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Lashgari NA, Khayatan D, Roudsari NM, Momtaz S, Dehpour AR, Abdolghaffari AH. Therapeutic approaches for cholestatic liver diseases: the role of nitric oxide pathway. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:1433-1454. [PMID: 37736835 DOI: 10.1007/s00210-023-02684-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 08/21/2023] [Indexed: 09/23/2023]
Abstract
Cholestasis describes bile secretion or flow impairment, which is clinically manifested with fatigue, pruritus, and jaundice. Neutrophils play a crucial role in many diseases such as cholestasis liver diseases through mediating several oxidative and inflammatory pathways. Data have been collected from clinical, in vitro, and in vivo studies published between 2000 and December 2021 in English and obtained from the PubMed, Google Scholar, Scopus, and Cochrane libraries. Although nitric oxide plays an important role in the pathogenesis of cholestatic liver diseases, excessive levels of NO in serum and affected tissues, mainly synthesized by the inducible nitric oxide synthase (iNOS) enzyme, can exacerbate inflammation. NO induces the inflammatory and oxidative processes, which finally leads to cell damage. We found that natural products such as baicalin, curcumin, resveratrol, and lycopene, as well as chemical likes ursodeoxycholic acid, dexamethasone, rosuvastatin, melatonin, and sildenafil, are able to markedly attenuate the NO production and iNOS expression, mainly through inducing the nuclear factor κB (NF-κB), Janus kinase and signal transducer and activator of transcription (JAK/STAT), and toll like receptor-4 (TLR4) signaling pathways. This study summarizes the latest scientific data about the bile acid signaling pathway, the neutrophil chemotaxis recruitment process during cholestasis, and the role of NO in cholestasis liver diseases. Literature review directed us to propose that suppression of NO and its related pathways could be a therapeutic option for preventing or treating cholestatic liver diseases.
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Affiliation(s)
- Naser-Aldin Lashgari
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, No. 99, Yakhchal, Gholhak, Shariati St., Tehran, Iran, P. O. Box: 19419-33111
- GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Danial Khayatan
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, No. 99, Yakhchal, Gholhak, Shariati St., Tehran, Iran, P. O. Box: 19419-33111
- GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Nazanin Momeni Roudsari
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, No. 99, Yakhchal, Gholhak, Shariati St., Tehran, Iran, P. O. Box: 19419-33111
- GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Saeideh Momtaz
- Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Tehran, Iran
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), and Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Ahmad Reza Dehpour
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran.
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Amir Hossein Abdolghaffari
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, No. 99, Yakhchal, Gholhak, Shariati St., Tehran, Iran, P. O. Box: 19419-33111.
- GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
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Mostafa DK, Eissa MM, Ghareeb DA, Abdulmalek S, Hewedy WA. Resveratrol protects against Schistosoma mansoni-induced liver fibrosis by targeting the Sirt-1/NF-κB axis. Inflammopharmacology 2024; 32:763-775. [PMID: 38041753 PMCID: PMC10907480 DOI: 10.1007/s10787-023-01382-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Accepted: 10/19/2023] [Indexed: 12/03/2023]
Abstract
Hepatic schistosomiasis is a prevalent form of chronic liver disease that drastically affects human health. Nevertheless, an antifibrotic drug that could suppress the development of hepatic fibrosis does not exist yet. The current study aimed to evaluate the effect of resveratrol, a natural polyphenol with multiple biological activities, on Schistosoma mansoni (S. mansoni)-induced hepatic fibrosis and delineate the underlying molecular mechanism. Swiss male albino mice were randomly assigned into infected and non-infected groups. Hepatic schistosomiasis infection was induced via exposure to S. mansoni cercariae. 6 weeks later, resveratrol was administrated either as 20 mg/kg/day or 100 mg/kg/day for 4 weeks to two infected groups. Another group received vehicle and served as infected control group. At the end of the study, portal hemodynamic, biochemical, and histopathological evaluation of liver tissues were conducted. Remarkably, resveratrol significantly reduced portal pressure, portal and mesenteric flow in a dose-dependent manner. It improved several key features of hepatic injury as evidenced biochemically by a significant reduction of bilirubin and liver enzymes, and histologically by amelioration of the granulomatous and inflammatory reactions. In line, resveratrol reduced the expression of pro-inflammatory markers; TNF-α, IL-1β and MCP-1 mRNA, together with fibrotic markers; collagen-1, TGF-β1 and α-SMA. Moreover, resveratrol restored SIRT1/NF-κB balance in hepatic tissues which is the main switch-off control for all the fibrotic and inflammatory mechanisms. Taken together, it can be inferred that resveratrol possesses a possible anti-fibrotic effect that can halt the progression of hepatic schistosomiasis via targeting SIRT1/ NF-κB signaling.
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Affiliation(s)
- Dalia Kamal Mostafa
- Clinical Pharmacology Department, Faculty of Medicine, Alexandria University, Al-Moassat Medical Campus, Elhadara, Alexandria, 21561, Egypt
| | - Maha M Eissa
- Medical Parasitology Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Doaa A Ghareeb
- Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt
| | - Shaymaa Abdulmalek
- Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt
| | - Wafaa A Hewedy
- Clinical Pharmacology Department, Faculty of Medicine, Alexandria University, Al-Moassat Medical Campus, Elhadara, Alexandria, 21561, Egypt.
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Menezes ACG, Brandão LSR, Portugal LC, Matsubara LM, Maia EMA, Sakoda JN, Providelo GA, Navarezi AG, Santos KCND, Guimarães RDECA, Souza ASDE, Souza MIL. Lipid profile and reproductive performance of female offspring of SWISS mouse females supplemented with resveratrol or canjiqueira (Byrsonima cydoniifolia A Juss) during gestation. AN ACAD BRAS CIENC 2023; 95:e20190804. [PMID: 38088694 DOI: 10.1590/0001-3765202320190804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Accepted: 12/17/2019] [Indexed: 12/18/2023] Open
Abstract
This study aimed to resveratrol supplementation (at 5 or 10 mg/kg) and a hydroethanolic extract of canjiqueira fruits (150 mg/kg) on female SWISS mice. Total cholesterol, high-density lipoprotein (HDL), triglyceride levels, gestation rates, and embryonic implantation rates in their female Offspring was evaluated. In conclusion, the consumption of canjiqueira fruit extract altered the lipid profile of their female offspring, and did not impact their reproductive performance. Supplementing female SWISS mice with 10 mg/kg of resveratrol increased total cholesterol, triglycerides, and HDL levels, thereby enhancing the reproductive efficiency of their offspring.
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Affiliation(s)
- Adriana C Guercio Menezes
- Mato Grosso do Sul Federal University, Animal Science Graduate Program, Senador Filinto Müller Ave., 2443, Vila Ipiranga, 79074-460 Campo Grande, MS, Brazil
- Mato Grosso do Sul Federal University, Central Vivarium, Senador Filinto Müller Ave., 1555, Vila Ipiranga, 79070-900 Campo Grande, MS, Brazil
| | - Lorena S R Brandão
- Mato Grosso do Sul Federal University, Animal Science Graduate Program, Senador Filinto Müller Ave., 2443, Vila Ipiranga, 79074-460 Campo Grande, MS, Brazil
| | - Luciane C Portugal
- Mato Grosso do Sul Federal University, Bioscience Institute, Cidade Universitária, 79002-970 Campo Grande, MS, Brazil
| | - Lidia M Matsubara
- Animal Care Veterinary, Leonardo Vilas Boas Ave., 314, Vila Nova, 18608-227 Botucatu, SP, Brazil
| | - Elaine Maria A Maia
- Animal Care Veterinary, Leonardo Vilas Boas Ave., 314, Vila Nova, 18608-227 Botucatu, SP, Brazil
| | - Jhessica N Sakoda
- Animal Care Veterinary, Leonardo Vilas Boas Ave., 314, Vila Nova, 18608-227 Botucatu, SP, Brazil
| | - Gilson A Providelo
- Animal Care Veterinary, Leonardo Vilas Boas Ave., 314, Vila Nova, 18608-227 Botucatu, SP, Brazil
| | - Amanda G Navarezi
- Mato Grosso do Sul Federal University, Bioscience Institute, Cidade Universitária, 79002-970 Campo Grande, MS, Brazil
| | - Kely Cristina N Dos Santos
- Mato Grosso do Sul Federal University, Bioscience Institute, Cidade Universitária, 79002-970 Campo Grande, MS, Brazil
| | - Rita DE Cássia A Guimarães
- Mato Grosso do Sul Federal University, Pharmaceutical Sciences, Food and Nutrition Faculty, University City, 79070-900 Campo Grande, MS, Brazil
| | - Albert S DE Souza
- Mato Grosso do Sul Federal University, Bioscience Institute, Cidade Universitária, 79002-970 Campo Grande, MS, Brazil
| | - Maria Inês L Souza
- Mato Grosso do Sul Federal University, Animal Science Graduate Program, Senador Filinto Müller Ave., 2443, Vila Ipiranga, 79074-460 Campo Grande, MS, Brazil
- Mato Grosso do Sul Federal University, Bioscience Institute, Cidade Universitária, 79002-970 Campo Grande, MS, Brazil
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Koc S, Aktas A, Sahin B, Ozer H, Zararsiz GE. Protective effect of ursodeoxycholic acid and resveratrol against tacrolimus induced hepatotoxicity. Biotech Histochem 2023; 98:471-478. [PMID: 37381715 DOI: 10.1080/10520295.2023.2228697] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/30/2023] Open
Abstract
Tacrolimus (TAC) is a potent and well-tolerated immunosuppressive drug, but serious side effects including nephrotoxicity and hepatotoxicity have been reported. Ursodeoxycholic acid (UDCA) and resveratrol (RSV) exhibit hepatoprotective effects in liver diseases. We investigated the hepatoprotective effect of UDCA and RSV against TAC induced hepatotoxicity. We divided 40 male rats into five equal groups: A) control group, B) TAC group, C) TAC + UDCA group, D) TAC + RSV group, E) TAC + UDCA + RSV group. We administered 0.5 mg/kg TAC once daily, 25 mg/kg UDCA twice daily and 10 mg/kg RSV once daily. The drugs in the experimental groups were given by gavage from the first day of the study and continued for 21 days. Histopathologic and biochemical analyses were performed on day 22. In group B, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor-alpha (TNF), interleukin-1 (IL-1), interleukin-6 (IL-6), total oxidative status (TOS) and malondialdehyde (MDA) levels were higher compared to group A, and catalase (CAT), superoxide dismutase (SOD) levels and total antioxidant status (TAS) were lower compared to group A. Severe cellular swelling, degeneration and focal necrosis were more evident in group B than in groups C-E. Histopathological improvement was observed in groups C-E, where UDCA and RSV were combined, compared to group B. We found that UDCA and RSV, together or separately, protected the liver against oxidative stress damage caused by TAC.
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Affiliation(s)
- Suleyman Koc
- Department of General Surgery, Faculty of Medicine, Sivas Cumhuriyet University, Sivas, Turkey
| | - Ahmet Aktas
- Department of İnternal Medicine, Faculty of Medicine, Sivas Cumhuriyet University, Sivas, Turkey
| | - Bilal Sahin
- Department of Physiology, Faculty of Medicine, Sivas Cumhuriyet University, Sivas, Turkey
| | - Hatice Ozer
- Department of Pathology, Faculty of Medicine, Sivas Cumhuriyet University, Sivas, Turkey
| | - Gozde Erturk Zararsiz
- Department of Biostatistics, Faculty of Medicine, Erciyes University, Kayseri, Turkey
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Oliveria decumbens Extract Exhibits Hepatoprotective Effects Against Bile Duct Ligation-Induced Liver Injury in Rats by Reducing Oxidative Stress. HEPATITIS MONTHLY 2023. [DOI: 10.5812/hepatmon-131160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
Background: Cholestasis is described as a disease in which bile flow from the liver is reduced or stopped, and due to its oxidative effects, irreversible consequences may occur. Due to the remarkable antioxidant properties of Oliveria decumbens (OD) and the contribution of oxidants to the progression of bile duct ligation (BDL)-induced cholestasis, Objectives: This research aimed to examine how the OD ethanolic extract affected liver damage and oxidant-antioxidant balance markers in BDL-induced cholestasis. Methods: Forty male Wistar rats weighing 200 - 250 g were used. Cholestasis was induced using the BDL approach. The rats were categorized into four groups: Group 1, sham control (SC); group 2, cholestatic; group 3, SC + OD; and group 4, cholestatic + OD. A dose of OD ethanolic extract was administered orally (500 mg/kg/day) to rats for seven days. Seven days following surgery, the rats’ blood samples were collected; after sacrifice, a part of the liver tissue was isolated. A histopathological examination was performed, while the rest was stored at -70°C in liquid nitrogen. Heparin-containing tubes were used to gather blood samples. In plasma and hepatic tissue, biochemical tests, histopathological evaluations, and oxidative stress markers staining levels were performed. Results: Our findings showed that OD could effectively reduce liver injury by reducing the activity of liver function enzymes (AST and ALP). At the same time, it did not affect total bilirubin and protein. Bile duct ligation-induced hepatic markers of protein oxidation (PCO) and reactive nitrogen species (NO) were significantly decreased by OD, and it also promoted liver antioxidant capacity by enhancing superoxide dismutase (SOD) activities. Moreover, OD treatment prevented liver bile duct proliferative changes in histopathologic analysis. Conclusions: Our study confirmed that OD exerts substantial hepatoprotective activities against BDL-induced cholestasis by improving liver damage markers and regulating oxidative stress. It may be a beneficial therapeutic agent for managing cholestasis. Bioassay-guided isolation and identification of bioactive OD secondary metabolites can further direct the discovery of potential natural-based drug candidates.
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Sheweita SA, El-Masry YM, Zaghloul TI, Mostafa SK, Elgindy NA. Preclinical studies on melanogenesis proteins using a resveratrol-nanoformula as a skin whitener. Int J Biol Macromol 2022; 223:870-881. [PMID: 36370858 DOI: 10.1016/j.ijbiomac.2022.11.036] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 11/03/2022] [Accepted: 11/04/2022] [Indexed: 11/10/2022]
Abstract
A naturally occurring polyphenol called trans-resveratrol has received a lot of attention due to its possible health advantages for humans. The low solubility of trans-resveratrol and its isomerization upon UV exposure strongly limit its application as a skin-whitening agent. In the present study, to increase trans-resveratrol solubility, a new nanoformula was created by combining hydrophilic surfactants and oils. Trans-Resveratrol nanoformula has been prepared, characterized, and applied as a skin-whitening agent on the dorsal skin of Guinea pigs. The optimized trans-resveratrol nanoformula with a particle size of 63.49 nm displayed a single peak and a polydispersity index [0.36 ± 0.02]. In addition, the zeta potential of the optimized formula was -30.4 mV, confirming the high stability of this nanoformula. The melanin contents in the trans-resveratrol nanoformula-treated group were substantially lower than those of the control and the blank nanoformula-treated groups after staining of the dorsal skins [black areas] of guinea pigs with Fontana Mountain dye. The pigmentation index in the control, blank nanoformula, and optimized trans-resveratrol nanoformula were 329.4 ± 36.9, 335.8 ± 71.4, and 124.8 ± 19.6 respectively. Confirming this finding, immunohistochemistry analysis of skin tissues revealed that the expressions of melanogenesis-regulating proteins such as tyrosinase and microphthalmia-associated transcription factor were down-regulated. The safety of topical application of trans-resveratrol nanoformula was validated by no changes in free radical levels and oxidative stress markers proteins in the livers and kidneys of guinea pigs at the end of the experiment. Conclusions: A novel trans-resveratrol nanoformula as well as the mechanism whereby it promotes skin whitening effects were presented. Furthermore, the study illustrated that trans-resveratrol nanoformula is safe, non-toxic, and can be applied for skin whitening, although more research on human skin is needed.
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Affiliation(s)
- Salah A Sheweita
- Department of Clinical Biochemistry, Faculty of Medicine, King Khalid University, Abha, KSA; Department of Biotechnology, Institute of Graduate Studies and Research, Alexandria University, Alexandria 21526, Egypt.
| | - Yassin M El-Masry
- Department of Biotechnology, Institute of Graduate Studies and Research, Alexandria University, Alexandria 21526, Egypt
| | - Taha I Zaghloul
- Department of Biotechnology, Institute of Graduate Studies and Research, Alexandria University, Alexandria 21526, Egypt
| | - Shaimaa K Mostafa
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Delta University for Science and Technology, Gamesa, Mansoura, Egypt
| | - Nazik A Elgindy
- Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Egypt
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Barmoudeh Z, Sadeghi H, Gheitasi I, Khalvati B, Omidifar N, Azizi M, Moslemi Z, Nikbakht J, Doustimotlagh AH. Fluvoxamine ameliorates oxidative stress and inflammation induced by bile-duct ligation in male rats. Heliyon 2022; 8:e12344. [PMID: 36590477 PMCID: PMC9800296 DOI: 10.1016/j.heliyon.2022.e12344] [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: 12/28/2021] [Revised: 06/14/2022] [Accepted: 12/06/2022] [Indexed: 12/23/2022] Open
Abstract
Introduction Cholestasis is a disorder that the bile ducts were narrowed and bile acids are not released simply. Bile acids-induced liver damage is exacerbated by inflammation and oxidative stress. The goal of the current study was to investigate the protective impacts of fluvoxamine (Flu) on oxidant-antioxidant balance and inflammatory cytokines in the bile duct ligated (BDL) rats. Methods Thirty-two male rats were arbitrarily allocated in 4 groups; sham-control (SC), SC+ 150 mg/kg Flu (SCF), bile duct ligation (BDL), and BDL+ 150 mg/kg Flu (BDLF). The rats received distilled water and Flu orally for one week. Biochemical analysis, hematoxylin and eosin staining, as well as oxidant/antioxidant status were evaluated. Also, the mRNA expression of TGF-β1, IL-1, TNF-α, and α-SMA were determined. Results The findings indicated serum values of ALT, total bilirubin, and ALP slightly declined in the BDL + Flu group in contrast to BDL rats. The plasma protein carbonyl and inflammatory markers were markedly increased in the BDL group in contrast with SC group (P ≤ 0.05). Treatment with Flu in BDL rats markedly reduced the values of hepatic nitric oxide metabolite and malondialdehyde, plasma protein carbonyl, as well as TNF-α mRNA level (P ≤ 0.05). Histological parameters were improved in the BDL + Flu group in comparison to BDL merely rats. Conclusion It seems that Flu declined oxidative stress probably by inhibiting lipid peroxidation, protein oxidation, and nitric oxide formation. Also, it reduced inflammation by decreasing TNF-α mRNA expression.
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Affiliation(s)
- Zahra Barmoudeh
- Student Research Committee, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Hossein Sadeghi
- Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Izadpanah Gheitasi
- Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Bahman Khalvati
- Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Navid Omidifar
- Biotechnology Research Center, Department of Pathology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mahdokht Azizi
- Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Zahra Moslemi
- Student Research Committee, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Jafar Nikbakht
- Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
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Alvi M, Rehman K, Akash MSH, Yaqoob A, Shoaib SM. Determination of Metabolomics Profiling in BPA-Induced Impaired Metabolism. Pharmaceutics 2022; 14:pharmaceutics14112496. [PMID: 36432690 PMCID: PMC9692868 DOI: 10.3390/pharmaceutics14112496] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 11/14/2022] [Accepted: 11/16/2022] [Indexed: 11/19/2022] Open
Abstract
Exposure to bisphenol A (BPA) is unavoidable and it has far-reaching negative effects on living systems. This study aimed to explore the toxic effects of BPA in an experimental animal model through a metabolomics approach that is useful in measuring small molecule perturbations. Beside this, we also examined the ameliorative effects of resveratrol (RSV) against BPA-induced disturbances in experimental mice. This study was conducted for 28 days, and the results showed that BPA indeed induced an impairment in amino acid metabolism, taking place in the mitochondria by significantly (p < 0.05) decreasing the levels of certain amino acids, i.e., taurine, threonine, asparagine, leucine, norleucine, and glutamic acid in the mice plasma. However, the administration of RSV did prove effective against the BPA-induced intoxication and significantly (p < 0.05) restored the level of free amino acids. Lipid metabolites, L-carnitine, sphinganine, phytosphingosine, and lysophosphatidylcholine were also determined in the mice serum. A significant (p < 0.05) decline in glutathione peroxidase (GPx), superoxide dismutase (SOD,) glutathione, and catalase levels and an elevation in malondialdehyde level in the BPA group confirmed the generation of oxidative stress and lipid peroxidation in experimental mice exposed to BPA. The expression of Carnitine palmitoyltransferase I (CPT-I), carnitine palmitoyltransferase II (CPT-II), lecithin−cholesterol acyltransferase (LCAT), carnitine O-octanoyltransferase (CROT), carnitine-acylcarnitine translocase (CACT), and 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR) genes was significantly upregulated in the liver tissue homogenates of experimental mice exposed to BPA, although RSV regulated the expression of these genes when compared with BPA treated experimental mice. CPT-I, CPT-II, and CACT genes are located in the mitochondria and are involved in the metabolism and transportation of carnitine. Hence, this study confirms that BPA exposure induced oxidative stress, upregulated gene expression, and impaired lipid and amino acid metabolism in experimental mice.
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Affiliation(s)
- Maria Alvi
- Department of Pharmaceutical Chemistry, Government College University, Faisalabad 38000, Pakistan
| | - Kanwal Rehman
- Department of Pharmacy, The Women University, Multan 66000, Pakistan
| | - Muhammad Sajid Hamid Akash
- Department of Pharmaceutical Chemistry, Government College University, Faisalabad 38000, Pakistan
- Correspondence:
| | - Azka Yaqoob
- Department of Pharmaceutical Chemistry, Government College University, Faisalabad 38000, Pakistan
| | - Syed Muhammad Shoaib
- Drugs Testing Laboratory, Faisalabad, Primary & Secondary Healthcare Department, Government of the Punjab, Lahore 54000, Pakistan
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Chupradit S, Bokov D, Zamanian MY, Heidari M, Hakimizadeh E. Hepatoprotective and therapeutic effects of resveratrol: A focus on anti-inflammatory and anti- oxidative activities. Fundam Clin Pharmacol 2021; 36:468-485. [PMID: 34935193 DOI: 10.1111/fcp.12746] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Revised: 11/16/2021] [Accepted: 12/17/2021] [Indexed: 11/26/2022]
Abstract
Being the most essential organ in the body, the liver performs critical functions. Hepatic disorders, such as alcoholic liver disease, hepatic steatosis, liver fibrosis, non-alcoholic fatty liver disease, hepatocellular carcinoma and hepatic failure, have an impact on the biochemical and physiological functions of the body. The main representative of the flavonoid subgroup of flavones, Resveratrol (RES), exhibits suitable pharmacological activities for treating various liver diseases, such as fatty hepatitis, liver steatosis, liver cancer and liver fibrosis. According to various studies, grapes and red wine are good sources of RES. RES has various health properties; it is anti-inflammatory, anti-apoptotic, anti-oxidative and hepatoprotective against several hepatic diseases and hepatoxicity. Therefore, we performed a thorough research and created a summary of the distinct targets of RES in various stages of liver diseases. We concluded that RES inhibited liver inflammation essentially by causing a significant decrease in the expression of various pro-inflammatory cytokines like TNF-α, IL-1α, IL-1β, and IL-6. It also inhibits the transcription factor nuclear NF-κB that brings about the inflammatory cascade. RES also inhibits the PI3K/Akt/mTOR pathway to induce apoptosis. Additionally, it reduces oxidative stress in hepatic tissue by markedly reducing MDA and NO contents, and significantly increasing the levels of CAT, SOD and reduced GSH, in addition to AST and ALT, against toxic chemicals like CC14, As2O3 and TTA. Due to its anti-oxidant, anti-inflammatory and anti-fibrotic properties, RES reduces liver injury markers. RES is safe natural antioxidant that provides pharmacological rectification of the hepatoxicity of toxic chemicals.
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Affiliation(s)
- Supat Chupradit
- Department of Occupational Therapy, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
| | - Dmitry Bokov
- Institute of Pharmacy, Sechenov First Moscow State Medical University, Moscow, Russian Federation.,Laboratory of Food Chemistry, Federal Research Center of Nutrition, Biotechnology and Food Safety, 2/14 Ustyinsky pr, Moscow, Russian Federation
| | - Mohammad Yassin Zamanian
- Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran.,School of Nahavand Paramedical, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Mahsa Heidari
- Department of Biochemistry, Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran
| | - Elham Hakimizadeh
- Physiology-Pharmacology Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
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Moslemi Z, Bardania H, Gheitasi I, Barmoudeh Z, Omidifar N, Parvin H, Khalvati B, Fouani MH, Alipour M, Doustimotlagh AH. Liposome Extract of Stachys pilifera Benth Effectively Improved Liver Damage due to Bile Duct Ligation Rats. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:8141563. [PMID: 34707781 PMCID: PMC8545598 DOI: 10.1155/2021/8141563] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 09/17/2021] [Accepted: 10/04/2021] [Indexed: 12/15/2022]
Abstract
Herbal medicines harbor essential therapeutic agents for the treatment of cholestasis. In this study, we have assessed the anticholestatic potential of Stachys pilifera Benth's (SPB's) hydroalcoholic extract encapsulated into liposomes using bile duct ligation- (BDL-) induced hepatic cholestasis in rats. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), malondialdehyde (MDA), total thiol (T-SH) content, protein carbonyl (PCO), total bilirubin (TBIL), albumin (ALB), and nitric oxide (NO) metabolite levels were measured in either liver tissue or plasma to assess liver damage. Moreover, expression of proinflammatory cytokines (IL-1β and TNF-α) and liver fibrosis markers (TGF-β and SM-α) which are driving forces of many liver disorders was also determined. The activity of AST, ALT, and ALP was significantly enhanced in the BDL group in comparison to the control group; however, treatment with liposomal (SPB) hydroalcoholic extract significantly reduced AST and ALT's activity. Increases in MDA, TBIL, and NO levels and T-SH content due to BDL were restored to control levels by liposomal (SPB) hydroalcoholic extract treatment. Similarly, hepatic and plasma oxidative marker MDA levels, significantly enhanced by BDL, were significantly decreased by liposomal (SPB) hydroalcoholic extract treatment. Moreover, histopathological findings further demonstrated a significant decrease in hepatic damage in the liposomal (SPB) hydroalcoholic extract-treated BDL group. In addition, liposomal (SPB) hydroalcoholic extract treatment decreased the liver expression of inflammatory cytokines (IL-1β, TNF-α) and liver fibrosis markers (TGF-β and SM-α). Since liposomal (SPB) hydroalcoholic extract treatment alleviated the BDL-induced injury of the liver and improved the hepatic structure and function more efficiently in comparison to free SPB hydroalcoholic extract, probable liposomal (SPB) hydroalcoholic extract exhibits required potential therapeutic value in protecting the liver against BDL-caused oxidative injury.
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Affiliation(s)
- Zahra Moslemi
- Student Research Committee, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Hassan Bardania
- Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
- Clinical Research Development Unit, Imamsajad Hospital, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Izadpanah Gheitasi
- Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Zahra Barmoudeh
- Student Research Committee, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Navid Omidifar
- Biotechnology Research Center, Department of Pathology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hamidreza Parvin
- Pharmaceutical Science Research Center, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Bahman Khalvati
- Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Mohamad Hassan Fouani
- Department of Nanobiotechnology, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mohsen Alipour
- Department of Advanced Medical Sciences & Technologies, School of Medicine, Jahrom University of Medical Sciences, Jahrom, Iran
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11
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ShamsEldeen AM, Al-Ani B, Ebrahim HA, Rashed L, Badr AM, Attia A, Farag AM, Kamar SS, Haidara MA, Al Humayed S, Ali Eshra M. Resveratrol suppresses cholestasis-induced liver injury and fibrosis in rats associated with the inhibition of TGFβ1-Smad3-miR21 axis and profibrogenic and hepatic injury biomarkers. Clin Exp Pharmacol Physiol 2021; 48:1402-1411. [PMID: 34157155 DOI: 10.1111/1440-1681.13546] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 05/30/2021] [Accepted: 06/18/2021] [Indexed: 02/05/2023]
Abstract
Cholestasis caused by slowing or blockage of bile flow is a serious liver disease that can lead to liver fibrosis and cirrhosis. The link between transforming growth factor beta 1 (TGFβ1), Smad family member 3 (Smad3), and microRNA 21 (miR21) in bile duct ligation (BDL)-induced liver fibrosis in the presence and absence of the anti-inflammatory and antioxidant compound, resveratrol (RSV), has not been previously studied. Therefore, we tested whether RSV can protect against BDL-induced liver fibrosis associated with the inhibition of the TGFβ1-Smad3-miR21 axis and profibrogenic and hepatic injury biomarkers. The model group of rats had their bile duct ligated (BDL) for 3 weeks before being killed, whereas, the BDL-treated rats were separated into three groups that received 10, 20, and 30 mg/kg RSV daily until the end of the experiment. Using light microscopy and ultrasound examinations, we documented in the BDL group, the development of hepatic injury and fibrosis as demonstrated by hepatocytes necrosis, bile duct hyperplasia, collagen deposition, enlarged liver with increased echogenicity, irregular nodular border and dilated common bile duct, which were more effectively inhibited by the highest used RSV dosage. In addition, RSV significantly (p ≤ 0.0027) inhibited BDL-induced hepatic TGFβ1, Smad3, miR21, the profibrogenic biomarker tissue inhibitor of metalloproteinases-1 (TIMP-1), malondialdehyde (MDA), interleukin-17a (IL-17a), and blood levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin. These findings show that RSV at 30 mg/kg substantially protects against BDL-induced liver injuries, which is associated with the inhibition of TGFβ1-Smad3-miR21 axis, and biomarkers of profibrogenesis, oxidative stress, and inflammation.
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Affiliation(s)
- Asmaa M ShamsEldeen
- Departments of Physiology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Bahjat Al-Ani
- Department of Physiology, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Hasnaa A Ebrahim
- Department of Basic Medical Sciences, College of Medicine, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Laila Rashed
- Medical Biochemistry and Molecular Biology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Amul M Badr
- Medical Biochemistry and Molecular Biology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Abeer Attia
- Public Health, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Ayman M Farag
- Radiology Department, Military Medical Academy, Cairo, Egypt
| | - Samaa S Kamar
- Histology and Cell Biology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mohamed A Haidara
- Departments of Physiology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Suliman Al Humayed
- Department of Internal Medicine, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Mohammed Ali Eshra
- Departments of Physiology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo, Egypt
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12
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Samarghandian S, Pourbagher-Shahri AM, Ashrafizadeh M, Khan H, Forouzanfar F, Aramjoo H, Farkhondeh T. A Pivotal Role of the Nrf2 Signaling Pathway in Spinal Cord Injury: A Prospective Therapeutics Study. CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS 2021; 19:207-219. [PMID: 32496994 DOI: 10.2174/1871527319666200604175118] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Revised: 02/27/2020] [Accepted: 04/11/2020] [Indexed: 12/15/2022]
Abstract
The nuclear erythroid 2-related factor 2 (Nrf2) signaling pathway has a main role against oxidative stress and inflammation. Spinal Cord Injury (SCI) leads to the high secretion of inflammatory cytokines and reactive oxygen species, which disturbs nervous system function and regeneration. Several studies have indicated that the activation of the Nrf2 signaling pathway may be effective against inflammation after SCI. The experimental studies have indicated that many chemical and natural agents act as Nrf2 inducer, which inhibits the SCI progression. Thus, the finding of novel Nrf2- inducer anti-inflammatory agents may be a valuable approach in drug discovery. In the present review, we discussed the Nrf2 signal pathway and crosstalk with the NF-κB pathway and also the impact of this pathway on inflammation in animal models of SCI. Furthermore, we discussed the regulation of Nrf2 by several phytochemicals and drugs, as well as their effects on the SCI inhibition. Therefore, the current study presented a new hypothesis of the development of anti-inflammatory agents that mediate the Nrf2 signaling pathway for treating the SCI outcomes.
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Affiliation(s)
- Saeed Samarghandian
- Healthy Ageing Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | | | - Milad Ashrafizadeh
- Department of Basic Science, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University, Mardan 23200, Pakistan
| | - Fatemeh Forouzanfar
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamed Aramjoo
- Student Research Committee, Lab Sciences Technology, Birjand University of Medical Sciences, Birjand, Iran
| | - Tahereh Farkhondeh
- Faculty of Pharmacy, Birjand University of Medical Sciences, Birjand, Iran
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ELKady AH, Elkafoury BM, Saad DA, Abd el-Wahed DM, Baher W, Ahmed MA. Hepatic ischemia reperfusion injury: effect of moderate intensity exercise and oxytocin compared to l-arginine in a rat model. EGYPTIAN LIVER JOURNAL 2021. [DOI: 10.1186/s43066-021-00111-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Abstract
Abstract
Background
Hepatic ischemia reperfusion (IR) injury is considered as a main cause of liver damage and dysfunction. The l-arginine/nitric oxide pathway seems to be relevant during this process of IR. Although acute intense exercise challenges the liver with increased reactive oxygen species (ROS), regular training improves hepatic antioxidant status. Also, oxytocin (Oxy), besides its classical functions, it exhibits a potent antistress, anti-inflammatory, and antioxidant effects. This study was designed to evaluate the hepatic functional and structural changes induced by hepatic IR injury in rats and to probe the effect and potential mechanism of moderate intensity exercise training and/or Oxy, in comparison to a nitric oxide donor, l-arginine, against liver IR-induced damage.
Results
Compared to the sham-operated control group, the hepatic IR group displayed a significant increase in serum levels of ALT and AST, plasma levels of MDA and TNF-α, and significant decrease in plasma TAC and nitrite levels together with the worsening of liver histological picture. L-Arg, Oxy, moderate intensity exercise, and the combination of both Oxy and moderate intensity exercises ameliorated these deleterious effects that were evident by the significant decrease in serum levels of ALT and AST, significant elevation in TAC and nitrite, and significant decline in lipid peroxidation (MDA) and TNF-α, besides regression of histopathological score regarding hepatocyte necrosis, vacuolization, and nuclear pyknosis. Both the moderate intensity exercise-trained group and Oxy-treated group showed a significant decline in TNF-α and nitrite levels as compared to l-Arg-treated group. The Oxy-treated group showed statistical insignificant changes in serum levels of ALT, AST, and plasma levels of nitrite, MDA, TAC, and TNF-α as compared to moderate intensity exercise-trained group.
Conclusion
The combination of both moderate intensity exercise and Oxy displayed more pronounced hepatoprotection on comparison with l-Arg which could be attributed to their more prominent antioxidant and anti-inflammatory effects but not due to their NO-enhancing effect.
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Griñán-Ferré C, Bellver-Sanchis A, Izquierdo V, Corpas R, Roig-Soriano J, Chillón M, Andres-Lacueva C, Somogyvári M, Sőti C, Sanfeliu C, Pallàs M. The pleiotropic neuroprotective effects of resveratrol in cognitive decline and Alzheimer's disease pathology: From antioxidant to epigenetic therapy. Ageing Res Rev 2021; 67:101271. [PMID: 33571701 DOI: 10.1016/j.arr.2021.101271] [Citation(s) in RCA: 139] [Impact Index Per Article: 34.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2020] [Revised: 02/03/2021] [Accepted: 02/03/2021] [Indexed: 12/12/2022]
Abstract
While the elderly segment of the population continues growing in importance, neurodegenerative diseases increase exponentially. Lifestyle factors such as nutrition, exercise, and education, among others, influence ageing progression, throughout life. Notably, the Central Nervous System (CNS) can benefit from nutritional strategies and dietary interventions that prevent signs of senescence, such as cognitive decline or neurodegenerative diseases such as Alzheimer's disease and Parkinson's Disease. The dietary polyphenol Resveratrol (RV) possesses antioxidant and cytoprotective effects, producing neuroprotection in several organisms. The oxidative stress (OS) occurs because of Reactive oxygen species (ROS) accumulation that has been proposed to explain the cause of the ageing. One of the most harmful effects of ROS in the cell is DNA damage. Nevertheless, there is also evidence demonstrating that OS can produce other molecular changes such as mitochondrial dysfunction, inflammation, apoptosis, and epigenetic modifications, among others. Interestingly, the dietary polyphenol RV is a potent antioxidant and possesses pleiotropic actions, exerting its activity through various molecular pathways. In addition, recent evidence has shown that RV mediates epigenetic changes involved in ageing and the function of the CNS that persists across generations. Furthermore, it has been demonstrated that RV interacts with gut microbiota, showing modifications in bacterial composition associated with beneficial effects. In this review, we give a comprehensive overview of the main mechanisms of action of RV in different experimental models, including clinical trials and discuss how the interconnection of these molecular events could explain the neuroprotective effects induced by RV.
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Affiliation(s)
- Christian Griñán-Ferré
- Pharmacology Section, Department of Pharmacology, Toxicology, and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Neuroscience, University of Barcelona (NeuroUB), Av Joan XXIII 27-31, 08028, Barcelona, Spain.
| | - Aina Bellver-Sanchis
- Pharmacology Section, Department of Pharmacology, Toxicology, and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Neuroscience, University of Barcelona (NeuroUB), Av Joan XXIII 27-31, 08028, Barcelona, Spain
| | - Vanessa Izquierdo
- Pharmacology Section, Department of Pharmacology, Toxicology, and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Neuroscience, University of Barcelona (NeuroUB), Av Joan XXIII 27-31, 08028, Barcelona, Spain
| | - Rubén Corpas
- Institut d'Investigacions Biomèdiques de Barcelona (IIBB), CSIC, IDIBAPS and CIBERESP, Barcelona, Spain
| | - Joan Roig-Soriano
- Department of Biochemistry and Molecular Biology, Universitat Autònoma Barcelona, Institut de Neurociènces (INc), Universitat Autònoma Barcelona, Bellaterra, Spain
| | - Miguel Chillón
- Department of Biochemistry and Molecular Biology, Universitat Autònoma Barcelona, Institut de Neurociènces (INc), Universitat Autònoma Barcelona, Bellaterra, Spain; Vall d'Hebron Institut de Recerca (VHIR), Research Group on Gene Therapy at Nervous System, Passeig de la Vall d'Hebron, Barcelona, Spain; Unitat producció de Vectors (UPV), Universitat Autònoma Barcelona, Bellaterra, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
| | - Cristina Andres-Lacueva
- Biomarkers and Nutrimetabolomics Laboratory, Department of Nutrition, Food Sciences and Gastronomy, Xarta, INSA, Faculty of Pharmacy and Food Sciences, Campus Torribera, University of Barcelona, Spain; CIBER de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salut Carlos III, Barcelona, Spain
| | - Milán Somogyvári
- Department of Medical Chemistry, Semmelweis University, Budapest, Hungary
| | - Csaba Sőti
- Department of Medical Chemistry, Semmelweis University, Budapest, Hungary
| | - Coral Sanfeliu
- Institut d'Investigacions Biomèdiques de Barcelona (IIBB), CSIC, IDIBAPS and CIBERESP, Barcelona, Spain
| | - Mercè Pallàs
- Pharmacology Section, Department of Pharmacology, Toxicology, and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Neuroscience, University of Barcelona (NeuroUB), Av Joan XXIII 27-31, 08028, Barcelona, Spain
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15
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Virk P, Al-Mukhaizeem NAR, Bin Morebah SH, Fouad D, Elobeid M. Protective effect of resveratrol against toxicity induced by the mycotoxin, zearalenone in a rat model. Food Chem Toxicol 2020; 146:111840. [PMID: 33137427 DOI: 10.1016/j.fct.2020.111840] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 10/24/2020] [Accepted: 10/27/2020] [Indexed: 12/18/2022]
Abstract
Contamination of cereal crops with zearalenone (ZEA), a mycotoxin produced by Fusarium fungi, is a worldwide health concern. The study assessed the ameliorative potential of resveratrol (RSV), a potent antioxidant against ZEA induced toxicity in adult male Wistar rats. Rats (n = 40), with an average weight of 100-150 g were used for the exposure study for three weeks. The animals were divided into four groups (I to IV) each comprising 10 rats. Group I was kept as negative control and was administered normal saline. Group II and III were exposed to 2 mg/kg of the mycotoxin, ZEA administered intraperitoneally once every week. Group III was treated with resveratrol (RSV) orally (5 mg/kg) daily. Group IV was treated only with resveratrol (5 mg/kg/daily) as a positive control. The protective effect of resveratrol was evaluated on; biochemical variables, biomarkers of oxidative stress, markers of immunotoxicity, and DNA damage. The findings showed that exposure to ZEA elicited oxidative stress and modulated the antioxidant enzyme activities. A disarray in the lipid profile, parameters of the humoral and cellular immune response; serum cytokines and immunoglobulins was also observed. Further, COMET assay showed detectable DNA lesions. Taken together, RSV was efficacious in reducing and/or reversing the ZEA induced toxicity.
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Affiliation(s)
- Promy Virk
- Department of Zoology, College of Science, King Saud University, P.O. Box 22452, Riyadh, 11459, Saudi Arabia.
| | | | - Sara Hamad Bin Morebah
- Department of Zoology, College of Science, King Saud University, P.O. Box 22452, Riyadh, 11459, Saudi Arabia
| | - Dalia Fouad
- Department of Zoology, College of Science, King Saud University, P.O. Box 22452, Riyadh, 11459, Saudi Arabia; Department of Zoology and Entomology Department, Faculty of Science, Helwan University, Ein Helwan, Cairo, Egypt
| | - Mai Elobeid
- Department of Zoology, College of Science, King Saud University, P.O. Box 22452, Riyadh, 11459, Saudi Arabia
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Ma X, Jiang Y, Zhang W, Wang J, Wang R, Wang L, Wei S, Wen J, Li H, Zhao Y. Natural products for the prevention and treatment of cholestasis: A review. Phytother Res 2020; 34:1291-1309. [PMID: 32026542 DOI: 10.1002/ptr.6621] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Revised: 12/26/2019] [Accepted: 01/13/2020] [Indexed: 12/16/2022]
Abstract
Cholestasis is a common manifestation of decreased bile flow in various liver diseases. It results in fibrosis and even cirrhosis without proper treatment. It is believed that a wide range of factors, including transporter dysfunction, oxidative stress, inflammatory damage, and immune disruption, can cause cholestasis. In recent years, natural products have drawn much attention for specific multiple-target activities in diseases. Many attempts have been made to investigate the anticholestatic effects of natural products with advanced technology. This review summarizes recent studies on the biological activities and mechanisms of recognized compounds for cholestasis treatment. Natural products, including various flavonoids, phenols, acids, quinones, saponins, alkaloids, glycosides, and so on, function as comprehensive regulators via ameliorating oxidative stress, inflammation, and apoptosis, restoring bile acid balance with hepatic transporters, and adjusting immune disruption. Moreover, in this progress, nuclear factor erythroid 2-related factor 2, reactive oxygen species production, heme oxygenase-1, NF-κB, cholesterol 7 alpha-hydroxylase, and farnesoid X receptors are thought as main targets for the activity of natural products. Therefore, this review presents the detailed mechanisms that include multiple targets and diverse signalling pathways. Natural products are the valuable when seeking novel therapeutic agents to treat cholestatic liver diseases.
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Affiliation(s)
- Xiao Ma
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yinxiao Jiang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Wenwen Zhang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jiabo Wang
- China Military Institute of Chinese Medicine, Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Ruilin Wang
- China Military Institute of Chinese Medicine, Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Lifu Wang
- China Military Institute of Chinese Medicine, Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Shizhang Wei
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.,Department of Pharmacy, Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Jianxia Wen
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.,Department of Pharmacy, Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Haotian Li
- Department of Pharmacy, Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Yanling Zhao
- Department of Pharmacy, Fifth Medical Center of PLA General Hospital, Beijing, China
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17
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Gong L, Guo S, Zou Z. Resveratrol ameliorates metabolic disorders and insulin resistance in high-fat diet-fed mice. Life Sci 2020; 242:117212. [DOI: 10.1016/j.lfs.2019.117212] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Revised: 12/12/2019] [Accepted: 12/18/2019] [Indexed: 12/23/2022]
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18
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Asis M, Hemmati N, Moradi S, Nagulapalli Venkata KC, Mohammadi E, Farzaei MH, Bishayee A. Effects of resveratrol supplementation on bone biomarkers: a systematic review and meta-analysis. Ann N Y Acad Sci 2019; 1457:92-103. [PMID: 31490554 DOI: 10.1111/nyas.14226] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 07/14/2019] [Accepted: 08/06/2019] [Indexed: 02/06/2023]
Abstract
The current study presents a comprehensive systematic review and meta-analysis of randomized controlled trials (RCTs) on resveratrol and bone health biomarkers. PubMed, Scopus, and Web of Science (until September 2018) were searched to identify the potential RCTs with information on resveratrol supplementation and bone metabolism biomarkers. Mean differences (MD) were analyzed using a random-effects model. Pooling six RCTs (eight treatment arms with 264 subjects) together identified no significant reduction of serum Ca, osteocalcin, C-terminal telopeptide of type I collagen, and procollagen I N-terminal propeptide values after resveratrol supplementation over placebo treatment. However, a significant increase in serum alkaline phosphatase (ALP) (MD: 5.69 mg/mL, 95% CI: 3.58-7.80, I2 = 95.7%, P < 0.001) and bone alkaline phosphatase (BAP) (MD: 10.57 mmHg, 95% CI: 5.36-15.78, I2 = 99.2%, P < 0.001) values was observed after resveratrol treatment relative to placebo. The findings of this study indicate that resveratrol supplementation increased some key bone biomarkers, such as ALP and BAP. Further precise clinical trials of the effects of resveratrol supplementation on bone health should be conducted.
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Affiliation(s)
- Marzieh Asis
- Internal Medicine Department, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Niloufar Hemmati
- Internal Medicine Department, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Sajjad Moradi
- Halal Research Center of IRI, FDA, Tehran, Iran.,Nutritional Sciences Department, School of Nutritional Sciences and Food Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | | | | | - Mohammad Hosein Farzaei
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Anupam Bishayee
- Lake Erie College of Osteopathic Medicine, Bradenton, Florida
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19
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Heidari R, Mohammadi H, Ghanbarinejad V, Ahmadi A, Ommati MM, Niknahad H, Jamshidzadeh A, Azarpira N, Abdoli N. Proline supplementation mitigates the early stage of liver injury in bile duct ligated rats. J Basic Clin Physiol Pharmacol 2018; 30:91-101. [PMID: 30205645 DOI: 10.1515/jbcpp-2017-0221] [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: 01/05/2018] [Accepted: 07/11/2018] [Indexed: 01/01/2023]
Abstract
Background Proline is a proteinogenic amino acid with multiple biological functions. Several investigations have been supposed that cellular proline accumulation is a stress response mechanism. This amino acid acts as an osmoregulator, scavenges free radical species, boosts cellular antioxidant defense mechanisms, protects mitochondria, and promotes energy production. The current study was designed to investigate the effect of proline treatment on the liver in bile duct ligated (BDL) rats as an animal model of cholestasis/cirrhosis. Methods BDL rats were supplemented with proline-containing drinking water (0.25% and 0.5% w:v), and samples were collected at scheduled time intervals (3, 7, 14, 28, and 42 days after BDL surgery). Results Drastic elevation in the serum level of liver injury biomarkers and significant tissue histopathological changes were evident in BDL rats. Markers of oxidative stress were also higher in the liver of BDL animals. It was found that proline supplementation attenuated BDL-induced alteration in serum biomarkers of liver injury, mitigated liver histopathological changes, and alleviated markers of oxidative stress at the early stage of BDL operation (3, 7, and 14 days after BDL surgery). Conclusions The hepatoprotection provided by proline in BDL animals might be associated with its ability to attenuate oxidative stress and its consequences.
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Affiliation(s)
- Reza Heidari
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, P. O. Box 1583; 71345, Roknabad, Karafarin St., Shiraz, Fars, Iran, Phone: 07131242627-282, Fax: 07131242626, E-mail:
| | - Hamidreza Mohammadi
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz7146864685,Iran
| | - Vahid Ghanbarinejad
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz7146864685,Iran
| | - Asrin Ahmadi
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz7146864685,Iran
| | - Mohammad Mehdi Ommati
- Department of Animal Sciences, School of Agriculture, Shiraz University, Shiraz 7144133111, Iran
| | - Hossein Niknahad
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz7146864685,Iran
| | - Akram Jamshidzadeh
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz7146864685,Iran
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz 7193711351, Iran
| | - Narges Abdoli
- Iran Food and Drug Administration (IFDA), Iran Ministry of Health, Fakhr-e Razi Street, Tehran Province, District 11, Tehran 1314715311, Iran, Phone: +98-216-1927429, Fax: +98-216-6427965
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Ahmad A, Ahmad R. Proteomic approach to identify molecular signatures during experimental hepatic fibrosis and resveratrol supplementation. Int J Biol Macromol 2018; 119:1218-1227. [DOI: 10.1016/j.ijbiomac.2018.08.062] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 08/03/2018] [Accepted: 08/12/2018] [Indexed: 12/15/2022]
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Heidari R, Niknahad H, Sadeghi A, Mohammadi H, Ghanbarinejad V, Ommati MM, Hosseini A, Azarpira N, Khodaei F, Farshad O, Rashidi E, Siavashpour A, Najibi A, Ahmadi A, Jamshidzadeh A. Betaine treatment protects liver through regulating mitochondrial function and counteracting oxidative stress in acute and chronic animal models of hepatic injury. Biomed Pharmacother 2018; 103:75-86. [DOI: 10.1016/j.biopha.2018.04.010] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2018] [Revised: 03/29/2018] [Accepted: 04/02/2018] [Indexed: 12/29/2022] Open
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22
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Heidari R, Ghanbarinejad V, Mohammadi H, Ahmadi A, Esfandiari A, Azarpira N, Niknahad H. Dithiothreitol supplementation mitigates hepatic and renal injury in bile duct ligated mice: Potential application in the treatment of cholestasis-associated complications. Biomed Pharmacother 2018; 99:1022-1032. [DOI: 10.1016/j.biopha.2018.01.018] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Revised: 12/29/2017] [Accepted: 01/03/2018] [Indexed: 01/18/2023] Open
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Dolezelova E, Prasnicka A, Cermanova J, Carazo A, Hyrsova L, Hroch M, Mokry J, Adamcova M, Mrkvicova A, Pavek P, Micuda S. Resveratrol modifies biliary secretion of cholephilic compounds in sham-operated and cholestatic rats. World J Gastroenterol 2017; 23:7678-7692. [PMID: 29209109 PMCID: PMC5703928 DOI: 10.3748/wjg.v23.i43.7678] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Revised: 08/15/2017] [Accepted: 09/05/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the effect of resveratrol on biliary secretion of cholephilic compounds in healthy and bile duct-obstructed rats.
METHODS Resveratrol (RSV) or saline were administered to rats by daily oral gavage for 28 d after sham operation or reversible bile duct obstruction (BDO). Bile was collected 24 h after the last gavage during an intravenous bolus dose of the Mdr1/Mrp2 substrate azithromycin. Bile acids, glutathione and azithromycin were measured in bile to quantify their level of biliary secretion. Liver expression of enzymes and transporters relevant for bile production and biliary secretion of major bile constituents and drugs were analyzed at the mRNA and protein levels using qRT-PCR and Western blot analysis, respectively. The TR-FRET PXR Competitive Binding Assay kit was used to determine the agonism of RSV at the pregnane X receptor.
RESULTS RSV increased bile flow in sham-operated rats due to increased biliary secretion of bile acids (BA) and glutathione. This effect was accompanied by the induction of the hepatic rate-limiting transporters for bile acids and glutathione, Bsep and Mrp2, respectively. RSV also induced Cyp7a1, an enzyme that is crucial for bile acid synthesis; Mrp4, a transporter important for BA secretion from hepatocytes to blood; and Mdr1, the major apical transporter for xenobiotics. The findings were supported by increased biliary secretion of azithromycin. The TR-FRET PXR competitive binding assay confirmed RSV as a weak agonist of the human nuclear receptor PXR, which is a transcriptional regulator of Mdr1/Mrp2. RSV demonstrated significant hepatoprotective properties against BDO-induced cirrhosis. RSV also reduced bile flow in BDO rats without any corresponding change in the levels of the transporters and enzymes involved in RSV-mediated hepatoprotection.
CONCLUSION Resveratrol administration for 28 d has a distinct effect on bile flow and biliary secretion of cholephilic compounds in healthy and bile duct-obstructed rats.
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Affiliation(s)
- Eva Dolezelova
- Department of Biological and Medical Sciences, Charles University, Faculty of Pharmacy in Hradec Kralove, 50003 Hradec Kralove, Czech Republic
| | - Alena Prasnicka
- Department of Pharmacology, Charles University, Faculty of Medicine in Hradec Kralove, 50003 Hradec Kralove, Czech Republic
| | - Jolana Cermanova
- Department of Pharmacology, Charles University, Faculty of Medicine in Hradec Kralove, 50003 Hradec Kralove, Czech Republic
| | - Alejandro Carazo
- Department of Pharmacology and Toxicology, Charles University, Faculty of Pharmacy in Hradec Kralove, 50003 Hradec Kralove, Czech Republic
| | - Lucie Hyrsova
- Department of Pharmacology and Toxicology, Charles University, Faculty of Pharmacy in Hradec Kralove, 50003 Hradec Kralove, Czech Republic
| | - Milos Hroch
- Department of Medical Biochemistry, Charles University, Faculty of Medicine in Hradec Kralove, 50003 Hradec Kralove, Czech Republic
| | - Jaroslav Mokry
- Department of Histology and Embryology, Charles University, Faculty of Medicine in Hradec Kralove, 50003 Hradec Kralove, Czech Republic
| | - Michaela Adamcova
- Department of Physiology, Charles University, Faculty of Medicine in Hradec Kralove, 50003 Hradec Kralove, Czech Republic
| | - Alena Mrkvicova
- Department of Medical Biochemistry, Charles University, Faculty of Medicine in Hradec Kralove, 50003 Hradec Kralove, Czech Republic
| | - Petr Pavek
- Department of Pharmacology and Toxicology, Charles University, Faculty of Pharmacy in Hradec Kralove, 50003 Hradec Kralove, Czech Republic
| | - Stanislav Micuda
- Department of Pharmacology, Charles University, Faculty of Medicine in Hradec Kralove, 50003 Hradec Kralove, Czech Republic
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Hepatoprotective effect of boldine in a bile duct ligated rat model of cholestasis/cirrhosis. PHARMANUTRITION 2017. [DOI: 10.1016/j.phanu.2017.07.001] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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25
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Shen K, Feng X, Pan H, Zhang F, Xie H, Zheng S. Baicalin Ameliorates Experimental Liver Cholestasis in Mice by Modulation of Oxidative Stress, Inflammation, and NRF2 Transcription Factor. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:6169128. [PMID: 28757911 PMCID: PMC5516718 DOI: 10.1155/2017/6169128] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/25/2017] [Revised: 05/18/2017] [Accepted: 05/28/2017] [Indexed: 12/21/2022]
Abstract
Experimental cholestatic liver fibrosis was performed by bile duct ligation (BDL) in mice, and significant liver injury was observed in 15 days. Administration of baicalin in mice significantly ameliorates liver fibrosis. Experimental cholestatic liver fibrosis was associated with induced gene expression of fibrotic markers such as collagen I, fibronectin, alpha smooth muscle actin (SMA), and connective tissue growth factor (CTGF); increased inflammatory cytokines (TNFα, MIP1α, IL1β, and MIP2); increased oxidative stress and reactive oxygen species- (ROS-) inducing enzymes (NOX2 and iNOS); dysfunctional mitochondrial electron chain complexes; and apoptotic/necrotic cell death markers (DNA fragmentation, caspase 3 activity, and PARP activity). Baicalin administration on alternate day reduced fibrosis along with profibrotic gene expression, proinflammatory cytokines, oxidative stress, and cell death whereas improving the function of mitochondrial electron transport chain. We observed baicalin enhanced NRF2 activation by nuclear translocation and induced its target genes HO-1 and GCLM, thus enhancing antioxidant defense. Interplay of oxidative stress/inflammation and NRF2 were key players for baicalin-mediated protection. Stellate cell activation is crucial for initiation of fibrosis. Baicalin alleviated stellate cell activation and modulated TIMP1, SMA, collagen 1, and fibronectin in vitro. This study indicates that baicalin might be beneficial for reducing inflammation and fibrosis in liver injury models.
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Affiliation(s)
- Kezhen Shen
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
| | - Xiaowen Feng
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
| | - Hao Pan
- Department of Urology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
| | - Feng Zhang
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
| | - Haiyang Xie
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
| | - Shusen Zheng
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
- Division of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China
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26
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Abd-Elbaset M, Arafa ESA, El Sherbiny GA, Abdel-Bakky MS, Elgendy ANAM. Thymoquinone mitigate ischemia-reperfusion-induced liver injury in rats: a pivotal role of nitric oxide signaling pathway. Naunyn Schmiedebergs Arch Pharmacol 2016; 390:69-76. [PMID: 27717985 DOI: 10.1007/s00210-016-1306-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2016] [Accepted: 09/23/2016] [Indexed: 01/07/2023]
Abstract
Oxidative and nitrosative stress-induced endothelial cell damage play an essential role in the pathogenesis of hepatic ischemia-reperfusion (IR) injury. IR is associated with reduced eNOS expression and exacerbated by superimposed stress. NOSTRIN induces intracellular endothelial nitric oxide synthase (eNOS) translocation and inducible nitric oxide synthase (iNOS) increases nitric oxide (NO) production. Our aim was to assess hepatic expression of iNOS, eNOS, and NOSTRIN in IR with or without N-acetylcysteine (NAC) or thymoquinone (TQ) pretreatment and to compare their hepatoprotective effects. Surgical induction of IR was performed by occlusion of hepatic pedicle for 30 min with mini-clamp and reperfused for 30 min. The effects of TQ (20 mg/kg/day) or NAC (300 mg/kg/day) administered orally for 10 days were evaluated by serum ALT and AST, oxidative stress parameters, NO production, and histopathological analysis. Also, localization and expression of iNOS, eNOS, and NOSTRIN were assessed by immunofluorescence. TQ or NAC pretreatment significantly decreased elevated serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and myeloperoxidase (MPO) activities, malondialdehyde (MDA) level, and NO production. In addition, they restored the depleted GSH content and alleviated histopathological changes. Furthermore, they up-regulated eNOS and down-regulated iNOS and NOSTRIN expressions. TQ exerts its hepatoprotective effect, at least in part, by nitric oxide signaling pathway through modulation of iNOS, eNOS, and NOSTRIN expressions as well as suppression of oxidative stress.
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Affiliation(s)
- Mohamed Abd-Elbaset
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt
| | - El-Shaimaa A Arafa
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt. .,Department of Pharmacology and Toxicology, College of Pharmacy and Health Sciences, Ajman University of Science and Technology, Ajman, United Arab Emirates.
| | - Gamal A El Sherbiny
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Kafr El-Sheikh University, Kafr El-Sheikh, Egypt
| | - Mohamed S Abdel-Bakky
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.,Department of Pharmacology, College of pharmacy, Al Jouf University, Al Jouf, Kingdom of Saudi Arabia
| | - Abdel Nasser A M Elgendy
- Department of Pharmacology, Faculty of Veterinary medicine, Beni-Suef University, Beni-Suef, 62514, Egypt
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27
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Ansar S, Siddiqi NJ, Zargar S, Ganaie MA, Abudawood M. Hepatoprotective effect of Quercetin supplementation against Acrylamide-induced DNA damage in wistar rats. Altern Ther Health Med 2016; 16:327. [PMID: 27576905 PMCID: PMC5004263 DOI: 10.1186/s12906-016-1322-7] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Accepted: 08/25/2016] [Indexed: 11/10/2022]
Abstract
Background Quercetin (QR), is a polyphenolic flavonoid compound which is found in large amounts in certain foods, and protects against oxidative stress. The current study was conducted to determine whether Quercetin can possibly exert hepatoprotective and antioxidant activity against acrylamide (ACR) induced toxicity in rats. Methods Four groups of Wistar rats consisting of six rats each: (i) control group; (ii) ACR treated group (50 mg/kg bw); (iii) QR group: rats were treated with QR (10 mg/kg bw); (iv) QR (10 mg/kg bw) was given i.p. for 5 days followed by ACR (50 mg/kg bw) on 5th day (single dose). Results ACR caused an elevation in 8-OH guanosine level and a reduction in Glutahione S-transferase (GST) activity. Administration of QR significantly protected liver tissue against hepatotoxic effect of acrylamide from amelioration of the marker enzyme (p < 0.05) and DNA damage (p < 0.01) as evident by comet assay and, besides some indices of histopathological alterations. Conclusion It is concluded that QR could protect the liver against DNA damage induced by ACR probably is thus capable of ameliorating ACR-induced changes in the rat livers.
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28
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Xia P, Deng Q, Gao J, Yu X, Zhang Y, Li J, Guan W, Hu J, Tan Q, Zhou L, Han W, Yuan Y, Yu Y. Therapeutic effects of antigen affinity-purified polyclonal anti-receptor of advanced glycation end-product (RAGE) antibodies on cholestasis-induced liver injury in rats. Eur J Pharmacol 2016; 779:102-10. [PMID: 26970185 DOI: 10.1016/j.ejphar.2016.03.017] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Revised: 03/04/2016] [Accepted: 03/07/2016] [Indexed: 01/22/2023]
Abstract
Cholestasis leads to acute hepatic injury, fibrosis/cirrhosis, inflammation, and duct proliferation. We investigated whether blocking receptor of advanced glycation end-products (RAGE) with polyclonal anti-RAGE antibodies (anti-RAGE) could regulate acute liver injury and fibrosis in a rat bile duct ligation (BDL) model. Male Wister rats received 0.5mg/kg rabbit anti-RAGE or an equal amount of rabbit IgG by subcutaneous injection twice a week after BDL. Samples of liver tissue and peripheral blood were collected at 14 days after BDL. Serum biochemistry and histology were used to analyze the degree of liver injury. Quantitative real-time PCR (qPCR) and immunohistochemical staining were used to further analyze liver injury. Anti-RAGE improved the gross appearance of the liver and the rat survival rate. Liver tissue histology and relevant serum biochemistry indicated that anti-RAGE attenuated liver necrosis, inflammation, liver fibrosis, and duct proliferation in the BDL model. qPCR and western blotting showed significant reductions in interleukin-1β expression levels in the liver by treatment with anti-RAGE. Anti-RAGE also significantly reduced the mRNA levels of α1(1) collagen (Col1α1) and cholesterol 7α-hydroxylase, and the ratio of tissue inhibitor of matrix metalloproteinase-1 to matrix metalloproteinases (MMPs) in the liver. In addition, anti-RAGE regulated the transcriptional level of Col1α1 and MMP-9 in transforming growth factor-β-induced activated LX-2 cells in vitro. Anti-RAGE was found to inhibit hepatic stellate cell proliferation in vivo and in vitro. Therefore, anti-RAGE can protect the liver from injury induced by BDL in rats.
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Affiliation(s)
- Peng Xia
- Shanghai Municipality Key Laboratory of Veterinary Biotechnology, School of Agriculture and Biology, Shanghai Jiao Tong University, 800 Dongchuan Rd., Minhang, Shanghai 200240, China
| | - Qing Deng
- Shanghai Municipality Key Laboratory of Veterinary Biotechnology, School of Agriculture and Biology, Shanghai Jiao Tong University, 800 Dongchuan Rd., Minhang, Shanghai 200240, China
| | - Jin Gao
- Laboratory of Regenerative Medicine, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Rd., Minhang, Shanghai 200240, China
| | - Xiaolan Yu
- Shanghai Municipality Key Laboratory of Veterinary Biotechnology, School of Agriculture and Biology, Shanghai Jiao Tong University, 800 Dongchuan Rd., Minhang, Shanghai 200240, China
| | - Yang Zhang
- Laboratory of Regenerative Medicine, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Rd., Minhang, Shanghai 200240, China
| | - Jingjing Li
- Laboratory of Regenerative Medicine, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Rd., Minhang, Shanghai 200240, China
| | - Wen Guan
- Shanghai Municipality Key Laboratory of Veterinary Biotechnology, School of Agriculture and Biology, Shanghai Jiao Tong University, 800 Dongchuan Rd., Minhang, Shanghai 200240, China
| | - Jianjun Hu
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Rd., Xuhui, Shanghai 200233, China
| | - Quanhui Tan
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Rd., Xuhui, Shanghai 200233, China
| | - Liang Zhou
- Shanghai Municipality Key Laboratory of Veterinary Biotechnology, School of Agriculture and Biology, Shanghai Jiao Tong University, 800 Dongchuan Rd., Minhang, Shanghai 200240, China
| | - Wei Han
- Laboratory of Regenerative Medicine, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Rd., Minhang, Shanghai 200240, China
| | - Yunsheng Yuan
- Laboratory of Regenerative Medicine, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Rd., Minhang, Shanghai 200240, China; Engineering Research Center of Cell and Therapeutic Antibody, Shanghai Jiao Tong University, 800 Dongchuan Rd., Minhang, Shanghai 200240, China.
| | - Yan Yu
- Shanghai Municipality Key Laboratory of Veterinary Biotechnology, School of Agriculture and Biology, Shanghai Jiao Tong University, 800 Dongchuan Rd., Minhang, Shanghai 200240, China.
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McGill MR, Du K, Weemhoff JL, Jaeschke H. Critical review of resveratrol in xenobiotic-induced hepatotoxicity. Food Chem Toxicol 2015; 86:309-18. [PMID: 26561740 DOI: 10.1016/j.fct.2015.11.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Revised: 10/30/2015] [Accepted: 11/02/2015] [Indexed: 02/07/2023]
Abstract
Use of natural products is increasingly popular. In fact, many patients with liver diseases self-medicate with herbal supplements. Resveratrol (RSV), in particular, is a common natural product that can reduce injury in experimental models of liver disease. Xenobiotic hepatotoxicity is a particularly important area-of-need for therapeutics. Drug-induced liver injury, for example, is the most common cause of acute liver failure (ALF) and ALF-induced deaths in many countries. Importantly, RSV protects against hepatotoxicity in animal models in vivo caused by several drugs and chemicals and may be an effective intervention. Although many mechanisms have been proposed to explain the protection, not all are consistent with other data. Furthermore, RSV suffers from other issues, including limited bioavailability due to extensive hepatic metabolism. The purpose of this article is to summarize recent findings on the protective effects of RSV in xenobiotic-induced liver injury and other forms of liver injury and to provide a critical review of the underlying mechanisms. New mechanisms that are more consistent with data emerging from the toxicology field are suggested. Efforts to move RSV into clinical use are also considered. Overall, RSV is a promising candidate for therapeutic use, but additional studies are needed to better understand its effects.
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Affiliation(s)
- Mitchell R McGill
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.
| | - Kuo Du
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - James L Weemhoff
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
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Özcan P, Fıçıcıoğlu C, Yıldırım ÖK, Özkan F, Akkaya H, Aslan İ. Protective effect of resveratrol against oxidative damage to ovarian reserve in female Sprague–Dawley rats. Reprod Biomed Online 2015. [DOI: 10.1016/j.rbmo.2015.06.007] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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31
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Abd-Elbaset M, Arafa ESA, El Sherbiny GA, Abdel-Bakky MS, Elgendy ANA. Quercetin modulates iNOS, eNOS and NOSTRIN expressions and attenuates oxidative stress in warm hepatic ischemia-reperfusion injury in rats. BENI-SUEF UNIVERSITY JOURNAL OF BASIC AND APPLIED SCIENCES 2015. [DOI: 10.1016/j.bjbas.2015.07.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
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Casas-Grajales S, Muriel P. Antioxidants in liver health. World J Gastrointest Pharmacol Ther 2015; 6:59-72. [PMID: 26261734 PMCID: PMC4526841 DOI: 10.4292/wjgpt.v6.i3.59] [Citation(s) in RCA: 75] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Revised: 06/04/2015] [Accepted: 06/18/2015] [Indexed: 02/06/2023] Open
Abstract
Liver diseases are a worldwide medical problem because the liver is the principal detoxifying organ and maintains metabolic homeostasis. The liver metabolizes various compounds that produce free radicals (FR). However, antioxidants scavenge FR and maintain the oxidative/antioxidative balance in the liver. When the liver oxidative/antioxidative balance is disrupted, the state is termed oxidative stress. Oxidative stress leads to deleterious processes in the liver and produces liver diseases. Therefore, restoring antioxidants is essential to maintain homeostasis. One method of restoring antioxidants is to consume natural compounds with antioxidant capacity. The objective of this review is to provide information pertaining to various antioxidants found in food that have demonstrated utility in improving liver diseases.
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Ahmed RF, Abdel-Rahman RF, Farid OA, El-Marasy SA, Hessin AF. Combined hepatoprotective and antidepressant effects of resveratrol in an acute model of depression. ACTA ACUST UNITED AC 2014. [DOI: 10.1016/j.bfopcu.2014.06.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Pifithrin-α ameliorates resveratrol-induced two-cell block in mouse preimplantation embryos in vitro. Theriogenology 2014; 83:862-73. [PMID: 25542456 DOI: 10.1016/j.theriogenology.2014.11.023] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2014] [Revised: 10/29/2014] [Accepted: 11/20/2014] [Indexed: 12/26/2022]
Abstract
Treatment with resveratrol at concentrations greater than 0.5 μmol/L resulted in the arrest of mouse embryo development at the two-cell stage. Resveratrol-induced cytotoxicity was investigated in embryos by evaluating morphologic features by using the bromodeoxyuridine assay and acridine orange and ethidium bromide double staining. Resveratrol was found to significantly increase the expressions of p53, p21, Atf3, smac/Diablo, Bax, Bak1, Bok, and Noxa mRNA in the embryos, whereas Cullin 3 and Cdk1 expressions were decreased. Furthermore, active p53 positive signal in embryos arrested at the two-cell stage was localized in the nucleus, whereas no active p53 signal was observed in control embryos. Pretreatment with pifithrin-α, a p53 inhibitor, downregulated active p53 in two-cell embryo nuclei and ameliorated approximately 50% of the embryonic developmental defect caused by resveratrol. The findings of the present study, therefore, suggest that pifithrin-α could be used as an effective cytoprotective agent against a reproductive toxin such as resveratrol.
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35
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KEMELO MK, WOJNAROVÁ L, KUTINOVÁ CANOVÁ N, FARGHALI H. D-Galactosamine/Lipopolysaccharide-Induced Hepatotoxicity Downregulates Sirtuin 1 in Rat Liver: Role of Sirtuin 1 Modulation in Hepatoprotection. Physiol Res 2014; 63:615-23. [DOI: 10.33549/physiolres.932761] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
D-Galactosamine/Lipopolysaccharide (D-GalN/LPS) is a well known model of hepatotoxicity that closely resembles acute liver failure (ALF) seen clinically. The role of sirtuin 1 in this model has not yet been documented. However, there have been a number of studies about the cytoprotective effects of resveratrol, a SIRT1 activator, in the liver. This study was aimed at elucidating the roles of SIRT1 protein expression or catalytic activity in D-GalN/LPS model of hepatotoxicity. ALF was induced in male Wistar rats by intraperitoneal injection of D-GalN and LPS. Some groups of animals were pretreated with resveratrol and/or EX-527 (SIRT1 inhibitor). The effects of these treatments were evaluated by biochemical and Western blot studies. D-GalN/LPS treatment was able to induce hepatotoxicity and significantly increase all markers of liver damage and lipid peroxidation. A dramatic decrease of SIRT1 levels in response to D-GalN/LPS treatment was also documented. Resveratrol pretreatment attenuated D-GalN/LPS-induced hepatotoxicity. EX-527 blocked the cytoprotective effects of resveratrol. However, both resveratrol and EX-527 pretreatments did not exhibit any significant effect on SIRT1 protein expression. Collectively, these results suggest that downregulation of SIRT1 expression is involved in the cytotoxic effects of D-GalN/LPS model and SIRT1 activity contributes to the cytoprotective effects of resveratrol in the liver.
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Affiliation(s)
- M. K. KEMELO
- Institute of Pharmacology, First Faculty of Medicine, Charles University, Prague, Czech Republic
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Temi V, Okay E, Güneş A, Simşek T, Cekmen M, Bilgili U, Gürbüz Y. Resveratrol attenuates both small bowel and liver changes in obstructive jaundice. Balkan Med J 2014; 31:95-9. [PMID: 25207176 DOI: 10.5152/balkanmedj.2013.9191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2013] [Accepted: 10/09/2013] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND It is well known that mucosal changes and alterations in liver function occur in the experimental obstructive jaundice model. AIMS We aimed to evaluate the effect of resveratrol on obstructive jaundice-induced changes in the small bowel mucosa and liver using ischaemia-modified albumin as a marker of oxidative damage. STUDY DESIGN Animal experimentation. METHODS The study used a rodent experimental model of obstructive jaundice, including a sham group (1), a control group (2), and a study group (3). Wistar albino rats were used. Jaundice was produced by ligation of the bile duct in Groups 2 and 3. In Group 3, resveratrol was administered intraperitoneally for 14 days. RESULTS In terms of the structure and the size of the mucosal villi, significant thickening and blunting were detected in Group 2 compared with Group 1. These changes were significantly less noticeable in Group 3 compared with Group 2. Levels of ischaemia-modified albumin were significantly higher in Group 2 compared with those in Group 1, and they were significantly decreased in Group 3 compared with Group 2. CONCLUSION Resveratrol administration to obstructive jaundiced rats reduced the organic effects of obstructive jaundice on small bowel mucosa and liver oxidative stress. We believe that this reduction might attenuate bacterial translocation and systemic effects of secreted cytokines.
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Affiliation(s)
- Volkan Temi
- Department of General Surgery, Kocaeli University School of Medicine, Kocaeli, Turkey
| | - Erdem Okay
- Department of General Surgery, Kocaeli University School of Medicine, Kocaeli, Turkey
| | - Abdullah Güneş
- Department of General Surgery, Kocaeli University School of Medicine, Kocaeli, Turkey
| | - Turgay Simşek
- Department of General Surgery, Kocaeli University School of Medicine, Kocaeli, Turkey
| | - Mustafa Cekmen
- Department of Medical Biochemistry, Kocaeli University School of Medicine, Kocaeli, Turkey
| | - Umit Bilgili
- Department of Medical Biochemistry, Kocaeli University School of Medicine, Kocaeli, Turkey
| | - Yeşim Gürbüz
- Department of Pathology, Kocaeli University School of Medicine, Kocaeli, Turkey
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Ahmad A, Ahmad R. Resveratrol mitigate structural changes and hepatic stellate cell activation in N'-nitrosodimethylamine-induced liver fibrosis via restraining oxidative damage. Chem Biol Interact 2014; 221:1-12. [PMID: 25064540 DOI: 10.1016/j.cbi.2014.07.007] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2014] [Revised: 06/13/2014] [Accepted: 07/16/2014] [Indexed: 01/30/2023]
Abstract
Resveratrol, a polyphenol, found in skin of red grapes, peanuts and berries possesses anti-inflammatory, anti-carcinogenic and lipid modulation properties. Here, we demonstrate in vivo antifibrotic activity of resveratrol in a mammalian model, wherein hepatic fibrosis was induced by N'-nitrosodimethylamine (NDMA) administration. Apart from being a potent hepatotoxin, NDMA is a known mutagen and carcinogen, as well. To induce hepatic fibrosis, rats were administered NDMA (i.p.) in 10mg/kgb.wt thrice/week for 21 days. Another group of animals received resveratrol supplement (10mg/kgb.wt) subsequent to NDMA administration and were sacrificed weekly. The changes in selected biomarkers were monitored to compare profibrotic effects of NDMA and antifibrotic activity of resveratrol. The selected biomarkers were: sera transaminases, ALP, bilirubin, liver glycogen, LPO, SOD, protein carbonyl content, ATPases (Ca(2+), Mg(2+), Na(+)/K(+)) and hydroxyproline/collagen content. Alterations in liver architecture were assessed by H&E, Masson's trichrome and reticulin staining of liver biopsies. Immuno-histochemistry and immunoblotting were employed to examine expression of α-SMA. Our results demonstrate that during NDMA-induced liver fibrosis transaminases, ALP, bilirubin, hydroxyproline and liver collagen increases, while liver glycogen is depleted. The decline in SOD (>65%) and ATPases, which were concomitant with the elevation in MDA and protein carbonyls, strongly indicate oxidative damage. Fibrotic transformation of liver in NDMA-treated rats was verified by histopathology, immuno-histochemistry and immunoblotting data, with the higher expressivity of α-SMA-positive HSCs being most established diagnostic immuno-histochemical marker of HSCs. Resveratrol-supplement refurbished liver architecture by significantly restoring levels of biomarkers of oxidative damage (MDA, SOD, protein carbonyls and membrane-bound ATPases). Therefore, we conclude that antifibrotic effect of resveratrol is due to restrained oxidative damage and down-regulation of α-SMA, which inhibits HSC activation to obstruct liver fibrosis.
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Affiliation(s)
- Areeba Ahmad
- Biochemical and Clinical Genetics Laboratory, Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh 202002, U.P., India
| | - Riaz Ahmad
- Biochemical and Clinical Genetics Laboratory, Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh 202002, U.P., India.
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Tomé-Carneiro J, Larrosa M, González-Sarrías A, Tomás-Barberán FA, García-Conesa MT, Espín JC. Resveratrol and clinical trials: the crossroad from in vitro studies to human evidence. Curr Pharm Des 2014; 19:6064-93. [PMID: 23448440 PMCID: PMC3782695 DOI: 10.2174/13816128113199990407] [Citation(s) in RCA: 324] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2013] [Accepted: 02/18/2013] [Indexed: 12/24/2022]
Abstract
Resveratrol (3,5,4’-trihydroxy-trans-stilbene) is a non-flavonoid polyphenol that may be present in a limited number of food-stuffs such as grapes and red wine. Resveratrol has been reported to exert a plethora of health benefits through many different mechanisms of action. This versatility and presence in the human diet have drawn the worldwide attention of many research groups over the past twenty years, which has resulted in a huge output of in vitro and animal (preclinical) studies. In line with this expectation, many resveratrol-based nutraceuticals are consumed all over the world with questionable clinical/scientific support. In fact, the confirmation of these benefits in humans through randomized clinical trials is still very limited. The vast majority of preclinical studies have been performed using assay conditions with a questionable extrapolation to humans, i.e. too high concentrations with potential safety concerns (adverse effects and drug interactions), short-term exposures, in vitro tests carried out with non-physiological metabolites and/or concentrations, etc. Unfortunately, all these hypothesis-generating studies have contributed to increased the number of ‘potential’ benefits and mechanisms of resveratrol but confirmation in humans is very limited. Therefore, there are many issues that should be addressed to avoid an apparent endless loop in resveratrol research. The so-called ‘Resveratrol Paradox’, i.e., low bioavailability but high bioactivity, is a conundrum not yet solved in which the final responsible actor (if any) for the exerted effects has not yet been unequivocally identified. It is becoming evident that resveratrol exerts cardioprotective benefits through the improvement of inflammatory markers, atherogenic profile, glucose metabolism and endothelial function. However, safety concerns remain unsolved regarding chronic consumption of high RES doses, specially in medicated people. This review will focus on the currently available evidence regarding resveratrol’s effects on humans obtained from randomized clinical trials. In addition, we will provide a critical outlook for further research on this molecule that is evolving from a minor dietary compound to a possible multi-target therapeutic drug.
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Affiliation(s)
- Joao Tomé-Carneiro
- Research Group of Quality, Safety and Bioactivity of Plant Foods, CEBAS-CSIC, 30100 Campus de Espinardo, Murcia, Spain.
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Di Pascoli M, Diví M, Rodríguez-Vilarrupla A, Rosado E, Gracia-Sancho J, Vilaseca M, Bosch J, García-Pagán JC. Resveratrol improves intrahepatic endothelial dysfunction and reduces hepatic fibrosis and portal pressure in cirrhotic rats. J Hepatol 2013; 58:904-10. [PMID: 23262250 DOI: 10.1016/j.jhep.2012.12.012] [Citation(s) in RCA: 112] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2012] [Revised: 11/29/2012] [Accepted: 12/04/2012] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Resveratrol, a polyphenol found in a variety of fruits, exerts a wide range of beneficial effects on the endothelium, regulates multiple vasoactive substances and decreases oxidative stress, factors involved in the pathophysiology of portal hypertension. Our study aimed at evaluating the effects of resveratrol on hepatic and systemic hemodynamics, hepatic endothelial dysfunction, and hepatic fibrosis in CCl₄ cirrhotic rats. METHODS Resveratrol (10 and 20 mg/kg/day) or its vehicle was administered to cirrhotic rats for two weeks and hepatic and systemic hemodynamics were measured. Moreover, we evaluated endothelial function by dose-relaxation curves to acetylcholine, hepatic NO bioavailability and TXA2 production. We also evaluated liver fibrosis by Sirius Red staining of liver sections, collagen-1, NFκB, TGFβ mRNA expression, and desmin and α-smooth muscle actin (α-SMA) protein expression, as a surrogate of hepatic stellate cell activation. RESULTS Resveratrol administration significantly decreased portal pressure compared to vehicle (12.1 ± 0.9 vs. 14.3 ± 2.2 mmHg; p <0.05) without significant changes in systemic hemodynamics. Reduction in portal pressure was associated with an improved vasodilatory response to acetylcholine, with decreased TXA2 production, increased endothelial NO, and with a significant reduction in liver fibrosis. The decrease in hepatic fibrosis was associated with a reduced collagen-1, TGFβ, NFκB mRNA expression and desmin and α-SMA protein expression. CONCLUSIONS Resveratrol administration reduces portal pressure, hepatic stellate cell activation and liver fibrosis, and improves hepatic endothelial dysfunction in cirrhotic rats, suggesting it may be a useful dietary supplement in the treatment of portal hypertension in patients with cirrhosis.
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Affiliation(s)
- Marco Di Pascoli
- Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer and Ciberehd, University of Barcelona, Spain
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FARGHALI H, KUTINOVÁ CANOVÁ N, LEKIĆ N. Resveratrol and Related Compounds as Antioxidants With an Allosteric Mechanism of Action in Epigenetic Drug Targets. Physiol Res 2013; 62:1-13. [DOI: 10.33549/physiolres.932434] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The present review is intended to focus on naturally occurring cytoprotective agents such as resveratrol (trans-3,4’,5-trihydroxystilbene) and other related compounds, probably with similar molecular mechanisms of action and high capacity to find applications in medical fields. Several physiological aspects have been ascribed to resveratrol and similar compounds. Resveratrol, among others, has been recently described as a silent information regulator T1 (SIRT1) activator that increases AMP-activated protein kinase (AMPK) phosphorylation and reduces the oxidative damage biomarkers during aging in laboratory settings. The reports on resveratrol and other SIRT1 activators from various sources are encouraging. The pharmacological strategies for modulation of sirtuins by small molecules through allosteric mechanisms should gain a greater momentum including human research. Resveratrol and resveratrol-like molecules seem to fulfill the requirement of a new horizon in drug research since these molecules cover a growing research means as antioxidants with allosteric mechanism in epigenetic drug targets. However, one should keep in mind the challenges of extrapolation of basic research into clinical results. Overall, the issue of sirtuins in biology and disease provides an insight on therapeutic potentials of sirtuin-based therapeutics and demonstrates the high complexity of drug-targeting these modalities for human applications.
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Affiliation(s)
- H. FARGHALI
- Institute of Pharmacology, First Faculty of Medicine, Charles University in Prague, Czech Republic
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Zverinsky I, Melnichenko N, Poplavsky V, Sutko I, Telegin P, Shlyahtun A. The effect of berberine administration of evaluation of the functional state of rat liver after ligation of common bile duct. ACTA ACUST UNITED AC 2013. [DOI: 10.18097/pbmc20135901090] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
On the eighth day after ligation of the common bile duct in rats a significant increase in the serum content of total lipids, cholesterol bilirubin and ALT, alkaline phosphatase, and gamma-glutamyltransferase was observed. In the microsomal fraction there was a marked decrease in the content and activity of microsomal monooxygenases. Introperitoneal injection of berberine (10 mg/kg) for 6 days caused a partial normalization of permeability of hepatocytes plasma membranes and activity of microsomal flavin-containing monooxygenases. It is suggested that berberine is a substrate and inducer of flavin-containing monooxygenases. Membrane-stabilizing effect of berberine is probably realized at the level of inhibition of prooxidant status of liver cells.
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Affiliation(s)
- I.V. Zverinsky
- Institute of Pharmacology and Biochemistry, National Academy of Sciences of Belarus
| | - N.G. Melnichenko
- Institute of Pharmacology and Biochemistry, National Academy of Sciences of Belarus
| | - V.A. Poplavsky
- Institute of Pharmacology and Biochemistry, National Academy of Sciences of Belarus
| | - I.P. Sutko
- Institute of Pharmacology and Biochemistry, National Academy of Sciences of Belarus
| | - P.G. Telegin
- Institute of Pharmacology and Biochemistry, National Academy of Sciences of Belarus
| | - A.G. Shlyahtun
- Institute of Pharmacology and Biochemistry, National Academy of Sciences of Belarus
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Şimşek G, Gürocak Ş, Karadaǧ N, Karabulut AB, Demirtaş E, Karataş E, Pepele E. Protective effects of resveratrol on salivary gland damage induced by total body irradiation in rats. Laryngoscope 2012; 122:2743-8. [DOI: 10.1002/lary.23609] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2012] [Revised: 06/25/2012] [Accepted: 06/26/2012] [Indexed: 12/17/2022]
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Ameliorative effects of resveratrol on acute ovarian toxicity induced by total body irradiation in young adult rats. J Pediatr Adolesc Gynecol 2012; 25:262-6. [PMID: 22840937 DOI: 10.1016/j.jpag.2012.04.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2012] [Revised: 03/29/2012] [Accepted: 04/04/2012] [Indexed: 11/22/2022]
Abstract
OBJECTIVE The purpose of this study was to investigate the ovarian protective effects of resveratrol in rats exposed to total body irradiation. DESIGN Experimental study. SETTINGS University hospital. PARTICIPANTS AND INTERVENTIONS Thirty female rats were randomized into four groups: (1) control group (n = 7); (2) low-dose (10 mg/kg) resveratrol group (n = 8); (3) high-dose (100 mg/kg) resveratrol group (n =7); and (4) sham irradiation group (n = 8). The drugs were administered intraperitoneally as single doses, and the rats were exposed to total body radiation 24 h after the treatment. The animals were sacrificed the following day, and their ovaries were excised for histopathological and biochemical analysis. MAIN OUTCOME MEASURES The ovarian follicle counts were calculated, and irradiation-dependent ovarian damage and tissue levels of antioxidant enzymes were evaluated. RESULTS Group 2 and Group 3 showed significantly higher numbers of total follicle counts compared with Group 1 (P < 0.01). The low-dose resveratrol treatment was associated with significantly higher numbers of primary follicles than the high-dose group. The tissue activities of glutathione peroxidase (GsH-Px) and catalase (CAT) were significantly elevated in the resveratrol-treated animals. Evaluation of ovarian histology revealed no remarkable changes in fibrosis and leucocyte infiltration among the resveratrol-treated and control rats; however, vascularity was significantly reduced in the high-dose group (P = 0.014). CONCLUSION Resveratrol attenuated irradiation-dependent ovarian damage, suggesting that this natural antioxidant is effective in reducing the follicle loss induced by ionizing radiation.
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The effect of the red wine polyphenol resveratrol on a rat model of biliary obstructed cholestasis: involvement of anti-apoptotic signalling, mitochondrial biogenesis and the induction of autophagy. Apoptosis 2012; 17:871-9. [DOI: 10.1007/s10495-012-0732-3] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Balamurugan K, Karthikeyan J. Evaluation of Luteolin in the Prevention of N-nitrosodiethylamine-induced Hepatocellular Carcinoma Using Animal Model System. Indian J Clin Biochem 2012; 27:157-63. [PMID: 23543260 PMCID: PMC3358363 DOI: 10.1007/s12291-011-0166-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2011] [Accepted: 09/12/2011] [Indexed: 11/24/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the commonest tumors worldwide. The treatment of HCC is vital for disease diagnosis and prognosis, as the liver is the most important organ controlling metabolic functions. Now-a-days, western folklore medicines are largely dependent on the phyto compounds which are highly effective in therapy and with low side effects. Luteolin is a flavonoid (3,4,5,7-Tetrahydro flavones) possess anti-inflammatory, anticancer and anti allergic property. The present study evaluates the efficacy of luteolin against N-nitrosodiethylamine (DEN) induced HCC in albino rats. In the highlight of the above, luteolin was evaluated for its efficacy against DEN induced HCC in male Wistar albino rats. The Biochemical parameters such as tissue damaging enzymes viz., AST, ALP, LDH and γ-GT, enzymatic antioxidants viz., SOD, CAT, GSH and GPx and histopathological changes have been estimated. The tissue damaging enzymes were found to be high in DEN alone treated group whereas the enzymatic antioxidants decreased destructively. Severe lesions and cirrhosis were observed in the toxin (DEN alone) treated group. The luteolin treated DEN group altered the tissue damaging enzymes and the enzymatic antioxidants. The damaged lesion in the histoarchitecture of DEN treated rat liver was almost completely restored. Finally this study strongly demonstrates that luteolin has potent curative property against HCC in albino rats.
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Affiliation(s)
- K. Balamurugan
- Department of Biochemistry, PRIST University, Thanjavur, South India
| | - J. Karthikeyan
- Centre for Research and Development, PRIST University, Thanjavur, South India
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Ghiselli R, Silvestri C, Cirioni O, Kamysz W, Orlando F, Calcinari A, Kamysz E, Casteletti S, Rimini M, Tocchini M, Giacometti A, Guerrieri M. Protective Effect of Citropin 1.1 and Tazobactam-Piperacillin Against Oxidative Damage and Lethality in Mice Models of Gram-Negative Sepsis. J Surg Res 2011; 171:726-33. [DOI: 10.1016/j.jss.2010.03.055] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2010] [Revised: 03/01/2010] [Accepted: 03/25/2010] [Indexed: 12/30/2022]
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Chan CC, Cheng LY, Lin CL, Huang YH, Lin HC, Lee FY. The protective role of natural phytoalexin resveratrol on inflammation, fibrosis and regeneration in cholestatic liver injury. Mol Nutr Food Res 2011; 55:1841-9. [PMID: 22086758 DOI: 10.1002/mnfr.201100374] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2011] [Revised: 08/23/2011] [Accepted: 08/29/2011] [Indexed: 12/21/2022]
Abstract
Liver injuries can trigger a cascade of inflammatory responses and as a result, initiate the process of hepatic regeneration and fibrogenesis. Resveratrol (RSV) has multiple health-promoting benefits. This study evaluated the potential protective effects and mechanism of RSV as related to cholestatic liver injury. RSV was given (4 mg/kg/day, i.p.) for either 3 days or 7 days after bile duct ligation (BDL) injury. RSV significantly reduced serum ALT, AST but not T-bil on Day 3. At this early stage of injury, RSV significantly reduced TNF-α and IL-6 mRNA and decreased the number of Kupffer cells (CD68(+) ) recruited in the injured liver. RSV decreased hepatic fibrosis and reduced collagen Iα1 and TIMP-1 mRNA on Day 7. At the later stages of injury, RSV increased the number of Ki67(+) hepatocytes indicating that RSV promoted hepatocyte proliferation. Additionally, it resulted in decreased expression of 4-hydroxynonenal and increased expression of the hepatocyte growth factor protein and mRNA in the RSV-treated BDL group. Meanwhile, RSV reduced the mortality rate of BDL mice. In conclusion, RSV attenuated inflammation and reduced Kupffer cells activation. RSV decreased fibrosis and promoted hepatocyte regeneration, which increased the survival of BDL mice. RSV was beneficial for the treatment of cholestatic liver injury.
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Affiliation(s)
- Che-Chang Chan
- Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
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Vieira EK, Bona S, Di Naso FC, Porawski M, Tieppo J, Marroni NP. Quercetin treatment ameliorates systemic oxidative stress in cirrhotic rats. ISRN GASTROENTEROLOGY 2011; 2011:604071. [PMID: 21991520 PMCID: PMC3168458 DOI: 10.5402/2011/604071] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/18/2011] [Accepted: 06/16/2011] [Indexed: 01/24/2023]
Abstract
Our aim was to investigate whether the antioxidant quercetin protects against liver injury and ameliorates the systemic oxidative stress in rats with common bile duct ligation. Secondary biliary cirrhosis was induced through 28 days of bile duct obstruction. Animals received quercetin (Q) after 14 days of obstruction. Groups of control (CO) and cirrhotic (CBDL) animals received a daily 50 mg/kg body weight i.p. injection of quercetin (CO + Q; CBDL + Q) or vehicle (CO; CBDL). Quercetin corrected the reduction in superoxide dismutase (SOD), catalase CAT, and glutathione peroxidase GPx activities and prevented the increase of thiobarbituric acid reactive substances (TBARS), aminotransferases, and alkaline phosphatase in cirrhotic animals. Quercetin administration also corrected the reduced total nitrate concentration in the liver and prevented liver fibrosis and necrosis. These effects suggest that quercetin might be a useful agent to preserve liver function and prevent systemic oxidative stress.
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Affiliation(s)
- Emanuelle Kerber Vieira
- Laboratory of Experimental Hepatology and Physiology, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, 90050170 Porto Alegre, RS, Brazil
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El-Mowafy AM, Salem HA, Al-Gayyar MM, El-Mesery ME, El-Azab MF. Evaluation of renal protective effects of the green-tea (EGCG) and red grape resveratrol: role of oxidative stress and inflammatory cytokines. Nat Prod Res 2011; 25:850-6. [PMID: 21462079 DOI: 10.1080/14786419.2010.533669] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Epigallocatechin-gallate (EGCG) and resveratrol (RSVL) are two of the most promising natural medicines. We verified their capacity to ameliorate cisplatin (CP)-induced disruption of renal glomerular filtration rate (GFR) in rats, and sought the mediatory involvement of lipid peroxidation (malondialdehyde [MDA]-level) and inflammatory cytokine (TNF-α) therein. CP (10 mg kg⁻¹), a single i.p. dose, disrupted GFR (11-fold-rise in proteinuria, 2-5-fold rise in serum creatinine/urea levels) after 7 days, and killed all animals after 10 days. Kidney-homogenates from CP-treated rats displayed higher MDA and TNF-α, but lower reduced-glutathione (GSH) levels. Rats treated with EGCG (50 mg kg⁻¹, but not 25 mg kg⁻¹) had no fatalities and showed significantly-recovered GFR; while their kidney-homogenates had markedly reduced MDA, TNF-α and enhanced GSH levels at 7 days. Conversely, RSVL or quercetin (25, 50 mg kg⁻¹) neither improved GFR nor reduced (MDA)/TNF-α levels after 7 days. Resuming treatment with 50 mg kg⁻¹ for 10 days rescued only 25% of animals (p > 0.05). Correlation studies showed a significant association between creatinine level, and each of MDA (r = 0.91), GSH (r = -0.87), and TNF-α (0.91). The study showed for the first time that EGCG, unlike RSVL, can protect against CP-induced nephrotoxicity. At the molecular level, CP triggers a high level of oxidative stress and systemic inflammation, events that were all abrogated with EGCG; better than RSVL or quercetin.
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Affiliation(s)
- A M El-Mowafy
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
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Resveratrol prevents inflammation-dependent hepatic melanoma metastasis by inhibiting the secretion and effects of interleukin-18. J Transl Med 2011; 9:59. [PMID: 21569399 PMCID: PMC3112440 DOI: 10.1186/1479-5876-9-59] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2010] [Accepted: 05/12/2011] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Implantation and growth of metastatic cancer cells at distant organs is promoted by inflammation-dependent mechanisms. A hepatic melanoma metastasis model where a majority of metastases are generated via interleukin-18-dependent mechanisms was used to test whether anti-inflammatory properties of resveratrol can interfere with mechanisms of metastasis. METHODS Two experimental treatment schedules were used: 1) Mice received one daily oral dose of 1 mg/kg resveratrol after cancer cell injection and the metastasis number and volume were determined on day 12. 2) Mice received one daily oral dose of 1 mg/kg resveratrol along the 5 days prior to the injection of cancer cells and both interleukin-18 (IL-18) concentration in the hepatic blood and microvascular retention of luciferase-transfected B16M cells were determined on the 18th hour. In vitro, primary cultured hepatic sinusoidal endothelial cells were treated with B16M-conditioned medium to mimic their in vivo activation by tumor-derived factors and the effect of resveratrol on IL-18 secretion, on vascular cell adhesion molecule-1 (VCAM-1) expression and on tumor cell adhesion were studied. The effect of resveratrol on melanoma cell activation by IL-18 was also studied. RESULTS Resveratrol remarkably inhibited hepatic retention and metastatic growth of melanoma cells by 50% and 75%, respectively. The mechanism involved IL-18 blockade at three levels: First, resveratrol prevented IL-18 augmentation in the blood of melanoma cell-infiltrated livers. Second, resveratrol inhibited IL-18-dependent expression of VCAM-1 by tumor-activated hepatic sinusoidal endothelium, preventing melanoma cell adhesion to the microvasculature. Third, resveratrol inhibited adhesion- and proliferation-stimulating effects of IL-18 on metastatic melanoma cells through hydrogen peroxide-dependent nuclear factor-kappaB translocation blockade on these cells. CONCLUSIONS These results demonstrate multiple sites for therapeutic intervention using resveratrol within the prometastatic microenvironment generated by tumor-induced hepatic IL-18, and suggest a remarkable effect of resveratrol in the prevention of inflammation-dependent melanoma metastasis in the liver.
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