between coffee consumption and liver cancer risk. The association was consistent throughout the various potential confounding factors explored including smoking status, hepatitis, etc. Increasing coffee consumption by one cup per day was associated with a 15% reduction in liver cancer risk (RR 0.85; 95% CI 0.82 to 0.88). Conclusions: The findings suggest that increased coffee consumption is associated with decreased risk of liver cancer, but not BTC.
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吴 兰, 刘 文. 肝纤维化逆转机制的研究进展及治疗概况. Shijie Huaren Xiaohua Zazhi 2017; 25:2123-2132. [DOI: 10.11569/wcjd.v25.i23.2123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
肝纤维化是肝脏对慢性损伤的一种修复反应, 多是持续性肝脏损伤或纤维化刺激因子刺激产生的共有病理改变, 是一项严重的全球性健康难题. 近年来临床研究发现, 由病毒性肝炎造成肝纤维化或肝硬化的患者, 在成功接受病毒性肝炎治疗后, 其肝纤维化甚至肝硬化发生了逆转现象. 因此研究和了解肝纤维化逆转的机制有利于发现新的针对肝纤维化的治疗靶向. 本文就近年来有关肝纤维化逆转机制的研究以及治疗概况作一综述, 以期为肝纤维化的研究提供帮助.
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Salomone F, Galvano F, Li Volti G. Molecular Bases Underlying the Hepatoprotective Effects of Coffee. Nutrients 2017; 9:nu9010085. [PMID: 28124992 PMCID: PMC5295129 DOI: 10.3390/nu9010085] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Revised: 11/29/2016] [Accepted: 01/09/2017] [Indexed: 12/29/2022] Open
Abstract
Coffee is the most consumed beverage worldwide. Epidemiological studies with prospective cohorts showed that coffee intake is associated with reduced cardiovascular and all-cause mortality independently of caffeine content. Cohort and case-control studies reported an inverse association between coffee consumption and the degree of liver fibrosis as well as the development of liver cancer. Furthermore, the beneficial effects of coffee have been recently confirmed by large meta-analyses. In the last two decades, various in vitro and in vivo studies evaluated the molecular determinants for the hepatoprotective effects of coffee. In the present article, we aimed to critically review experimental evidence regarding the active components and the molecular bases underlying the beneficial role of coffee against chronic liver diseases. Almost all studies highlighted the beneficial effects of this beverage against liver fibrosis with the most solid results indicating a pivot role for both caffeine and chlorogenic acids. In particular, in experimental models of fibrosis, caffeine was shown to inhibit hepatic stellate cell activation by blocking adenosine receptors, and emerging evidence indicated that caffeine may also favorably impact angiogenesis and hepatic hemodynamics. On the other side, chlorogenic acids, potent phenolic antioxidants, suppress liver fibrogenesis and carcinogenesis by reducing oxidative stress and counteract steatogenesis through the modulation of glucose and lipid homeostasis in the liver. Overall, these molecular insights may have translational significance and suggest that coffee components need clinical evaluation.
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Affiliation(s)
- Federico Salomone
- Division of Gastroenterology, Ospedale di Acireale, Azienda Sanitaria Provinciale di Catania, 95124 Catania, Italy.
| | - Fabio Galvano
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95125 Catania, Italy.
| | - Giovanni Li Volti
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95125 Catania, Italy.
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Cachón AU, Quintal-Novelo C, Medina-Escobedo G, Castro-Aguilar G, Moo-Puc RE. Hepatoprotective Effect of Low Doses of Caffeine on CCl4-Induced Liver Damage in Rats. J Diet Suppl 2016; 14:158-172. [DOI: 10.1080/19390211.2016.1207003] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Tatler AL, Barnes J, Habgood A, Goodwin A, McAnulty RJ, Jenkins G. Caffeine inhibits TGFβ activation in epithelial cells, interrupts fibroblast responses to TGFβ, and reduces established fibrosis in ex vivo precision-cut lung slices. Thorax 2016; 71:565-7. [PMID: 26911575 PMCID: PMC4893128 DOI: 10.1136/thoraxjnl-2015-208215] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Accepted: 02/01/2016] [Indexed: 01/12/2023]
Abstract
Caffeine is a commonly used food additive found naturally in many products. In addition to potently stimulating the central nervous system caffeine is able to affect various systems within the body including the cardiovascular and respiratory systems. Importantly, caffeine is used clinically to treat apnoea and bronchopulmonary dysplasia in premature babies. Recently, caffeine has been shown to exhibit antifibrotic effects in the liver in part through reducing collagen expression and deposition, and reducing expression of the profibrotic cytokine TGFβ. The potential antifibrotic effects of caffeine in the lung have not previously been investigated. Using a combined in vitro and ex vivo approach we have demonstrated that caffeine can act as an antifibrotic agent in the lung by acting on two distinct cell types, namely epithelial cells and fibroblasts. Caffeine inhibited TGFβ activation by lung epithelial cells in a concentration-dependent manner but had no effect on TGFβ activation in fibroblasts. Importantly, however, caffeine abrogated profibrotic responses to TGFβ in lung fibroblasts. It inhibited basal expression of the α-smooth muscle actin gene and reduced TGFβ-induced increases in profibrotic genes. Finally, caffeine reduced established bleomycin-induced fibrosis after 5 days treatment in an ex vivo precision-cut lung slice model. Together, these findings suggest that there is merit in further investigating the potential use of caffeine, or its analogues, as antifibrotic agents in the lung.
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Affiliation(s)
- Amanda L Tatler
- Division of Respiratory Medicine, Nottingham City Hospital, University of Nottingham, Nottingham, UK
| | - Josephine Barnes
- UCL Respiratory Centre for Inflammation and Tissue Repair, University College London, London, UK
| | - Anthony Habgood
- Division of Respiratory Medicine, Nottingham City Hospital, University of Nottingham, Nottingham, UK
| | - Amanda Goodwin
- Division of Respiratory Medicine, Nottingham City Hospital, University of Nottingham, Nottingham, UK
| | - Robin J McAnulty
- UCL Respiratory Centre for Inflammation and Tissue Repair, University College London, London, UK
| | - Gisli Jenkins
- Division of Respiratory Medicine, Nottingham City Hospital, University of Nottingham, Nottingham, UK
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Caffeine Mitigates Lung Inflammation Induced by Ischemia-Reperfusion of Lower Limbs in Rats. Mediators Inflamm 2015; 2015:361638. [PMID: 26648663 PMCID: PMC4663348 DOI: 10.1155/2015/361638] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Revised: 10/28/2015] [Accepted: 11/04/2015] [Indexed: 12/21/2022] Open
Abstract
Reperfusion of ischemic limbs can induce inflammation and subsequently cause acute lung injury. Caffeine, a widely used psychostimulant, possesses potent anti-inflammatory capacity. We elucidated whether caffeine can mitigate lung inflammation caused by ischemia-reperfusion (IR) of the lower limbs. Adult male Sprague-Dawley rats were randomly allocated to receive IR, IR plus caffeine (IR + Caf group), sham-operation (Sham), or sham plus caffeine (n = 12 in each group). To induce IR, lower limbs were bilaterally tied by rubber bands high around each thigh for 3 hours followed by reperfusion for 3 hours. Caffeine (50 mg/kg, intraperitoneal injection) was administered immediately after reperfusion. Our histological assay data revealed characteristics of severe lung inflammation in the IR group and mild to moderate characteristic of lung inflammation in the IR + Caf group. Total cells number and protein concentration in bronchoalveolar lavage fluid of the IR group were significantly higher than those of the IR + Caf group (P < 0.001 and P = 0.008, resp.). Similarly, pulmonary concentrations of inflammatory mediators (tumor necrosis factor-α, interleukin-1β, and macrophage inflammatory protein-2) and pulmonary myeloperoxidase activity of the IR group were significantly higher than those of the IR + Caf group (all P < 0.05). These data clearly demonstrate that caffeine could mitigate lung inflammation induced by ischemia-reperfusion of the lower limbs.
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Domitrović R, Potočnjak I. A comprehensive overview of hepatoprotective natural compounds: mechanism of action and clinical perspectives. Arch Toxicol 2015; 90:39-79. [DOI: 10.1007/s00204-015-1580-z] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2015] [Accepted: 08/11/2015] [Indexed: 12/22/2022]
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Li T, Niu L, Li M, Liu Y, Xu Z, Gao X, Liu D. Effects of small interfering RNA-mediated downregulation of the Krüppel-like factor 4 gene on collagen metabolism in human hepatic stellate cells. Mol Med Rep 2015; 12:3972-3978. [PMID: 26018498 DOI: 10.3892/mmr.2015.3848] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Accepted: 05/01/2015] [Indexed: 11/06/2022] Open
Abstract
The nuclear transcription factor Krüppel-like factor 4 (KLF4) has an important role in cellular biological processes. However, the influence of KLF4 on collagen metabolism remains to be elucidated. In the present study, the effects and underlying mechanism of action of KLF4 on collagen metabolism was investigated in human hepatic stellate cells (HSC), by downregulating KLF4 expression using small interfering RNA (siRNA). The effects of KLF4 silencing by three predesigned siRNAs (siRNA1‑3) were evaluated using both reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and western blotting in the human LX2 HSC line. The mRNA expression levels of KLF4 were decreased by ~34, 40, and 69% in the siRNA1, siRNA2, and siRNA3 groups, respectively, as compared with the control group. These results were concordant with the protein expression levels of KLF4, as determined by western blot analysis. In the siRNA3 group, the quantity of type Ⅰ and type III collagen, and the expression levels of collagen metabolism proteins including matrix metalloproteinase‑1 (MMP‑1) and tissue inhibitors of metalloproteinases‑1 (TIMP‑1), were determined using both RT‑qPCR and western blotting. Both the mRNA and protein expression levels of type I and type III collagen were significantly decreased in the siRNA3 group, as compared with the control group. The mRNA and protein expression levels of TIMP‑1 were also significantly reduced in the siRNA3‑treated cells, whereas the mRNA and protein expression levels of MMP‑1 were significantly upregulated. Furthermore, KLF4 gene silencing significantly decreased the expression levels of numerous cytokines, including transforming grow factor‑β1, tumor necrosis factor‑α, and interleukin‑1β. The results of the present study provide evidence of siRNA‑mediated silencing of KLF4 expression, which may promote extracellular matrix (ECM) degradation, and inhibition of ECM synthesis. Therefore, KLF4 may be a promising target for the development of novel antifibrotic therapies.
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Affiliation(s)
- Tao Li
- Department of Epidemiology and Health Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Lijuan Niu
- Department of Oncology, The Third Hospital of Shijiazhuang, Shijiazhuang, Hebei 050000, P.R. China
| | - Man Li
- Department of Epidemiology and Health Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Ying Liu
- Department of Epidemiology and Health Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Zhengrong Xu
- Department of Epidemiology and Health Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Xia Gao
- Department of Epidemiology and Health Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Dianwu Liu
- Department of Epidemiology and Health Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
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Bi J, Ge S. Potential roles of BMP9 in liver fibrosis. Int J Mol Sci 2014; 15:20656-67. [PMID: 25393508 PMCID: PMC4264188 DOI: 10.3390/ijms151120656] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2014] [Revised: 10/13/2014] [Accepted: 11/04/2014] [Indexed: 02/07/2023] Open
Abstract
Liver fibrosis is a common phenomenon that is associated with several pathologies and is characterized by excessive extracellular matrix deposition that leads to progressive liver dysfunction. Bone morphogenetic protein 9 (BMP9) is the most recently discovered member of the BMP family. BMP9 bound with high affinity to activin receptor-like kinase 1 (ALK1) and endoglin in non-parenchymal liver cells. In addition, BMP9 activated Smad1/Smad5/Smad8 and induced the expression of the target genes inhibitor of differentiation 1 (Id1), hepcidin, Snail and the co-receptor endoglin in liver cells. Although the role of BMP9 in liver fibrosis is currently poorly understood, the presence of BMP9-activated proteins and its target genes have been reported to be associated with liver fibrosis development. This review summarizes the indirect connection between BMP9 and liver fibrosis, with a focus on the BMP9 signaling pathway members ALK1, endoglin, Id1, hepcidin and Snail. The observations on the role of BMP9 in regulating liver fibrosis may help in understanding the pathology mechanisms of liver disease. Furthermore, BMP9 could be served as a potent biomarker and the target of potential therapeutic drugs to treat hepatocytes fibrosis.
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Affiliation(s)
- Jianjun Bi
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
| | - Shengfang Ge
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
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Cui XF, Zhou WM, Yang Y, Zhou J, Li XL, Lin L, Zhang HJ. Epidermal growth factor upregulates serotonin transporter and its association with visceral hypersensitivity in irritable bowel syndrome. World J Gastroenterol 2014; 20:13521-13529. [PMID: 25309082 PMCID: PMC4188903 DOI: 10.3748/wjg.v20.i37.13521] [Citation(s) in RCA: 16] [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: 10/29/2013] [Revised: 03/10/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the role of epidermal growth factor (EGF) in visceral hypersensitivity and its effect on the serotonin transporter (SERT).
METHODS: A rat model for visceral hypersensitivity was established by intra-colonic infusion of 0.5% acetic acid in 10-d-old Sprague-Dawley rats. The visceral sensitivity was assessed by observing the abdominal withdrawal reflex and recording electromyographic activity of the external oblique muscle in response to colorectal distension. An enzyme-linked immunosorbent assay was used to measure the EGF levels in plasma and colonic tissues. SERT mRNA expression was detected by real-time PCR while protein level was determined by Western blot. The correlation between EGF and SERT levels in colon tissues was analyzed by Pearson’s correlation analysis. SERT function was examined by tritiated serotonin (5-HT) uptake experiments. Rat intestinal epithelial cells (IEC-6) were used to examine the EGF regulatory effect on SERT expression and function via the EGF receptor (EGFR).
RESULTS: EGF levels were significantly lower in the rats with visceral hypersensitivity as measured in plasma (2.639 ± 0.107 ng/mL vs 4.066 ± 0.573 ng/mL, P < 0.01) and in colonic tissue (3.244 ± 0.135 ng/100 mg vs 3.582 ± 0.197 ng/100 mg colon tissue, P < 0.01) compared with controls. Moreover, the EGF levels were positively correlated with SERT levels (r = 0.820, P < 0.01). EGF displayed dose- and time-dependent increased SERT gene expressions in IEC-6 cells. An EGFR kinase inhibitor inhibited the effect of EGF on SERT gene upregulation. SERT activity was enhanced following treatment with EGF (592.908 ± 31.515 fmol/min per milligram vs 316.789 ± 85.652 fmol/min per milligram protein, P < 0.05) and blocked by the EGFR kinase inhibitor in IEC-6 cells (590.274 ± 25.954 fmol/min per milligram vs 367.834 ± 120.307 fmol/min per milligram protein, P < 0.05).
CONCLUSION: A decrease in EGF levels may contribute to the formation of visceral hypersensitivity through downregulation of SERT-mediated 5-HT uptake into enterocytes.
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Tang W, Jiang YF, Ponnusamy M, Diallo M. Role of Nrf2 in chronic liver disease. World J Gastroenterol 2014; 20:13079-13087. [PMID: 25278702 PMCID: PMC4177487 DOI: 10.3748/wjg.v20.i36.13079] [Citation(s) in RCA: 174] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2014] [Revised: 05/08/2014] [Accepted: 05/26/2014] [Indexed: 02/06/2023] Open
Abstract
Nuclear erythroid 2-related factor 2 (Nrf2) is a central regulator of antioxidative response elements-mediated gene expression. It has a significant role in adaptive responses to oxidative stress by interacting with the antioxidant response element, which induces the expression of a variety of downstream targets aimed at cytoprotection. Previous studies suggested oxidative stress and associated damage could represent a common link between different forms of diseases. Oxidative stress has been implicated in various liver diseases, including viral hepatitis, nonalcoholic fatty liver disease/steatohepatitis, alcoholic liver disease and drug-induced liver injury. Nrf2 activation is initiated by oxidative or electrophilic stress, and aids in the detoxification and elimination of potentially harmful exogenous chemicals and their metabolites. The expression of Nrf2 has been observed throughout human tissue, with high expression in detoxification organs, especially the liver. Thus, Nrf2 may serve as a major regulator of several cellular defense associated pathways by which hepatic cells combat oxidative stress. We review the relevant literature concerning the crucial role of Nrf2 and its signaling pathways against oxidative stress to protect hepatic cell from oxidative damage during development of common chronic liver diseases. We also review the use of Nrf2 as a therapeutic target to prevent and treat liver diseases.
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Maotai ameliorates diethylnitrosamine-initiated hepatocellular carcinoma formation in mice. PLoS One 2014; 9:e93599. [PMID: 24690765 PMCID: PMC3972115 DOI: 10.1371/journal.pone.0093599] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2013] [Accepted: 03/04/2014] [Indexed: 12/20/2022] Open
Abstract
Consumption of alcohol is closely related to liver disease, such as hepatic fibrosis or even hepatocellular carcinoma (HCC). However, epidemiological and experimental studies indicated that consumption of Maotai, one of the famous liquors in China, exhibits no significant correlation with hepatic fibrosis or cirrhosis as other beverage sources do. This study detected the relationship of Maotai consumption and HCC development in a diethylnitrosamine (DEN)-initiated HCC animal model. DEN was given to mice at a dose of 100 mg/kg, ip, and 50 mg/kg, ip in the following week. Mice were simultaneously given Maotai or an equal amount of ethanol (53%, 5 ml/kg/day, 5days/week for up to 35weeks). At 3-week and 35- week of the experiment, serum and livers were collected for biochemical and histopathological examination of liver injury and incidence of HCC. Real-time RT-PCR, immunohistochemistry and Western blotting were used to examine the expression of metallothionein-1/2 (MT-1/2), NF-E2-related factor 2 (Nrf2), glutamate-cysteine ligase catalytic subunit (GCLC) and modified subunit (GCLM). We identified tissue damage and dysfunction of liver in ethanol + DEN-treated mice, whereas the extent of injury was reduced in Maotai+ DEN –treated mice. Significant Glypican-3(GPC3) expression and precancerous injury or HCC were seen in approximately 50% of mice with ethanol+ DEN, but barely be seen in Maotai + DEN-treated mice. A higher expression of MT-1/2, Nrf2 and GCLC could be seen in Maotai + DEN-treated mice. Thus, Maotai liquor ameliorates the formation of DEN-induced HCC in mice, and the protection mechanism is possibly related with the activation of anti-oxidation factors, such as MTs, Nrf2 and GCLC.
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