|
1
|
Sun S, Zhang G, Lv S, Sun J. Potential mechanisms of traditional Chinese medicine in the treatment of liver cirrhosis: a focus on gut microbiota. Front Microbiol 2024; 15:1407991. [PMID: 39234554 PMCID: PMC11371771 DOI: 10.3389/fmicb.2024.1407991] [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: 03/27/2024] [Accepted: 07/29/2024] [Indexed: 09/06/2024] Open
Abstract
Cirrhosis, a pathological stage that develops from various chronic liver diseases, is characterized by liver fibrosis, pseudolobular formation, and chronic inflammation. When it progresses to the decompensated phase, the mortality rate of cirrhosis can reach 80%. The role of gut microbiota in the progression of liver diseases has received significant attention. Numerous studies have shown that regulating gut microbiota has significant therapeutic effects on preventing and reversing liver cirrhosis. This article reviewed the mechanisms by which gut microbiota influence liver cirrhosis, explaining the effective therapeutic effects of traditional Chinese medicine. Through multi-directional regulation involving signaling pathways, gut microbiota diversity, and restoration of intestinal barrier function, traditional Chinese medicine has been promising in ameliorating liver cirrhosis, providing treatment options and pharmacological guidance for the occurrence and development of liver cirrhosis.
Collapse
Affiliation(s)
- Siyuan Sun
- First Clinical Medical College, Beijing University of Chinese Medicine, Beijing, China
| | - Guangheng Zhang
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Shimeng Lv
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Jinhui Sun
- Gastroenterology Department, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| |
Collapse
|
|
2
|
Das SK, Nerune SM, Das KK. Antioxidant therapy for hepatic diseases: a double-edged sword. J Basic Clin Physiol Pharmacol 2024; 35:7-14. [PMID: 38234261 DOI: 10.1515/jbcpp-2023-0156] [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: 06/20/2023] [Accepted: 01/02/2024] [Indexed: 01/19/2024]
Abstract
Liver diseases are complex conditions, significantly influenced by oxidative stress. This comprehensive review assesses the therapeutic role of antioxidants like l-ascorbic acid and α tocopherol, beta-carotene, various minerals, and plant-based ingredients in mitigating oxidative stress-induced liver diseases. The manuscript delves into the critical influence of genetic and epigenetic factors on disease susceptibility, progression, and response to antioxidant therapy. While animal studies suggest antioxidant efficacy in liver disease treatment, human trials remain inconclusive, and caution is advised due to its possible potential pro-oxidant effects. Moreover, the interactions of antioxidants with other drugs necessitate careful consideration in the management of polypharmacy in liver disease patients. The review underscores the need for further research to establish the clinical benefits of antioxidants with understanding of possible antioxidant toxicities to elucidate the intricate interplay of genetic, epigenetic, and environmental factors in liver diseases. The aim is to foster a better understanding of the knowledge on hepatic disease management with judicial antioxidant therapies.
Collapse
Affiliation(s)
- Sayandeep K Das
- Department of Pathology, Shri B. M. Patil Medical College, Hospital and Research Centre, BLDE (Deemed to be University), Vijayapur, Karnataka, India
| | - Savitri M Nerune
- Department of Pathology, Shri B. M. Patil Medical College, Hospital and Research Centre, BLDE (Deemed to be University), Vijayapur, Karnataka, India
| | - Kusal K Das
- Laboratory of Vascular Physiology and Medicine, Department of Physiology, Shri B. M. Patil Medical College, Hospital and Research Centre, BLDE (Deemed to be University), Vijayapur, Karnataka, India
| |
Collapse
|
|
3
|
Glal KAM, El-Haggar SM, Abdel-Salam SM, Mostafa TM. Allopurinol Prevents Cirrhosis-Related Complications: A Quadruple Blind Placebo-Controlled Trial. Am J Med 2024; 137:55-64. [PMID: 37832758 DOI: 10.1016/j.amjmed.2023.09.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Revised: 09/06/2023] [Accepted: 09/19/2023] [Indexed: 10/15/2023]
Abstract
BACKGROUND Complications associated with liver cirrhosis are various and potentially fatal. The treatment options to counteract hepatic decompensation are limited. Therefore, the study aimed to explore the use of allopurinol in preventing the recurrence of liver cirrhosis-related complications. METHODS One hundred patients with hepatic decompensation were randomized into 1:1 ratio to receive either allopurinol 300 mg or placebo tablets once daily for 6 months. The primary endpoint was the incidence of cirrhosis-related complications (overt ascites, spontaneous bacterial peritonitis, variceal bleeding, hepatorenal syndrome, and hepatic encephalopathy). RESULTS Six months following treatment, allopurinol reduced the relative risk (RR) of any first complication experienced after enrollment by 56% (hazard ratio [HR] 0.44; 95% confidence interval [CI], 0.27-0.62); P ˂ .001). Allopurinol decreased the RR of overt ascites by 67% (HR 0.33; 95% CI, 0.0098-0.94); P = .039] and reduced the RR of spontaneous bacterial peritonitis by about 75% (HR 0.25; 95% CI, 0.05-0.76; P = .01). Likewise, allopurinol was linked to an 80% reduction in the RR of developing hepatorenal syndrome (HR 0.2; 95% CI, 0.04-0.87; P = .033). CONCLUSION Allopurinol significantly decreased the recurrence of overall liver cirrhosis-related complications. Therefore, allopurinol may constitute a promising agent for patients with hepatic decompensation. These positive outcomes could be a result of its ability to reduce bacterial translocation and inflammation. CLINICALTRIALS GOV IDENTIFIER NCT005545670.
Collapse
Affiliation(s)
| | | | - Sherief M Abdel-Salam
- Department of Tropical Medicine and Infectious Diseases, Faculty of Medicine, Tanta University, Tanta, Egypt
| | | |
Collapse
|
|
4
|
Zhou Z, Ryan J, Nelson MR, Woods RL, Orchard SG, Zhu C, Gilmartin-Thomas JFM, Fravel MA, Owen AJ, Murray AM, Espinoza SE, Ernst ME. The association of allopurinol with persistent physical disability and frailty in a large community based older cohort. J Am Geriatr Soc 2023; 71:2798-2809. [PMID: 37158186 PMCID: PMC10524392 DOI: 10.1111/jgs.18395] [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: 11/23/2022] [Revised: 03/12/2023] [Accepted: 04/12/2023] [Indexed: 05/10/2023]
Abstract
BACKGROUND The protective effects of allopurinol on physical function in older adults are not well understood, despite its potential to improve functional gains and reduce sarcopenia. This study aims to determine the association between allopurinol, persistent physical disability, and frailty in older gout patients. METHODS This analysis used data from a randomized trial in an older cohort, ASPirin in Reducing Events in the Elderly (ASPREE). ASPREE recruited 19,114 participants aged ≥65 years without prior cardiovascular events, dementia, or independence-limiting physical disability at trial enrolment. This analysis examined the association of baseline and time-varying allopurinol use with persistent physical disability and new-onset frailty in participants with gout at baseline (self-report or use of any anti-gout medications). Frailty was measured using the Fried frailty phenotype (score ≥3/5) and a deficit accumulation frailty index (FI) (score >0.21/1.0). Multivariable Cox proportional-hazards models were used for main analyses. RESULTS This analysis included 1155 gout participants, with 630 taking allopurinol at baseline and 525 not. During a median follow-up of 5.7 years, 113 new allopurinol users were identified. Compared with nonusers, baseline allopurinol use was associated with a significant risk reduction of persistent physical disability (Adjusted HR 0.46, 95% CI 0.23-0.92, p = 0.03). The strength of the association was modestly attenuated in the time-varying analysis (Adjusted HR 0.56, 0.29-1.08, p = 0.08). No significant associations with frailty measures were observed for either baseline allopurinol use (Fried frailty: Adjusted HR 0.83, 0.62-1.12; FI: Adjusted HR 0.96, 0.74-1.24) or time-varying allopurinol use (Fried frailty: Adjusted HR 0.92, 0.69-1.24; FI: Adjusted HR 1.02, 0.78-1.33). CONCLUSIONS Allopurinol use in older adults with gout is associated with a reduced risk of persistent physical disability but not associated with risk of frailty.
Collapse
Affiliation(s)
- Zhen Zhou
- Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia
- School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia
| | - Joanne Ryan
- School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia
| | - Mark R. Nelson
- Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia
| | - Robyn L. Woods
- School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia
| | - Suzanne G. Orchard
- School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia
| | - Chao Zhu
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, Australia
| | - Julia F-M Gilmartin-Thomas
- School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia
- Institute for Health & Sport, Victoria University, VIC, Australia
- Australian Institute for Musculoskeletal Science, VIC, Australia
| | - Michelle A. Fravel
- Department of Pharmacy Practice and Science, College of Pharmacy, The University of Iowa, Iowa, IA, USA
| | - Alice J. Owen
- School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia
| | - Anne M. Murray
- Berman Center for Outcomes & Clinical Research, Hennepin HealthCare Research Institute, and Department of Medicine, Geriatrics Division, Hennepin Healthcare, Minneapolis, MN, USA
| | - Sara E. Espinoza
- University of Texas Health Science Center and Geriatric Research, Education & Clinical Center, San Antonio and South Texas Veterans Health Care System, San Antonio, TX, USA
| | - Michael E. Ernst
- Department of Pharmacy Practice and Science, College of Pharmacy, The University of Iowa, Iowa, IA, USA
- Department of Family Medicine, Carver College of Medicine, The University of Iowa, Iowa, IA, USA
| |
Collapse
|
|
5
|
Balzano T, Llansola M, Arenas YM, Izquierdo-Altarejos P, Felipo V. Hepatic encephalopathy: investigational drugs in preclinical and early phase development. Expert Opin Investig Drugs 2023; 32:1055-1069. [PMID: 37902074 DOI: 10.1080/13543784.2023.2277386] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 10/26/2023] [Indexed: 10/31/2023]
Abstract
INTRODUCTION Hepatic encephalopathy (HE) is a neuropsychiatric syndrome, in patients with liver disease, which affects life quality and span. Current treatments are lactulose or rifaximin, acting on gut microbiota. Treatments aiming ammonia levels reduction have been tested with little success. AREAS COVERED Pre-clinical research shows that the process inducing HE involves sequentially: liver failure, altered microbiome, hyperammonemia, peripheral inflammation, changes in immunophenotype and extracellular vesicles and neuroinflammation, which alters neurotransmission impairing cognitive and motor function. HE may be reversed using drugs acting at any step: modulating microbiota with probiotics or fecal transplantation; reducing peripheral inflammation with anti-TNFα, autotaxin inhibitors or silymarin; reducing neuroinflammation with sulforaphane, p38 MAP kinase or phosphodiesteras 5 inhibitors, antagonists of sphingosine-1-phosphate receptor 2, enhancing meningeal lymphatic drainage or with extracellular vesicles from mesenchymal stem cells; reducing GABAergic neurotransmission with indomethacin or golexanolone. EXPERT OPINION A factor limiting the progress of HE treatment is the lack of translation of research advances into clinical trials. Only drugs acting on microbiota or ammonia reduction have been tested in patients. It is urgent to change the mentality on how to approach HE treatment to develop clinical trials to assess drugs acting on the immune system/peripheral inflammation, neuroinflammation or neurotransmission to improve HE.
Collapse
Affiliation(s)
- Tiziano Balzano
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain
- HM CINAC (Centro Integral de Neurociencias Abarca Campal), Hospital Universitario HM Puerta del Sur, HM Hospitales, Madrid, Spain
| | - Marta Llansola
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain
| | - Yaiza M Arenas
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain
- Departamento de Patología, Facultad de Medicina, Universidad Valencia, Valencia, Spain
| | | | - Vicente Felipo
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain
| |
Collapse
|
|
6
|
Rusticeanu M, Zimmer V, Lammert F. Visualising and quantifying intestinal permeability -where do we stand. Ann Hepatol 2022; 23:100266. [PMID: 33045414 DOI: 10.1016/j.aohep.2020.09.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 09/20/2020] [Accepted: 09/20/2020] [Indexed: 02/04/2023]
Abstract
Intestinal permeability is getting more and more attention in gastrointestinal research. Although well recognized, its exact role in health and disease is yet to be defined. There are many methods of quantifying intestinal permeability, but most of them fail to deliver tangible information about the morphological integrity of the intestinal barrier. In this review we aim to describe imaging options for the assessment of intestinal barrier integrity and their potential relevance for clinical practice. Our focus is on confocal laser endomicroscopy, which is at this time the only method for visualizing not only functional but also morphological aspects of the gut barrier in vivo.
Collapse
Affiliation(s)
- Monica Rusticeanu
- Department of Medicine, Krankenhaus Vilshofen, Krankenhausstrasse 32, 94474 Vislhofen an der Donau, Germany.
| | - Vincent Zimmer
- Department of Medicine, Marienhausklinik St. Josef Kohlhof, Klinikweg 1-5, 66539 Neunkirchen, Germany; Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany.
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany.
| |
Collapse
|
|
7
|
Wang Z, Wang Q, Gong L, Liu T, Wang P, Yuan Z, Wang W. The NF-κB-regulated miR-221/222/syndecan-1 axis restores intestinal mucosal barrier function in radiation enteritis. Int J Radiat Oncol Biol Phys 2022; 113:166-176. [PMID: 35033585 DOI: 10.1016/j.ijrobp.2022.01.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Revised: 12/15/2021] [Accepted: 01/07/2022] [Indexed: 11/28/2022]
Abstract
PURPOSE Radiation enteritis (RE) is the most common complication of pelvic radiotherapy, but proven therapies are lacking. Barrier function defects are closely associated with numerous inflammatory disorders. In this study, we investigated whether barrier dysfunction contributes to RE and whether syndecan-1 (Sdc1) protects intestinal barrier function in RE. The mechanism was also elucidated. MATERIALS AND METHODS Blood, urine, and tissue samples were collected from 21 patients with cervical cancer who experienced RE during radiotherapy and used to detect inflammatory responses and barrier function. The role of Sdc1 in barrier function was examined in cultured fetal human colon (FHC) cells exposed to radiation and an induced mouse RE model. Barrier function was determined by zonula occludens (ZO)-1 and occludin expression, transepithelial electrical resistance (TEER), and FITC-dextran (FD4) flux. The role of the nuclear factor (NF)-κB-P65 pathway was detected by Western blotting and chromatin immunoprecipitation. The role of miR-221/222 was assessed by real-time PCR and luciferase reporter assays. RESULTS Patients with RE exhibited obvious pathological and ultra-microstructural inflammatory injury and barrier disruption in the intestinal mucosa, as well as higher serum lipopolysaccharide (LPS), LPS-binding protein, and cytokine levels and a higher urine lactulose/mannitol ratio. Sdc1 overexpression in irradiated FHC cells reversed TEER suppression, repressed FD4 flux, and upregulated ZO-1 and occludin expression. Exogenous low-molecular-weight heparin supplementation in RE mice ameliorated the activity of enteritis and barrier defects. Mechanistically, irradiation-activated P65 increased the transcription of miR-221/222 via direct binding to their promoter regions, and miR-221/222 then post-transcriptionally suppressed the Sdc1 gene by binding to its 3'-untranslated region. CONCLUSIONS Sdc1 protects barrier function and controls inflammation during RE under transcriptional regulation by the NF-κB pathway and miR-221/222. The network including NF-κB, miR-221/222, and Sdc1 is important in the pathogenesis of RE. Sdc1 might represent a therapeutic target for novel anti-RE strategies.
Collapse
Affiliation(s)
- Zhongqiu Wang
- Department of Radiation Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, West Huanhu Road, West River District, Tianjin 300060, China.
| | - Qingxin Wang
- Department of Radiation Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, West Huanhu Road, West River District, Tianjin 300060, China; School of Precision Instruments and Optoelectronics Engineering, Tianjin University, Nankai District, Tianjin, 300073, China
| | - Linlin Gong
- Department of Radiation Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, West Huanhu Road, West River District, Tianjin 300060, China
| | - Tao Liu
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China
| | - Peiguo Wang
- Department of Radiation Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, West Huanhu Road, West River District, Tianjin 300060, China
| | - Zhiyong Yuan
- Department of Radiation Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, West Huanhu Road, West River District, Tianjin 300060, China
| | - Wei Wang
- Department of Radiation Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, West Huanhu Road, West River District, Tianjin 300060, China.
| |
Collapse
|
|
8
|
4-Acetylantroquinonol B ameliorates nonalcoholic steatohepatitis by suppression of ER stress and NLRP3 inflammasome activation. Biomed Pharmacother 2021; 138:111504. [PMID: 33773468 DOI: 10.1016/j.biopha.2021.111504] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 03/09/2021] [Accepted: 03/11/2021] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVE Nonalcoholic fatty liver disease (NAFLD) is an inflammatory lipotoxic disorder with a prevalence of over 25% worldwide. However, safe and effective therapeutic agents for the management of NAFLD are still lacking. We aimed to investigate the hepatoprotective effect and molecular mechanism of 4-acetylantroquinonol B (4-AAQB), a natural ubiquinone derivative obtained from the mycelia of Antrodia cinnamomea. METHODS RAW264.7 and J774A.1 cells were treated with 4-AAQB and then stimulated with LPS or tunicamycin (TM) for 24 h. Inflammatory responses, markers of endoplasmic reticulum (ER) stress, and NOD-like receptor protein 3 (NLRP3) inflammasome were analyzed in both cell lines. In the applied in vivo model, male C57BL/6J mice were fed with chow or a methionine/choline-deficient (MCD) diet along with vehicle or 4-AAQB (10 mg/kg, i.p. injected, once a day) for 10 consecutive days. Plasma levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured. Liver tissues were analyzed using histological techniques; protein levels involved in ER stress, NLRP3 inflammasome, and inflammatory responses were measured. RESULTS 4-AAQB significantly ameliorated the plasma levels of ALT and AST as well as the NAFLD activity score (NAS) in mice fed the MCD diet. In addition, 4-AAQB suppressed inflammatory responses, ER stress, and NLRP3 inflammasome activation, but increased the nuclear factor erythroid 2-related factor 2 (Nrf2) and Sirtuin 1 (SIRT1) signaling pathways in both in vitro and in vivo models. CONCLUSIONS We suggest that 4-AAQB treatment might be a tangible therapeutic strategy in the management of NAFLD/NASH.
Collapse
|
|
9
|
Bai M, Wang L, Liu H, Xu K, Deng J, Huang R, Yin Y. Imbalanced dietary methionine-to-sulfur amino acid ratio can affect amino acid profiles, antioxidant capacity, and intestinal morphology of piglets. ACTA ACUST UNITED AC 2020; 6:447-456. [PMID: 33364461 PMCID: PMC7750798 DOI: 10.1016/j.aninu.2020.03.009] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2019] [Revised: 03/15/2020] [Accepted: 03/16/2020] [Indexed: 12/24/2022]
Abstract
Animal protein sources such as fishmeal and plasma powder are excellent and indispensable sources of energy, amino acids, and minerals in animal production. Amino acid imbalance, especially methionine-to-sulfur amino acid (Met:SAA) ratio, caused by an imbalance of animal protein meal leads to growth restriction. This study was conducted to evaluate the effects of imbalanced Met:SAA ratio supplementation of different animal protein source diets on growth performance, plasma amino acid profiles, antioxidant capacity and intestinal morphology in a piglet model. Twenty-four weaned piglets (castrated males; BW = 10.46 ± 0.34 kg), assigned randomly into 3 groups (8 piglets/group), were fed for 28 d. Three experimental diets of equal energy and crude protein levels were as follows: 1) a corn-soybean basal diet with a Met:SAA ratio at 0.51 (BD); 2) a plasma powder diet with a low Met:SAA ratio at 0.41 (L-MR); 3) a fishmeal diet with a high Met:SAA ratio at 0.61 (H-MR). Results revealed that compared to BD, L-MR significantly decreased (P < 0.05) the activities of plasma total antioxidant capacity and glutathione peroxidase, plasma amino acid profiles, and significantly reduced (P < 0.05) villus height and crypt depth in the duodenum and jejunum. Additionally, L-MR significantly reduced (P < 0.05) the mRNA expression level of solute carrier family 7 member 9 (SlC7A9) in the ileum, and significantly increased (P < 0.05) mRNA expression levels of zonula occludens-1 (ZO-1) in the duodenum, and Claudin-1, ZO-1, sodium-coupled neutral amino acid transporters 2 (SNAT2) and SlC7A7 in the jejunum. H-MR significantly increased (P < 0.05) plasma SAA levels, and significantly reduced (P < 0.05) average daily feed intake, villus height, and villus height-to-crypt depth (VH:CD) ratio in the ileum compared to BD. In conclusion, L-MR may result in oxidative stress and villous atrophy but proves beneficial in improving intestinal barrier function and the activity of amino acid transporters for compensatory growth. H-MR may impair intestinal growth and development for weaned piglets. The research provides a guidance on the adequate Met:SAA ratio (0.51) supplementation in diet structure for weaned piglets.
Collapse
Affiliation(s)
- Miaomiao Bai
- College of Animal Science, South China Agricultural University, Guangzhou 510642, China.,Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Key Laboratory of Agro-ecological Processes in Subtropical Region, Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
| | - Lei Wang
- Laboratory of Animal Nutrition and Human Health, Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, College of Life Science, Hunan Normal University, Changsha 410081, China
| | - Hongnan Liu
- Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Key Laboratory of Agro-ecological Processes in Subtropical Region, Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China.,Hunan Co-Innovation Center of Safety Animal Production (CICSAP), Changsha 410128, China
| | - Kang Xu
- Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Key Laboratory of Agro-ecological Processes in Subtropical Region, Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China.,Hunan Co-Innovation Center of Safety Animal Production (CICSAP), Changsha 410128, China
| | - Jinping Deng
- College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Ruilin Huang
- Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Key Laboratory of Agro-ecological Processes in Subtropical Region, Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China.,Hunan Co-Innovation Center of Safety Animal Production (CICSAP), Changsha 410128, China
| | - Yulong Yin
- College of Animal Science, South China Agricultural University, Guangzhou 510642, China.,Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Key Laboratory of Agro-ecological Processes in Subtropical Region, Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China.,Laboratory of Animal Nutrition and Human Health, Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, College of Life Science, Hunan Normal University, Changsha 410081, China.,Hunan Co-Innovation Center of Safety Animal Production (CICSAP), Changsha 410128, China
| |
Collapse
|
|
10
|
Menini S, Iacobini C, Vitale M, Pugliese G. The Inflammasome in Chronic Complications of Diabetes and Related Metabolic Disorders. Cells 2020; 9:E1812. [PMID: 32751658 PMCID: PMC7464565 DOI: 10.3390/cells9081812] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 07/24/2020] [Accepted: 07/28/2020] [Indexed: 12/14/2022] Open
Abstract
Diabetes mellitus (DM) ranks seventh as a cause of death worldwide. Chronic complications, including cardiovascular, renal, and eye disease, as well as DM-associated non-alcoholic fatty liver disease (NAFLD) account for most of the morbidity and premature mortality in DM. Despite continuous improvements in the management of late complications of DM, significant gaps remain. Therefore, searching for additional strategies to prevent these serious DM-related conditions is of the utmost importance. DM is characterized by a state of low-grade chronic inflammation, which is critical in the progression of complications. Recent clinical trials indicate that targeting the prototypic pro-inflammatory cytokine interleukin-1β (IL-1 β) improves the outcomes of cardiovascular disease, which is the first cause of death in DM patients. Together with IL-18, IL-1β is processed and secreted by the inflammasomes, a class of multiprotein complexes that coordinate inflammatory responses. Several DM-related metabolic factors, including reactive oxygen species, glyco/lipoxidation end products, and cholesterol crystals, have been involved in the pathogenesis of diabetic kidney disease, and diabetic retinopathy, and in the promoting effect of DM on the onset and progression of atherosclerosis and NAFLD. These metabolic factors are also well-established danger signals capable of regulating inflammasome activity. In addition to presenting the current state of knowledge, this review discusses how the mechanistic understanding of inflammasome regulation by metabolic danger signals may hopefully lead to novel therapeutic strategies targeting inflammation for a more effective treatment of diabetic complications.
Collapse
Affiliation(s)
| | | | | | - Giuseppe Pugliese
- Department of Clinical and Molecular Medicine, “La Sapienza” University, 00189 Rome, Italy; (S.M.); (C.I.); (M.V.)
| |
Collapse
|
|
11
|
Beyond urate lowering: Analgesic and anti-inflammatory properties of allopurinol. Semin Arthritis Rheum 2020; 50:444-450. [DOI: 10.1016/j.semarthrit.2019.11.009] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 10/30/2019] [Accepted: 11/08/2019] [Indexed: 01/09/2023]
|
|
12
|
Rahmat A, Ahmad NSS, Ramli NS. Parsley (Petroselinum crispum) supplementation attenuates serum uric acid level and improves liver and kidney structures in oxonate-induced hyperuricemic rats. ACTA ACUST UNITED AC 2018. [DOI: 10.1007/s13596-018-0353-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
|
|
13
|
Ding Y, Wang L, Song J, Zhou S. Protective effects of ellagic acid against tetrachloride-induced cirrhosis in mice through the inhibition of reactive oxygen species formation and angiogenesis. Exp Ther Med 2017; 14:3375-3380. [PMID: 29042921 PMCID: PMC5639323 DOI: 10.3892/etm.2017.4966] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2015] [Accepted: 12/09/2016] [Indexed: 12/13/2022] Open
Abstract
Ellagic acid has been proven to have anticancer, antimutation, antimicrobial and antiviral functions. The present study investigated whether treatment with ellagic acid was able to prevent tetrachloride (CCl4)-induced cirrhosis through the inhibition of reactive oxygen species (ROS) formation and angiogenesis. CCl4 diluted in olive oil at a final concentration of 10% was used to induce a cirrhosis model. A total of 40 mice were random allocated into four groups, as follows: Control, cirrhosis model, 7.5 mg/kg ellagic acid and 15 mg/kg ellagic acid groups. In the control group, mice were given normal saline. The results indicated that ellagic acid exerted a protective effect, evidently preventing CCl4-induced cirrhosis. In addition, treatment with ellagic acid significantly inhibited collagen I and inducible nitric oxide synthase protein expression levels in CCl4-induced cirrhosis mice. Oxidative stress and ROS formation were also significantly reduced by ellagic acid treatment. The protein expression levels of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2), and the caspase-3 activity were significantly inhibited by treatment with ellagic acid. In conclusions, these results suggest that ellagic acid exerted protective effects against CCl4-induced cirrhosis through the inhibition of ROS formation and angiogenesis.
Collapse
Affiliation(s)
- Yuan Ding
- Department of Interventional Radiology, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
| | - Lizhou Wang
- Department of Interventional Radiology, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
| | - Jie Song
- Department of Interventional Radiology, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
| | - Shi Zhou
- Department of Interventional Radiology, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
| |
Collapse
|
|
14
|
Prymont-Przyminska A, Bialasiewicz P, Zwolinska A, Sarniak A, Wlodarczyk A, Markowski J, Rutkowski KP, Nowak D. Addition of strawberries to the usual diet increases postprandial but not fasting non-urate plasma antioxidant activity in healthy subjects. J Clin Biochem Nutr 2016; 59:191-198. [PMID: 27895386 PMCID: PMC5110932 DOI: 10.3164/jcbn.15-113] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2015] [Accepted: 01/05/2016] [Indexed: 11/22/2022] Open
Abstract
Strawberries can augment plasma antioxidant activity, but this may be confounded by selection of methods, time of blood sampling and concomitant dietary restrictions. We examined the effect of strawberry consumption on ferric reducing ability (FRAP) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity (DPPH-test) of native and non-urate plasma in healthy subjects on their usual diet. Eleven subjects consumed strawberries (500 g daily) for 9 days. Fasting and 3-h postprandial plasma and 24-h urine collection were obtained before, during and after strawberry course for FRAP, DPPH-test and polyphenols determination. Fifteen subjects served as a control in respect to plasma antioxidant activity changes and effect of 300 mg of oral ascorbate. First, 5th and 9th strawberry dose increased 3-h postprandial DPPH-test by 17.4, 17.6 and 12.6%, and FRAP by 15.5, 25.6 and 21.4% in comparison to fasting values in non-urate plasma (p<0.05). In native plasma only a trend was observed to higher postprandial values for both tests. Strawberries increased urinary urolithin A and 4-hydroxyhippuric acid whereas plasma polyphenols were stable. No changes of FRAP and DPPH-test were noted in controls and after ascorbate intake. Strawberries transiently increased non-urate plasma antioxidant activity but this cannot be attributed to direct antioxidant effect of polyphenols and ascorbate.
Collapse
Affiliation(s)
| | - Piotr Bialasiewicz
- Department of Sleep Medicine and Metabolic Disorders, Medical University of Lodz, Lodz, Poland
| | - Anna Zwolinska
- Cell-to-Cell Communication Department, Medical University of Lodz, Lodz, Poland
| | - Agata Sarniak
- Department of General Physiology, Medical University of Lodz, Lodz, Poland
| | - Anna Wlodarczyk
- Department of Sleep Medicine and Metabolic Disorders, Medical University of Lodz, Lodz, Poland
| | - Jaroslaw Markowski
- Fruit Storage and Processing Department, Division of Pomology, Research Institute of Horticulture, Skierniewice, Poland
| | - Krzysztof P Rutkowski
- Fruit Storage and Processing Department, Division of Pomology, Research Institute of Horticulture, Skierniewice, Poland
| | - Dariusz Nowak
- Department of Clinical Physiology, Medical University of Lodz, Lodz, Poland
| |
Collapse
|
|
15
|
Catanzaro R, Zerbinati N, Solimene U, Marcellino M, Mohania D, Italia A, Ayala A, Marotta F. Beneficial effect of refined red palm oil on lipid peroxidation and monocyte tissue factor in HCV-related liver disease: a randomized controlled study. Hepatobiliary Pancreat Dis Int 2016; 15:165-172. [PMID: 27020633 DOI: 10.1016/s1499-3872(16)60072-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND A large amount of endotoxin can be detected in the peripheral venous blood of patients with liver cirrhosis, contributing to the pathogenesis of hepatotoxicity because of its role in oxidative stress. The present study aimed to test the effect of the supplementation with red palm oil (RPO), which is a natural oil obtained from oil palm fruit (Elaeis guineensis) rich in natural fat-soluble tocopherols, tocotrienols and carotenoids, on lipid peroxidation and endotoxemia with plasma endotoxin-inactivating capacity, proinflammatory cytokines profile, and monocyte tissue factor in patients with chronic liver disease. METHODS The study group consisted of sixty patients (34 males and 26 females; mean age 62 years, range 54-75) with Child A/B, genotype 1 HCV-related cirrhosis without a history of ethanol consumption, randomly enrolled into an 8-week oral daily treatment with either vitamin E or RPO. All patients had undergone an upper gastrointestinal endoscopy 8 months before, and 13 out of them showed esophageal varices. RESULTS Both treatments significantly decreased erythrocyte malondialdehyde and urinary isoprostane output, only RPO significantly affected macrophage-colony stimulating factor and monocyte tissue factor. Liver ultrasound imaging did not show any change. CONCLUSIONS RPO beneficially modulates oxidative stress and, not least, downregulates macrophage/monocyte inflammatory parameters. RPO can be safely advised as a valuable nutritional implementation tool in the management of chronic liver diseases.
Collapse
Affiliation(s)
- Roberto Catanzaro
- Department of Clinical and Experimental Medicine, Gastroenterology Section, University of Catania, Catania, Italy.
| | | | | | | | | | | | | | | |
Collapse
|
|
16
|
Li S, Tan HY, Wang N, Zhang ZJ, Lao L, Wong CW, Feng Y. The Role of Oxidative Stress and Antioxidants in Liver Diseases. Int J Mol Sci 2015; 16:26087-26124. [PMID: 26540040 PMCID: PMC4661801 DOI: 10.3390/ijms161125942] [Citation(s) in RCA: 1067] [Impact Index Per Article: 106.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2015] [Revised: 09/20/2015] [Accepted: 10/19/2015] [Indexed: 12/15/2022] Open
Abstract
A complex antioxidant system has been developed in mammals to relieve oxidative stress. However, excessive reactive species derived from oxygen and nitrogen may still lead to oxidative damage to tissue and organs. Oxidative stress has been considered as a conjoint pathological mechanism, and it contributes to initiation and progression of liver injury. A lot of risk factors, including alcohol, drugs, environmental pollutants and irradiation, may induce oxidative stress in liver, which in turn results in severe liver diseases, such as alcoholic liver disease and non-alcoholic steatohepatitis. Application of antioxidants signifies a rational curative strategy to prevent and cure liver diseases involving oxidative stress. Although conclusions drawn from clinical studies remain uncertain, animal studies have revealed the promising in vivo therapeutic effect of antioxidants on liver diseases. Natural antioxidants contained in edible or medicinal plants often possess strong antioxidant and free radical scavenging abilities as well as anti-inflammatory action, which are also supposed to be the basis of other bioactivities and health benefits. In this review, PubMed was extensively searched for literature research. The keywords for searching oxidative stress were free radicals, reactive oxygen, nitrogen species, anti-oxidative therapy, Chinese medicines, natural products, antioxidants and liver diseases. The literature, including ours, with studies on oxidative stress and anti-oxidative therapy in liver diseases were the focus. Various factors that cause oxidative stress in liver and effects of antioxidants in the prevention and treatment of liver diseases were summarized, questioned, and discussed.
Collapse
Affiliation(s)
- Sha Li
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
| | - Hor-Yue Tan
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
| | - Ning Wang
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
| | - Zhang-Jin Zhang
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
| | - Lixing Lao
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
| | - Chi-Woon Wong
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
| | - Yibin Feng
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
| |
Collapse
|
|
17
|
Wang W, Ding XQ, Gu TT, Song L, Li JM, Xue QC, Kong LD. Pterostilbene and allopurinol reduce fructose-induced podocyte oxidative stress and inflammation via microRNA-377. Free Radic Biol Med 2015; 83:214-26. [PMID: 25746774 DOI: 10.1016/j.freeradbiomed.2015.02.029] [Citation(s) in RCA: 107] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2014] [Revised: 02/08/2015] [Accepted: 02/23/2015] [Indexed: 02/07/2023]
Abstract
High dietary fructose is an important causative factor in the development of metabolic syndrome-associated glomerular podocyte oxidative stress and injury. Here, we identified microRNA-377 (miR-377) as a biomarker of oxidative stress in renal cortex of fructose-fed rats, which correlated with podocyte injury and albuminuria in metabolic syndrome. Fructose feeding increased miR-377 expression, decreased superoxide dismutase (SOD) expression and activity, and caused O2(-) and H2O2 overproduction in kidney cortex or glomeruli of rats. This reactive oxygen species induction increased p38 MAPK phosphorylation and thioredoxin-interacting protein (TXNIP) expression and activated the NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome to produce interleukin-1β in kidney glomeruli of fructose-fed rats. These pathological processes were further evaluated in cultured differentiated podocytes exposed to 5mM fructose, or transfected with miR-377 mimic/inhibitor and TXNIP siRNA, or co-incubated with p38 MAPK inhibitor, demonstrating that miR-377 overexpression activates the O2(-)/p38 MAPK/TXNIP/NLRP3 inflammasome pathway to promote oxidative stress and inflammation in fructose-induced podocyte injury. Antioxidants pterostilbene and allopurinol were found to ameliorate fructose-induced hyperuricemia, podocyte injury, and albuminuria in rats. More importantly, pterostilbene and allopurinol inhibited podocyte miR-377 overexpression to increase SOD1 and SOD2 levels and suppress the O2(-)/p38 MAPK/TXNIP/NLRP3 inflammasome pathway activation in vivo and in vitro, consistent with the reduction of oxidative stress and inflammation. These findings suggest that miR-377 plays an important role in glomerular podocyte oxidative stress, inflammation, and injury driven by high fructose. Inhibition of miR-377 by antioxidants may be a promising therapeutic strategy for the prevention of metabolic syndrome-associated glomerular podocyte injury.
Collapse
Affiliation(s)
- Wei Wang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, People׳s Republic of China
| | - Xiao-Qin Ding
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, People׳s Republic of China
| | - Ting-Ting Gu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, People׳s Republic of China
| | - Lin Song
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, People׳s Republic of China
| | - Jian-Mei Li
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, People׳s Republic of China
| | - Qiao-Chu Xue
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, People׳s Republic of China
| | - Ling-Dong Kong
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, People׳s Republic of China.
| |
Collapse
|
|
18
|
Abstract
OBJECTIVE We prospectively studied children with portal hypertension (PHT) for portal hypertensive duodenopathy (PHTD) and small bowel intestinal permeability (SIP) with the objectives of defining histopathological parameters for PHTD and to find out whether any association existed among structural changes, SIP, and nutritional status. METHOD SIP was assessed by using lactulose and mannitol sugar probes in 31 children with PHT (cirrhosis n = 15 and extrahepatic portal venous obstruction n = 16) and 15 healthy children as controls. Morphometric assessment from duodenal biopsies was done in children with PHT. SIP and morphometric parameters were correlated with nutritional status and dietary intake. RESULTS Among children with PHT, 48% had PHTD defined as presence of villous atrophy (villous to crypt ratio < 2.5:1), dilated capillaries (capillary diameter > 16.8 μm, capillary area > 151 μm, capillary perimeter > 56 μm), and thickened muscularis mucosae (>22.2 μm). Lactulose excretion alone was increased in children with PHT as compared with healthy children (median %: 0.03, 0.02, and 0.01 for cirrhosis, extrahepatic portal venous obstruction, and controls, respectively [P < 0.01]) signifying increased paracellular permeability in PHT. Children with PHT had significantly lower z scores for height, weight, and triceps skin-fold thickness (<-2SD), whereas no differences were found in dietary intake between patients and controls. Increased SIP, nutritional compromise, and PHTD in our patients had no correlation. CONCLUSIONS PHT is often associated with duodenopathy. SIP does occur as a result of increased paracellular permeability. Factors of increased SIP, undernutrition, and PHTD do not have correlation in childhood PHT.
Collapse
|
|
19
|
Bosoi CR, Tremblay M, Rose CF. Induction of systemic oxidative stress leads to brain oedema in portacaval shunted rats. Liver Int 2014; 34:1322-9. [PMID: 25354203 DOI: 10.1111/liv.12414] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2013] [Accepted: 11/16/2013] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS The pathogenesis of hepatic encephalopathy (HE) is multifactorial and often associated with the development of brain oedema. In addition to ammonia playing a central role, systemic oxidative stress is believed to aggravate the neuropsychological effects of ammonia in patients with chronic liver disease (CLD). The aim of this study was to (i) induce systemic oxidative stress in hyperammonaemic portacaval anastomosed (PCA) rats by inhibiting the antioxidant glutathione using Dimethyl maleate (DEM) and (ii) investigate whether a synergistic relationship between ammonia and oxidative stress contributes to the pathogenesis of brain oedema in CLD. METHODS Four-week PCA and sham-operated rats received DEM (0.4-4 mg/kg/day) for the last 10 days before sacrifice when oxidative stress markers [reactive oxygen species (ROS) and malondialdehyde (MDA)] were assessed in blood and frontal cortex. Brain water content was measured using a specific gravimetric technique. RESULTS Dimethyl maleate induced an increase in ROS and MDA in the blood, but not in the brain, of the PCA rats, compared with non-treated PCA rats. This was accompanied with an increase in brain water content (PCA+DEM: 78.45 ± 0.13% vs. PCA: 77.38 ± 0.11%, P < 0.001). Higher doses of DEM induced systemic oxidative stress in sham-operated controls, but brain oedema did not develop. CONCLUSIONS Dimethyl maleate provoked systemic, not central, oxidative stress in PCA rats, resulting in the development of brain oedema. Independently, hyperammonaemia and systemic oxidative stress do not precipitate brain oedema; therefore, our findings sustain that a synergistic effect between hyperammonaemia and systemic oxidative stress is responsible for the development of brain oedema in HE.
Collapse
Affiliation(s)
- Cristina R Bosoi
- Neuroscience Research Unit, Hôpital Saint-Luc (CRCHUM), Université de Montréal, Québec, Canada
| | | | | |
Collapse
|
|
20
|
Wang W, Wang C, Ding XQ, Pan Y, Gu TT, Wang MX, Liu YL, Wang FM, Wang SJ, Kong LD. Quercetin and allopurinol reduce liver thioredoxin-interacting protein to alleviate inflammation and lipid accumulation in diabetic rats. Br J Pharmacol 2014; 169:1352-71. [PMID: 23647015 DOI: 10.1111/bph.12226] [Citation(s) in RCA: 133] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2012] [Revised: 02/21/2013] [Accepted: 04/11/2013] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND AND PURPOSE Thioredoxin-interacting protein (TXNIP), a regulator of cellular oxidative stress, has been associated with activation of NOD-like receptor 3 (NLRP3) inflammasome, inflammation and lipid metabolism, suggesting it has a role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) in diabetes. In this study we investigated whether TXNIP is involved in type 1 diabetes-associated NAFLD and whether antioxidants, quercetin and allopurinol, alleviate NAFLD by targeting TXNIP. EXPERIMENTAL APPROACH Diabetes was induced in male Sprague-Dawley rats by a single i.p. injection of 55 mg · kg⁻¹ streptozotocin. Quercetin and allopurinol were given p.o. to diabetic rats for 7 weeks. Hepatic function, oxidative stress, inflammation and lipid levels were determined. Rat BRL-3A and human HepG2 cells were exposed to high glucose (30 mM) in the presence and absence of antioxidants, TXNIP siRNA transfection or caspase-1 inhibitor, Ac-YVAD-CMK. KEY RESULTS Quercetin and allopurinol significantly inhibited the TXNIP overexpression, activation of NLRP3 inflammasome, down-regulation of PPARα and up-regulation of sterol regulatory element binding protein-1c (SREBP-1c), SREBP-2, fatty acid synthase and liver X receptor α, as well as elevation of ROS and IL-1β in diabetic rat liver. These effects were confirmed in hepatocytes in vitro and it was further shown that TXNIP down-regulation contributed to the suppression of NLRP3 inflammasome activation, inflammation and changes in PPARα and SREBPs. CONCLUSIONS AND IMPLICATIONS Inhibition of hepatic TXNIP by quercetin and allopurinol contributes to the reduction in liver inflammation and lipid accumulation under hyperglycaemic conditions. The targeting of hepatic TXNIP by quercetin and allopurinol may have therapeutic implications for prevention of type 1 diabetes-associated NAFLD.
Collapse
Affiliation(s)
- Wei Wang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
21
|
Vonlaufen A, Spahr L, Apte MV, Frossard JL. Alcoholic pancreatitis: A tale of spirits and bacteria. World J Gastrointest Pathophysiol 2014; 5:82-90. [PMID: 24891979 PMCID: PMC4025076 DOI: 10.4291/wjgp.v5.i2.82] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Accepted: 04/29/2014] [Indexed: 02/06/2023] Open
Abstract
Alcohol is a major cause of chronic pancreatitis. About 5% of alcoholics will ever suffer from pancreatitis, suggesting that additional co-factors are required to trigger an overt disease. Experimental work has implicated lipopolysaccharide, from gut-derived bacteria, as a potential co-factor of alcoholic pancreatitis. This review discusses the effects of alcohol on the gut flora, the gut barrier, the liver-and the pancreas and proposes potential interventional strategies. A better understanding of the interaction between the gut, the liver and the pancreas may provide valuable insight into the pathophysiology of alcoholic pancreatitis.
Collapse
|
|
22
|
Liboredo JC, Vilela EG, Ferrari MDLDA, Lima AS, Correia MITD. Nutrition status and intestinal permeability in patients eligible for liver transplantation. JPEN J Parenter Enteral Nutr 2013; 39:163-70. [PMID: 24255087 DOI: 10.1177/0148607113513465] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Increased intestinal permeability has been reported in multiple studies of cirrhotic patients, although specific factors associated with this finding have not been fully elucidated. Thus, the aim of this study was to investigate whether there was an association between nutrition status measured by different methods and intestinal permeability in cirrhotic patients who were candidates for liver transplantation. MATERIALS AND METHODS The study group comprised 18 cirrhotic patients and 15 healthy controls. Patients' nutrition status was evaluated by Subjective Global Assessment (SGA), anthropometry, dynamometry, and phase angle, which was determined by bioelectrical impedance analysis. Intestinal permeability was assessed by the lactulose/mannitol test. RESULTS The prevalence of malnutrition showed wide variance between different assessment methods (5.5%-77.8%). Intestinal permeability was significantly higher in cirrhotic patients than in healthy controls. In relation to nutrition status, intestinal permeability and phase angle did not differ significantly between patients who were considered well nourished (median intestinal permeability, 0.010 [range, 0.001-0.198]; median phase angle, 6.0 [range, 4.2-6.9]) and malnourished patients (intestinal permeability, 0.032 [range, 0.002-0.079]; phase angle, 4.8 [range, 2.2-6.1]) by SGA. In addition, no correlation was found between nutrition diagnosis as assessed by different methods, patient age, liver disease severity scores, and laboratory measurements with intestinal permeability. CONCLUSION Although intestinal permeability was increased in cirrhotic patients, this finding was not associated with nutrition status.
Collapse
|
|
23
|
Pijls KE, Jonkers DMAE, Elamin EE, Masclee AAM, Koek GH. Intestinal epithelial barrier function in liver cirrhosis: an extensive review of the literature. Liver Int 2013; 33:1457-69. [PMID: 23879434 DOI: 10.1111/liv.12271] [Citation(s) in RCA: 96] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2013] [Accepted: 06/23/2013] [Indexed: 12/12/2022]
Abstract
Recent evidence suggests that translocation of bacteria and bacterial products, such as endotoxin from the intestinal lumen into the systemic circulation is a contributing factor in the pathogenesis of chronic liver diseases and the development of complications in cirrhosis. In addition to alterations in the intestinal microbiota and immune system, dysfunction of the intestinal epithelial barrier may be an important factor facilitating bacterial translocation. This review aims to provide an overview of the current evidence of intestinal epithelial barrier dysfunction in human chronic liver diseases and cirrhosis, and to discuss possible contributing factors and mechanisms. Data suggest the presence of intestinal epithelial barrier dysfunction in patients with chronic liver diseases, but are more convincing in patients with cirrhosis, especially in those with complications. The barrier dysfunction can result from both direct and indirect effects of aetiological factors, such as alcohol and obesity, which can cause chronic liver diseases and ultimately cirrhosis. On the other hand characteristics of cirrhosis itself, including portal hypertension, alterations in the intestinal microbiota, inflammation and oxidative stress can affect barrier function of both small and large intestine and may contribute to the development of complications. In conclusion, there are indications for intestinal epithelial barrier dysfunction in patients with chronic liver diseases and especially in patients with cirrhosis, which can be caused by various factors affecting both the small and large intestine.
Collapse
Affiliation(s)
- Kirsten E Pijls
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Maastricht University Medical Center, Maastricht, the Netherlands; School for Nutrition, Toxicology and Metabolism (NUTRIM), Maastricht University Medical Center, Maastricht, the Netherlands
| | | | | | | | | |
Collapse
|
|
24
|
Bosoi CR, Rose CF. Oxidative stress: a systemic factor implicated in the pathogenesis of hepatic encephalopathy. Metab Brain Dis 2013; 28:175-8. [PMID: 23124921 DOI: 10.1007/s11011-012-9351-5] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2012] [Accepted: 10/22/2012] [Indexed: 12/16/2022]
Abstract
Although ammonia is considered the main factor involved in the pathogenesis of hepatic encephalopathy (HE), it correlates well with the severity of HE in acute liver failure, but not in chronic liver disease. Oxidative stress is another factor believed to play a role in the pathogenesis of this syndrome; it represents an imbalance between the production and neutralization of reactive oxygen species, which leads to cellular dysfunction. In the setting of liver disease, oxidative stress represents a systemic phenomenon induced by several mechanisms: decreased antioxidant synthesis, increased systemic release of oxidant enzymes, generation of reactive oxygen species, and impaired neutrophil function. High ammonia concentrations induce cerebral oxidative stress, thus contributing to severe hepatic encephalopathy, as observed in acute liver failure. In chronic liver disease, significantly lower degrees of hyperammonemia (<500 μM) do not induce cerebral nor systemic oxidative stress. Data from both animal and human studies sustain that there is a synergistic effect between systemic oxidative stress, and ammonia that is implicated in the pathogenesis of hepatic encephalopathy.
Collapse
Affiliation(s)
- Cristina R Bosoi
- Neuroscience Research Unit, Hôpital Saint-Luc (CRCHUM), Université de Montréal, Montreal, Québec, Canada
| | | |
Collapse
|
|
25
|
Assimakopoulos SF, Tsamandas AC, Tsiaoussis GI, Karatza E, Zisimopoulos D, Maroulis I, Kontogeorgou E, Georgiou CD, Scopa CD, Thomopoulos KC. Intestinal mucosal proliferation, apoptosis and oxidative stress in patients with liver cirrhosis. Ann Hepatol 2013; 12:301-307. [PMID: 23396742 DOI: 10.1016/s1665-2681(19)31369-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/01/2023]
Abstract
BACKGROUND Intestinal mucosal barrier dysfunction in liver cirrhosis and its implicated mechanisms is of great clinical importance because it is associated with the development of serious complications from diverse organs through promotion of systemic endotoxemia. AIM The present study was designed to investigate whether enterocytes' proliferation, apoptosis and intestinal oxidative stress are altered in the intestinal mucosa of patients with compensated and decompensated liver cirrhosis. MATERIAL AND METHODS Twelve healthy controls (group A) and twenty four cirrhotic patients at a compensated (n = 12, group B) or decompensated condition (n = 12, group C) were subjected to duodenal biopsy. In intestinal specimens mucosal apoptotic and mitotic activity and their ratio were recorded by means of morphological assessment and mucosal lipid hydroperoxides were measured. Plasma endotoxin concentration, an index of gut barrier function, was also determined. RESULTS Cirrhotic patients presented significantly higher serum endotoxin concentrations as compared to healthy controls (P < 0.001), whilst endotoxemia was higher in decompensated disease (P < 0.05 vs. compensated cirrhosis). Intestinal mucosal mitotic count was significantly lower in patients with compensated and decompensated cirrhosis compared to controls (P < 0.01, respectively), whilst a trend towards increased apoptosis was recorded. The mitotic/apoptotic ratio was significantly reduced in groups B (P < 0.05) and C (P < 0.01) as compared to controls. Intestinal lipid peroxidation was significantly increased in decompensated cirrhotics (P < 0.001 vs. groups A and B). CONCLUSIONS The present study demonstrates for the first time that human liver cirrhosis is associated with decreased intestinal mucosal proliferation and proliferation/apoptosis ratio even at early stages of cirrhosis and increased intestinal oxidative stress in advanced liver disease.
Collapse
|
|
26
|
Yamamoto Y, Hiasa Y, Murakami H, Ikeda Y, Yamanishi H, Abe M, Matsuura B, Onji M. Rapid alternative absorption of dietary long-chain fatty acids with upregulation of intestinal glycosylated CD36 in liver cirrhosis. Am J Clin Nutr 2012; 96:90-101. [PMID: 22648712 DOI: 10.3945/ajcn.111.033084] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Dietary long-chain fatty acid (LCFA) intake is an important risk factor for hepatic inflammation and hepatocarcinogenesis. An alternate route of dietary LCFA absorption has been suggested in patients with liver cirrhosis (LC). OBJECTIVE We aimed to determine this alternate route and to identify its mechanism. DESIGN Twenty healthy control subjects and 47 patients with LC-n = 23 with portal hypertension [PH(+)LC] and 24 without portal hypertension [PH(-)LC)]-were enrolled. [¹³C]Palmitate (an LCFA) and octanoate (a medium-chain fatty acid [MCFA]) were administered by using gastrointestinal endoscopy. Breath ¹³CO₂ was measured to quantify metabolized fatty acids. We also examined intestinal specimens of patients in these groups. RESULTS A more rapid increase in metabolized palmitate, which showed a pattern similar to that of octanoate metabolism, was observed in patients with LC than in healthy control subjects. The increase in the PH(-)LC group was higher than that in the PH(+)LC group. However, the concentration of metabolized palmitate increased with treatment of the PH(+)LC group with a portal-systemic shunt. Morphologic changes such as expanded lymph and blood vessels were present, and glycosylated CD36 increased in the jejunum of the PH(+)LC group. This group had high serum concentrations of glucagon-like peptide-2. These data suggest that dietary LCFAs, similar to MCFAs, are absorbed via blood vessels in patients with LC. CONCLUSIONS Rapid absorption of LCFAs by an alternative method occurred in patients with LC. This altered LCFA processing is likely related to upregulation of intestinal glycosylated CD36 and could contribute to pathogenesis in patients with LC.
Collapse
Affiliation(s)
- Yasunori Yamamoto
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan
| | | | | | | | | | | | | | | |
Collapse
|
|
27
|
Dixit P, Jain DK, Rajpoot JS. Differential effect of oxidative stress on intestinal apparent permeability of drugs transported by paracellular and transcellular route. Eur J Drug Metab Pharmacokinet 2012; 37:203-9. [PMID: 22718103 DOI: 10.1007/s13318-012-0099-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2011] [Accepted: 06/01/2012] [Indexed: 11/28/2022]
Abstract
Increased intestinal permeability of macromolecules is a common feature of oxidative stress-induced gastrointestinal diseases; how it affects the absorption of drugs is not investigated. Hence, it was proposed to study the influence of hydrogen peroxide-induced oxidative stress on permeability of atenolol and metoprolol using a modified everted rat intestine technique. Atenolol was chosen as a marker of paracellular drug transport and metoprolol was selected to represent transcellular drug transport. Wistar rats were used as a source of intestine, which was everted using a glass rod, mounted on permeability apparatus, having test drug (100 μg/ml in Krebs) in donor compartment. Samples were taken from receiver compartment every 5 min for 60 min, and analyzed by HPLC. For induction of oxidative stress isolated ileum was incubated in H₂O₂ (200 μM) containing Krebs for 15 min and then again permeability was estimated. Extent of oxidative stress was determined by estimating lipid peroxidation using thiobarbituric acid assay, which was found to be increased by 42 % in hydrogen peroxide treated rat intestine as compared to control group. The mean apparent permeability of atenolol and metoprolol was found to be 0.054 ± 0.024 × 10⁻⁴ and 0.84 ± 0.14 × 10⁻⁴ cm/s, respectively, in control group rat intestinal segments. After exposure to hydrogen peroxide, there was a significant increase in the mean permeability of atenolol (0.11 ± 0.01 × 10⁻⁴ cm/s), however, metoprolol permeability was unaltered (0.94 ± 0.047 × 10⁻⁴ cm/s). The marked increase in the apparent permeability of atenolol may be attributed to rupture of intestinal barrier. In conclusion, the present study reports the differential effect of oxidative stress-induced damage on drug transport across rat intestine.
Collapse
Affiliation(s)
- Pankaj Dixit
- College of Pharmacy, IPS Academy, Rajendranagar, A-B Road, Indore 452012, MP, India.
| | | | | |
Collapse
|
|
28
|
Assimakopoulos SF, Tsamandas AC, Tsiaoussis GI, Karatza E, Triantos C, Vagianos CE, Spiliopoulou I, Kaltezioti V, Charonis A, Nikolopoulou VN, Scopa CD, Thomopoulos KC. Altered intestinal tight junctions' expression in patients with liver cirrhosis: a pathogenetic mechanism of intestinal hyperpermeability. Eur J Clin Invest 2012; 42:439-446. [PMID: 22023490 DOI: 10.1111/j.1365-2362.2011.02609.x] [Citation(s) in RCA: 138] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Increased intestinal permeability in cirrhosis exerts a pivotal role in the pathogenesis of spontaneous bacterial peritonitis and other complications of cirrhosis through promotion of systemic endotoxemia. This study was designed to investigate whether the expression of tight junction (TJ) proteins, which regulate gut paracellular permeability, is altered in the intestinal mucosa of patients with liver cirrhosis and study its potential association with the stage of liver disease and the development of systemic endotoxemia. DESIGN Twenty-four patients with cirrhosis at a decompensated (n = 12, group A) or compensated condition (n = 12, group B) and 12 healthy controls (group C) were subjected to duodenal biopsy. The expression of the TJ proteins occludin and claudin-1 in the intestinal epithelium was evaluated by immunohistochemistry. Plasma endotoxin concentrations were also determined. RESULTS Patients with cirrhosis presented significantly higher serum endotoxin concentrations as compared to healthy controls (P < 0·001), whilst endotoxemia was higher in decompensated disease (P < 0·05 vs. compensated cirrhosis). Patients with decompensated and compensated cirrhosis presented significantly reduced expression of occludin and claudin-1 as compared to controls (P < 0·01, respectively). These alterations were significantly more pronounced in decompensated patients as compared to compensated (P < 0·05). Regarding occludin, in patients with cirrhosis, a specific pattern of expression in the intestinal epithelium was observed, with a gradually increasing loss of expression from crypt to tip of the villi. Occludin and claudin-1 expression were inversely correlated with Child-Pugh score (P < 0·001), the grade of oesophageal varices (P < 0·01) and endotoxin concentrations (P < 0·001). CONCLUSIONS This study demonstrates for the first time that human liver cirrhosis induces significant alterations in enterocytes' TJs. These changes might represent an important cellular mechanism for intestinal barrier dysfunction and hyperpermeability in patients with liver cirrhosis.
Collapse
|
|
29
|
Bosoi CR, Yang X, Huynh J, Parent-Robitaille C, Jiang W, Tremblay M, Rose CF. Systemic oxidative stress is implicated in the pathogenesis of brain edema in rats with chronic liver failure. Free Radic Biol Med 2012; 52:1228-35. [PMID: 22300646 DOI: 10.1016/j.freeradbiomed.2012.01.006] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2011] [Revised: 01/05/2012] [Accepted: 01/12/2012] [Indexed: 12/16/2022]
Abstract
Chronic liver failure leads to hyperammonemia, a central component in the pathogenesis of hepatic encephalopathy (HE); however, a correlation between blood ammonia levels and HE severity remains controversial. It is believed oxidative stress plays a role in modulating the effects of hyperammonemia. This study aimed to determine the relationship between chronic hyperammonemia, oxidative stress, and brain edema (BE) in two rat models of HE: portacaval anastomosis (PCA) and bile-duct ligation (BDL). Ammonia and reactive oxygen species (ROS) levels, BE, oxidant and antioxidant enzyme activities, as well as lipid peroxidation were assessed both systemically and centrally in these two different animal models. Then, the effects of allopurinol (xanthine oxidase inhibitor, 100mg/kg for 10days) on ROS and BE and the temporal resolution of ammonia, ROS, and BE were evaluated only in BDL rats. Similar arterial and cerebrospinal fluid ammonia levels were found in PCA and BDL rats, both significantly higher compared to their respective sham-operated controls (p<0.05). BE was detected in BDL rats (p < 0.05) but not in PCA rats. Evidence of oxidative stress was found systemically but not centrally in BDL rats: increased levels of ROS, increased activity of xanthine oxidase (oxidant enzyme), enhanced oxidative modifications on lipids, as well as decreased antioxidant defense. In PCA rats, a preserved oxidant/antioxidant balance was demonstrated. Treatment with allopurinol in BDL rats attenuated both ROS and BE, suggesting systemic oxidative stress is implicated in the pathogenesis of BE. Analysis of ROS and ammonia temporal resolution in the plasma of BDL rats suggests systemic oxidative stress might be an important "first hit", which, followed by increases in ammonia, leads to BE in chronic liver failure. In conclusion, chronic hyperammonemia and oxidative stress in combination lead to the onset of BE in rats with chronic liver failure.
Collapse
Affiliation(s)
- Cristina R Bosoi
- Neuroscience Research Unit, Hôpital Saint-Luc (CRCHUM), Université de Montréal, Montréal, QC H2X 1P1, Canada
| | | | | | | | | | | | | |
Collapse
|
|
30
|
Assimakopoulos SF, Gogos C, Labropoulou-Karatza C. Could antioxidants be the “magic pill” for cirrhosis-related complications? A pathophysiological appraisal. Med Hypotheses 2011; 77:419-23. [DOI: 10.1016/j.mehy.2011.05.034] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2011] [Accepted: 05/29/2011] [Indexed: 12/12/2022]
|
|
31
|
Higgins P, Dawson J, Lees KR, McArthur K, Quinn TJ, Walters MR. Xanthine Oxidase Inhibition For The Treatment Of Cardiovascular Disease: A Systematic Review and Meta-Analysis. Cardiovasc Ther 2011; 30:217-26. [DOI: 10.1111/j.1755-5922.2011.00277.x] [Citation(s) in RCA: 120] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
|
|
32
|
Abstract
BACKGROUND Pregnancy is the only physiologic condition in which we encounter chronically elevated intra-abdominal pressure (IAP), while pathologically several pathologies, such as ascites and morbid obesity, are affected by this phenomenon. This paper introduces and validates a new model that is able to create and maintain chronically increased IAP, facilitating the study of phenomena related to chronically elevated IAP, i.e., obesity. METHODS An experimental device was implanted in 15 rabbits, which consisted of an intra-abdominal balloon (IAB), an external control valve, and a connecting tube. A Foley catheter was inserted in their urinary bladders. IAPs were measured simultaneously transvesically and via the device. During the acute phase, IAB was gradually inflated to 16 cmH(2)O, and IAPs were consecutively measured. During the chronic phase, residual IAPs were measured in a weekly rate for 8 weeks. Statistical significances, mean bias, and precisions were calculated. RESULTS During the acute phase, the saline in the IAB efficiently increases IAP to 16 cmH(2)O. IAPs measured both through the urinary bladder and the device correlate well with small bias and high precision. Our model maintains sufficiently chronically increased IAP for at least 8 weeks. No mortality was observed. CONCLUSIONS A rabbit model establishing and maintaining chronically increased IAP was successfully created and proved to be simple, effective, and repeatable. This model established chronically increased IAP permitting this way the study of its effect on organs and systems.
Collapse
|
|
33
|
The potential for xanthine oxidase inhibition in the prevention and treatment of cardiovascular and cerebrovascular disease. Cardiovasc Psychiatry Neurol 2009; 2009:282059. [PMID: 20029618 PMCID: PMC2790135 DOI: 10.1155/2009/282059] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2009] [Accepted: 09/08/2009] [Indexed: 02/07/2023] Open
Abstract
There is a now a wealth of epidemiological, animal, and clinical data to suggest the benefits of uric acid reduction and hxanthine oxidase inhibition in prevention of vascular disease. This review discusses the available epidemiological, preclinical, and clinical data and considers arguments for and against a role for serum uric acid in common cardiovascular disorders. It concludes that large scale trials with clinical endpoints are justified to address this important question and to define whether use of drugs such as allopurinol should be a routine part of preventative strategies.
Collapse
|
|
34
|
Chowdhury P, Walker A. A cell-based approach to study changes in the pancreas following nicotine exposure in an animal model of injury. Langenbecks Arch Surg 2008; 393:547-55. [PMID: 18204935 DOI: 10.1007/s00423-007-0267-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2007] [Accepted: 11/14/2007] [Indexed: 10/22/2022]
Abstract
BACKGROUND Cigarette smoking is a recognized risk factor for the induction of pancreatic diseases and is suspected to play a major role in the development of pancreatic cancer in smokers. MATERIALS AND METHODS This study was designed to characterize the mechanisms of nicotine-induced injury to the pancreas. AR42Jcells, a stable mutant pancreatic tumor cell line, was chosen for the study because of its stability in culture media and also because of its known secretory capacity, which is like that of a normal pancreatic acinar cell. It is hypothesized that nicotine-induced effects on the pancreas are triggered by oxidative stress induced in pancreatic acinar cell via oxidative stress signaling pathways. RESULTS The results from our study showed that, in vitro, nicotine induced generation of oxygen free radicals measured as malondialdehyde, an end product of lipid peroxidation. Treatment of AR42J cells with nicotine induced p-ERK 1/2 activation as confirmed by Western blot and immunofluorescence imaging of cytoplasmic localization of mitogen-activated protein kinase (MAPK) signals. Nicotine enhanced AR42J cell proliferation and cholecystokinin-stimulated amylase release in AR42J cells. These effects of nicotine were confirmed by simultaneous studies conducted on the same cells by hydrogen peroxide, a known oxidative biomarker. Allopurinol, a XOD inhibitor, suppressed these effects induced by nicotine and H(2)O(2) with the exception that cholecystokinin-stimulated amylase release by H(2)O(2) remained unaltered when AR42J cells were preincubated with allopurinol. These results suggest that nicotine-induced effects on pancreatic acinar cells were associated with generation of oxyradical mediated via the XOD pathway. The results have a direct impact on cell proliferation, MAPK signaling, and acinar cell function. CONCLUSION We conclude that nicotine induces oxidative stress in pancreatic acinar cells and that these events trigger pathophysiological changes in the pancreas, leading to increased cell proliferation and injury.
Collapse
Affiliation(s)
- Parimal Chowdhury
- Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
| | | |
Collapse
|
|
35
|
Comert B, Isik AT, Aydin S, Bozoglu E, Unal B, Deveci S, Mas N, Cinar E, Mas MR. Combination of allopurinol and hyperbaric oxygen therapy: a new treatment in experimental acute necrotizing pancreatitis? World J Gastroenterol 2007; 13:6203-6207. [PMID: 18069760 DOI: 10.3748/wjg.13.6203] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the individual and combined effects of allopurinol and hyperbaric oxygen (HBO) therapy on biochemical and histopathological changes, oxidative stress, and bacterial translocation (BT) in the experimental rat acute pancreatitis (AP). METHODS Eighty-five Sprague-Dawley rats were included in the study. Fifteen of the eighty-five rats were used as controls (sham, Group I). AP was induced via intraductal taurocholate infusion in the remaining seventy rats. Rats that survived to induction of acute necrotizing pancreatitis were randomized into four groups. Group II received saline, Group III allopurinol, Group IV allopurinol plus HBO and Group V HBO alone. Serum amylase levels, oxidative stress parameters, BT and histopathologic scores were determined. RESULTS Serum amylase levels were lower in Groups III, IV and V compared to Group II (974 +/- 110, 384 +/- 40, 851 +/- 56, and 1664 +/- 234 U/L, respectively, P < 0.05, for all). Combining the two treatment options revealed significantly lower median [25-75 percentiles] histopathological scores when compared to individual administrations (13 [12.5-15] in allopurinol group, 9.5 [7-11.75] in HBO group, and 6 [4.5-7.5] in combined group, P < 0.01). Oxidative stress markers were significantly better in all treatment groups compared to the controls. Bacterial translocation into the pancreas and mesenteric lymph nodes was lower in Groups III, IV and V compared to Group II (54%, 23%, 50% vs 100% for translocation to pancreas, and 62%, 46%, 58% vs 100% for translocation to mesenteric lymph nodes, respectively, P < 0.05 for all). CONCLUSION The present study confirms the benefit of HBO and allopurinol treatment when administered separately in experimental rat AP. Combination of these treatment options appears to prevent progression of pancreatic injury parameters more effectively.
Collapse
Affiliation(s)
- Bilgin Comert
- Division of Intensive Care, Departments of Internal Medicine, Gulhane School of Medicine, GATA Geriatri BD, Etlik, Ankara 06018, Turkey
| | | | | | | | | | | | | | | | | |
Collapse
|
|
36
|
Comert B, Isik AT, Aydin S, Bozoglu E, Unal B, Deveci S, Mas N, Cinar E, Mas MR. Combination of allopurinol and hyperbaric oxygen therapy: a new treatment in experimental acute necrotizing pancreatitis? World J Gastroenterol 2007; 13:6203-6207. [PMID: 18069760 PMCID: PMC4171230 DOI: 10.3748/wjg.v13.i46.6203] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2007] [Revised: 09/16/2007] [Accepted: 10/28/2007] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the individual and combined effects of allopurinol and hyperbaric oxygen (HBO) therapy on biochemical and histopathological changes, oxidative stress, and bacterial translocation (BT) in the experimental rat acute pancreatitis (AP). METHODS Eighty-five Sprague-Dawley rats were included in the study. Fifteen of the eighty-five rats were used as controls (sham, Group I). AP was induced via intraductal taurocholate infusion in the remaining seventy rats. Rats that survived to induction of acute necrotizing pancreatitis were randomized into four groups. Group II received saline, Group III allopurinol, Group IV allopurinol plus HBO and Group V HBO alone. Serum amylase levels, oxidative stress parameters, BT and histopathologic scores were determined. RESULTS Serum amylase levels were lower in Groups III, IV and V compared to Group II (974 +/- 110, 384 +/- 40, 851 +/- 56, and 1664 +/- 234 U/L, respectively, P < 0.05, for all). Combining the two treatment options revealed significantly lower median [25-75 percentiles] histopathological scores when compared to individual administrations (13 [12.5-15] in allopurinol group, 9.5 [7-11.75] in HBO group, and 6 [4.5-7.5] in combined group, P < 0.01). Oxidative stress markers were significantly better in all treatment groups compared to the controls. Bacterial translocation into the pancreas and mesenteric lymph nodes was lower in Groups III, IV and V compared to Group II (54%, 23%, 50% vs 100% for translocation to pancreas, and 62%, 46%, 58% vs 100% for translocation to mesenteric lymph nodes, respectively, P < 0.05 for all). CONCLUSION The present study confirms the benefit of HBO and allopurinol treatment when administered separately in experimental rat AP. Combination of these treatment options appears to prevent progression of pancreatic injury parameters more effectively.
Collapse
|