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Raza MZ, Nadeem AA, Khwaja HF, Omais M, Arshad HME, Maqsood M. Dexamethasone-Based Prophylactic Therapy for Prevention of Post-Embolization Syndrome: A Systematic Review and Meta-Analysis Assessing Its Efficacy and Influence of Dosage and Timing in Patients Undergoing Arterial Embolization. Ann Vasc Surg 2025; 113:95-111. [PMID: 39863273 DOI: 10.1016/j.avsg.2024.12.079] [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: 10/07/2024] [Revised: 12/26/2024] [Accepted: 12/27/2024] [Indexed: 01/27/2025]
Abstract
BACKGROUND Postembolization syndrome (PES), characterized by pain, fever, nausea, and vomiting, is a common but nonserious adverse event following arterial embolization, negatively impacting patient satisfaction with the procedure. This study aimed to evaluate the efficacy of dexamethasone-based prophylactic therapy in preventing PES, as well as to assess the effects of its dosage and timing of administration. METHODS A systematic search was conducted across 3 databases, 2 trial registries, and citation searches to identify relevant studies. Data related to postoperative pain, fever, nausea, and vomiting were extracted and meta-analyzed using a random-effects model and the Mantel-Haenszel method. Meta-regression was performed to examine the role of dexamethasone dose and timing of administration as mediators. RESULTS Dexamethasone-based prophylactic therapy significantly reduced the risk of postoperative pain (risk ratio (RR) = 0.58, 95% confidence interval (CI): 0.48-0.69; P < 0.00001), fever (RR = 0.36, 95% CI: 0.22-0.61; P < 0.00001), nausea (RR = 0.52, 95% CI: 0.41-0.67; P < 0.00001), and vomiting (RR = 0.54, 95% CI: 0.36-0.82; P = 0.004) compared to placebo or no treatment. A higher dose of dexamethasone was associated with a significantly lower incidence of postoperative pain (P = 0.038). Regarding timing, postoperative and continuous (extending throughout the perioperative period) administration, was more effective than preoperative administration (P = 0.024; P = 0.007). A dosage of 6-12 mg was particularly effective in reducing the risk for all 4 symptoms. CONCLUSION Dexamethasone effectively prevents PES in patients undergoing arterial embolization. An optimal protocol may involve a divided dose regimen within the range of 6-12 mg, extending throughout the recovery period for maximum benefit.
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Affiliation(s)
- Muhammad Zain Raza
- Department of Medicine, King Edward Medical University, Lahore, Punjab, Pakistan.
| | - Ali Ahmad Nadeem
- Department of Medicine, King Edward Medical University, Lahore, Punjab, Pakistan
| | | | - Muhammad Omais
- Department of Medicine, King Edward Medical University, Lahore, Punjab, Pakistan
| | | | - Musab Maqsood
- Department of Medicine, King Edward Medical University, Lahore, Punjab, Pakistan
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Yang Q, He WH, Xie L, Chen T, Liu RF, Hu JJ, Guo JY, Tan GZ, Wu FL, Gu P, Chen P, Chen Y. Oral administration of astilbin mitigates acetaminophen-induced acute liver injury in mice by modulating the gut microbiota. Acta Pharmacol Sin 2025; 46:416-429. [PMID: 39313515 PMCID: PMC11747501 DOI: 10.1038/s41401-024-01383-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 08/16/2024] [Accepted: 08/18/2024] [Indexed: 09/25/2024]
Abstract
Acetaminophen (APAP) overdose-induced acute liver injury (ALI) is characterized by extensive oxidative stress, and the clinical interventions for this adverse effect remain limited. Astilbin is an active compound found in the rhizome of Smilax glabra Roxb. with anti-inflammatory and antioxidant activities. Due to its low oral bioavailability, astilbin can accumulate in the intestine, which provides a basis for the interaction between astilbin and gut microbiota (GM). In the present study we investigated the protective effects of astilbin against APAP-induced ALI by focusing on the interaction between astilbin and GM. Mice were treated with astilbin (50 mg·kg-1·d-1, i.g.) for 7 days. After the last administration of astilbin for 2 h, the mice received APAP (300 mg/kg, i.g.) to induce ALI. We showed that oral administration of astilbin significantly alleviated APAP-induced ALI by altering the composition of GM and enriching beneficial metabolites including hydroxytyrosol (HT). GM depletion using an "antibiotics cocktail" or paraoral administration of astilbin abolished the hepatoprotective effects of astilbin. On the other hand, administration of HT (10 mg/kg, i.g.) caused similar protective effects in APAP-induced ALI mice. Transcriptomic analysis of the liver tissue revealed that HT inhibited reactive oxygen species and inflammation-related signaling in APAP-induced ALI; HT promoted activation of the Nrf2 signaling pathway to combat oxidative stress following APAP challenge in a sirtuin-6-dependent manner. These results highlight that oral astilbin ameliorates APAP-induced ALI by manipulating the GM and metabolites towards a more favorable profile, and provide an alternative therapeutic strategy for alleviating APAP-induced ALI.
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Affiliation(s)
- Qin Yang
- Department of Gastroenterology, The Seventh Affiliated Hospital of Southern Medical University, Foshan, 528244, China
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Wen-Hao He
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Li Xie
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Tao Chen
- Department of Physiology, School of Basic Medical Sciences, Gannan Medical University, Ganzhou, 341000, China
| | - Ruo-Fan Liu
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Jia-Jia Hu
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Jia-Yin Guo
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Guo-Zhu Tan
- Department of Gastroenterology, The Seventh Affiliated Hospital of Southern Medical University, Foshan, 528244, China
- Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Biomaterials Research Center, School of Biomedical Engineering, Southern Medical University, Guangzhou, 510515, China
| | - Fu-Ling Wu
- Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Peng Gu
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.
| | - Peng Chen
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.
| | - Yu Chen
- Department of Gastroenterology, The Seventh Affiliated Hospital of Southern Medical University, Foshan, 528244, China.
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Roydeva A, Beleva G, Gadzhakov D, Milanova A. Pharmacokinetics of N-acetyl-l-cysteine in chickens. J Vet Pharmacol Ther 2024; 47:403-415. [PMID: 38751162 DOI: 10.1111/jvp.13452] [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: 02/09/2024] [Revised: 04/24/2024] [Accepted: 04/28/2024] [Indexed: 11/15/2024]
Abstract
N-acetyl-l-cysteine (NAC) has been suggested as an antioxidant that can alleviate the negative effects of stress conditions in broilers. However, knowledge of its pharmacokinetics (PK) in this avian species is very limited. Therefore, the study aimed to shed more light on the PK properties of NAC in chickens. Broilers were subjected to single intravenous (i.v.) or oral (p.o.) treatment or multiple NAC administrations via the feed. Drug concentrations were determined by LC-MS/MS, and the data were subjected to non-compartmental analysis and modeled by non-linear mixed effect approach. NAC was eliminated in a short time after i.v. treatment, with a t 1/2el of 0.93 (0.59-2.09) h. It showed limited distribution with population mean of volumes of distribution in the central and peripheral compartments V 1 of 0.148 L/kg and V 2 of 0.199 L/kg, respectively, and V darea of 0.39 (0.258-0.635) L/kg. The value of MRT was 1.76 h (range of 0.96-2.69, p < .05) after single p.o. treatment, indicating a twofold increase if compared to i.v. administration (0.87 h, 0.55-1.78). Both methods of Pk analysis revealed very limited bioavailability, <10%. Feeding behavior led to a later achievement of lower maximum plasma concentrations (5.74, range of 3.44-9.32 μg/mL, p < .05), which were maintained during the 5 days of treatment.
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Affiliation(s)
- Albena Roydeva
- Department of Pharmacology, Animal Physiology, Biochemistry and Chemistry, Faculty of Veterinary Medicine, Trakia University, Stara Zagora, Bulgaria
| | - Gabriela Beleva
- Students at Faculty of Veterinary Medicine, Trakia University, Stara Zagora, Bulgaria
| | - Daniel Gadzhakov
- Students at Faculty of Veterinary Medicine, Trakia University, Stara Zagora, Bulgaria
| | - Aneliya Milanova
- Department of Pharmacology, Animal Physiology, Biochemistry and Chemistry, Faculty of Veterinary Medicine, Trakia University, Stara Zagora, Bulgaria
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Li Y, Yang X, Bao T, Sun X, Li X, Zhu H, Zhang B, Ma T. Radix Astragali decoction improves liver regeneration by upregulating hepatic expression of aquaporin-9. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 122:155166. [PMID: 37918281 DOI: 10.1016/j.phymed.2023.155166] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 10/09/2023] [Accepted: 10/24/2023] [Indexed: 11/04/2023]
Abstract
BACKGROUND The therapeutic efficacy of liver injuries heavily relies on the liver's remarkable regenerative capacity, necessitating the maintenance of glycose/lipids homeostasis and oxidative eustasis during the recovery process. Astragali Radix, an herbal tonic widely used in China and many other countries, is believed to have many positive effects, including immune stimulation, nourishing, antioxidant, liver protection, diuresis, anti-diabetes, anti-cancer and expectorant. Astragali Radix is widely integrated into hepatoprotective formulas as it is believed to facilitate liver regeneration. Nevertheless, the precise molecular pharmacological mechanisms underlying this hepatoprotective effect remain elusive. PURPOSE To investigate the improving effects of Astragali Radix on liver regeneration and the underlying mechanisms. METHODS A mouse model of 70% partial hepatectomy (PHx) was employed to investigate the impact of Radix Astragali decoction (HQD) on liver regeneration. HQD was orally administered for 7 days before the PHx procedure and throughout the experiment. N-acetylcysteine (NAC) was used as a positive control for liver regeneration. Liver regeneration was assessed by evaluating the liver-to-body weight ratio (LW/BW) and the expression of representative cell proliferation marker proteins. Oxidative stress and glucose metabolism were analyzed using biochemical assays, Western blotting, dihydroethidium (DHE) fluorescence, and periodic acid-Schiff (PAS) staining methods. To understand the role of AQP9 as a potential molecular target of HQD in promoting liver regeneration, td-Tomato-tagged AQP9 transgenic mice (AQP9-RFP) were employed to determine the expression pattern of AQP9 protein. AQP9 knockout mice (AQP9-/-) were used to assess the specific targeting of AQP9 in the promotion of liver regeneration by HQD. RESULTS HQD significantly upregulated hepatic AQP9 expression, alleviated liver injury and promoted liver regeneration in wild-type (AQP9+/+) mice after 70% PHx. However, the beneficial impact of HQD on liver regeneration was absent in AQP9 gene knockout (AQP9-/-) mice. Moreover, HQD facilitated the uptake of glycerol by hepatocytes, enhanced gluconeogenesis, and concurrently reduced H2O2 content and oxidative stress levels in AQP9+/+ but not AQP9-/- mouse livers. Additionally, main active substance of Radix Astragali, astragaloside IV (AS-IV) and cycloastragenol (CAG), demonstrated substantial upregulation of AQP9 expression and promoted liver regeneration in AQP9+/+ but not AQP9-/- mice. CONCLUSION This study is the first to demonstrate that Radix Astragali and its main active constituents (AS-IV and CAG) improve liver regeneration by upregulating the expression of AQP9 in hepatocytes to increase gluconeogenesis and reduce oxidative stress. The study revealed novel molecular pharmacological mechanisms of Radix Astragali and provided a promising therapeutic target of liver diseases.
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Affiliation(s)
- Yanghao Li
- School of Medicine & Holistic Integrative Medicine, Department of Pathology and Pathophysiology, Nanjing University of Chinese Medicine, Xianlin Avenue 138, Nanjing, Jiangsu 210023, China
| | - Xu Yang
- School of Medicine & Holistic Integrative Medicine, Department of Pathology and Pathophysiology, Nanjing University of Chinese Medicine, Xianlin Avenue 138, Nanjing, Jiangsu 210023, China
| | - Tiantian Bao
- School of Medicine & Holistic Integrative Medicine, Department of Pathology and Pathophysiology, Nanjing University of Chinese Medicine, Xianlin Avenue 138, Nanjing, Jiangsu 210023, China
| | - Xiaojuan Sun
- School of Medicine & Holistic Integrative Medicine, Department of Pathology and Pathophysiology, Nanjing University of Chinese Medicine, Xianlin Avenue 138, Nanjing, Jiangsu 210023, China
| | - Xiang Li
- School of Medicine & Holistic Integrative Medicine, Department of Pathology and Pathophysiology, Nanjing University of Chinese Medicine, Xianlin Avenue 138, Nanjing, Jiangsu 210023, China
| | - Huilin Zhu
- School of Medicine & Holistic Integrative Medicine, Department of Pathology and Pathophysiology, Nanjing University of Chinese Medicine, Xianlin Avenue 138, Nanjing, Jiangsu 210023, China
| | - Bo Zhang
- School of Medicine & Holistic Integrative Medicine, Department of Pathology and Pathophysiology, Nanjing University of Chinese Medicine, Xianlin Avenue 138, Nanjing, Jiangsu 210023, China.
| | - Tonghui Ma
- School of Medicine & Holistic Integrative Medicine, Department of Pathology and Pathophysiology, Nanjing University of Chinese Medicine, Xianlin Avenue 138, Nanjing, Jiangsu 210023, China.
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Yiew NKH, Vazquez JH, Martino MR, Kennon-McGill S, Price JR, Allard FD, Yee EU, Layman AJ, James LP, McCommis KS, Finck BN, McGill MR. Hepatic pyruvate and alanine metabolism are critical and complementary for maintenance of antioxidant capacity and resistance to oxidative insult. Mol Metab 2023; 77:101808. [PMID: 37716594 PMCID: PMC10561123 DOI: 10.1016/j.molmet.2023.101808] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 08/16/2023] [Accepted: 09/12/2023] [Indexed: 09/18/2023] Open
Abstract
OBJECTIVE Mitochondrial pyruvate is a critical intermediary metabolite in gluconeogenesis, lipogenesis, and NADH production. As a result, the mitochondrial pyruvate carrier (MPC) complex has emerged as a promising therapeutic target in metabolic diseases. Clinical trials are currently underway. However, recent in vitro data indicate that MPC inhibition diverts glutamine/glutamate away from glutathione synthesis and toward glutaminolysis to compensate for loss of pyruvate oxidation, possibly sensitizing cells to oxidative insult. Here, we explored this in vivo using the clinically relevant acetaminophen (APAP) overdose model of acute liver injury, which is driven by oxidative stress. METHODS We used pharmacological and genetic approaches to inhibit MPC2 and alanine aminotransferase 2 (ALT2), individually and concomitantly, in mice and cell culture models and determined the effects on APAP hepatotoxicity. RESULTS We found that MPC inhibition sensitizes the liver to APAP-induced injury in vivo only with concomitant loss of alanine aminotransferase 2 (ALT2). Pharmacological and genetic manipulation of neither MPC2 nor ALT2 alone affected APAP toxicity, but liver-specific double knockout (DKO) significantly worsened APAP-induced liver damage. Further investigation indicated that DKO impaired glutathione synthesis and increased urea cycle flux, consistent with increased glutaminolysis, and these results were reproducible in vitro. Finally, induction of ALT2 and post-treatment with dichloroacetate both reduced APAP-induced liver injury, suggesting new therapeutic avenues. CONCLUSIONS Increased susceptibility to APAP toxicity requires loss of both the MPC and ALT2 in vivo, indicating that MPC inhibition alone is insufficient to disrupt redox balance. Furthermore, the results from ALT2 induction and dichloroacetate in the APAP model suggest new metabolic approaches to the treatment of liver damage.
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Affiliation(s)
- Nicole K H Yiew
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Joel H Vazquez
- Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA; Department of Environmental Health Sciences, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Michael R Martino
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Stefanie Kennon-McGill
- Department of Environmental Health Sciences, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Jake R Price
- Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA; Department of Environmental Health Sciences, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Felicia D Allard
- Department of Pathology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Eric U Yee
- Department of Pathology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Alexander J Layman
- Department of Environmental Health Sciences, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Laura P James
- Department of Pediatrics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Kyle S McCommis
- Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, USA
| | - Brian N Finck
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Mitchell R McGill
- Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA; Department of Environmental Health Sciences, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Department of Pathology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
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Gu L, Zhu Y, Watari K, Lee M, Liu J, Perez S, Thai M, Mayfield JE, Zhang B, Cunha E Rocha K, Li F, Kim LC, Jones AC, Wierzbicki IH, Liu X, Newton AC, Kisseleva T, Lee JH, Ying W, Gonzalez DJ, Saltiel AR, Simon MC, Karin M. Fructose-1,6-bisphosphatase is a nonenzymatic safety valve that curtails AKT activation to prevent insulin hyperresponsiveness. Cell Metab 2023; 35:1009-1021.e9. [PMID: 37084733 PMCID: PMC10430883 DOI: 10.1016/j.cmet.2023.03.021] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 02/16/2023] [Accepted: 03/30/2023] [Indexed: 04/23/2023]
Abstract
Insulin inhibits gluconeogenesis and stimulates glucose conversion to glycogen and lipids. How these activities are coordinated to prevent hypoglycemia and hepatosteatosis is unclear. Fructose-1,6-bisphosphatase (FBP1) is rate controlling for gluconeogenesis. However, inborn human FBP1 deficiency does not cause hypoglycemia unless accompanied by fasting or starvation, which also trigger paradoxical hepatomegaly, hepatosteatosis, and hyperlipidemia. Hepatocyte FBP1-ablated mice exhibit identical fasting-conditional pathologies along with AKT hyperactivation, whose inhibition reversed hepatomegaly, hepatosteatosis, and hyperlipidemia but not hypoglycemia. Surprisingly, fasting-mediated AKT hyperactivation is insulin dependent. Independently of its catalytic activity, FBP1 prevents insulin hyperresponsiveness by forming a stable complex with AKT, PP2A-C, and aldolase B (ALDOB), which specifically accelerates AKT dephosphorylation. Enhanced by fasting and weakened by elevated insulin, FBP1:PP2A-C:ALDOB:AKT complex formation, which is disrupted by human FBP1 deficiency mutations or a C-terminal FBP1 truncation, prevents insulin-triggered liver pathologies and maintains lipid and glucose homeostasis. Conversely, an FBP1-derived complex disrupting peptide reverses diet-induced insulin resistance.
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Affiliation(s)
- Li Gu
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Yahui Zhu
- School of Medicine, Chongqing University, Chongqing 400030, China
| | - Kosuke Watari
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Maiya Lee
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Junlai Liu
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Sofia Perez
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Melinda Thai
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Joshua E Mayfield
- Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA
| | - Bichen Zhang
- Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Karina Cunha E Rocha
- Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Fuming Li
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200438, China
| | - Laura C Kim
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Alexander C Jones
- Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA
| | - Igor H Wierzbicki
- Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA
| | - Xiao Liu
- Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Surgery, University of California, San Diego, La Jolla, CA 92093, USA
| | - Alexandra C Newton
- Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA
| | - Tatiana Kisseleva
- Department of Surgery, University of California, San Diego, La Jolla, CA 92093, USA
| | - Jun Hee Lee
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Wei Ying
- Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - David J Gonzalez
- Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA
| | - Alan R Saltiel
- Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - M Celeste Simon
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
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Wang S, Huo H, Wu H, Ma F, Liao J, Li X, Ding Q, Tang Z, Guo J. Effects of NAC assisted insulin on cholesterol metabolism disorders in canine type 1 diabetes mellitus. Life Sci 2023; 313:121193. [PMID: 36463942 DOI: 10.1016/j.lfs.2022.121193] [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: 10/16/2022] [Revised: 11/06/2022] [Accepted: 11/10/2022] [Indexed: 12/05/2022]
Abstract
Type 1 diabetes mellitus (T1DM) is a metabolic disease characterized by insulin deficiency and often accompanied by hypercholesterolemia. NAC is an effective antioxidative drug, but its application in the treatment of diabetes is still rare. A total of forty beagles were randomly divided into five groups: control group, DM group, INS group, INS with NAC group, and NAC group. The experiment lasted for 120 days. Results revealed that biochemical criterion increased in the DM group, while the indicators significantly decreased on the INS combined with NAC treatment group. Moreover, the insulin released test demonstrated that the model of T1DM was successfully constructed. The result of B ultrasound of gallbladder showed remarkable cholestasis in DM group. The cholesterol metabolism-related enzyme activity (HMGCR and SQLE) was evidently increased in DM group, but decreased in INS and NAC group. The content of TG, LDL-c, and HDL-c in liver was detected by the kit, and it was found that the content of TG, LDL-c, and HDL-c in DM group were reduced. Histopathological observation revealed that the cholestasis of liver cells and hepatic cords were disordered in DM group, the symptoms were alleviated under INS and NAC treatment. Additionally, the protein and mRNA expression of HMGCR and LDLR were obviously increased in DM group, but down regulated in INS and NAC treatment group. Overall, the liver function injury and secondary hypercholesterolemia can be found in T1DM canines, and NAC can relieve cholesterol metabolism disorder in the treatment of canine T1DM.
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Affiliation(s)
- Shuzhou Wang
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, PR China.
| | - Haihua Huo
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, PR China.
| | - Haitong Wu
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, PR China.
| | - Feiyang Ma
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, PR China
| | - Jianzhao Liao
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, PR China.
| | - Xinrun Li
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, PR China.
| | - Qingyu Ding
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, PR China.
| | - Zhaoxin Tang
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, PR China.
| | - Jianying Guo
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, PR China.
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Lee JH, Park HJ, Kim YA, Lee DH, Noh JK, Jung JG, Yoon HH, Lee SK, Lee S. Establishment of a Serum-Free Hepatocyte Cryopreservation Process for the Development of an "Off-the-Shelf" Bioartificial Liver System. Bioengineering (Basel) 2022; 9:738. [PMID: 36550944 PMCID: PMC9774268 DOI: 10.3390/bioengineering9120738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 11/15/2022] [Accepted: 11/23/2022] [Indexed: 12/05/2022] Open
Abstract
To use hepatocytes immediately when necessary for hepatocyte transplantation and bioartificial liver (BAL) systems, a serum-free cryopreservation protocol ensuring the high survival of hepatocytes and maintenance of their functions should be developed. We established a serum-free protocol for the cryopreservation of primary hepatocytes, hepatocyte spheroids, and hepatocyte spheroid beads in liquid nitrogen. The serum-free cryopreservation solutions showed a significantly higher performance in maintaining enhanced viability and ammonia removal, urea secretion, and the albumin synthesis of hepatocyte spheroids and spheroid beads. The serum-free thawing medium, containing human serum albumin (HSA) and N-acetylcysteine (NAC), was compared with a fetal bovine serum-containing thawing medium for the development of a serum-free thawing medium. Our results show that hepatocyte spheroids and spheroid beads thawed using a serum-free thawing medium containing HSA and NAC exhibited increased hepatocyte viability, ammonia removal, urea secretion, and albumin synthesis compared to those thawed using the serum-containing medium. Finally, we evaluated the liver functions of the cryopreserved BAL system-applied serum-free cryopreservation process compared to the fresh BAL system. The ammonia removal efficiency of the cryopreserved hepatocyte spheroids BAL was lower than or similar to that of the fresh BAL system. Additionally, the urea concentrations in the media of all three BAL systems were not significantly different during BAL system operation. This cryopreserved spheroid-based BAL system using a serum-free process will be a good candidate for the treatment of patients.
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Affiliation(s)
- Ji-Hyun Lee
- Stem Cell and Regenerative Medicine Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Republic of Korea
| | - Hey-Jung Park
- Stem Cell and Regenerative Medicine Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Republic of Korea
| | - Young-A Kim
- Stem Cell and Regenerative Medicine Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Republic of Korea
| | - Doo-Hoon Lee
- Research Institute, HLB Cell Co., Ltd., Hwaseong 18469, Republic of Korea
| | - Jeong-Kwon Noh
- Research Institute, HLB Cell Co., Ltd., Hwaseong 18469, Republic of Korea
| | - Jong-Gab Jung
- Research Institute, HLB Cell Co., Ltd., Hwaseong 18469, Republic of Korea
| | - Hee-Hoon Yoon
- Research Institute, HLB Cell Co., Ltd., Hwaseong 18469, Republic of Korea
| | - Suk-Koo Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
| | - Sanghoon Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
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9
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Seesen M, Pratchayasakul W, Pintana H, Chattipakorn N, Chattipakorn SC. Exposure to organophosphates in association with the development of insulin resistance: Evidence from in vitro, in vivo, and clinical studies. Food Chem Toxicol 2022; 168:113389. [PMID: 36031162 DOI: 10.1016/j.fct.2022.113389] [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: 04/26/2022] [Revised: 07/21/2022] [Accepted: 08/19/2022] [Indexed: 10/15/2022]
Abstract
Insulin resistance is an underlying condition prior to the development of several diseases, including type 2 diabetes, cardiovascular diseases, cognitive impairment, and cerebrovascular complications. Organophosphates (OPs) are one of several factors thought to induce insulin resistance. Previous studies showed that the exposure to OPs pesticides induced insulin resistance through the impairment of hepatic glucose metabolism, pancreatic damage, and disruption of insulin signaling of both adipose tissues and skeletal muscles. Several studies reported possible mechanisms associated with OPs-induced insulin resistance in different models in in vivo studies including those in adult animals, obese animals, and offspring models, as well as in clinical studies. In addition, pharmacological interventions in OPs-induced insulin resistance have been previously investigated. This review aims to summarize and discuss all the evidence concerning OPs-induced insulin resistance in different models including in vitro, in vivo and clinical studies. The interventions of OPs-induced insulin resistance are also discussed. Any contradictory findings also considered. The information from this review will provide insight for possible therapeutic approaches to OPs-induced insulin resistance in the future.
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Affiliation(s)
- Mathuramat Seesen
- Department of Community Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Wasana Pratchayasakul
- Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand; Center of Excellence in Cardiac Electrophysiology, Chiang Mai University, Chiang Mai, 50200, Thailand; Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Hiranya Pintana
- Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand; Center of Excellence in Cardiac Electrophysiology, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Nipon Chattipakorn
- Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand; Center of Excellence in Cardiac Electrophysiology, Chiang Mai University, Chiang Mai, 50200, Thailand; Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Siriporn C Chattipakorn
- Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand; Center of Excellence in Cardiac Electrophysiology, Chiang Mai University, Chiang Mai, 50200, Thailand; Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai, 50200, Thailand.
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10
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Jiang SX, Hussaini T, Yoshida EM. N-acetylcysteine for non-acetaminophen induced acute liver failure: A review. Saudi J Gastroenterol 2022; 28:85-91. [PMID: 35142656 PMCID: PMC9007071 DOI: 10.4103/sjg.sjg_406_21] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
The use of N-acetylcysteine (NAC) for non-acetaminophen-induced acute liver failure (NAI-ALF) has been increasing despite controversy in its efficacy. National guidelines are in disagreement for NAC use as standard of care; however, many healthcare centers continue to adopt the use of NAC outside of acetaminophen poisoning. While NAC may have multiple mechanisms of action in treatment of ALF, this has not translated to clinical benefit. Murine models have reported antioxidant and anti-inflammatory properties, as well as improvement in liver-specific microcirculation. Multiple case studies and series have reported positive outcomes of NAC treatment for ALF of various etiologies. While prospective studies suggested the benefit of NAC treatment, these studies have methodological and statistical shortcomings that affect the validity of the results. In this review, we aimed to summarize the existing literature on the efficacy of NAC for NAI-ALF including mechanism of action, case studies and series demonstrating outcomes, and prospective studies that have led to its current widespread use, along with the reported rate of adverse events.
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Affiliation(s)
- Shirley Xue Jiang
- Department of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Trana Hussaini
- Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Eric M. Yoshida
- Division of Gastroenterology, University of British Columbia, Vancouver General Hospital, Vancouver, BC, Canada,Address for correspondence: Dr. Eric M. Yoshida, Division of Gastroenterology, Faculty of Medicine, 5th Floor-2775 Laurel St., Vancouver, BC, Canada. E-mail:
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11
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Mitochondrial glutamine metabolism regulates sensitivity of cancer cells after chemotherapy via amphiregulin. Cell Death Discov 2021; 7:395. [PMID: 34924566 PMCID: PMC8685276 DOI: 10.1038/s41420-021-00792-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 11/24/2021] [Accepted: 12/07/2021] [Indexed: 11/15/2022] Open
Abstract
The DNA damage response is essential for sustaining genomic stability and preventing tumorigenesis. However, the fundamental question about the cellular metabolic response to DNA damage remains largely unknown, impeding the development of metabolic interventions that might prevent or treat cancer. Recently, it has been reported that there is a link between cell metabolism and DNA damage response, by repression of glutamine (Gln) entry into mitochondria to support cell cycle arrest and DNA repair. Here, we show that mitochondrial Gln metabolism is a crucial regulator of DNA damage-induced cell death. Mechanistically, inhibition of glutaminase (GLS), the first enzyme for Gln anaplerosis, sensitizes cancer cells to DNA damage by inducing amphiregulin (AREG) that promotes apoptotic cell death. GLS inhibition increases reactive oxygen species production, leading to transcriptional activation of AREG through Max-like protein X (MLX) transcription factor. Moreover, suppression of mitochondrial Gln metabolism results in markedly increased cell death after chemotherapy in vitro and in vivo. The essentiality of this molecular pathway in DNA damage-induced cell death may provide novel metabolic interventions for cancer therapy.
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12
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N-Acetyl Cysteine Overdose Inducing Hepatic Steatosis and Systemic Inflammation in Both Propacetamol-Induced Hepatotoxic and Normal Mice. Antioxidants (Basel) 2021; 10:antiox10030442. [PMID: 33809388 PMCID: PMC8000488 DOI: 10.3390/antiox10030442] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 03/04/2021] [Accepted: 03/08/2021] [Indexed: 12/21/2022] Open
Abstract
Acetaminophen (APAP) overdose induces acute liver damage and even death. The standard therapeutic dose of N-acetyl cysteine (NAC) cannot be applied to every patient, especially those with high-dose APAP poisoning. There is insufficient evidence to prove that increasing NAC dose can treat patients who failed in standard treatment. This study explores the toxicity of NAC overdose in both APAP poisoning and normal mice. Two inbred mouse strains with different sensitivities to propacetamol-induced hepatotoxicity (PIH) were treated with different NAC doses. NAC therapy decreased PIH by reducing lipid oxidation, protein nitration and inflammation, and increasing glutathione (GSH) levels and antioxidative enzyme activities. However, the therapeutic effects of NAC on PIH were dose-dependent from 125 (N125) to 275 mg/kg (N275). Elevated doses of NAC (400 and 800 mg/kg, N400 and N800) caused additional deaths in both propacetamol-treated and normal mice. N800 treatments significantly decreased hepatic GSH levels and induced inflammatory cytokines and hepatic microvesicular steatosis in both propacetamol-treated and normal mice. Furthermore, both N275 and N400 treatments decreased serum triglyceride (TG) and induced hepatic TG, whereas N800 treatment significantly increased interleukin-6, hepatic TG, and total cholesterol levels. In conclusion, NAC overdose induces hepatic and systemic inflammations and interferes with fatty acid metabolism.
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13
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Colaco CMG, Basile K, Draper J, Ferguson PE. Fulminant Bacillus cereus food poisoning with fatal multi-organ failure. BMJ Case Rep 2021; 14:14/1/e238716. [PMID: 33462030 PMCID: PMC7813301 DOI: 10.1136/bcr-2020-238716] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
This case represents a rare fulminant course of fried-rice associated food poisoning in an immunocompetent person due to pre-formed exotoxin produced by Bacillus cereus, with severe manifestations of sepsis, including multi-organ (hepatic, renal, cardiac, respiratory and neurological) failure, shock, metabolic acidosis, rhabdomyolysis and coagulopathy. Despite maximal supportive measures (continuous renal replacement therapy, plasmapheresis, N-acetylcysteine infusion and blood products, and broad-spectrum antimicrobials) and input from a multidisciplinary team (consisting of infectious diseases, intensive care, gastroenterology, surgery, toxicology, immunology and haematology), mortality resulted. This case is the first to use whole genome sequencing techniques to confirm the toxigenic potential of B. cereus It has important implications for food preparation and storage, particularly given its occurrence in home isolation during the COVID-19 pandemic.
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Affiliation(s)
- Clinton M G Colaco
- Centre for Infectious Diseases and Microbiology Laboratory Services, Westmead Hospital, Westmead, Sydney, Australia,Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Kerri Basile
- Centre for Infectious Diseases and Microbiology Laboratory Services, Westmead Hospital, Westmead, Sydney, Australia,Institute of Clinical Pathology and Medical Research, NSW Health Pathology, Westmead, Sydney, Australia
| | - Jenny Draper
- Centre for Infectious Diseases and Microbiology Laboratory Services, Westmead Hospital, Westmead, Sydney, Australia,Institute of Clinical Pathology and Medical Research, NSW Health Pathology, Westmead, Sydney, Australia
| | - Patricia E Ferguson
- Centre for Infectious Diseases and Microbiology Laboratory Services, Westmead Hospital, Westmead, Sydney, Australia
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14
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Mishra S, Divakar A, Srivastava S, Dewangan J, Sharma D, Asthana S, Chaturvedi S, Wahajuddin M, Kumar S, Rath SK. N-acetyl-cysteine in combination with celecoxib inhibits Deoxynivalenol induced skin tumor initiation via induction of autophagic pathways in swiss mice. Free Radic Biol Med 2020; 156:70-82. [PMID: 32561319 DOI: 10.1016/j.freeradbiomed.2020.06.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Accepted: 06/01/2020] [Indexed: 02/07/2023]
Abstract
Deoxynivalenol is a trichothecene mycotoxin which naturally contaminates small grain, cereals intended for human and animal consumption. Investigations for dermal toxicity of DON has been needed and highlighted by WHO. Previous studies on dermal toxicity suggest that DON has DNA damaging potential leading to skin tumor initiation in mice skin. However, considering its toxicological manifestations arising after dermal exposure, strategies for its prevention/protection are barely available in literatute. Collectively, our study demonstrated that N-acetylcysteine (NAC), precursor of glutathione, significantly alters the genotoxic potential of DON. Further NAC in combination with Celecoxib (CXB) inhibits tumor growth by altering antioxidant status and increasing autophagy in DON initiated Swiss mice. Despite the broad spectrum use of CXB, its use is limited by the concerns about its adverse effects on the cardiovascular system. Serum parameters and histology analysis revealed that CXB (2 mg) when applied topically for 24 weeks did not impart any cardiovascular toxicity which could be because skin permeation potential of CXB was quite low when analyzed through HPLC analysis. Although the anticancer effects of CXB and NAC have been studied, however, the combination of NAC and CXB has yet not been explored for any cancer treatment. Therefore our observations provide additional insights into the therapeutic effects of combinatorial treatment of CXB and NAC against skin tumor prevention. This approach might form a novel alternative strategy for skin cancer treatment as well as skin associated toxicities caused by mycotoxins such as DON. This combinatorial approach can overcome the limitations associated with the use of CXB for long term as topical application of the same seems to be safe in comparison to the oral mode of administration.
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Affiliation(s)
- Sakshi Mishra
- Genotoxicity Laboratory, Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow, 226031, Uttar Pradesh, India
| | - Aman Divakar
- Genotoxicity Laboratory, Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow, 226031, Uttar Pradesh, India
| | - Sonal Srivastava
- Genotoxicity Laboratory, Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow, 226031, Uttar Pradesh, India
| | - Jayant Dewangan
- Genotoxicity Laboratory, Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow, 226031, Uttar Pradesh, India
| | - Divyansh Sharma
- Genotoxicity Laboratory, Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow, 226031, Uttar Pradesh, India
| | - Somya Asthana
- Food Drug and Chemical Toxicology Division, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, 226 001, Uttar Pradesh, India
| | - Swati Chaturvedi
- Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow, 226031, Uttar Pradesh, India
| | - Muhammad Wahajuddin
- Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow, 226031, Uttar Pradesh, India
| | - Sadan Kumar
- Immunotoxicity Laboratory, Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow, 226031, Uttar Pradesh, India
| | - Srikanta Kumar Rath
- Genotoxicity Laboratory, Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow, 226031, Uttar Pradesh, India.
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15
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Mohammadi H, Sayad A, Mohammadi M, Niknahad H, Heidari R. N-acetyl cysteine treatment preserves mitochondrial indices of functionality in the brain of hyperammonemic mice. Clin Exp Hepatol 2020; 6:106-115. [PMID: 32728627 PMCID: PMC7380475 DOI: 10.5114/ceh.2020.95814] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Accepted: 02/20/2020] [Indexed: 12/11/2022] Open
Abstract
AIM OF THE STUDY Acute or chronic live failure could result in hyperammonemia and hepatic encephalopathy (HE). HE is a clinical complication characterized by severe cognitive dysfunction and coma. The ammonium ion (NH4 +) is the most suspected toxic molecule involved in the pathogenesis of HE. NH4 + is a neurotoxic agent. Different mechanisms, including oxidative/nitrosative stress, inflammatory response, excitotoxicity, and mitochondrial impairment, are proposed for NH4 +-induced neurotoxicity. N-acetyl cysteine (NAC) is a well-known thiol-reductant and antioxidant agent. Several investigations also mentioned the positive effects of NAC on mitochondrial function. In the current study, the effect of NAC treatment on brain mitochondrial indices and energy status was investigated in an animal model of HE. MATERIAL AND METHODS Acetaminophen (APAP)-induced acute liver failure was induced by a single dose of the drug (800 mg/kg, i.p.) to C57BL/6J mice. Plasma and brain levels of NH4 + were measured. Then, brain mitochondria were isolated, and several indices, including mitochondrial depolarization, ATP level, lipid peroxidation, glutathione content, mitochondrial permeabilization, and dehydrogenase activity, were assessed. RESULTS A significant increase in plasma and brain NH4 + was evident in APAP-treated animals. Moreover, mitochondrial indices of functionality were impaired, and mitochondrial oxidative stress biomarkers were significantly increased in APAP-treated mice. It was found that NAC treatment (100, 200, and 400 mg/kg, i.p.) significantly mitigated mitochondrial impairment in the brain of APAP-treated animals. CONCLUSIONS These data suggest the effects of NAC on brain mitochondrial function and energy status as a pivotal mechanism involved in its neuroprotective properties during HE.
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Affiliation(s)
- 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, Shiraz, Iran
| | - Abolfazl Sayad
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohsen Mohammadi
- Hepatitis Research Center, Lorestan University of Medical Sciences, Khorramabad, 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, Shiraz, Iran
| | - Reza Heidari
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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16
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Boşgelmez Iİ, Güvendik G. Beneficial Effects of N-Acetyl-L-cysteine or Taurine Pre- or Post-treatments in the Heart, Spleen, Lung, and Testis of Hexavalent Chromium-Exposed Mice. Biol Trace Elem Res 2019; 190:437-445. [PMID: 30417263 DOI: 10.1007/s12011-018-1571-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 11/06/2018] [Indexed: 12/13/2022]
Abstract
Hexavalent chromium[Cr(VI)] compounds may induce toxic effects, possibly via reactive intermediates and radicals formed during Cr(VI) reduction. In this study, we probed the possible effects of N-acetyl-L-cysteine (NAC) and taurine pre- or post-treatments on Cr(VI)-induced changes in lipid peroxidation and nonprotein thiols (NPSH) in mice heart, lung, spleen, and testis tissues. The mice were randomly assigned to six groups, consisting of control, Cr(VI)-exposed (20 mg Cr/kg, intraperitoneal ,ip), NAC (200 mg/kg, ip) as pre-treatment and post-treatment, and taurine (1 g/kg, ip) pre-treatment and post-treatment groups. Lipid peroxidation and NPSH levels were determined and the results were compared with regard to tissue- and antioxidant-specific basis. Exposure to Cr(VI) significantly increased lipid peroxidation in all tissues as compared to the control (p < 0.05); and consistent with this data, NPSH levels were significantly decreased (p < 0.05). Notably, administration of NAC and taurine, either before or after Cr(VI) exposure, was able to ameliorate the lipid peroxidation (p < 0.05) in all tissues. In the case of NPSH content, while the decline could be alleviated by both NAC and taurine pre- and post-treatments in the spleen, diverging results were obtained in other tissues. The effects of Cr(VI) on the lung thiols were abolished by pre-treatment with NAC and taurine; however, post-treatments could not exert significant effect. While thiol depletion in the heart was totally replenished by NAC and taurine administrations, NAC pre-treatment was partially more effective than post-treatment. In contrast with lipid peroxidation data, NAC treatment could not provide a statistically significant beneficial effect on NPSH content of the testis, whereas the effect in this tissue by taurine was profound. Thus, these data highlight the importance of tissue-specific factors and the critical role of administration time. Overall, our data suggest that NAC and taurine may have potential in prevention of Cr(VI)-induced toxicity in the heart, lung, spleen, and testis tissues.
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Affiliation(s)
- I İpek Boşgelmez
- Department of Toxicology, Faculty of Pharmacy, Erciyes University, 38280, Kayseri, Turkey.
| | - Gülin Güvendik
- Department of Toxicology, Faculty of Pharmacy, Ankara University, 06100, Ankara, Turkey
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17
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Zhang Y, Zhao W, Xu H, Hu M, Guo X, Jia W, Liu G, Li J, Cui P, Lager S, Sferruzzi-Perri AN, Li W, Wu XK, Han Y, Brännström M, Shao LR, Billig H. Hyperandrogenism and insulin resistance-induced fetal loss: evidence for placental mitochondrial abnormalities and elevated reactive oxygen species production in pregnant rats that mimic the clinical features of polycystic ovary syndrome. J Physiol 2019; 597:3927-3950. [PMID: 31206177 DOI: 10.1113/jp277879] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Accepted: 05/28/2019] [Indexed: 12/28/2022] Open
Abstract
KEY POINTS Women with polycystic ovary syndrome (PCOS) commonly suffer from miscarriage, but the underlying mechanisms remain unknown. Herein, pregnant rats chronically treated with 5α-dihydrotestosterone (DHT) and insulin exhibited hyperandrogenism and insulin resistance, as well as increased fetal loss, and these features are strikingly similar to those observed in pregnant PCOS patients. Fetal loss in our DHT+insulin-treated pregnant rats was associated with mitochondrial dysfunction, disturbed superoxide dismutase 1 and Keap1/Nrf2 antioxidant responses, over-production of reactive oxygen species (ROS) and impaired formation of the placenta. Chronic treatment of pregnant rats with DHT or insulin alone indicated that DHT triggered many of the molecular pathways leading to placental abnormalities and fetal loss, whereas insulin often exerted distinct effects on placental gene expression compared to co-treatment with DHT and insulin. Treatment of DHT+insulin-treated pregnant rats with the antioxidant N-acetylcysteine improved fetal survival but was deleterious in normal pregnant rats. Our results provide insight into the fetal loss associated with hyperandrogenism and insulin resistance in women and suggest that physiological levels of ROS are required for normal placental formation and fetal survival during pregnancy. ABSTRACT Women with polycystic ovary syndrome (PCOS) commonly suffer from miscarriage, but the underlying mechanism of PCOS-induced fetal loss during pregnancy remains obscure and specific therapies are lacking. We used pregnant rats treated with 5α-dihydrotestosterone (DHT) and insulin to investigate the impact of hyperandrogenism and insulin resistance on fetal survival and to determine the molecular link between PCOS conditions and placental dysfunction during pregnancy. Our study shows that pregnant rats chronically treated with a combination of DHT and insulin exhibited endocrine aberrations such as hyperandrogenism and insulin resistance that are strikingly similar to those in pregnant PCOS patients. Of pathophysiological significance, DHT+insulin-treated pregnant rats had greater fetal loss and subsequently decreased litter sizes compared to normal pregnant rats. This negative effect was accompanied by impaired trophoblast differentiation, increased glycogen accumulation, and decreased angiogenesis in the placenta. Mechanistically, we report that over-production of reactive oxygen species (ROS) in the placenta, mitochondrial dysfunction, and disturbed superoxide dismutase 1 (SOD1) and Keap1/Nrf2 antioxidant responses constitute important contributors to fetal loss in DHT+insulin-treated pregnant rats. Many of the molecular pathways leading to placental abnormalities and fetal loss in DHT+insulin treatment were also seen in pregnant rats treated with DHT alone, whereas pregnant rats treated with insulin alone often exerted distinct effects on placental gene expression compared to insulin treatment in combination with DHT. We also found that treatment with the antioxidant N-acetylcysteine (NAC) improved fetal survival in DHT+insulin-treated pregnant rats, an effect related to changes in Keap1/Nrf2 and nuclear factor-κB signalling. However, NAC administration resulted in fetal loss in normal pregnant rats, most likely due to PCOS-like endocrine abnormality induced by the treatment. Our results suggest that the deleterious effects of hyperandrogenism and insulin resistance on fetal survival are related to a constellation of mitochondria-ROS-SOD1/Nrf2 changes in the placenta. Our findings also suggest that physiological levels of ROS are required for normal placental formation and fetal survival during pregnancy.
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Affiliation(s)
- Yuehui Zhang
- Department of Obstetrics and Gynecology, Key Laboratory and Unit of Infertility in Chinese Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, 150040, Harbin, China.,Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 40530, Gothenburg, Sweden
| | - Wei Zhao
- Department of Obstetrics and Gynecology, Key Laboratory and Unit of Infertility in Chinese Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, 150040, Harbin, China
| | - Hongfei Xu
- Department of Obstetrics and Gynecology, Key Laboratory and Unit of Infertility in Chinese Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, 150040, Harbin, China
| | - Min Hu
- Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 40530, Gothenburg, Sweden.,Department of Traditional Chinese Medicine, The First Affiliated Hospital of Guangzhou Medical University, 510120, Guangzhou, China.,Institute of Integrated Traditional Chinese Medicine and Western Medicine, Guangzhou Medical University, 510120, Guangzhou, China
| | - Xiaozhu Guo
- Department of Obstetrics and Gynecology, Key Laboratory and Unit of Infertility in Chinese Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, 150040, Harbin, China
| | - Wenyan Jia
- Department of Obstetrics and Gynecology, Key Laboratory and Unit of Infertility in Chinese Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, 150040, Harbin, China
| | - Guoqi Liu
- Department of Obstetrics and Gynecology, Key Laboratory and Unit of Infertility in Chinese Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, 150040, Harbin, China
| | - Juan Li
- Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 40530, Gothenburg, Sweden.,Department of Traditional Chinese Medicine, The First Affiliated Hospital of Guangzhou Medical University, 510120, Guangzhou, China
| | - Peng Cui
- Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 40530, Gothenburg, Sweden
| | - Susanne Lager
- Department of Women's and Children's Health, Uppsala University, 75185, Uppsala, Sweden
| | - Amanda Nancy Sferruzzi-Perri
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 3EG, UK
| | - Wei Li
- Department of Obstetrics and Gynecology, Key Laboratory and Unit of Infertility in Chinese Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, 150040, Harbin, China
| | - Xiao-Ke Wu
- Department of Obstetrics and Gynecology, Key Laboratory and Unit of Infertility in Chinese Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, 150040, Harbin, China
| | - Yanhua Han
- Department of Obstetrics and Gynecology, Key Laboratory and Unit of Infertility in Chinese Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, 150040, Harbin, China
| | - Mats Brännström
- Department of Obstetrics and Gynecology, Sahlgrenska University Hospital, Sahlgrenska Academy, University of Gothenburg, 41345, Gothenburg, Sweden
| | - Linus R Shao
- Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 40530, Gothenburg, Sweden
| | - Håkan Billig
- Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 40530, Gothenburg, Sweden
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Ansari FA, Khan AA, Mahmood R. Ameliorative effect of carnosine and N-acetylcysteine against sodium nitrite induced nephrotoxicity in rats. J Cell Biochem 2019; 120:7032-7044. [PMID: 30368897 DOI: 10.1002/jcb.27971] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Accepted: 10/04/2018] [Indexed: 01/24/2023]
Abstract
The widespread use of sodium nitrite (NaNO2 ) for various industrial purposes has increased human exposure to alarmingly high levels of nitrate/nitrite. Because NaNO 2 is a strong oxidizing agent, induction of oxidative stress is one of the mechanisms by which it can exert toxicity in humans and animals. We have investigated the possible protection offered by carnosine (CAR) and N-acetylcysteine (NAC) against NaNO 2 -induced nephrotoxicity in rats. Animals orally received CAR at 100 mg/kg body weight/d for seven days or NAC at 100 mg/kg body weight/d for five days followed by a single oral dose of NaNO 2 at 60 mg/kg body weight. The rats were killed after 24 hours, and the kidneys were removed and processed for various analyses. NaNO 2 induced oxidative stress in kidneys, as shown by the decreased activities of antioxidant defense, brush border membrane, and metabolic enzymes. DNA-protein crosslinking and DNA fragmentation were also observed. CAR/NAC pretreatment significantly protected the kidney against these biochemical alterations. Histological studies supported these findings, showing kidney damage in NaNO 2 -treated animals and reduced tissue impairment in the combination groups. The protection offered by CAR and NAC against NaNO 2 -induced damage, and their nontoxic nature, makes them potential therapeutic agents against nitrite-induced nephrotoxicity.
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Affiliation(s)
- Fariheen Aisha Ansari
- Department of Biochemistry, Faculty of Life Sciences, Aligarh Muslim University, Aligarh, UP, India
| | - Aijaz Ahmed Khan
- Department of Anatomy, Faculty of Medicine, J.N. Medical College, Aligarh Muslim University, Aligarh, UP, India
| | - Riaz Mahmood
- Department of Biochemistry, Faculty of Life Sciences, Aligarh Muslim University, Aligarh, UP, India
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Xu Q, Li M, Yang M, Yang J, Xie J, Lu X, Wang F, Chen W. α-pinene regulates miR-221 and induces G 2/M phase cell cycle arrest in human hepatocellular carcinoma cells. Biosci Rep 2018; 38:BSR20180980. [PMID: 30473536 PMCID: PMC6294613 DOI: 10.1042/bsr20180980] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Revised: 11/15/2018] [Accepted: 11/20/2018] [Indexed: 01/25/2023] Open
Abstract
The naturally occurring compound α-pinene induces cell cycle arrest and antitumor activity. We examined effects of α-pinene on cell cycle regulation in hepatocellular carcinoma cells (HepG2) cells to establish a foundation for its development as a novel treatment for hepatocellular carcinoma (HCC). HepG2 cells treated with α-pinene exhibited dose-dependent growth inhibition as a result of G2/M-phase cell cycle arrest. Cell cycle arrest was associated with down-regulated cyclin-dependent kinase 1 (CDK1) and miR-221 levels and up-regulated levels of CDKN1B/p27, γ-H2AX, phosphorylated ATM, phosphorylated Chk2 and phosphorylated p53. Our observations are consistent with a model in which α-pinene inhibits miR221 expression, which leads to G2/M-phase arrest and activation of CDKN1B/p27-CDK1 and ATM-p53-Chk2 pathways that suppress human hepatoma tumor progression. Additionally, α-pinene was found to trigger oxidative stress and induce apoptosis of HepG2 cells. α-pinene, therefore, represents a potential chemotherapeutic compound for the treatment of HCC.
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Affiliation(s)
- Qiuxiang Xu
- School of Basic Medicine, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, Outer Ring East Road No. 280, Panyu District, Guangzhou 510006, Guangdong Province, China
| | - Ming Li
- School of Basic Medicine, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, Outer Ring East Road No. 280, Panyu District, Guangzhou 510006, Guangdong Province, China
| | - Mengdie Yang
- School of Basic Medicine, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, Outer Ring East Road No. 280, Panyu District, Guangzhou 510006, Guangdong Province, China
| | - Jiebo Yang
- School of Basic Medicine, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, Outer Ring East Road No. 280, Panyu District, Guangzhou 510006, Guangdong Province, China
| | - Jingjing Xie
- School of Basic Medicine, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, Outer Ring East Road No. 280, Panyu District, Guangzhou 510006, Guangdong Province, China
| | - Xinshuo Lu
- School of Basic Medicine, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, Outer Ring East Road No. 280, Panyu District, Guangzhou 510006, Guangdong Province, China
| | - Fang Wang
- School of Basic Medicine, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, Outer Ring East Road No. 280, Panyu District, Guangzhou 510006, Guangdong Province, China
| | - Weiqiang Chen
- School of Basic Medicine, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, Outer Ring East Road No. 280, Panyu District, Guangzhou 510006, Guangdong Province, China
- Guangdong Province Precise Medicine and Big Data Engineering Technology Research Center for Traditional Chinese medicine, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, Outer Ring East Road No. 280, Panyu District, Guangzhou 510006, Guangdong Province, China
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Heil J, Schultze D, Schemmer P, Bruns H. N-acetylcysteine protects hepatocytes from hypoxia-related cell injury. Clin Exp Hepatol 2018; 4:260-266. [PMID: 30603674 PMCID: PMC6311746 DOI: 10.5114/ceh.2018.80128] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Accepted: 06/06/2018] [Indexed: 02/06/2023] Open
Abstract
AIM OF THE STUDY Hepatocyte transplantation has been discussed as an alternative to liver transplantation in selected cases of acute and chronic liver failure and metabolic diseases. Immediately after infusion of hepatocytes, hypoxia-related cell injury is inevitable. N-acetylcysteine (NAC) has been suggested to attenuate hypoxic damage. This study's objective was to evaluate NAC's protective effect in a model of hypoxia-related hepatocyte injury. MATERIAL AND METHODS HepG2 cells were used as a model for hepatocytes and were cultured under standardized hypoxia or normoxia for 24 hours with or without NAC. Growth kinetics were monitored using trypan blue staining. The activation of apoptotic pathways was measured using quantitative real-time PCR for Bcl-2/Bax and p53. The proportions of vital, apoptotic and necrotic cells were verified by fluorescence activated cell sorting using annexin V-labelling. The expression of hypoxia inducible factor 1 (HIF-1) was measured indirectly using its downstream target vascular endothelial growth factor A (VEGF-A). RESULTS After NAC, cell proliferation increased under both hypoxia and normoxia by 528% and 320% (p < 0.05), while VEGF-A expression decreased under normoxia by 67% and 37% (p < 0.05). Compared to cells treated without NAC under hypoxia, the Bcl-2/Bax ratio increased significantly in cells treated with NAC. This finding was confirmed by an increased number of vital cells in FACS analysis. CONCLUSIONS NAC protects hepatocytes from hypoxic injury and ultimately activates anti-apoptotic pathways.
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Affiliation(s)
- Jan Heil
- Department of General and Visceral Surgery, Goethe-University Hospital Frankfurt, Frankfurt/M., Germany
| | - Daniel Schultze
- Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Peter Schemmer
- Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Helge Bruns
- European Medical School, University Hospital for General and Visceral Surgery, Klinikum Oldenburg, Carl von Ossietzky University, Oldenburg, Germany
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21
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Ansari FA, Khan AA, Mahmood R. Protective effect of carnosine and N-acetylcysteine against sodium nitrite-induced oxidative stress and DNA damage in rat intestine. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2018; 25:19380-19392. [PMID: 29728968 DOI: 10.1007/s11356-018-2133-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Accepted: 04/25/2018] [Indexed: 06/08/2023]
Abstract
The widespread use of sodium nitrite (NaNO2) as food preservative, rampant use of nitrogenous fertilizers for agricultural practices, and improper disposal of nitrogenous wastes have drastically increased human exposure to high nitrite levels causing various health disorders and death. In the present study, the protective effect of carnosine and N-acetylcysteine (NAC) against NaNO2-induced intestinal toxicity in rats was investigated. Animals were given a single acute oral dose of NaNO2 at 60 mg/kg body weight with or without prior administration of either carnosine at 100 mg/kg body weight/day for 7 days or NAC at 100 mg/kg body weight/day for 5 days. Rats were killed after 24 h, and intestinal preparations were used for the evaluation of biochemical alterations and histological abrasions. Administration of NaNO2 alone decreased the activities of intestinal brush border membrane and metabolic enzymes and significantly weakened the anti-oxidant defense system. DNA damage was also evident as observed by increased DNA-protein crosslinking and fragmentation. However, prior administration of carnosine or NAC significantly ameliorated NaNO2-induced damage in intestinal cells. Histological studies support these biochemical results, showing intestinal damage in NaNO2-treated animals and reduced tissue injury in the combination groups. The intrinsic anti-oxidant properties of carnosine and NAC must have contributed to the observed mitigation of nitrite-induced metabolic alterations and oxidative damage. Based on further validation from clinical trials, carnosine and NAC can potentially be used as chemo-preventive agents against NaNO2 toxicity.
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Affiliation(s)
- Fariheen Aisha Ansari
- Department of Biochemistry, Faculty of Life Sciences, Aligarh Muslim University, Aligarh, UP, 202002, India
| | - Aijaz Ahmed Khan
- Department of Anatomy, Faculty of Medicine, J. N. Medical College, Aligarh Muslim University, Aligarh, UP, 202002, India
| | - Riaz Mahmood
- Department of Biochemistry, Faculty of Life Sciences, Aligarh Muslim University, Aligarh, UP, 202002, India.
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22
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Grisanti S, Cosentini D, Tovazzi V, Bianchi S, Lazzari B, Consoli F, Roca E, Berruti A, Ferrari VD. Hepatoprotective effect of N-acetylcysteine in trabectedin-induced liver toxicity in patients with advanced soft tissue sarcoma. Support Care Cancer 2018; 26:2929-2935. [PMID: 29546526 DOI: 10.1007/s00520-018-4129-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Accepted: 02/20/2018] [Indexed: 12/24/2022]
Abstract
PURPOSE Trabectedin is one of the few active agents in soft tissue sarcoma (STS) but hepatotoxicity is frequent and represents a dose-limiting factor. Protective strategies aiming at counteracting this important side effect have a crucial clinical impact. Due to its antioxidant properties, N-acetylcysteine (NAC) has a recognized hepatoprotective effect and this provides the rationale for testing NAC in the management of trabectedin-induced hepatotoxicity. METHODS Patients with recurrent or metastatic soft tissue sarcoma, consecutively observed at our institution, who were considered eligible to trabectedin, received concomitant NAC if they had impaired hepatic or renal function at baseline or developed hepatotoxicity during treatment. The study aim was to retrospectively explore trabectedin administration in terms of number of cycles, mean dose, and dose intensity (DI) in patients who received NAC as compared with those who did not. Secondary end points were progression-free survival (PFS) and overall survival (OS). RESULTS A total number of 18 patients were enrolled in this study. Nine received NAC and nine did not. The median number of administered trabectedin cycles, mean trabectedin dose/cycles, and median DI was comparable in the two groups (p = 0.450, p = 0.534, and p = 0.450, respectively). The PFS and OS curves overlapped. CONCLUSION This explorative study suggests that NAC can have a hepatoprotective activity in patients receiving trabectedin allowing to maintain an adequate dose intensity and continuative administration in patients with impaired liver and renal function or developing treatment-induced hepatotoxicity. A prospective randomized trial is warranted.
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Affiliation(s)
- Salvatore Grisanti
- Dipartimento di Specialità Medico-Chirurgiche, Scienze Radiologiche e Sanità Pubblica, Oncologia Medica, Università degli Studi di Brescia, ASST Spedali Civili, Brescia, Italy
| | - Deborah Cosentini
- Dipartimento di Specialità Medico-Chirurgiche, Scienze Radiologiche e Sanità Pubblica, Oncologia Medica, Università degli Studi di Brescia, ASST Spedali Civili, Brescia, Italy
| | - Valeria Tovazzi
- Dipartimento di Specialità Medico-Chirurgiche, Scienze Radiologiche e Sanità Pubblica, Oncologia Medica, Università degli Studi di Brescia, ASST Spedali Civili, Brescia, Italy
| | - Susanna Bianchi
- Dipartimento di Specialità Medico-Chirurgiche, Scienze Radiologiche e Sanità Pubblica, Oncologia Medica, Università degli Studi di Brescia, ASST Spedali Civili, Brescia, Italy
| | - Barbara Lazzari
- Dipartimento di Specialità Medico-Chirurgiche, Scienze Radiologiche e Sanità Pubblica, Oncologia Medica, Università degli Studi di Brescia, ASST Spedali Civili, Brescia, Italy
| | - Francesca Consoli
- Dipartimento di Specialità Medico-Chirurgiche, Scienze Radiologiche e Sanità Pubblica, Oncologia Medica, Università degli Studi di Brescia, ASST Spedali Civili, Brescia, Italy
| | - Elisa Roca
- Dipartimento di Specialità Medico-Chirurgiche, Scienze Radiologiche e Sanità Pubblica, Oncologia Medica, Università degli Studi di Brescia, ASST Spedali Civili, Brescia, Italy
| | - Alfredo Berruti
- Dipartimento di Specialità Medico-Chirurgiche, Scienze Radiologiche e Sanità Pubblica, Oncologia Medica, Università degli Studi di Brescia, ASST Spedali Civili, Brescia, Italy. .,Oncologia Medica, ASST Spedali Civili, Piazzale Spedali Civili 1, 20123, Brescia, Italy.
| | - Vittorio D Ferrari
- Dipartimento di Specialità Medico-Chirurgiche, Scienze Radiologiche e Sanità Pubblica, Oncologia Medica, Università degli Studi di Brescia, ASST Spedali Civili, Brescia, Italy
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23
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Boşgelmez Iİ, Güvendik G. N-Acetyl-L-Cysteine Protects Liver and Kidney Against Chromium(VI)-Induced Oxidative Stress in Mice. Biol Trace Elem Res 2017; 178:44-53. [PMID: 27888451 DOI: 10.1007/s12011-016-0901-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2016] [Accepted: 11/14/2016] [Indexed: 12/28/2022]
Abstract
Acute hexavalent chromium [Cr(VI)] compound exposure may lead to hepatotoxic and nephrotoxic effects. Cr(VI) reduction may generate reactive intermediates and radicals which might be associated with damage. We investigated effects of N-acetyl-l-cysteine (NAC) pre- or post-treatment on oxidative stress and accumulation of Cr in liver and kidney of Cr(VI)-exposed mice. Intraperitoneal potassium dichromate injection (20 mg Cr/kg) caused a significant elevation of lipid peroxidation in both tissues as compared to control (p < 0.05). Significant decreases in non-protein sulfhydryl (NPSH) level, as well as enzyme activities of catalase (CAT) and superoxide dismutase (SOD) along with significant accumulation of Cr in the tissues (p < 0.05) were of note. NAC pre-treatment (200 mg/kg, ip) provided a noticeable alleviation of lipid peroxidation (p < 0.05) in both tissues, whereas post-treatment exerted significant effect only in kidney. Similarly, Cr(VI)-induced NPSH decline was restored by NAC pre-treatment in both tissues (p < 0.05); however, NAC post-treatment could only replenish NPSH in liver (p < 0.05). Regarding enzyme activities, in liver tissue NAC pre-treatment provided significant restoration on Cr(VI)-induced CAT inhibition (p < 0.05), while SOD enzyme activity was regulated to some extent. In kidney, SOD activity was efficiently restored by both treatments (p < 0.05), whereas CAT enzyme alteration could not be totally relieved. Additionally, NAC pre-treatment in both tissues and post-treatment in liver exerted significant tissue Cr level decreases (p < 0.05). Overall, especially NAC pre-treatment seems to provide beneficial effects in regulating pro-oxidant/antioxidant balance and Cr accumulation caused by Cr(VI) in liver and kidney. This finding may be due to several mechanisms including extracellular reduction or chelation of Cr(VI) by readily available NAC.
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Affiliation(s)
- I İpek Boşgelmez
- Department of Toxicology, Faculty of Pharmacy, Erciyes University, 38039, Kayseri, Turkey.
| | - Gülin Güvendik
- Department of Toxicology, Faculty of Pharmacy, Ankara University, 06100, Ankara, Turkey
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24
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Yu YC, Mao YM, Chen CW, Chen JJ, Chen J, Cong WM, Ding Y, Duan ZP, Fu QC, Guo XY, Hu P, Hu XQ, Jia JD, Lai RT, Li DL, Liu YX, Lu LG, Ma SW, Ma X, Nan YM, Ren H, Shen T, Wang H, Wang JY, Wang TL, Wang XJ, Wei L, Xie Q, Xie W, Yang CQ, Yang DL, Yu YY, Zeng MD, Zhang L, Zhao XY, Zhuang H. CSH guidelines for the diagnosis and treatment of drug-induced liver injury. Hepatol Int 2017; 11:221-241. [PMID: 28405790 PMCID: PMC5419998 DOI: 10.1007/s12072-017-9793-2] [Citation(s) in RCA: 202] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Accepted: 03/14/2017] [Indexed: 02/07/2023]
Abstract
Drug-induced liver injury (DILI) is an important clinical problem, which has received more attention in recent decades. It can be induced by small chemical molecules, biological agents, traditional Chinese medicines (TCM), natural medicines (NM), health products (HP), and dietary supplements (DS). Idiosyncratic DILI is far more common than intrinsic DILI clinically and can be classified into hepatocellular injury, cholestatic injury, hepatocellular-cholestatic mixed injury, and vascular injury based on the types of injured target cells. The CSH guidelines summarized the epidemiology, pathogenesis, pathology, and clinical manifestation and gives 16 evidence-based recommendations on diagnosis, differential diagnosis, treatment, and prevention of DILI.
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Affiliation(s)
- Yue-Cheng Yu
- Liver Disease Center of PLA, Bayi Hospital, Nanjing University of Chinese Medicine, Nanjing, 210002, China
| | - Yi-Min Mao
- Department of Gastroenterology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200001, China.
| | - Cheng-Wei Chen
- Shanghai Liver Diseases Research Center, 85th Hospital, Nanjing Military Command, Shanghai, 200235, China.
| | - Jin-Jun Chen
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Jun Chen
- Liver Diseases Center, Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Wen-Ming Cong
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 201805, China
| | - Yang Ding
- Department of Infectious Disease, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Zhong-Ping Duan
- Artificial Liver Center, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China
| | - Qing-Chun Fu
- Shanghai Liver Diseases Research Center, 85th Hospital, Nanjing Military Command, Shanghai, 200235, China
| | - Xiao-Yan Guo
- Department of Gastroenterology, Second Affiliated Hospital, Xi'an Jiaotong University, Xian, 710004, China
| | - Peng Hu
- Department of Infectious Diseases, Institute for Viral Hepatitis, Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China
| | - Xi-Qi Hu
- Department of Pathology, School of Medicine, Fudan University, Shanghai, 200433, China
| | - Ji-Dong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medial University, Beijing, 100069, China
| | - Rong-Tao Lai
- Department of Infectious Diseases, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200025, China
| | - Dong-Liang Li
- Department of Hepatobiliary Disease, Fuzhou General Hospital of PLA, Fuzhou, 350025, China
| | - Ying-Xia Liu
- Department of Liver Disease, Shenzhen Third People's Hospital, Shenzhen, 518040, China
| | - Lun-Gen Lu
- Department of Gastroenterology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200080, China
| | - Shi-Wu Ma
- Department of Infectious Diseases, Kunming General Hospital of PLA, Kunming, 650032, China
| | - Xiong Ma
- Department of Gastroenterology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200001, China
| | - Yue-Min Nan
- Department of Traditional and Western Medical Hepatology, Third Affiliated Hospital, Hebei Medical University, Shijiazhuang, 050051, China
| | - Hong Ren
- Department of Infectious Diseases, Institute for Viral Hepatitis, Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China
| | - Tao Shen
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Beijing University, Beijing, 100083, China
| | - Hao Wang
- Institute of Hepatology, People's Hospital, Beijing University, Beijing, 100044, China
| | - Ji-Yao Wang
- Department of Gastroenterology, Zhongshan Hospital, School of Medicine, Fudan University, Shanghai, 200032, China
| | - Tai-Ling Wang
- Department of Pathology, China-Japan Friendship Hospital, Capital Medical University, Beijing, 100029, China
| | - Xiao-Jin Wang
- Shanghai Liver Diseases Research Center, 85th Hospital, Nanjing Military Command, Shanghai, 200235, China
| | - Lai Wei
- Institute of Hepatology, People's Hospital, Beijing University, Beijing, 100044, China
| | - Qing Xie
- Department of Infectious Diseases, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200025, China
| | - Wen Xie
- Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100011, China
| | - Chang-Qing Yang
- Department of Gastroenterology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065c, China
| | - Dong-Liang Yang
- Department of Infectious Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yan-Yan Yu
- Department of Infectious Disease, Beijing University First Hospital, Beijing, 100034, China
| | - Min-de Zeng
- Department of Gastroenterology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200001, China
| | - Li Zhang
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, 100078c, China
| | - Xin-Yan Zhao
- Liver Research Center, Beijing Friendship Hospital, Capital Medial University, Beijing, 100069, China
| | - Hui Zhuang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Beijing University, Beijing, 100083, China
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25
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N-Acetylcysteine Prevents Retrograde Motor Neuron Death after Neonatal Peripheral Nerve Injury. Plast Reconstr Surg 2017; 139:1105e-1115e. [DOI: 10.1097/prs.0000000000003257] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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26
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Nabi T, Nabi S, Rafiq N, Shah A. Role of N-acetylcysteine treatment in non-acetaminophen-induced acute liver failure: A prospective study. Saudi J Gastroenterol 2017; 23:169-175. [PMID: 28611340 PMCID: PMC5470376 DOI: 10.4103/1319-3767.207711] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND/AIMS Acute liver failure (ALF) is a rare but severe medical emergency. To date, there is no established treatment for non-acetaminophen-induced acute liver failure (NAI-ALF) other than liver transplantation, and little is known about the use of N-acetylcysteine (NAC) in NAI-ALF. A randomized case control study was conducted with the aim to determine the effect of NAC on the mortality of NAI-ALF patients, as well as to evaluate the safety and efficacy of NAC use. PATIENTS AND METHODS A total of 80 patients diagnosed with NAI-ALF were included in the study. Forty patients received NAC infusion for 72 h whereas the control group received placebo. The variables evaluated were demographic characteristics, signs and symptoms, biochemical parameters, and clinical course during hospitalization. RESULTS The two groups (NAC and control) were comparable for various baseline characteristics (such as etiology of ALF, INR, alanine aminotransferase, creatinine, albumin, and grade of encephalopathy), except for age. Although majority of patients had undetermined etiology (32.5% in NAC group and 42.5% in control group), the second main cause was acute hepatitis E and drug or toxin-induced ALF. The mortality decreased to 28% with the use of NAC versus 53% in the control group (P = 0.023). The use of NAC was associated with shorter length of hospital stay in survived patients (P = 0.002). Moreover, the survival of patients was improved by NAC (P = 0.025). Also, drug-induced ALF showed improved outcome compared to other etiologies. CONCLUSION The findings of the study recommend the use of NAC along with conventional treatments in patients with NAI-ALF in non-transplant centers while awaiting referrals and conclude the use of NAC as safe.
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Affiliation(s)
- Tauseef Nabi
- Department of Endocrinology, SKIMS, Soura, Srinagar, Jammu and Kashmir, India
| | - Sumaiya Nabi
- Department of Bio-chemistry, University of Kashmir, Srinagar, Jammu and Kashmir, India
| | - Nadeema Rafiq
- Department of Physiology, GMC, Srinagar, Jammu and Kashmir, India
| | - Altaf Shah
- Department of Gastroenterology, SKIMS, Srinagar, Jammu and Kashmir, India
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27
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Effect of N-Acetylcysteine on Mortality and Liver Transplantation Rate in Non-Acetaminophen-Induced Acute Liver Failure: A Multicenter Study. Clin Drug Investig 2017; 37:473-482. [DOI: 10.1007/s40261-017-0505-4] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
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28
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Bartlett DC, Newsome PN. A Modified Protocol for the Isolation of Primary Human Hepatocytes with Improved Viability and Function from Normal and Diseased Human Liver. Methods Mol Biol 2017; 1506:61-73. [PMID: 27830545 DOI: 10.1007/978-1-4939-6506-9_4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Successful hepatocyte isolation is critical for continued development of cellular transplantation. However, most tissue available for research is from diseased liver and the results of hepatocyte isolation from such tissue are inferior compared to normal tissue. Here we describe a modified method, combining the use of Liberase and N-acetylcysteine (NAC), for the isolation of primary human hepatocytes with high viability from normal and diseased liver.
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Affiliation(s)
- David C Bartlett
- National Institute for Health Research (NIHR) Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, UK. .,The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, UK.
| | - Philip N Newsome
- National Institute for Health Research (NIHR) Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, UK. .,The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, UK.
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N-Acetyl-L-cysteine Protects the Enterocyte against Oxidative Damage by Modulation of Mitochondrial Function. Mediators Inflamm 2016; 2016:8364279. [PMID: 28003713 PMCID: PMC5149690 DOI: 10.1155/2016/8364279] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Revised: 09/05/2016] [Accepted: 10/23/2016] [Indexed: 11/30/2022] Open
Abstract
The neonatal small intestine is susceptible to damage caused by oxidative stress. This study aimed to evaluate the protective role of antioxidant N-acetylcysteine (NAC) in intestinal epithelial cells against oxidative damage induced by H2O2. IPEC-J2 cells were cultured in DMEM-H with NAC and H2O2. After 2-day incubation, IPEC-J2 cells were collected for analysis of DNA synthesis, antioxidation capacity, mitochondrial respiration, and cell apoptosis. The results showed that H2O2 significantly decreased (P < 0.05) proliferation rate, mitochondrial respiration, and antioxidation capacity and increased cell apoptosis and the abundance of associated proteins, including cytochrome C, Bcl-XL, cleaved caspase-3, and total caspase-3. NAC supplementation remarkably increased (P < 0.05) proliferation rate, antioxidation capacity, and mitochondrial bioenergetics but decreased cell apoptosis. These findings indicate that NAC might rescue the intestinal injury induced by H2O2.
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30
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Abstract
Liver disease is a leading cause of morbidity and mortality. Liver transplantation remains the only proven treatment for end-stage liver failure but is limited by the availability of donor organs. Hepatocyte cell therapy, either with bioartificial liver devices or hepatocyte transplantation, may help address this by delaying or preventing liver transplantation. Early clinical studies have shown promising results, however in most cases, the benefit has been short lived and so further research into these therapies is required. Alternative sources of hepatocytes, including stem cell-derived hepatocytes, are being investigated as the isolation of primary human hepatocytes is limited by the same shortage of donor organs. This review summarises the current clinical experience of hepatocyte cell therapy together with an overview of possible alternative sources of hepatocytes. Current and future areas for research that might lead towards the realisation of the full potential of hepatocyte cell therapy are discussed.
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Affiliation(s)
- David Christopher Bartlett
- a NIHR Centre for Liver Research and Biomedical Research Unit, University of Birmingham, Birmingham, UK.,b Liver Unit, University Hospital Birmingham NHS Foundation Trust, Birmingham, UK
| | - Philip N Newsome
- a NIHR Centre for Liver Research and Biomedical Research Unit, University of Birmingham, Birmingham, UK.,b Liver Unit, University Hospital Birmingham NHS Foundation Trust, Birmingham, UK
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31
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Aubdool AA, Kodji X, Abdul-Kader N, Heads R, Fernandes ES, Bevan S, Brain SD. TRPA1 activation leads to neurogenic vasodilatation: involvement of reactive oxygen nitrogen species in addition to CGRP and NO. Br J Pharmacol 2016; 173:2419-33. [PMID: 27189253 PMCID: PMC4945766 DOI: 10.1111/bph.13519] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2015] [Revised: 05/02/2016] [Accepted: 05/05/2016] [Indexed: 01/08/2023] Open
Abstract
Background and Purpose Transient receptor potential ankyrin‐1 (TRPA1) activation is known to mediate neurogenic vasodilatation. We investigated the mechanisms involved in TRPA1‐mediated peripheral vasodilatation in vivo using the TRPA1 agonist cinnamaldehyde. Experimental Approach Changes in vascular ear blood flow were measured in anaesthetized mice using laser Doppler flowmetry. Key Results Topical application of cinnamaldehyde to the mouse ear caused a significant increase in blood flow in the skin of anaesthetized wild‐type (WT) mice but not in TRPA1 knockout (KO) mice. Cinnamaldehyde‐induced vasodilatation was inhibited by the pharmacological blockade of the potent microvascular vasodilator neuropeptide CGRP and neuronal NOS‐derived NO pathways. Cinnamaldehyde‐mediated vasodilatation was significantly reduced by treatment with reactive oxygen nitrogen species (RONS) scavenger such as catalase and the SOD mimetic TEMPOL, supporting a role of RONS in the downstream vasodilator TRPA1‐mediated response. Co‐treatment with a non‐selective NOS inhibitor L‐NAME and antioxidant apocynin further inhibited the TRPA1‐mediated vasodilatation. Cinnamaldehyde treatment induced the generation of peroxynitrite that was blocked by the peroxynitrite scavenger FeTPPS and shown to be dependent on TRPA1, as reflected by an increase in protein tyrosine nitration in the skin of WT, but not in TRPA1 KO mice. Conclusion and Implications This study provides in vivo evidence that TRPA1‐induced vasodilatation mediated by cinnamaldehyde requires neuronal NOS‐derived NO, in addition to the traditional neuropeptide component. A novel role of peroxynitrite is revealed, which is generated downstream of TRPA1 activation by cinnamaldehyde. This mechanistic pathway underlying TRPA1‐mediated vasodilatation may be important in understanding the role of TRPA1 in pathophysiological situations.
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Affiliation(s)
- Aisah A Aubdool
- Cardiovascular Division, BHF Centre of Excellence, King's College London, London, UK
| | - Xenia Kodji
- Cardiovascular Division, BHF Centre of Excellence, King's College London, London, UK
| | - Nayaab Abdul-Kader
- Cardiovascular Division, BHF Centre of Excellence, King's College London, London, UK
| | - Richard Heads
- Cardiovascular Division, BHF Centre of Excellence, King's College London, London, UK
| | - Elizabeth S Fernandes
- Cardiovascular Division, BHF Centre of Excellence, King's College London, London, UK.,Programa de Pós-graduação, Universidade CEUMA, São Luís, MA, Brazil
| | - Stuart Bevan
- Wolfson Centre for Age Related Diseases, King's College London, London, UK
| | - Susan D Brain
- Cardiovascular Division, BHF Centre of Excellence, King's College London, London, UK
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Abstract
Animal experiments cannot predict the probability of idiosyncratic drug toxicity; consequently, an important goal of the pharmaceutical industry is to develop a new methodology for preventing this form of drug reaction. Although the mechanism remains unclear, immune reactions are likely involved in the toxic processes underlying idiosyncratic drug toxicity: the drug is first activated into a chemically reactive metabolite that binds covalently to proteins and then acts as an immunogen. Therefore, screening tests to detect chemically reactive metabolites are conducted early during drug development and typically involve trapping with glutathione. More quantitative methods are then used in a later stage of drug development and frequently employ (14)Cor (3)H-labeled compounds. It has recently been demonstrated that a zone classification system can be used to separate risky drugs from likely safe drugs: by plotting the amount of each protein-bound reactive metabolite in vitro against the dose levels in vivo, the risk associated with each drug candidate can be assessed. A mechanism for idiosyncratic drug-induced hepatotoxicity was proposed by analogy to virus-induced hepatitis, in which cytotoxic T lymphocytes play an important role. This mechanism suggests that polymorphism in human leukocyte antigens is involved in idiosyncrasy, and a strong correlation with a specific genotype of human leukocyte antigens has been found in many cases of idiosyncratic drug toxicity. Therefore, gene biomarkers hold promise for reducing the clinical risk and prolonging the life cycle of otherwise useful drugs.
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Affiliation(s)
- Toshihiko Ikeda
- Laboratory of Drug Metabolism and Pharmacokinetics, Yokohama College of Pharmacy
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33
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Tsai MS, Chien CC, Lin TH, Liu CC, Liu RH, Su HL, Chiu YT, Wang SH. Galangin Prevents Acute Hepatorenal Toxicity in Novel Propacetamol-Induced Acetaminophen-Overdosed Mice. J Med Food 2015; 18:1187-97. [PMID: 26501381 DOI: 10.1089/jmf.2014.3328] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Acetaminophen (APAP) overdose causes severe liver and kidney damage. APAP-induced liver injury (AILI) represents the most frequent cause of drug-induced liver failure. APAP is relatively insoluble and can only be taken orally; however, its prodrug, propacetamol, is water soluble and usually injected directly. In this study, we examined the time-dependent effects of AILI after propacetamol injection in mice. After analyses of alanine aminotransferase and aspartate aminotransferase activities and liver histopathology, we demonstrated that a novel AILI mouse model can be established by single propacetamol injection. Furthermore, we compared the protective and therapeutic effects of galangin with a known liver protective extract, silymarin, and the only clinical agent for treating APAP toxicity, N-acetylcysteine (NAC), at the same dose in the model mice. We observed that galangin and silymarin were more effective than NAC for protecting against AILI. However, only NAC greatly improved both the survival time and rate consequent to a lethal dose of propacetamol. To decipher the hepatic protective mechanism(s) of galangin, galangin pretreatment significantly decreased the hepatic oxidative stress, increased hepatic glutathione level, and decreased hepatic microsomal CYP2E1 levels induced by propacetamol injection. In addition, propacetamol injection also reproduced the probability of APAP-induced kidney injury (AIKI), appearing similar to a clinical APAP overdose. Only galangin pretreatment showed the protective effect of AIKI. Thus, we have established a novel mouse model for AILI and AIKI using a single propacetamol injection. We also demonstrated that galangin provides significant protection against AILI and AIKI in this mouse model.
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Affiliation(s)
- Ming-Shiun Tsai
- 1 Department of Bioindustry Technology, Da-Yeh University , Taiwan, Republic of China
| | - Chia-Chih Chien
- 2 Department of Biomedical Sciences, Chung Shan Medical University , Taiwan, Republic of China
| | - Ting-Hui Lin
- 2 Department of Biomedical Sciences, Chung Shan Medical University , Taiwan, Republic of China
| | - Chia-Chi Liu
- 2 Department of Biomedical Sciences, Chung Shan Medical University , Taiwan, Republic of China
| | - Rosa Huang Liu
- 3 Department of Nutrition, Chung Shan Medical University , Taiwan, Republic of China
| | - Hong-Lin Su
- 4 Department of Life Sciences, National Chung Hsing University , Taiwan, Republic of China
| | - Yung-Tsung Chiu
- 5 Laboratory of Comparative Pathology, Department of Education and Research, Taichung Veterans General Hospital , Taiwan, Republic of China
| | - Sue-Hong Wang
- 2 Department of Biomedical Sciences, Chung Shan Medical University , Taiwan, Republic of China .,6 Department of Medical Research, Chung Shan Medical University Hospital , Taiwan, Republic of China
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Kosharskyy B, Vydyanathan A, Zhang L, Shaparin N, Geohagen BC, Bivin W, Liu Q, Gavin T, LoPachin RM. 2-Acetylcyclopentanone, an enolate-forming 1,3-dicarbonyl compound, is cytoprotective in warm ischemia-reperfusion injury of rat liver. J Pharmacol Exp Ther 2015; 353:150-8. [PMID: 25659651 PMCID: PMC4366758 DOI: 10.1124/jpet.114.221622] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2014] [Accepted: 02/05/2015] [Indexed: 01/07/2023] Open
Abstract
We have previously shown that 2-acetylcyclopentanone (2-ACP), an enolate-forming 1,3-dicarbonyl compound, provides protection in cell culture and animal models of oxidative stress. The pathophysiology of ischemia-reperfusion injury (IRI) involves oxidative stress, and, therefore, we determined the ability of 2-ACP to prevent this injury in a rat liver model. IRI was induced by clamping the portal vasculature for 45 minutes (ischemia phase), followed by recirculation for 180 minutes (reperfusion phase). This sequence was associated with substantial derangement of plasma liver enzyme activities, histopathological indices, and markers of oxidative stress. The 2-ACP (0.80-2.40 mmol/kg), administered by intraperitoneal injection 10 minutes prior to reperfusion, provided dose-dependent cytoprotection, as indicated by normalization of the IRI-altered liver histologic and biochemical parameters. The 2-ACP (2.40 mmol/kg) was also hepatoprotective when injected before clamping the circulation (ischemia phase). In contrast, an equimolar dose of N-acetylcysteine (2.40 mmol/kg) was not hepatoprotective when administered prior to reperfusion. Our studies to date suggest that during reperfusion the enolate nucleophile of 2-ACP limits the consequences of mitochondrial-based oxidative stress through scavenging unsaturated aldehyde electrophiles (e.g., acrolein) and chelation of metal ions that catalyze the free radical-generating Fenton reaction. The ability of 2-ACP to reduce IRI when injected prior to ischemia most likely reflects the short duration of this experimental phase (45 minutes) and favorable pharmacokinetics that maintain effective 2-ACP liver concentrations during subsequent reperfusion. These results provide evidence that 2-ACP or an analog might be useful in treating IRI and other conditions that have oxidative stress as a common molecular etiology.
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Affiliation(s)
- Boleslav Kosharskyy
- Departments of Anesthesiology (B.K., A.V., L.Z., N.S., B.C.G., R.M.L.) and Pathology (W.B., Q.L.), Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York; and Department of Chemistry, Iona College, New Rochelle, New York (T.G.)
| | - Amaresh Vydyanathan
- Departments of Anesthesiology (B.K., A.V., L.Z., N.S., B.C.G., R.M.L.) and Pathology (W.B., Q.L.), Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York; and Department of Chemistry, Iona College, New Rochelle, New York (T.G.)
| | - Lihai Zhang
- Departments of Anesthesiology (B.K., A.V., L.Z., N.S., B.C.G., R.M.L.) and Pathology (W.B., Q.L.), Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York; and Department of Chemistry, Iona College, New Rochelle, New York (T.G.)
| | - Naum Shaparin
- Departments of Anesthesiology (B.K., A.V., L.Z., N.S., B.C.G., R.M.L.) and Pathology (W.B., Q.L.), Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York; and Department of Chemistry, Iona College, New Rochelle, New York (T.G.)
| | - Brian C Geohagen
- Departments of Anesthesiology (B.K., A.V., L.Z., N.S., B.C.G., R.M.L.) and Pathology (W.B., Q.L.), Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York; and Department of Chemistry, Iona College, New Rochelle, New York (T.G.)
| | - William Bivin
- Departments of Anesthesiology (B.K., A.V., L.Z., N.S., B.C.G., R.M.L.) and Pathology (W.B., Q.L.), Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York; and Department of Chemistry, Iona College, New Rochelle, New York (T.G.)
| | - Qiang Liu
- Departments of Anesthesiology (B.K., A.V., L.Z., N.S., B.C.G., R.M.L.) and Pathology (W.B., Q.L.), Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York; and Department of Chemistry, Iona College, New Rochelle, New York (T.G.)
| | - Terrence Gavin
- Departments of Anesthesiology (B.K., A.V., L.Z., N.S., B.C.G., R.M.L.) and Pathology (W.B., Q.L.), Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York; and Department of Chemistry, Iona College, New Rochelle, New York (T.G.)
| | - Richard M LoPachin
- Departments of Anesthesiology (B.K., A.V., L.Z., N.S., B.C.G., R.M.L.) and Pathology (W.B., Q.L.), Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York; and Department of Chemistry, Iona College, New Rochelle, New York (T.G.)
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Mudalel ML, Dave KP, Hummel JP, Solga SF. N-acetylcysteine treats intravenous amiodarone induced liver injury. World J Gastroenterol 2015; 21:2816-2819. [PMID: 25759554 PMCID: PMC4351236 DOI: 10.3748/wjg.v21.i9.2816] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2014] [Revised: 10/07/2014] [Accepted: 11/19/2014] [Indexed: 02/06/2023] Open
Abstract
We report a case of intravenous (IV) amiodarone drug induced liver injury (DILI). The patient received IV N-acetylcysteine (NAC) which resulted in a rapid improvement in liver enzymes. While the specific mechanisms for the pathogenesis of IV amiodarone DILI and the therapeutic action of IV NAC are both unknown, this case strongly implies at least some commonality. Because IV amiodarone is indicated for the treatment of serious cardiac arrhythmias in an intensive care unit setting, some degree of ischemic hepatitis is likely a cofactor in most cases.
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36
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Soliman MM, Nassan MA, Ismail TA. Immunohistochemical and molecular study on the protective effect of curcumin against hepatic toxicity induced by paracetamol in Wistar rats. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2014; 14:457. [PMID: 25432491 PMCID: PMC4258929 DOI: 10.1186/1472-6882-14-457] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Accepted: 11/21/2014] [Indexed: 12/21/2022]
Abstract
Background An overdose of paracetamol is a frequent reason for liver and renal toxicity and possible death and curcumin has hepatoprotective properties against liver damage. The exact mechanism of such protection is not clear. Therefore, this study was conducted to examine the molecular levels of the protective effect of curcumin on paracetamol overdose induced hepatic toxicity in rats. Methods Male Wistar rats were allocated into 4 groups. Control group, administered corn oil; curcumin group, administered curcumin (400 mg/kg BW daily intra-gastric) dissolved in corn oil; paracetamol group, administered corn oil with a single dose of paracetamol (500 mg/kg BW intra-gastric) and protective group, administered curcumin with a single dose of paracetamol. Curcumin was administered for 7 successive days, while paracetamol was administered at day six of treatment. Blood and liver tissues were collected for biochemical, histopathological, immunohistochemical and molecular examination. Results Serum analysis revealed an alteration in parameters of kidney and liver. A decrease in the antioxidant activity of liver was recorded in paracetamol group while curcumin administration restored it. Histopathological findings showed an extensive coagulative necrosis in hepatocytes together with massive neutrophilic and lymphocytic infiltration. Immunostaining of liver matrix metalloproteinase-8 (MMP-8) in paracetamol administered rats showed an increase in MMP-8 expression in the area of coagulative necrosis surrounding the central vein of hepatic lobules. Curcumin administration decreased MMP-8 expression in liver of paracetamol administered rats. Gene expression measurements revealed that paracetamol decreased the expression of antioxidant genes and increased the expression of interleukin-1β (IL-1β), IL-8, tumor necrosis factor-α (TNF-α) and acute phase proteins. Curcumin administration ameliorated paracetamol-induced alterations in genes expression of antioxidant and inflammatory cytokines. Conclusion The results clarified the strong protective effect of curcumin on paracetamol induced hepatic toxicity in rats at the immunohistochemical and molecular levels.
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37
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Wang F, Liu S, Shen Y, Zhuang R, Xi J, Fang H, Pan X, Sun J, Cai Z. Protective effects of N-acetylcysteine on cisplatin-induced oxidative stress and DNA damage in HepG2 cells. Exp Ther Med 2014; 8:1939-1945. [PMID: 25371760 PMCID: PMC4218661 DOI: 10.3892/etm.2014.2019] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2014] [Accepted: 09/24/2014] [Indexed: 11/13/2022] Open
Abstract
Hepatocyte injury is a common pathological effect of cisplatin (CDDP) in various solid tumor therapies. Thus, strategies for minimizing CDDP toxicity are of great clinical interest. N-acetylcysteine (NAC), a known antioxidant, is often used as an antidote for acetaminophen overdose in the clinic due to its ability to increase the levels of glutathione (GSH). In the present study, the aim was to investigate the protective effects of NAC against CDDP-induced apoptosis in human-derived HepG2 cells. The results showed that upon exposure of the cells to CDDP, oxidative stress was significantly induced. DNA damage caused by CDDP was associated with cell apoptosis. NAC pre-treatment significantly reduced the malondialdehyde (MDA) levels and ameliorated the GSH modulation induced by CDDP. NAC also protected against DNA damage and cell apoptosis. These data suggest the protective role of NAC against hepatocyte apoptosis induced by CDDP was achieved through the inhibition of DNA damage and alterations of the redox status in human derived HepG2 cells. These results indicate that NAC administration may protect against CDDP-induced damage.
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Affiliation(s)
- Fugen Wang
- The Xixi Hospital of Hangzhou Affiliated to Zhejiang University of Traditional Chinese Medicine, Hangzhou, Zhejiang 310023, P.R. China
| | - Shourong Liu
- The Xixi Hospital of Hangzhou Affiliated to Zhejiang University of Traditional Chinese Medicine, Hangzhou, Zhejiang 310023, P.R. China
| | - Yiqin Shen
- The Xixi Hospital of Hangzhou Affiliated to Zhejiang University of Traditional Chinese Medicine, Hangzhou, Zhejiang 310023, P.R. China
| | - Rangxiao Zhuang
- The Xixi Hospital of Hangzhou Affiliated to Zhejiang University of Traditional Chinese Medicine, Hangzhou, Zhejiang 310023, P.R. China
| | - Jianjun Xi
- The Xixi Hospital of Hangzhou Affiliated to Zhejiang University of Traditional Chinese Medicine, Hangzhou, Zhejiang 310023, P.R. China
| | - Hongying Fang
- The Xixi Hospital of Hangzhou Affiliated to Zhejiang University of Traditional Chinese Medicine, Hangzhou, Zhejiang 310023, P.R. China
| | - Xuwan Pan
- The Xixi Hospital of Hangzhou Affiliated to Zhejiang University of Traditional Chinese Medicine, Hangzhou, Zhejiang 310023, P.R. China
| | - Jingjing Sun
- The Xixi Hospital of Hangzhou Affiliated to Zhejiang University of Traditional Chinese Medicine, Hangzhou, Zhejiang 310023, P.R. China
| | - Zhaobin Cai
- The Xixi Hospital of Hangzhou Affiliated to Zhejiang University of Traditional Chinese Medicine, Hangzhou, Zhejiang 310023, P.R. China
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Tobwala S, Khayyat A, Fan W, Ercal N. Comparative evaluation of N-acetylcysteine and N-acetylcysteineamide in acetaminophen-induced hepatotoxicity in human hepatoma HepaRG cells. Exp Biol Med (Maywood) 2014; 240:261-72. [PMID: 25245075 DOI: 10.1177/1535370214549520] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
Acetaminophen (N-acetyl-p-aminophenol, APAP) is one of the most widely used over-the-counter antipyretic analgesic medications. Despite being safe at therapeutic doses, an accidental or intentional overdose can result in severe hepatotoxicity; a leading cause of drug-induced liver failure in the U.S. Depletion of glutathione (GSH) is implicated as an initiating event in APAP-induced toxicity. N-acetylcysteine (NAC), a GSH precursor, is the only currently approved antidote for an APAP overdose. Unfortunately, fairly high doses and longer treatment times are required due to its poor bioavailability. In addition, oral and intravenous administration of NAC in a hospital setting are laborious and costly. Therefore, we studied the protective effects of N-acetylcysteineamide (NACA), a novel antioxidant, with higher bioavailability and compared it with NAC in APAP-induced hepatotoxicity in a human-relevant in vitro system, HepaRG. Our results indicated that exposure of HepaRG cells to APAP resulted in GSH depletion, reactive oxygen species (ROS) formation, increased lipid peroxidation, mitochondrial dysfunction (assessed by JC-1 fluorescence), and lactate dehydrogenase release. Both NAC and NACA protected against APAP-induced hepatotoxicity by restoring GSH levels, scavenging ROS, inhibiting lipid peroxidation, and preserving mitochondrial membrane potential. However, NACA was better than NAC at combating oxidative stress and protecting against APAP-induced damage. The higher efficiency of NACA in protecting cells against APAP-induced toxicity suggests that NACA can be developed into a promising therapeutic option for treatment of an APAP overdose.
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Affiliation(s)
- Shakila Tobwala
- Department of Chemistry, Missouri University of Science and Technology, Rolla, MO 65409, USA
| | - Ahdab Khayyat
- Department of Chemistry, Missouri University of Science and Technology, Rolla, MO 65409, USA
| | - Weili Fan
- Department of Chemistry, Missouri University of Science and Technology, Rolla, MO 65409, USA
| | - Nuran Ercal
- Department of Chemistry, Missouri University of Science and Technology, Rolla, MO 65409, USA
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Combined use of N-acetylcysteine and Liberase improves the viability and metabolic function of human hepatocytes isolated from human liver. Cytotherapy 2014; 16:800-9. [PMID: 24642019 PMCID: PMC4029080 DOI: 10.1016/j.jcyt.2014.01.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2013] [Revised: 01/07/2014] [Accepted: 01/14/2014] [Indexed: 12/17/2022]
Abstract
Background aims Successful hepatocyte isolation is critical for continued development of cellular transplantation. However, most tissue available for research is from diseased liver, and the results of hepatocyte isolation from such tissue are inferior compared with normal tissue. Liberase and N-acetylcysteine (NAC) have been shown separately to improve viability of isolated hepatocytes. This study aims to determine the effect of Liberase and NAC in combination on human hepatocyte isolation from normal and diseased liver tissues. Methods Hepatocytes were isolated from 30 liver specimens through the use of a standard collagenase digestion technique (original protocol) and another 30 with the addition of NAC and standard collagenase substituted by Liberase (new protocol). Viability and success, defined as maintenance of cell adhesion and morphology for 48 hours, were assessed. Metabolic function was assessed by means of albumin and urea synthesis. Results Baseline factors were similar for both groups. The delay to tissue processing was slightly shorter in the new protocol group (median, 2 versus 4 hours; P = 0.007). The success rate improved from 12 of 30 (40.0%) to 21 of 30 (70.0%) with the use of the new protocol (P = 0.037), and median viable cell yield increased from 7.3 × 104 to 28.3 × 104 cells/g tissue (P = 0.003). After adjusting for delay, success rate (P = 0.014) and viable cell yield/g tissue (P = 0.001) remained significantly improved. Albumin and urea synthesis were similar or superior in the new protocol group. Conclusions NAC and Liberase improve the success of hepatocyte isolation, with a significantly higher yield of viable cells. The use of these agents may improve the availability of hepatocytes for transplantation and laboratory research.
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Zhang L, Gavin T, Geohagen BC, Liu Q, Downey KJ, LoPachin RM. Protective properties of 2-acetylcyclopentanone in a mouse model of acetaminophen hepatotoxicity. J Pharmacol Exp Ther 2013; 346:259-69. [PMID: 23759509 PMCID: PMC3716311 DOI: 10.1124/jpet.113.205435] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2013] [Accepted: 06/11/2013] [Indexed: 12/19/2022] Open
Abstract
Our previous research showed that enolates formed from 1,3-dicarbonyl compounds, such as 2-acetylcyclopentanone (2-ACP), could provide protection in cell culture models from electrophile- or oxidative stress-induced toxicity. In the present study, we evaluated the protective abilities of 2-ACP in a mouse model of acetaminophen (APAP) hepatotoxicity. Results show that oral APAP overdose (500 mg/kg) was nearly 90% lethal within 72 hours and that the resulting hepatotoxicity was associated with substantial changes in plasma liver enzyme activities, histopathological indices, and markers of hepatocyte oxidative stress. 2-ACP administered intraperitoneally 20 minutes before APAP completely prevented lethality over a 7-day observation period. This effect was dose-dependent (0.80-2.40 mmol/kg) and was correlated with normalization of measured parameters. Nearly complete protection was afforded when 2-ACP was administered 20 minutes post-APAP, but not 60 minutes after intoxication. Although intraperitoneal administration of N-acetylcysteine (NAC) was not effective over a broad dose range (2.40-7.20 mmol/kg), temporal studies indicated that intraperitoneal NAC was hepatoprotective when injected 60 minutes after APAP intoxication. Because of a loss of function in stomach acid, oral administration of 2-ACP was associated with modest APAP protection. In contrast, NAC administered orally provided dose-dependent (0.80-2.40 mmol/kg) protection against APAP hepatotoxicity. In chemico studies and quantum mechanical calculations indicated that 2-ACP acted as a surrogate nucleophilic target for the reactive electrophilic APAP metabolite N-acetyl-p-benzoquinone imine. Our findings suggest that 2-ACP or a derivative might be useful in treating acquired toxicities associated with electrophilic drugs and metabolites or environmental toxicants.
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Affiliation(s)
- Lihai Zhang
- Department of Anesthesiology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY 10467, USA
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Park JH, Seo KS, Tadi S, Ahn BH, Lee JU, Heo JY, Han J, Song MS, Kim SH, Yim YH, Choi HS, Shong M, Kweon G. An indole derivative protects against acetaminophen-induced liver injury by directly binding to N-acetyl-p-benzoquinone imine in mice. Antioxid Redox Signal 2013; 18:1713-22. [PMID: 23121402 PMCID: PMC3619205 DOI: 10.1089/ars.2012.4677] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
AIMS Acetaminophen (APAP)-induced liver injury is mainly due to the excessive formation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) through the formation of a reactive intermediate, N-acetyl-p-benzoquinone imine (NAPQI), in both humans and rodents. Here, we show that the indole-derived synthetic compound has a protective effect against APAP-induced liver injury in C57Bl/6 mice model. RESULTS NecroX-7 decreased tert-butylhydroperoxide (t-BHP)- and APAP-induced cell death and ROS/RNS formation in HepG2 human hepatocarcinoma and primary mouse hepatocytes. In mice, NecroX-7 decreased APAP-induced phosphorylation of c-Jun N-terminal kinase (JNK) and 3-nitrotyrosine (3-NT) formation, and also protected mice from APAP-induced liver injury and lethality by binding directly to NAPQI. The binding of NecroX-7 to NAPQI did not require any of cofactors or proteins. NecroX-7 could only scavenge NAPQI when hepatocellular GSH levels were very low. INNOVATION NecroX-7 is an indole-derived potent antioxidant molecule, which can be bound to some types of radicals and especially NAPQI. It is well known that the NAPQI is a major intermediate of APAP, which causes necrosis of hepatocytes in rodents and humans. Thus, blocking NAPQI formation or eliminating NAPQI are novel strategies for the treatment or prevention of APAP-induced liver injury instead of GSH replenishment. CONCLUSION Our data suggest that the indole-derivative, NecroX-7, directly binds to NAPQI when hepatic GSH levels are very low and the NAPQI-NecroX-7 complex is secreted to the blood from the liver. NecroX-7 shows more preventive and similar therapeutic effects against APAP-induced liver injury when compared to the effect of N-acetylcysteine in C57Bl/6 mice.
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Affiliation(s)
- Ji-Hoon Park
- Department of Biochemistry, School of Medicine, Chungnam National University, Daejeon, Korea
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de Castro NM, Yaqoob P, de la Fuente M, Baeza I, Claus SP. Premature Impairment of Methylation Pathway and Cardiac Metabolic Dysfunction in fa/fa Obese Zucker Rats. J Proteome Res 2013; 12:1935-45. [DOI: 10.1021/pr400025y] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Affiliation(s)
- Nuria M. de Castro
- Department of Animal Physiology,
Faculty of Biology, Complutense University of Madrid, 28040 Madrid, Spain
| | - Parveen Yaqoob
- Department of Food and Nutritional
Sciences, The University of Reading, Whiteknights
campus, P.O. Box 226, Reading RG6 6AP, U.K
| | - Mónica de la Fuente
- Department of Animal Physiology,
Faculty of Biology, Complutense University of Madrid, 28040 Madrid, Spain
| | - Isabel Baeza
- Department of Animal Physiology,
Faculty of Biology, Complutense University of Madrid, 28040 Madrid, Spain
| | - Sandrine P. Claus
- Department of Food and Nutritional
Sciences, The University of Reading, Whiteknights
campus, P.O. Box 226, Reading RG6 6AP, U.K
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Nutrient deprivation induces the Warburg effect through ROS/AMPK-dependent activation of pyruvate dehydrogenase kinase. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2013; 1833:1147-56. [PMID: 23376776 DOI: 10.1016/j.bbamcr.2013.01.025] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 08/13/2012] [Revised: 01/18/2013] [Accepted: 01/22/2013] [Indexed: 01/24/2023]
Abstract
The Warburg effect is known to be crucial for cancer cells to acquire energy. Nutrient deficiencies are an important phenomenon in solid tumors, but the effect on cancer cell metabolism is not yet clear. In this study, we demonstrate that starvation of HeLa cells by incubation with Hank's buffered salt solution (HBSS) induced cell apoptosis, which was accompanied by the induction of reactive oxygen species (ROS) production and AMP-activated protein kinase (AMPK) phosphorylation. Notably, HBSS starvation increased lactate production, cytoplasmic pyruvate content and decreased oxygen consumption, but failed to change the lactate dehydrogenase (LDH) activity or the glucose uptake. We found that HBSS starvation rapidly induced pyruvate dehydrogenase kinase (PDK) activation and pyruvate dehydrogenase (PDH) phosphorylation, both of which were inhibited by compound C (an AMPK inhibitor), NAC (a ROS scavenger), and the dominant negative mutant of AMPK. Our data further revealed the involvement of ROS production in AMPK activation. Moreover, DCA (a PDK inhibitor), NAC, and compound C all significantly decreased HBSS starvation-induced lactate production accompanied by enhancement of HBSS starvation-induced cell apoptosis. Not only in HeLa cells, HBSS-induced lactate production and PDH phosphorylation were also observed in CL1.5, A431 and human umbilical vein endothelial cells. Taken together, we for the first time demonstrated that a low-nutrient condition drives cancer cells to utilize glycolysis to produce ATP, and this increases the Warburg effect through a novel mechanism involving ROS/AMPK-dependent activation of PDK. Such an event contributes to protecting cells from apoptosis upon nutrient deprivation.
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Coen M, Rademacher PM, Zou W, Scott M, Ganey PE, Roth R, Nelson SD. Comparative NMR-Based Metabonomic Investigation of the Metabolic Phenotype Associated with Tienilic Acid and Tienilic Acid Isomer. Chem Res Toxicol 2012; 25:2412-22. [DOI: 10.1021/tx3002803] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Muireann Coen
- Biomolecular
Medicine, Department
of Surgery and Cancer, Faculty of Medicine, Imperial College London, London SW7 2AZ, United Kingdom
| | - Peter M. Rademacher
- Department of Medicinal Chemistry, University of Washington, 1959 NE Pacific Street, Health
Sciences Building, Seattle, Washington 98195-7610, United States
| | - Wei Zou
- Department of Microbiology and
Molecular Genetics, 2215 Biomedical Physical Sciences, Michigan State University, East Lansing, Michigan 48824-1302,
United States
| | - Michael Scott
- Department
of Pathobiology and
Diagnostic Investigation, G-347 Veterinary Medical Center, Michigan State University, East Lansing, Michigan 48824-1314,
United States
| | - Patricia E. Ganey
- Department
of Pharmacology and
Toxicology, 221 Food Safety and Toxicology Building, Michigan State University, East Lansing, Michigan 48824-1302,
United States
| | - Robert Roth
- Department
of Pharmacology and
Toxicology, 221 Food Safety and Toxicology Building, Michigan State University, East Lansing, Michigan 48824-1302,
United States
| | - Sidney D. Nelson
- Department of Medicinal Chemistry, University of Washington, 1959 NE Pacific Street, Health
Sciences Building, Seattle, Washington 98195-7610, United States
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Saritas A, Kandis H, Baltaci D, Yildirim U, Kaya H, Karakus A, Colakoglu S, Memisogullari R, Kara IH. N-Acetyl cysteine and erdosteine treatment in acetaminophen-induced liver damage. Toxicol Ind Health 2012; 30:670-8. [PMID: 23070635 DOI: 10.1177/0748233712463780] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVE This study is aimed to investigate the efficacy of erdosteine usage in acetaminophen-induced liver damage and to compare it with N-acetyl cysteine (NAC) in the treatment and prevention of liver toxicity due to overdose of acetaminophen. METHODS The rats were separated into the following six groups of seven rats each: control group; acetaminophen (1 g/kg, orally); acetaminophen (1 g/kg, orally) + erdosteine (150 mg/kg/day, orally); acetaminophen (1 g/kg, orally) + NAC (140 mg/kg loading dose, followed by 70 mg/kg, orally); NAC (140 mg/kg loading dose, followed by 70 mg/kg, orally); erdosteine (150 mg/kg/kg, orally), subsequently. In all the groups, potential liver injuries were evaluated using biochemical and hematological analyses, oxidant-antioxidant parameters and histopathological parameters. RESULTS In acetaminophen-treated group, levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total oxidant status (TOS) in the blood, prothrombin time (PT) and international normalized ratio (INR) were significantly increased when compared with controls. However, total antioxidant capacity (TAC) and glutathione (GSH) levels were decreased in group treated with acetaminophen, when compared with control group. Levels of AST, ALT and TOS, PT and INR were decreased in groups treated with NAC and erdosteine after acetaminophen administration, but the levels of TAC and GSH were increased. Histopathological improvements were observed in the groups treated with NAC and erdosteine after acetaminophen administration. CONCLUSION The present study demonstrated that, in the prevention of liver damage induced by acetaminophen intoxication, an early treatment with a single dose of erdosteine was beneficial instead of NAC administration.
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Affiliation(s)
- Ayhan Saritas
- Department of Emergency Medicine, Duzce University School of Medicine, Duzce, Turkey
| | - Hayati Kandis
- Department of Emergency Medicine, Duzce University School of Medicine, Duzce, Turkey
| | - Davut Baltaci
- Department of Family Medicine, Duzce University School of Medicine, Duzce, Turkey
| | - Umran Yildirim
- Department of Pathology, Duzce University School of Medicine, Duzce, Turkey
| | - Halil Kaya
- Department of Emergency Medicine, Harran University School of Medicine, Sanliurfa, Turkey
| | - Ali Karakus
- Department of Emergency Medicine, Mustafa Kemal University School of Medicine, Hatay, Turkey
| | - Serdar Colakoglu
- Department of Anatomy, Duzce University School of Medicine, Duzce, Turkey
| | | | - Ismail Hamdi Kara
- Department of Family Medicine, Duzce University School of Medicine, Duzce, Turkey
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de Melo FT, de Oliveira IM, Greggio S, Dacosta JC, Guecheva TN, Saffi J, Henriques JAP, Rosa RM. DNA damage in organs of mice treated acutely with patulin, a known mycotoxin. Food Chem Toxicol 2012; 50:3548-55. [DOI: 10.1016/j.fct.2011.12.022] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2010] [Revised: 10/21/2011] [Accepted: 12/16/2011] [Indexed: 10/14/2022]
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Gottschalk S, Zwingmann C, Raymond VA, Hohnholt MC, Chan TS, Bilodeau M. Hepatocellular apoptosis in mice is associated with early upregulation of mitochondrial glucose metabolism. Apoptosis 2012; 17:143-53. [PMID: 22109881 DOI: 10.1007/s10495-011-0669-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Hepatocyte death due to apoptosis is a hallmark of almost every liver disease. Manipulation of cell death regulatory steps during the apoptotic process is therefore an obvious goal of biomedical research. To clarify whether metabolic changes occur prior to the characteristic apoptotic events, we used ex vivo multinuclear NMR-spectroscopy to study metabolic pathways of [U-(13)C]glucose in mouse liver during Fas-induced apoptosis. We addressed whether these changes could be associated with protection against apoptosis afforded by Epidermal Growth Factor (EGF). Our results show that serum alanine and aspartate aminotransferase levels, caspase-3 activity, BID cleavage and changes in cellular energy stores were not observed before 3 h following anti-Fas injection. However, as early as 45 min after anti-Fas treatment, we observed upregulation of carbon entry (i.e. flux) from glucose into the Krebs-cycle via pyruvate dehydrogenase (PDH) and pyruvate carboxylase (PC) (up to 139% and 123% of controls, respectively, P < 0.001). This was associated with increased glutathione synthesis. EGF treatment significantly attenuated Fas-induced apoptosis, liver injury and the late decrease in energy stores, as well as the early fluxes through PDH and PC which were comparable to untreated controls. Using ex vivo multinuclear NMR-spectroscopic analysis, we have shown that Fas receptor activation in mouse liver time-dependently affects specific metabolic pathways of glucose. These early upregulations in glucose metabolic pathways occur prior to any visible signs of apoptosis and may have the potential to contribute to the initiation of apoptosis by maintaining mitochondrial energy production and cellular glutathione stores.
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Affiliation(s)
- Sven Gottschalk
- Centre de recherche, Centre hospitalier du l'Université de Montréal, Hôpital Saint-Luc, Montréal, QC, H2X 1P1, Canada.
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N-acetylcysteine (NAC) diminishes the severity of PCB 126-induced fatty liver in male rodents. Toxicology 2012; 302:25-33. [PMID: 22824115 DOI: 10.1016/j.tox.2012.07.007] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2012] [Revised: 07/09/2012] [Accepted: 07/15/2012] [Indexed: 01/15/2023]
Abstract
Potent aryl hydrocarbon receptor agonists like PCB 126 (3,3',4,4',5-pentachlorobiphenyl) cause oxidative stress and liver pathology, including fatty liver. Our question was whether dietary supplementation with N-acetylcysteine (NAC), an antioxidant, can prevent these adverse changes. Male Sprague-Dawley rats were fed a standard AIN-93G diet (sufficient in cysteine) or a modified diet supplemented with 1.0% NAC. After one week, rats on each diet were exposed to 0, 1, or 5μmol/kg body weight PCB 126 by i.p. injection (6 rats per group) and euthanized two weeks later. PCB-treatment caused a dose-dependent reduction in growth, feed consumption, relative thymus weight, total glutathione and glutathione disulfide (GSSG), while relative liver weight, glutathione transferase activity and hepatic lipid content were dose-dependently increased with PCB dose. Histologic examination of liver tissue showed PCB 126-induced hepatocellular steatosis with dose dependent increase in lipid deposition and distribution. Dietary NAC resulted in a reduction in hepatocellular lipid in both PCB groups. This effect was confirmed by gravimetric analysis of extracted lipids. Expression of CD36, a scavenger receptor involved in regulating hepatic fatty acid uptake, was reduced with high dose PCB treatment but unaltered in PCB-treated rats on NAC-supplemented diet. These results demonstrate that NAC has a protective effect against hepatic lipid accumulation in rats exposed to PCB 126. The mechanism of this protective effect appears to be independent of NAC as a source of cysteine/precursor of glutathione.
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Saleh M, Al Nakib M, Doloy A, Jacqmin S, Ghiglione S, Verroust N, Poyart C, Ozier Y. Bacillus cereus, an unusual cause of fulminant liver failure: diagnosis may prevent liver transplantation. J Med Microbiol 2012; 61:743-745. [DOI: 10.1099/jmm.0.038547-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Affiliation(s)
- Mohamed Saleh
- Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
- Service d’Anesthésie-Réanimation Chirurgicale, Groupe Hospitalier Cochin Hôtel Dieu Broca, Assistance Publique – Hôpitaux de Paris, Paris, France
| | - Malik Al Nakib
- Service de Bactériologie, Groupe Hospitalier Cochin Hôtel Dieu Broca, Assistance Publique – Hôpitaux de Paris, Paris, France
- Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Alexandra Doloy
- Service de Bactériologie, Groupe Hospitalier Cochin Hôtel Dieu Broca, Assistance Publique – Hôpitaux de Paris, Paris, France
| | - Sébastien Jacqmin
- Service d’Anesthésie-Réanimation Chirurgicale, Groupe Hospitalier Cochin Hôtel Dieu Broca, Assistance Publique – Hôpitaux de Paris, Paris, France
| | - Sébastien Ghiglione
- Service d’Anesthésie-Réanimation Chirurgicale, Groupe Hospitalier Cochin Hôtel Dieu Broca, Assistance Publique – Hôpitaux de Paris, Paris, France
| | - Nicolas Verroust
- Service d’Anesthésie-Réanimation Chirurgicale, Groupe Hospitalier Cochin Hôtel Dieu Broca, Assistance Publique – Hôpitaux de Paris, Paris, France
| | - Claire Poyart
- Service de Bactériologie, Groupe Hospitalier Cochin Hôtel Dieu Broca, Assistance Publique – Hôpitaux de Paris, Paris, France
- Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Yves Ozier
- Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
- Service d’Anesthésie-Réanimation Chirurgicale, Groupe Hospitalier Cochin Hôtel Dieu Broca, Assistance Publique – Hôpitaux de Paris, Paris, France
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Winbladh A, Björnsson B, Trulsson L, Bojmar L, Sundqvist T, Gullstrand P, Sandström P. N-acetyl cysteine improves glycogenesis after segmental liver ischemia and reperfusion injury in pigs. Scand J Gastroenterol 2012; 47:225-36. [PMID: 22242616 DOI: 10.3109/00365521.2011.643480] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE N-acetylcysteine (NAC) is an antioxidative molecule known to protect liver tissue from oxygen radical species generated during ischemia and reperfusion (IR). Nutritional and toxicology studies have shown that NAC also improves glucose metabolism and glycogen stores. We hypothesized that NAC improves glycogenesis and that impaired glycogenesis is a key element in IR injury. MATERIAL AND METHODS In an experimental model, 80 min of segmental liver ischemia was induced in 16 pigs and the reperfusion was followed for 360 min. Eight animals received NAC 150 mg/kg as a bolus injection followed by an infusion of NAC 50 mg/kg/h intravenously. RESULTS AST and leukocyte density were lower in the NAC-treated animals, unrelated to the glutathione levels or apoptosis. Glycogen stores returned to a higher degree in the NAC-treated animals and microdialysis revealed lower levels of lactate during the reperfusion phase. Nitrite/Nitrate levels in the NAC group were lower in both serum and microdialysates, indicating that NAC scavenges radical nitrosative species. CONCLUSIONS NAC treatment improves glycogenesis after liver IR injury and reduces the level of intraparenchymal lactate during reperfusion, possibly due to the scavenging of radical nitrosative species.
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Affiliation(s)
- Anders Winbladh
- Division of Surgery, University Hospital, Linköping, Sweden.
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