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Králová A, Montaser AB, Tampio J, Adla SK, Jalkanen A, Rysä J, Huttunen KM. A novel paracetamol derivative alleviates lipopolysaccharide-induced neuroinflammation. Eur J Pharmacol 2025; 995:177409. [PMID: 39986592 DOI: 10.1016/j.ejphar.2025.177409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 02/10/2025] [Accepted: 02/19/2025] [Indexed: 02/24/2025]
Abstract
Neuroinflammation has been implicated as a pathological contributor to several neurodegenerative disorders. Increasing evidence suggests that paracetamol (PCM, acetaminophen) has unappreciated anti-neuroinflammatory properties. However, PCM possesses hepatotoxicity in higher dosages, which are needed for achieving therapeutic concentrations in the brain. To lessen this effect and improve drug efficacy, PCM was in this study converted into an L-type amino acid transporter 1 (LAT1)-utilizing derivative and tested whether this LAT1-mediated delivery approach could enhance the relief of neuroinflammation, using both in vitro and in vivo lipopolysaccharide (LPS)-stimulated models. The gained results confirmed the derivative's improved transport into mouse primary astrocytes, immortalized microglia (BV2), and human immortalized microglia (SV40) via LAT1. In the LPS-stimulated BV2 model, the derivative effectively reduced the prostaglandin E2 (PGE2) level by 57% compared to the LPS treatment. Moreover, a more profound reduction of brain PGE2 production was confirmed in the LPS-stimulated mouse model. Finally, the global proteome of the whole mouse brain revealed that the derivative was able to reverse the altered expression of several inflammatory biomarkers, including ras-related C3 botulinum toxin substrate 1 (Rac1), cytochrome c oxidase subunit 2 (COX2), phospholipid phosphatase-related protein type 2 (Plppr2), ubiquitin-conjugating enzyme E2 variant 1 (Ube2v1) and A-kinase anchor protein 1, mitochondrial (Akap1).
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Affiliation(s)
- Adéla Králová
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland.
| | - Ahmed B Montaser
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland
| | - Janne Tampio
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland
| | - Santosh Kumar Adla
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland
| | - Aaro Jalkanen
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland
| | - Jaana Rysä
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland
| | - Kristiina M Huttunen
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland
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Bıçakçı N, Karaboğa İ, Bıçakçı S, Okuyan HM, Duran Y, Polat FR, Çelikkol A, Yılmaz A. Apilarnil alleviates paracetamol-induced hepatotoxicity by modulating apoptosis and oxidative stress. Biotech Histochem 2025; 100:119-128. [PMID: 40260732 DOI: 10.1080/10520295.2025.2486453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/24/2025] Open
Abstract
Paracetamol (PAR) is a drug that is widely used throughout the world and has limited treatment options in case of use-related hepatotoxicity. Apilarnil (AP), a bee product has high levels of antioxidant properties, which result from the rich polyphenols found in its structure. Despite it being shown that AP treatment might have a protective effect on liver damage induced by carbon tetrachloride and lipopolysaccharide, there is no study investigating the possible role of this agent in PAR-induced hepatotoxicity using an experimental in vivo model. Therefore, we aimed to investigate the therapeutic effects of AP on paracetamol-induced hepatotoxicity and its relationship with apoptosis and oxidative stress. Our results indicated that PAR administration caused irregularities in hepatocyte cords, bleeding and dilatation of sinusoids, and inflammatory cell infiltration in the portal area and liver parenchyma. PAR caused an increase in p53 and caspase3 expressions and malondialdehyde (MDA) levels, while it caused a decrease in catalase (CAT) and glutathione peroxidase (GSHpx) levels. AP treatment significantly improved histopathological changes in liver tissues and decreased p53 and caspase3 expressions. Our data suggest that AP alleviates paracetamolinduced hepatotoxicity by regulating p53 and caspase-3 expressions and modulating oxidative stress mechanisms.
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Affiliation(s)
- Nurcan Bıçakçı
- Emergency and Disaster Management Department, Tekirdag Namık Kemal University, Faculty of Health Sciences, Tekirdag, Türkiye
| | - İhsan Karaboğa
- Department of Histology and Embryology, Kırklareli University, Faculty of Medicine, Kırklareli, Türkiye
| | - Sercan Bıçakçı
- Department of Emergency Medicine, Tekirdag Namık Kemal University, Faculty of Medicine, Tekirdag, Türkiye
| | - Hamza Malik Okuyan
- Department of Physiotherapy and Rehabilitation, Sakarya University of Applied Sciences, Faculty of Health Sciences, Sakarya, Türkiye
| | - Yasin Duran
- Pathology Laboratory Technigues Department, TC Istanbul Rumeli University, Vocational School of Health Services, İstanbul, Türkiye
| | - Fatin Rüştü Polat
- Department of General Surgery, Tekirdag Namık Kemal University, Faculty of Medicine, Tekirdag, Türkiye
| | - Aliye Çelikkol
- Department of Medical Biochemistry, Tekirdag Namık Kemal University, Faculty of Medicine, Tekirdag, Türkiye
| | - Ahsen Yılmaz
- Department of Medical Biochemistry, Tekirdag Namık Kemal University, Faculty of Medicine, Tekirdag, Türkiye
- Department of Medical Biochemistry, Istanbul University-Cerrahpasa, Cerrahpasa Faculty of Medicine, Istanbul, Türkiye
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Wang H, Ciccocioppo R, Terai S, Shoeibi S, Carnevale G, De Marchi G, Tsuchiya A, Ishii S, Tonouchi T, Furuyama K, Yang Y, Mito M, Abe H, Di Tinco R, Cardinale V. Targeted animal models for preclinical assessment of cellular and gene therapies in pancreatic and liver diseases: regulatory and practical insights. Cytotherapy 2025; 27:259-278. [PMID: 39755978 PMCID: PMC12068232 DOI: 10.1016/j.jcyt.2024.11.008] [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: 05/31/2024] [Revised: 11/08/2024] [Accepted: 11/10/2024] [Indexed: 01/07/2025]
Abstract
Cellular and gene therapy (CGT) products have emerged as a popular approach in regenerative medicine, showing promise in treating various pancreatic and liver diseases in numerous clinical trials. Before these therapies can be tested in human clinical trials, it is essential to evaluate their safety and efficacy in relevant animal models. Such preclinical testing is often required to obtain regulatory approval for investigational new drugs. However, there is a lack of detailed guidance on selecting appropriate animal models for CGT therapies targeting specific pancreatic and liver conditions, such as pancreatitis and chronic liver diseases. In this review, the gastrointestinal committee for the International Society for Cell and Gene Therapy provides a summary of current recommendations for animal species and disease model selection, as outlined by the US Food and Drug Administration, with references to EU EMA and Japan PMDA. We discuss a range of small and large animal models, as well as humanized models, that are suitable for preclinical testing of CGT products aimed at treating pancreatic and liver diseases. For each model, we cover the associated pathophysiology, commonly used metrics for assessing disease status, the pros and limitations of the models, and the relevance of these models to human conditions. We also summarize the use and application of humanized mouse and other animal models in evaluating the safety and efficacy of CGT products. This review aims to provide comprehensive guidance for selecting appropriate animal species and models to help bridge the gap between the preclinical research and clinical trials using CGT therapies for specific pancreatic and liver diseases.
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Affiliation(s)
- Hongjun Wang
- Department of Surgery, Medical University of South Carolina, Charleston, South Carolina, USA; Ralph H Johnson Veteran Medical Center, Charleston, South Carolina, USA.
| | - Rachele Ciccocioppo
- Department of Medicine, Gastroenterology Unit, Pancreas Institute, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Verona, Italy
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Sara Shoeibi
- Department of Surgery, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Gianluca Carnevale
- Department of Surgery, Medicine, Dentistry and Morphological Sciences with Interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Giulia De Marchi
- Department of Medicine, Gastroenterology Unit, Pancreas Institute, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Verona, Italy
| | - Atsunori Tsuchiya
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Soichi Ishii
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Takafumi Tonouchi
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Kaito Furuyama
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Yuan Yang
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Masaki Mito
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Hiroyuki Abe
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Rosanna Di Tinco
- Department of Surgery, Medicine, Dentistry and Morphological Sciences with Interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Vincenzo Cardinale
- Department of Translational and Precision Medicine, University of Rome, Rome, Italy.
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Allen HN, Hestehave S, Duran P, Nelson TS, Khanna R. Uncoupling the CRMP2-Ca V2.2 Interaction Reduces Pain-Like Behavior in a Preclinical Joint-Pain Model. THE JOURNAL OF PAIN 2024; 25:104664. [PMID: 39233208 PMCID: PMC11560641 DOI: 10.1016/j.jpain.2024.104664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 08/29/2024] [Accepted: 08/29/2024] [Indexed: 09/06/2024]
Abstract
Osteoarthritis (OA) represents a significant pain challenge globally, as current treatments are limited and come with substantial and adverse side effects. Voltage-gated calcium channels have proved to be pharmacologically effective targets, with multiple Food and Drug Administration-approved CaV2.2 modulators available for the treatment of pain. Although effective, drugs targeting CaV2.2 are complicated by the same obstacles facing other pain therapeutics-invasive routes of administration, narrow therapeutic windows, side effects, and addiction potential. We have identified a key regulator of CaV2.2 channels, collapsin response mediator protein 2, that allows us to indirectly regulate CaV2.2 expression and function. We previously developed a peptidomimetic modulator of collapsin response mediator protein 2, CBD3063, that effectively reverses neuropathic and inflammatory pain without negative side effects by reducing membrane expression of CaV2.2. The potent analgesic properties of CBD3063, combined with the lack of negative side effects, prompted us to assess the efficacy of CBD3063 in a rodent model of OA pain. Here, we demonstrate the intraperitoneal administration of CBD3063 alleviates both evoked and nonevoked behavioral hallmarks of OA pain. Further, we reveal that CBD3063 reduces OA-induced increased neural activity in the parabrachial nucleus, a key supraspinal site modulating the pain experience. Together, these studies suggest that CBD3063 is an effective analgesic for OA pain. PERSPECTIVE: Despite the high prevalence of OA pain worldwide, current treatment options remain limited. We demonstrate that CBD3063-mediated disruption of the CaV2.2-collapsin response mediator protein 2 interaction alleviates pain in a preclinical joint pain model, providing a promising basis for the development of new OA pain treatments.
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Affiliation(s)
- Heather N Allen
- Department of Pharmacology & Therapeutics, University of Florida College of Medicine, Gainesville, Florida
| | - Sara Hestehave
- Department of Molecular Pathobiology, College of Dentistry, New York University, New York, New York; Department of Experimental Medicine, University of Copenhagen, 2200 Copenhagen N, Denmark
| | - Paz Duran
- Department of Molecular Pathobiology, College of Dentistry, New York University, New York, New York
| | - Tyler S Nelson
- Department of Pharmacology & Therapeutics, University of Florida College of Medicine, Gainesville, Florida
| | - Rajesh Khanna
- Department of Pharmacology & Therapeutics, University of Florida College of Medicine, Gainesville, Florida.
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Coelho AM, Queiroz IF, Perucci LO, Menezes TP, Lima WG, Talvani A, Costa DC. Piperine as an Herbal Alternative for the Prevention of Drug-Induced Liver Damage Caused by Paracetamol. Pharmaceuticals (Basel) 2024; 17:1477. [PMID: 39598389 PMCID: PMC11597450 DOI: 10.3390/ph17111477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 10/28/2024] [Accepted: 10/31/2024] [Indexed: 11/29/2024] Open
Abstract
Background/Objective: Hepatic drug intoxication is becoming increasingly common with the increasing use of chronic medications. Piperine has emerged as a promising alternative for protecting the liver against drug-induced injury. We evaluated the prophylactic effects of piperine in C57BL/6 mice with an acute liver injury induced by a paracetamol (APAP) overdose. Methods: Piperine was administered at a dose of 20 mg/kg (P20) or 40 mg/kg (P40) for eight consecutive days before the animals were exposed to a hepatotoxic dose of paracetamol (500 mg/kg). The animals were euthanized 3 h after the paracetamol overdose. Results: The prophylactic treatment with piperine (P20 and P40) maintained the levels of alanine aminotransferase (ALT) and the biomarkers of oxidative damage (TBARS and carbonylated proteins), which were statistically similar to those for the control group. The extent of hepatocyte necrosis and TNF-α (tumor necrosis factor-alpha) levels were lower than those in the group exposed to liver injury (APAP group). Piperine modulated the gene expression of CYP2E1 (cytochrome P4502E1) and the inflammasome pathway (NLRP3, CASP-1, IL-1β, and IL-18), which play a crucial role in the inflammatory response. In the P40 group, the degree of hepatic hyperemia was similar to that in the control group, as was the increase in metalloproteinase 9 (MMP-9) activity. Conclusion: Piperine has demonstrated beneficial and promising effects for the prevention of liver injury resulting from paracetamol-induced drug intoxication.
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Affiliation(s)
- Aline Meireles Coelho
- Department of Biological Sciences (DECBI), Federal University of Ouro Preto (UFOP), Minas Gerais 35400-000, Brazil; (A.M.C.)
- Graduate Program in Biological Sciences (CBIOL), Federal University of Ouro Preto (UFOP), Minas Gerais 35400-000, Brazil
| | - Isabela Ferreira Queiroz
- Department of Biological Sciences (DECBI), Federal University of Ouro Preto (UFOP), Minas Gerais 35400-000, Brazil; (A.M.C.)
| | - Luiza Oliveira Perucci
- Center for Research in Biological Sciences (NUPEB), Federal University of Ouro Preto (UFOP), Minas Gerais 35400-000, Brazil
| | - Tatiana Prata Menezes
- Graduate Program in Health and Nutrition (PPGSN), Federal University of Ouro Preto (UFOP), Minas Gerais 35400-000, Brazil
| | - Wanderson Geraldo Lima
- Department of Biological Sciences (DECBI), Federal University of Ouro Preto (UFOP), Minas Gerais 35400-000, Brazil; (A.M.C.)
- Graduate Program in Biological Sciences (CBIOL), Federal University of Ouro Preto (UFOP), Minas Gerais 35400-000, Brazil
| | - André Talvani
- Department of Biological Sciences (DECBI), Federal University of Ouro Preto (UFOP), Minas Gerais 35400-000, Brazil; (A.M.C.)
- Graduate Program in Health and Nutrition (PPGSN), Federal University of Ouro Preto (UFOP), Minas Gerais 35400-000, Brazil
| | - Daniela Caldeira Costa
- Department of Biological Sciences (DECBI), Federal University of Ouro Preto (UFOP), Minas Gerais 35400-000, Brazil; (A.M.C.)
- Graduate Program in Biological Sciences (CBIOL), Federal University of Ouro Preto (UFOP), Minas Gerais 35400-000, Brazil
- Graduate Program in Health and Nutrition (PPGSN), Federal University of Ouro Preto (UFOP), Minas Gerais 35400-000, Brazil
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Tangpradubkiat P, Chayanupatkul M, Werawatganone P, Somanawat K, Siriviriyakul P, Klaikeaw N, Werawatganon D. Gardenia jasminoides extract mitigates acetaminophen-induced liver damage in mice. BMC Complement Med Ther 2024; 24:371. [PMID: 39427207 PMCID: PMC11490086 DOI: 10.1186/s12906-024-04676-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 10/08/2024] [Indexed: 10/21/2024] Open
Abstract
BACKGROUND Acetaminophen (APAP)-induced hepatotoxicity is a potentially life-threatening condition. Gardenia jasminoides fruit extract (GJE), which contains geniposide (Gen) as its major active constituent, possesses anti-inflammatory and antioxidant properties and may help address the underlying pathogenesis of APAP-induced hepatotoxicity. This study aimed to evaluate the effects of GJE in a mouse model of APAP-induced hepatotoxicity. METHODS Twenty-four male ICR mice were divided into 4 groups (n = 6/group): [1] Control group, mice were given distilled water; [2] APAP group, mice received a single dose of 600 mg/kg APAP; [3] APAP + low-dose GJE group, mice received APAP followed 30 min later by 2 doses of low-dose GJE (0.44 g/kg/dose, containing Gen 100 mg/kg/dose) 8 h apart; [4] APAP + high-dose GJE group, mice received APAP followed by 2 doses of high-dose GJE (0.88 g/kg/dose, containing Gen 200 mg/kg/dose). All mice were euthanized 24 h after APAP administration. Liver tissue was used for histological examination and to measure glutathione (GSH) and malondialdehyde (MDA) levels. Serum was used to determine levels of ALT and inflammatory cytokines (tumor necrosis factor- α (TNF-α) and interleukin-6 (IL-6)). RESULTS Liver histopathology showed moderate to severe hepatic necroinflammation in the APAP group, whereas only mild necroinflammation was observed in both treatment groups. Serum ALT levels were significantly elevated in the APAP group compared to the control group but were significantly reduced after low- and high-dose GJE treatment. Serum TNF- α levels were significantly higher in the APAP group than in the control group and were significantly lower after high-dose GJE treatment (135.5 ± 477.2 vs. 35.5 ± 25.8 vs. 74.7 ± 47.2 vs. 41.4 ± 50.8 pg/mL, respectively). Serum IL-6 followed a similar pattern. Hepatic GSH levels were significantly lower in the APAP group compared to the control group but significantly increased after both low- and high-dose GJE treatment (19.9 ± 4.5 vs. 81.5 ± 12.4 vs. 71.4 ± 7.8 vs. 82.6 ± 6.6 nmol/mg protein, respectively). Conversely, hepatic MDA levels were significantly elevated in the APAP group compared with the control group but significantly decreased after high-dose GJE treatment (108.6 ± 201.5 vs. 40.5 ± 18.0 vs. 40.5 ± 16.8 nmol/mg protein, respectively). CONCLUSIONS Treatment with G. jasminoides fruit extract can alleviate APAP-induced hepatotoxicity, likely through its anti-inflammatory and antioxidant properties.
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Affiliation(s)
- Peenaprapa Tangpradubkiat
- Center of Excellence in Alternative and Complementary Medicine for Gastrointestinal and Liver Diseases, Department of Physiology, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Maneerat Chayanupatkul
- Center of Excellence in Alternative and Complementary Medicine for Gastrointestinal and Liver Diseases, Department of Physiology, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand.
| | - Pornpen Werawatganone
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand
| | - Kanjana Somanawat
- Center of Excellence in Alternative and Complementary Medicine for Gastrointestinal and Liver Diseases, Department of Physiology, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Prasong Siriviriyakul
- Center of Excellence in Alternative and Complementary Medicine for Gastrointestinal and Liver Diseases, Department of Physiology, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Naruemon Klaikeaw
- Department of Pathology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Duangporn Werawatganon
- Center of Excellence in Alternative and Complementary Medicine for Gastrointestinal and Liver Diseases, Department of Physiology, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
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Monroe HL, El Jabbour T. Educational Case: Acetaminophen hepatotoxicity: Pathophysiology and evaluation of acute liver failure. Acad Pathol 2024; 11:100146. [PMID: 39309105 PMCID: PMC11414483 DOI: 10.1016/j.acpath.2024.100146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 12/15/2023] [Accepted: 08/02/2024] [Indexed: 09/25/2024] Open
Affiliation(s)
- Hunter L. Monroe
- Department of Pathology, Anatomy, and Laboratory Medicine, West Virginia University, Morgantown, WV, USA
| | - Tony El Jabbour
- Department of Pathology, Anatomy, and Laboratory Medicine, West Virginia University, Morgantown, WV, USA
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Doi K, Inoue J, Ninomiya M, Sano A, Tsuruoka M, Sato K, Onuki M, Sawahashi S, Ouchi K, Masamune A. Three consecutive cases of acute liver failure in young women due to acetaminophen overdose: insights into Japanese social issues and transplantation landscape. Clin J Gastroenterol 2024; 17:948-954. [PMID: 39060756 DOI: 10.1007/s12328-024-02024-8] [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: 04/03/2024] [Accepted: 07/18/2024] [Indexed: 07/28/2024]
Abstract
Acetaminophen (APAP) is an over-the-counter (OTC) drug known worldwide for its safety and efficacy. However, in Japan, OTC drug overdose has become a prominent social problem in recent years due to stricter regulations for other drugs, especially among young people, and APAP is an increasing cause of acute liver injury due to overdose. This report describes three consecutive cases of acute liver failure in young women (22, 22 and 19 years old) due to APAP overdose in December 2023. Despite severe liver injury, indicated by high ALT levels and coagulopathy, these cases recovered without requiring liver transplantation. This report discusses three cases of acute liver failure in young Japanese women following APAP overdose, reflecting a national increase in such cases due to increased misuse of OTC drugs and societal factors. Key findings include the need for early treatment with N-acetylcysteine (NAC) and the importance of mental health assessment in the management of overdose patients. The cases underscore the need for prompt team-based care to prevent serious outcomes and highlight the complexity of liver transplantation decisions in Japan, highlighting the need for comprehensive strategies to address the escalating problem of APAP overdose.
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Affiliation(s)
- Kotaro Doi
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-Machi, Aoba-Ku, Sendai, 980-8574, Japan
| | - Jun Inoue
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-Machi, Aoba-Ku, Sendai, 980-8574, Japan.
| | - Masashi Ninomiya
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-Machi, Aoba-Ku, Sendai, 980-8574, Japan
| | - Akitoshi Sano
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-Machi, Aoba-Ku, Sendai, 980-8574, Japan
| | - Mio Tsuruoka
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-Machi, Aoba-Ku, Sendai, 980-8574, Japan
| | - Kosuke Sato
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-Machi, Aoba-Ku, Sendai, 980-8574, Japan
| | - Masazumi Onuki
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-Machi, Aoba-Ku, Sendai, 980-8574, Japan
| | - Satoko Sawahashi
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-Machi, Aoba-Ku, Sendai, 980-8574, Japan
| | - Keishi Ouchi
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-Machi, Aoba-Ku, Sendai, 980-8574, Japan
| | - Atsushi Masamune
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-Machi, Aoba-Ku, Sendai, 980-8574, Japan
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Tsien J, Hu C, Merchant RR, Qin T. Three-dimensional saturated C(sp 3)-rich bioisosteres for benzene. Nat Rev Chem 2024; 8:605-627. [PMID: 38982260 DOI: 10.1038/s41570-024-00623-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/24/2024] [Indexed: 07/11/2024]
Abstract
Benzenes, the most ubiquitous structural moiety in marketed small-molecule drugs, are frequently associated with poor 'drug-like' properties, including metabolic instability, and poor aqueous solubility. In an effort to overcome these limitations, recent developments in medicinal chemistry have demonstrated the improved physicochemical profiles of C(sp3)-rich bioisosteric scaffolds relative to arenes. In the past two decades, we have witnessed an exponential increase in synthetic methods for accessing saturated bioisosteres of monosubstituted and para-substituted benzenes. However, until recent discoveries, analogous three-dimensional ortho-substituted and meta-substituted biososteres have remained underexplored, owing to their ring strain and increased s-character hybridization. This Review summarizes the emerging synthetic methodologies to access such saturated motifs and their impact on the application of bioisosteres for ortho-substituted, meta-substituted and multi-substituted benzene rings. It concludes with a perspective on the development of next-generation bioisosteres, including those within novel chemical space.
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Affiliation(s)
- Jet Tsien
- Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Chao Hu
- Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Rohan R Merchant
- Department of Discovery Chemistry, Merck & Co., Inc., South San Francisco, CA, USA
| | - Tian Qin
- Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
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Yang D, Jeong H, Kim MS, Oh SI, Lee K, Kim JW, Kim B. Prenatal cigarette smoke exposure sensitizes acetaminophen-induced liver injury by modulating miR-34a-5p in male offspring mice. Front Cell Dev Biol 2024; 12:1393618. [PMID: 39139452 PMCID: PMC11319911 DOI: 10.3389/fcell.2024.1393618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Accepted: 07/01/2024] [Indexed: 08/15/2024] Open
Abstract
Introduction: Cigarette smoke (CS) exacerbates the severity of diseases not only in lungs, but also in systemic organs having no direct contact with smoke. In addition, smoking during pregnancy can have severe health consequences for both the mother and the fetus. Therefore, our aim was to evaluate effects of prenatal exposure to CS on acetaminophen (APAP)-induced acute liver injury (ALI) in offspring. Methods: Female C57BL/6 mice on day 6 of gestation were exposed to mainstream CS (MSCS) at 0, 150, 300, or 600 μg/L for 2 h a day, 5 days a week for 2 weeks using a nose-only exposure system. At four weeks old, male offspring mice were injected intraperitoneally with a single dose of APAP at 300 mg/kg body weight to induce ALI. Results: Maternal MSCS exposure significantly amplified pathological effects associated with ALI as evidenced by elevated serum alanine aminotransferase levels, increased hepatocellular apoptosis, higher oxidative stress, and increased inflammation. Interestingly, maternal MSCS exposure reduced microRNA (miR)-34a-5p expression in livers of offspring. Moreover, treatment with a miR-34a-5p mimic significantly mitigated the severity of APAP-induced hepatotoxicity. Overexpression of miR-34a-5p completely abrogated adverse effects of maternal MSCS exposure in offspring with ALI. Mechanistically, miR-34a-5p significantly decreased expression levels of hepatocyte nuclear factor 4 alpha, leading to down-regulated expression of cytochrome P450 (CYP)1A2 and CYP3A11. Discussion: Prenatal exposure to MSCS can alter the expression of miRNAs, even in the absence of additional MSCS exposure, potentially increasing susceptibility to APAP exposure in male offspring mice.
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Affiliation(s)
- Daram Yang
- Biosafety Research Institute and College of Veterinary Medicine, Jeonbuk National University, Iksan, Republic of Korea
| | - Hyuneui Jeong
- Biosafety Research Institute and College of Veterinary Medicine, Jeonbuk National University, Iksan, Republic of Korea
| | - Min-Seok Kim
- Inhalation Toxicology Center, Jeonbuk Department of Inhalation Research, Korea Institute of Toxicology, Jeongeup, Jeonbuk, Republic of Korea
| | - Sang-Ik Oh
- Biosafety Research Institute and College of Veterinary Medicine, Jeonbuk National University, Iksan, Republic of Korea
| | - Kyuhong Lee
- Inhalation Toxicology Center, Jeonbuk Department of Inhalation Research, Korea Institute of Toxicology, Jeongeup, Jeonbuk, Republic of Korea
| | - Jong-Won Kim
- Biosafety Research Institute and College of Veterinary Medicine, Jeonbuk National University, Iksan, Republic of Korea
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, United States
| | - Bumseok Kim
- Biosafety Research Institute and College of Veterinary Medicine, Jeonbuk National University, Iksan, Republic of Korea
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11
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Alsabbagh Alchirazi K, Bhavsar-Burke I, Syed H, Alkhayyat M, Bass S, Kapoor A, Lindenmeyer CC. Molecular Adsorbent Recirculating System in Acute Liver Failure. ACG Case Rep J 2024; 11:e01389. [PMID: 38988717 PMCID: PMC11236392 DOI: 10.14309/crj.0000000000001389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 05/07/2024] [Indexed: 07/12/2024] Open
Abstract
Acetaminophen (APAP) overdose is the most common cause of acute liver failure (ALF) in the United States. Liver transplantation (LT) is potentially lifesaving for patients with ALF, but its feasibility in clinical practice is limited. Liver assist devices, such as the Molecular Adsorbent Recirculating System (MARS), are used in some centers as a "bridge" to liver transplantation or as a means of liver recovery, but their role in the treatment of ALF is not well-defined. We present the case of a 44-year-old man with APAP-associated ALF who experienced hepatic recovery after treatment with MARS.
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Affiliation(s)
| | - Indira Bhavsar-Burke
- Department of Gastroenterology, Hepatology and Nutrition, Cleveland Clinic Foundation, Cleveland, OH
| | - Hareem Syed
- Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, OH
| | - Motasem Alkhayyat
- Department of Gastroenterology, Hepatology and Nutrition, Cleveland Clinic Foundation, Cleveland, OH
| | | | - Aanchal Kapoor
- Department of Critical Care, Cleveland Clinic Foundation, Cleveland, OH
| | - Christina C. Lindenmeyer
- Department of Gastroenterology, Hepatology and Nutrition, Cleveland Clinic Foundation, Cleveland, OH
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12
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Allen HN, Hestehave S, Duran P, Nelson TS, Khanna R. Uncoupling the CRMP2-Ca V2.2 interaction reduces pain-like behavior in a preclinical osteoarthritis model. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.05.596514. [PMID: 38895294 PMCID: PMC11185632 DOI: 10.1101/2024.06.05.596514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/21/2024]
Abstract
Osteoarthritis (OA) represents a significant pain challenge globally, as current treatments are limited and come with substantial and adverse side effects. Voltage-gated calcium channels have proved to be pharmacologically effective targets, with multiple FDA-approved CaV2.2 modulators available for the treatment of pain. Although effective, drugs targeting CaV2.2 are complicated by the same obstacles facing other pain therapeutics-invasive routes of administration, narrow therapeutic windows, side effects, and addiction potential. We have identified a key regulator of CaV2.2 channels, collapsing response mediator protein 2 (CRMP2), that allows us to indirectly regulate CaV2.2 expression and function. We developed a peptidomimetic modulator of CRMP2, CBD3063, that effectively reverses neuropathic and inflammatory pain without negative side effects by reducing membrane expression of CaV2.2. Using a rodent model of OA, we demonstrate the intraperitoneal administration of CBD3063 alleviates both evoked and non-evoked behavioral hallmarks of OA pain. Further, we reveal that CBD3063 reduces OA-induced increased neural activity in the parabrachial nucleus, a key supraspinal site modulating the pain experience. Together, these studies suggest CBD3063 is an effective analgesic for OA pain.
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Affiliation(s)
- Heather N. Allen
- Department of Pharmacology & Therapeutics, University of Florida College of Medicine, Gainesville, Florida 32610, USA
| | - Sara Hestehave
- Department of Molecular Pathobiology, College of Dentistry, New York University, New York, New York 10010, USA
| | - Paz Duran
- Department of Molecular Pathobiology, College of Dentistry, New York University, New York, New York 10010, USA
| | - Tyler S. Nelson
- Department of Pharmacology & Therapeutics, University of Florida College of Medicine, Gainesville, Florida 32610, USA
| | - Rajesh Khanna
- Department of Pharmacology & Therapeutics, University of Florida College of Medicine, Gainesville, Florida 32610, USA
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13
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Indumathi MC, Swetha K, Abhilasha KV, Siddappa S, Kumar SM, Prasad GK, Chen CH, Marathe GK. Selenium Ameliorates Acetaminophen-Induced Oxidative Stress via MAPK and Nrf2 Pathways in Mice. Biol Trace Elem Res 2024; 202:2598-2615. [PMID: 37702962 DOI: 10.1007/s12011-023-03845-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Accepted: 09/05/2023] [Indexed: 09/14/2023]
Abstract
Overdose of acetaminophen (paracetamol), a widely used non-prescriptive analgesic and antipyretic medication, is one of the main causes of drug-induced acute liver failure around the world. Oxidative stress contributes to this hepatotoxicity. Antioxidants are known to protect the liver from oxidative stress. Selenium, a potent antioxidant, is a commonly used micronutrient. Here, we evaluated the protective effect of selenium on acetaminophen-induced hepatotoxicity. Treating Wistar albino mice with sodium selenite (1 mg/kg) before or after inducing hepatotoxicity with acetaminophen (150 mg/kg) significantly reduced the levels of liver injury biomarkers such as serum glutamate oxaloacetate transaminase and serum glutamate pyruvate transaminase. In addition, selenium-treated mice showed decreased levels of oxidative stress markers such as protein carbonyls and myeloperoxidase. Acetaminophen treatment stimulated all three mitogen-activated protein kinases (MAPKs) and Keap1 and decreased the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 in liver and in isolated mouse peritoneal macrophages, which was reversed by selenium treatment. Our findings suggest that the reactive oxygen species-mediated Nrf2 and MAPK pathways are critical players in acetaminophen-induced hepatotoxicity. These key findings offer an alternative therapeutic target for addressing acetaminophen-induced hepatotoxicity.
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Affiliation(s)
| | - Kamatam Swetha
- Department of Studies in Biochemistry, 8J8C+98P, University of Mysore, Manasagangotri, Mysore, 570006, Karnataka, India
| | | | - Shiva Siddappa
- Division of Biochemistry, School of Life Sciences, 8MV2+MPG, Sri Shivarathreeshwara Nagara, JSS Academy of Higher Education and Research, Bannimantap A Layout, Bannimantap, Mysuru, Karnataka, 570015, India
| | - Shivamadhaiah Manjula Kumar
- Department of Studies in Biochemistry, 8J8C+98P, University of Mysore, Manasagangotri, Mysore, 570006, Karnataka, India
| | - Govinda Keerthi Prasad
- Department of Studies in Biochemistry, 8J8C+98P, University of Mysore, Manasagangotri, Mysore, 570006, Karnataka, India
| | - Chu-Huang Chen
- Vascular and Medicinal Research, The Texas Heart Institute, 6770 Bertner Avenue, Houston, TX, 77030, USA
| | - Gopal Kedihithlu Marathe
- Department of Studies in Biochemistry, 8J8C+98P, University of Mysore, Manasagangotri, Mysore, 570006, Karnataka, India.
- Department of Studies in Molecular Biology, 8J8C+JFP, University of Mysore, Manasagangotri, Mysore, 570006, Karnataka, India.
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14
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Wang Y, Ren J, Ren S. Larsucosterol: endogenous epigenetic regulator for treating chronic and acute liver diseases. Am J Physiol Endocrinol Metab 2024; 326:E577-E587. [PMID: 38381400 PMCID: PMC11376820 DOI: 10.1152/ajpendo.00406.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 02/15/2024] [Accepted: 02/15/2024] [Indexed: 02/22/2024]
Abstract
Larsucosterol, a potent endogenous epigenetic regulator, has been reported to play a significant role in lipid metabolism, inflammatory responses, and cell survival. The administration of larsucosterol has demonstrated a reduction in lipid accumulation within hepatocytes and the attenuation of inflammatory responses induced by lipopolysaccharide (LPS) and TNFα in macrophages, alleviating LPS- and acetaminophen (ATMP)-induced multiple organ injury, and decreasing mortalities in animal models. Results from phase 1 and 2 clinical trials have shown that larsucosterol has potential as a biomedicine for the treatment of acute and chronic liver diseases. Recent evidence suggests that larsucosterol is a promising candidate for treating alcohol-associated hepatitis with positive results from a phase 2a clinical trial, and for metabolic dysfunction-associated steatohepatitis (MASH) from a phase 1b clinical trial. In this review, we present a culmination of our recent research efforts spanning two decades. We summarize the discovery, physiological and pharmacological mechanisms, and clinical applications of larsucosterol. Furthermore, we elucidate the pathophysiological pathways of metabolic dysfunction-associated steatotic liver diseases (MASLD), metabolic dysfunction-associated steatohepatitis (MASH), and acute liver injuries. A central focus of the review is the exploration of the therapeutic potential of larsucosterol in treating life-threatening conditions, including acetaminophen overdose, endotoxin shock, MASLD, MASH, hepatectomy, and alcoholic hepatitis.
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Affiliation(s)
- Yaping Wang
- Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, United States
- McGuire Veterans Affairs Medical Center, Richmond, Virginia, United States
| | - Jenna Ren
- Department of Pharmacology, Virginia Commonwealth University, Richmond, Virginia, United States
| | - Shunlin Ren
- Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, United States
- McGuire Veterans Affairs Medical Center, Richmond, Virginia, United States
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15
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Sadeghinejad S, Mousavi M, Zeidooni L, Mansouri E, Mohtadi S, Khodayar MJ. Ameliorative effects of umbelliferone against acetaminophen-induced hepatic oxidative stress and inflammation in mice. Res Pharm Sci 2024; 19:83-92. [PMID: 39006976 PMCID: PMC11244709 DOI: 10.4103/1735-5362.394823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Revised: 06/28/2023] [Accepted: 01/22/2024] [Indexed: 07/16/2024] Open
Abstract
Background and purpose Acetaminophen (APAP) is a commonly used antipyretic and pain reliever that its overdose causes acute liver toxicity. Umbelliferone (UMB) has many pharmacological effects. In this study, the hepatoprotective effect of UMB on acute hepatotoxicity induced by APAP was investigated. Experimental approach Forty-nine male mice were separated into seven groups. The control received vehicle (i.p.), UMB group received UMB (120 mg/kg, i.p.), APAP group was treated with a single dose of APAP (350 mg/kg, i.p.), and pretreated groups received N-acetylcysteine (NAC, 200 mg/kg, i.p.) or different doses of UMB (30, 60, and 120 mg/kg, i.p.), respectively before APAP. Twenty-four hours after APAP injection, mice were sacrificed and blood and liver samples were collected. Then, serum and tissue samples were investigated for biochemical and histological studies. Findings/Results A single dose of APAP caused elevation in the serum liver enzymes, including alanine aminotransferase, aspartate transaminase, and alkaline phosphatase. The amounts of thiobarbituric acid reactive substances, tumor necrosis factor-alpha, and nitric oxide increased in the mice's liver tissue. Moreover, the amount of total thiol and the activity of antioxidant enzymes (catalase, superoxide dismutase, and glutathione peroxidase) significantly diminished in the APAP group. Histological results confirmed the hepatotoxicity induced by APAP. However, UMB (more effective at 60 and 120 mg/kg) lessened APAP-induced hepatic injuries, which is comparable with NAC effects. Conclusion and implications The findings of this study provided evidence that UMB ameliorates liver injury induced by APAP through its antioxidant and anti-inflammatory effects.
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Affiliation(s)
- Saeed Sadeghinejad
- Medicinal Plant Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mehrnoosh Mousavi
- Toxicology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Department of Toxicology, Faculty of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Leila Zeidooni
- Toxicology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Department of Toxicology, Faculty of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Esrafil Mansouri
- Cellular and Molecular Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Shokooh Mohtadi
- Department of Toxicology, Faculty of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mohammad Javad Khodayar
- Toxicology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Department of Toxicology, Faculty of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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16
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Tian L, Mi N, Wang L, Huang C, Fu W, Bai M, Gao L, Ma H, Zhang C, Lu Y, Zhao J, Zhang X, Jiang N, Lin Y, Yue P, Xia B, He Q, Yuan J, Meng W. Regular use of paracetamol and risk of liver cancer: a prospective cohort study. BMC Cancer 2024; 24:33. [PMID: 38178090 PMCID: PMC10765829 DOI: 10.1186/s12885-023-11767-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Accepted: 12/15/2023] [Indexed: 01/06/2024] Open
Abstract
BACKGROUND Paracetamol induces hepatotoxicity and subsequent liver injury, which may increase the risk of liver cancer, but epidemiological evidence remains unclear. We conducted this study to evaluate the association between paracetamol use and the risk of liver cancer. METHODS This prospective study included 464,244 participants free of cancer diagnosis from the UK Biobank. Incident liver cancer was identified through linkage to cancer and death registries and the National Health Service Central Register using the International Classification of Diseases (ICD)-10 codes (C22). An overlap-weighted Cox proportional hazards model was utilized to calculate the hazard ratio (HR) and 95% confidence interval (CI) for the risk of liver cancer associated with paracetamol use. The number needed to harm (NNH) was calculated at 10 years of follow-up. RESULTS During a median of 12.6 years of follow-up, 627 cases of liver cancer were identified. Paracetamol users had a 28% higher risk of liver cancer than nonusers (HR 1.28, 95% CI 1.06-1.54). This association was robust in several sensitivity analyses and subgroup analyses, and the quantitative bias analysis indicated that the result remains sturdy to unmeasured confounding factors (E-value 1.88, lower 95% CI 1.31). The NNH was 1106.4 at the 10 years of follow-up. CONCLUSION The regular use of paracetamol was associated with a higher risk of liver cancer. Physicians should be cautious when prescribing paracetamol, and it is recommended to assess the potential risk of liver cancer to personalize the use of paracetamol.
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Affiliation(s)
- Liang Tian
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, 730000, China
| | - Ningning Mi
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, 730000, China
| | - Leiqing Wang
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, 730000, China
| | - Chongfei Huang
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, 730000, China
| | - Wenkang Fu
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, 730000, China
| | - Mingzhen Bai
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, 730000, China
| | - Long Gao
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, 730000, China
| | - Haidong Ma
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, 730000, China
| | - Chao Zhang
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, 730000, China
| | - Yawen Lu
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, 730000, China
| | - Jinyu Zhao
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, 730000, China
| | - Xianzhuo Zhang
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, 730000, China
| | - Ningzu Jiang
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, 730000, China
| | - Yanyan Lin
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, 730000, China
| | - Ping Yue
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, 730000, China
| | - Bin Xia
- Clinical Research Center, Big Data Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, Guangdong, 518107, China
| | - Qiangsheng He
- Clinical Research Center, Big Data Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, Guangdong, 518107, China.
| | - Jinqiu Yuan
- Clinical Research Center, Big Data Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, Guangdong, 518107, China.
| | - Wenbo Meng
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China.
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, 730000, China.
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17
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Wieczorkiewicz F, Sojka J, Poprawa I. Effect of paracetamol on the storage cells of Hypsibius exemplaris—ultrastructural analysis. Zool J Linn Soc 2024; 200:258-268. [DOI: 10.1093/zoolinnean/zlad051] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Abstract
Tardigrades in their natural environment are exposed to various environmental toxicants, including non-steroidal anti-inflammatory drugs (NSAIDs) or antipyretics such as paracetamol. This drug can enter the animal’s body through the body wall or the digestive system with food and can affect the biology of organisms. In this paper, we report for the first time the effects of paracetamol on tardigrade storage cells. We analyzed the effects of short-term (7 days) and long-term (28 days) exposure of Hypsibius exemplaris storage cells to three paracetamol concentrations (0.2 µgxL−1, 230 µgxL−1, 1 mgxL−1). Our results showed that increasing paracetamol concentration and incubation time increases the number of damaged mitochondria in storage cells, and autophagy is activated and intensified. Moreover, the relocation of some organelles and cell deformation may indicate cytoskeleton damage.
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Affiliation(s)
- Filip Wieczorkiewicz
- Institute of Biology, Biotechnology and Environmental Protection, Faculty of Natural Sciences, University of Silesia in Katowice , Bankowa 9, 40-007 Katowice , Poland
| | - Julia Sojka
- Institute of Biology, Biotechnology and Environmental Protection, Faculty of Natural Sciences, University of Silesia in Katowice , Bankowa 9, 40-007 Katowice , Poland
| | - Izabela Poprawa
- Institute of Biology, Biotechnology and Environmental Protection, Faculty of Natural Sciences, University of Silesia in Katowice , Bankowa 9, 40-007 Katowice , Poland
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18
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Rodrigues K, Hussain R, Cooke S, Zhang G, Zhang D, Yin L, Tong X. Fructose as a novel nutraceutical for acetaminophen (APAP)-induced hepatotoxicity. METABOLISM AND TARGET ORGAN DAMAGE 2023; 3:20. [PMID: 39193224 PMCID: PMC11349303 DOI: 10.20517/mtod.2023.28] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/29/2024]
Abstract
Acetaminophen (APAP) is the most widely used analgesic in the world. APAP overdose can cause severe hepatotoxicity and therefore is the most common cause of drug-induced liver injury. The only approved treatment for APAP overdose is N-acetyl-cysteine (NAC) supplementation. However, the narrow efficacy window of the drug severely limits its clinical use, prompting the search for other therapeutic options to counteract APAP toxicity. Recent research has pointed to fructose as a novel nutraceutical for APAP-induced liver injury. This review summarizes the current understanding of the molecular mechanisms underlying APAP-induced liver injury, introduces how fructose supplementation could prevent and treat APAP liver toxicity with a focus on the ChREBPα-FGF21 pathway, and proposes possible future directions of study.
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Affiliation(s)
- Kyle Rodrigues
- Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48105, USA
- Caswell Diabetes Institute, University of Michigan Medical School, Ann Arbor, MI 48105, USA
| | - Rawdat Hussain
- Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48105, USA
- Caswell Diabetes Institute, University of Michigan Medical School, Ann Arbor, MI 48105, USA
| | - Sarah Cooke
- Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48105, USA
- Caswell Diabetes Institute, University of Michigan Medical School, Ann Arbor, MI 48105, USA
| | - Gary Zhang
- Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48105, USA
- Caswell Diabetes Institute, University of Michigan Medical School, Ann Arbor, MI 48105, USA
| | - Deqiang Zhang
- Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48105, USA
- Caswell Diabetes Institute, University of Michigan Medical School, Ann Arbor, MI 48105, USA
| | - Lei Yin
- Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48105, USA
- Caswell Diabetes Institute, University of Michigan Medical School, Ann Arbor, MI 48105, USA
| | - Xin Tong
- Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48105, USA
- Caswell Diabetes Institute, University of Michigan Medical School, Ann Arbor, MI 48105, USA
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19
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Zhou W, He H, Wei Q, Che L, Zhao X, Liu W, Yan Y, Hu L, Du Y, Yin Z, Shuai Y, Yang L, Feng R. Puerarin protects against acetaminophen-induced oxidative damage in liver through activation of the Keap1/Nrf2 signaling pathway. Food Sci Nutr 2023; 11:6604-6615. [PMID: 37823166 PMCID: PMC10563760 DOI: 10.1002/fsn3.3609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 07/08/2023] [Accepted: 07/22/2023] [Indexed: 10/13/2023] Open
Abstract
Puerarin (Pue) is a kind of isoflavone compound extracted from Pueraria lobata, which has significant antioxidant activity. Excessive use of acetaminophen (APAP) can cause oxidative stress in the liver and eventually lead to acute liver injury. The purpose of this study was to investigate the protective effect and the mechanism of puerarin on APAP-induced liver oxidative damage. In in vitro experiments, puerarin significantly increased the cell activity of HepG2 cells, reduced the ROS accumulation, alleviated the oxidative damage and mitochondrial dysfunction. In in vivo studies, our results showed that puerarin enhanced antioxidant activity and alleviated histopathological damage. Further studies showed that puerarin decreased the expression of Keap1, promoted the nuclear migration of Nrf2, and up-regulated the expression of GCLC, GCLM, HO-1 and NQO1. This study demonstrated that puerarin can protect APAP-induced liver injury via alleviating oxidative stress and mitochondrial dysfunction by affecting the nuclear migration of Nrf2 via inhibiting Keap1.
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Affiliation(s)
- Wanhai Zhou
- Sichuan Oil Cinnamon Engineering Technology Research CenterYibin UniversityYibinChina
- Faculty of Agriculture, Forestry and Food EngineeringYiBin UniversityYibinChina
| | - Heng He
- Natural Medicine Research Center, College of Veterinary MedicineSichuan Agricultural UniversityChengduChina
| | - Qin Wei
- Sichuan Oil Cinnamon Engineering Technology Research CenterYibin UniversityYibinChina
| | - Litao Che
- Sichuan Oil Cinnamon Engineering Technology Research CenterYibin UniversityYibinChina
- Faculty of Agriculture, Forestry and Food EngineeringYiBin UniversityYibinChina
| | - Xin Zhao
- Sichuan Oil Cinnamon Engineering Technology Research CenterYibin UniversityYibinChina
- Faculty of Agriculture, Forestry and Food EngineeringYiBin UniversityYibinChina
| | - Wenwen Liu
- Sichuan Oil Cinnamon Engineering Technology Research CenterYibin UniversityYibinChina
- Faculty of Agriculture, Forestry and Food EngineeringYiBin UniversityYibinChina
| | - Yue Yan
- Sichuan Oil Cinnamon Engineering Technology Research CenterYibin UniversityYibinChina
- Faculty of Agriculture, Forestry and Food EngineeringYiBin UniversityYibinChina
| | - Lianqing Hu
- Sichuan Oil Cinnamon Engineering Technology Research CenterYibin UniversityYibinChina
- Faculty of Agriculture, Forestry and Food EngineeringYiBin UniversityYibinChina
| | - Yonghua Du
- Sichuan Oil Cinnamon Engineering Technology Research CenterYibin UniversityYibinChina
- Faculty of Agriculture, Forestry and Food EngineeringYiBin UniversityYibinChina
| | - Zhongqiong Yin
- Natural Medicine Research Center, College of Veterinary MedicineSichuan Agricultural UniversityChengduChina
| | - Yongkang Shuai
- Sichuan Oil Cinnamon Engineering Technology Research CenterYibin UniversityYibinChina
| | - Li Yang
- Sichuan Oil Cinnamon Engineering Technology Research CenterYibin UniversityYibinChina
| | - Ruizhang Feng
- Sichuan Oil Cinnamon Engineering Technology Research CenterYibin UniversityYibinChina
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20
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Kamaraj S, Vuppu S. Recent Review on the Extraction and Qualitative Assay of Cysteine and Other Amino Acids from Vellore Feather Waste and Molecular Docking Studies of Cysteine for Pharmacological Applications. Mol Biotechnol 2023:10.1007/s12033-023-00862-4. [PMID: 37715883 DOI: 10.1007/s12033-023-00862-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 08/06/2023] [Indexed: 09/18/2023]
Abstract
Products produced from waste are a relatively recent innovation. Feather substrates are abundant in keratin content and improper disposal can cause ecosystem contamination. However, these pollutants can be transformed into value-added products for industrial application. Physical, chemical and cutting-edge microbiological methods were utilized for decomposing keratin and aid in the identification and estimation of amino acids from poultry feather wastes. These beneficial approaches are receiving more attention due to their retrieval of harmless and value added byproducts. These keratin-based compounds are used widely in pharmaceutical, livestock feed, fertilizer, and a variety of other industrial sectors. Since keratin is primarily consisting of amino acids, it can be utilized to affirm and estimate the amino acids in these feather substrates. This study primarily highlights the various methodologies employed for the qualitative estimation of amino acids in feather waste samples and the inhibitory activity of keratinase enzyme by EDTA and pepstatin in order to accumulate amino acids for drug delivery purpose and their importance in various pharmaceutical industries. In addition to that, molecular docking studies of cysteine with many standard pharmaceutical drugs like acetaminophen, pethidine, methylphenidate, carbamazepine, cillin and amlodipine were performed using autodock to demonstrate how cysteine greatly reduces conventional drug toxicity and its side effects.
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Affiliation(s)
- Sathvika Kamaraj
- School of Biosciences and Technology, Department of Biotechnology, VIT University, Vellore, Tamil Nadu, 632014, India
| | - Suneetha Vuppu
- School of Biosciences and Technology, Department of Biotechnology, VIT University, Vellore, Tamil Nadu, 632014, India.
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21
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Hirano K, Igarashi T, Murotani K, Tanaka N, Sakurai T, Miwa T, Watanabe T, Shibuya K, Yoshioka I, Fujii T. Efficacy and feasibility of scheduled intravenous acetaminophen administration after pancreatoduodenectomy: a propensity score-matched study. Surg Today 2023; 53:1047-1056. [PMID: 36746797 DOI: 10.1007/s00595-023-02647-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Accepted: 12/31/2022] [Indexed: 02/08/2023]
Abstract
PURPOSE The efficiency and safety of routine intravenous administration of acetaminophen after highly invasive hepatobiliary pancreatic surgery remain unclear. In particular, there have been no studies focusing on pancreatoduodenectomy. The present study clarified its clinical utility for patients undergoing pancreatoduodenectomy. METHODS We retrospectively collected 179 patients who underwent open pancreatoduodenectomy from 2015 to 2020. The analgesic effects and adverse events in patients with scheduled intravenous administration of acetaminophen were evaluated using propensity score matching. RESULTS After 40 patients from each group were selected by propensity score matching, the postoperative liver function tests were not significantly different between the control and acetaminophen groups. No significant differences were found in the self-reported pain intensity score or postoperative nausea and vomiting; however, the rate of pentazocine use and the total number of additional analgesics were significantly lower in the acetaminophen group than in the control group (p = 0.003 and 0.002, respectively). CONCLUSION The scheduled intravenous administration of acetaminophen did not affect the postoperative liver function and had a good analgesic effect after pancreatoduodenectomy.
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Affiliation(s)
- Katsuhisa Hirano
- Department of Surgery and Science, Faculty of Medicine, Academic Assembly, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Takamichi Igarashi
- Department of Surgery and Science, Faculty of Medicine, Academic Assembly, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Kenta Murotani
- Biostatistics Center, Graduate School of Medicine, Kurume University, 67 Asahi-Machi, Kurume, Fukuoka, Japan
| | - Nobutake Tanaka
- Department of Surgery and Science, Faculty of Medicine, Academic Assembly, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Taro Sakurai
- Department of Surgery and Science, Faculty of Medicine, Academic Assembly, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Takeshi Miwa
- Department of Surgery and Science, Faculty of Medicine, Academic Assembly, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Toru Watanabe
- Department of Surgery and Science, Faculty of Medicine, Academic Assembly, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Kazuto Shibuya
- Department of Surgery and Science, Faculty of Medicine, Academic Assembly, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Isaku Yoshioka
- Department of Surgery and Science, Faculty of Medicine, Academic Assembly, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Tsutomu Fujii
- Department of Surgery and Science, Faculty of Medicine, Academic Assembly, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
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22
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Gharous M, Bounab L, Pereira FJ, Choukairi M, López R, Aller AJ. Electrochemical Kinetics and Detection of Paracetamol by Stevensite-Modified Carbon Paste Electrode in Biological Fluids and Pharmaceutical Formulations. Int J Mol Sci 2023; 24:11269. [PMID: 37511028 PMCID: PMC10378910 DOI: 10.3390/ijms241411269] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 06/30/2023] [Accepted: 07/07/2023] [Indexed: 07/30/2023] Open
Abstract
Paracetamol (PCT), or acetaminophen, is an important drug used worldwide for various clinical purposes. However, the excessive or indiscriminate use of PCT can provoke liver and kidney dysfunction; hence, it is essential to determine the amount of this target in biological samples. In this work, we develop a quick, simple, and sensitive voltammetric method using chemically modified electrodes to determine PCT in complex matrices, including human serum and commercial solid formulations. We modify the carbon paste electrode with stevensite monoclinic clay mineral (Stv-CPE), using cyclic voltammetry, differential pulse voltammetry, and electrochemical impedance spectroscopy to characterise and detect PCT. The kinetics study provides a better electrochemical characterisation of the electrode behaviour, finding the detection and quantitation limits of 0.2 μM and 0.5 μM under favourable conditions. Further, the best linear working concentration range is 0.6-100 μM for PCT, applying the proposed method to the quantitative determination of PCT content in reference tablet formulations and biological samples for validation.
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Affiliation(s)
- Moaad Gharous
- Laboratory of Materials and Interfacial Systems, Faculty of Science, Abdelmalek Essaadi University, BP 2121, Tetouan 93002, Morocco
- Research Group of Advanced Materials, Structures and Civil Engineering, National School of Applied Sciences of Tetouan, Abdelmalek Essaadi University, BP 2121, Tetouan 93002, Morocco
| | - Loubna Bounab
- Research Group of Advanced Materials, Structures and Civil Engineering, National School of Applied Sciences of Tetouan, Abdelmalek Essaadi University, BP 2121, Tetouan 93002, Morocco
| | - Fernando J Pereira
- Department of Applied Chemistry and Physics, Faculty of Biological and Environmental Sciences, Campus de Vegazana, s/n, University of León, E-24071 León, Spain
| | - Mohamed Choukairi
- Laboratory of Materials and Interfacial Systems, Faculty of Science, Abdelmalek Essaadi University, BP 2121, Tetouan 93002, Morocco
| | - Roberto López
- Department of Applied Chemistry and Physics, Faculty of Biological and Environmental Sciences, Campus de Vegazana, s/n, University of León, E-24071 León, Spain
| | - A Javier Aller
- Department of Applied Chemistry and Physics, Faculty of Biological and Environmental Sciences, Campus de Vegazana, s/n, University of León, E-24071 León, Spain
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23
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Gold JR, Grubb T, Court MH, Villarino NF. Pharmacokinetics of acetaminophen after a single Oral administration of 20 or 40 mg/kg to 7-9 Day-old foals. Front Vet Sci 2023; 10:1198940. [PMID: 37483288 PMCID: PMC10359069 DOI: 10.3389/fvets.2023.1198940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Accepted: 06/23/2023] [Indexed: 07/25/2023] Open
Abstract
Background Acetaminophen is utilized in human infants for pain management and fever. Neonatal foals might benefit from administration of acetaminophen but effective and safe dosage regimens for neonatal foals remains to be determined. Objective The objective was to determine the plasma pharmacokinetics of acetaminophen following oral administration of a single dose of 20 mg/kg or 40 mg/kg to neonatal foals. A secondary objective was to evaluate any changes in hematology and biochemistry profiles. Study design Randomized study. Methods Eight clinically healthy 7-9-day old Quarter Horse foals (3 colts and 5 fillies) received a single oral dose of acetaminophen either 20 (n = 4) or 40 (n = 4) mg/kg. Hematology and biochemistry profiles were evaluated before and 7 days after drug administration. Blood samples were collected before and 8 times after acetaminophen administration for 48 h to quantify plasma acetaminophen concentrations. Plasma pharmacokinetic parameters were estimated using non- compartmental analysis. Results The median peak plasma concentrations (and range) occurred at 1.5 (0.5-2) hours, and 1.0 (1-2) hours for the 20 and 40 mg/kg doses. The maximum plasma concentration (and range) was 12 (7.9-17.4) μg/mL for the 20 mg/kg dose and 14 (11-18) μg/mL for 40 mg/kg dose. The median AUC0-∞ ranged from 46 to 100 and 79 to 160 h*-μg/mL for the 20 and 40 mg/kg dose, respectively. Hematology and biochemistry profiles remained within normal limits. Conclusion Plasma disposition of acetaminophen after oral administration of 20 and 40 mg/kg to neonates is comparable to adult horses. However, safety and the optimal dosage regimen of acetaminophen for treating pain and or pyrexia in neonates in this age group remains to be determined.
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Affiliation(s)
- Jenifer R. Gold
- Wisconsin Equine Clinic and Hospital, Oconomowoc, WI, United States
| | - Tamara Grubb
- Department of Veterinary Clinical Sciences, Washington State University, Pullman, WA, United States
| | - Michael H. Court
- Department of Veterinary Clinical Sciences, Washington State University, Pullman, WA, United States
| | - Nicolas F. Villarino
- Department of Veterinary Clinical Sciences, Washington State University, Pullman, WA, United States
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24
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Ishida Y, Zhang S, Kuninaka Y, Ishigami A, Nosaka M, Harie I, Kimura A, Mukaida N, Kondo T. Essential Involvement of Neutrophil Elastase in Acute Acetaminophen Hepatotoxicity Using BALB/c Mice. Int J Mol Sci 2023; 24:7845. [PMID: 37175553 PMCID: PMC10177873 DOI: 10.3390/ijms24097845] [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: 01/11/2023] [Revised: 04/22/2023] [Accepted: 04/24/2023] [Indexed: 05/15/2023] Open
Abstract
Intense neutrophil infiltration into the liver is a characteristic of acetaminophen-induced acute liver injury. Neutrophil elastase is released by neutrophils during inflammation. To elucidate the involvement of neutrophil elastase in acetaminophen-induced liver injury, we investigated the efficacy of a potent and specific neutrophil elastase inhibitor, sivelestat, in mice with acetaminophen-induced acute liver injury. Intraperitoneal administration of 750 mg/kg of acetaminophen caused severe liver damage, such as elevated serum transaminase levels, centrilobular hepatic necrosis, and neutrophil infiltration, with approximately 50% mortality in BALB/c mice within 48 h of administration. However, in mice treated with sivelestat 30 min after the acetaminophen challenge, all mice survived, with reduced serum transaminase elevation and diminished hepatic necrosis. In addition, mice treated with sivelestat had reduced NOS-II expression and hepatic neutrophil infiltration after the acetaminophen challenge. Furthermore, treatment with sivelestat at 3 h after the acetaminophen challenge significantly improved survival. These findings indicate a new clinical application for sivelestat in the treatment of acetaminophen-induced liver failure through mechanisms involving the regulation of neutrophil migration and NO production.
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Affiliation(s)
- Yuko Ishida
- Department of Forensic Medicine, Wakayama Medical University, Wakayama 641-0012, Japan
| | | | | | | | | | | | | | | | - Toshikazu Kondo
- Department of Forensic Medicine, Wakayama Medical University, Wakayama 641-0012, Japan
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25
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Polasek TM, Leelasena I, Betscheider I, Marolt M, Kohlhof H, Vitt D, Fliegert F, Muehler AR. Safety, Tolerability, and Pharmacokinetics of IMU-935, a Novel Inverse Agonist of Retinoic Acid Receptor-Related Orphan Nuclear Receptor γt: Results From a Double-Blind, Placebo-Controlled, First-in-Human Phase 1 Study. Clin Pharmacol Drug Dev 2023; 12:525-534. [PMID: 36938862 DOI: 10.1002/cpdd.1243] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 02/16/2023] [Indexed: 03/21/2023]
Abstract
Retinoic acid receptor-related orphan nuclear receptor (ROR)γt regulates the transcription of interleukin-17 and other cytokines implicated in inflammatory and autoimmune diseases. We assessed the safety, tolerability, and pharmacokinetics (PK) of IMU-935, an inverse agonist of RORγt, in a first-in-human phase 1 study. This was a double-blind, placebo-controlled trial that randomly assigned healthy subjects single ascending doses (25-400 mg) or multiple ascending doses (150 mg once or twice daily for 14 days) of IMU-935 or placebo. Dose escalation was determined by the safety, tolerability, and PK. Twenty-four and 70 subjects received placebo or IMU-935, respectively. Of the 70 subjects who received IMU-935, 59 received a single dose and 11 received multiple doses. Treatment-emergent adverse events (TEAEs) occurred in 21 subjects (88%) and 58 (83%) given any dose of placebo or IMU-935, respectively. Treatment-related TEAEs occurred in 6 (30%) and 25 (42%) subjects given a single dose of placebo and IMU-935, respectively. All treatment-related TEAEs were mild except for 2 moderate TEAEs and 1 moderate TEAE in the IMU-935 group and placebo group, respectively. No treatment-related discontinuations or serious adverse events occurred. The PK of IMU-935 were dose proportional with a half-life of ≈24 hours. In conclusion, IMU-935 was safe with no dose-limiting toxicities and had a PK profile that supports once-daily dosing.
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Affiliation(s)
- Thomas M Polasek
- CMAX Clinical Research Pty Ltd, Adelaide, South Australia, Australia.,Certara, Princeton, New Jersey, USA.,Centre for Medicines Use and Safety, Monash University, Melbourne, Victoria, Australia
| | - Indika Leelasena
- University of the Sunshine Coast Clinical Trials Centre, Morayfield, Queensland, Australia
| | | | - Marija Marolt
- Immunic AG, Lochhamer Schlag 21, Gräfelfing, Germany
| | - Hella Kohlhof
- Immunic AG, Lochhamer Schlag 21, Gräfelfing, Germany
| | - Daniel Vitt
- Immunic AG, Lochhamer Schlag 21, Gräfelfing, Germany
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26
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Azharuddin S, Ogbebor O, Shuster M, Smith B, Arshad H, Cheema T. Toxicological Emergencies. Crit Care Nurs Q 2023; 46:82-99. [PMID: 36415069 DOI: 10.1097/cnq.0000000000000439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Poisoning, drug overdose, and adverse drug effects continue to be a common encounter, especially in the intensive care unit (ICU). Patients are often critically ill or have a potential to rapidly deteriorate and warrant ICU admission. Adults suffering from overdoses rarely give a complete and accurate description of the quantity or type of medications ingested. In most adult cases, multiple substances are involved. A tentative diagnosis in most overdose and poisoning cases can be made by physical examination and simple laboratory tests (electrolyte panel, creatinine, serum osmolarity, urinalysis, etc). Supportive care, with particular attention to airway management, oxygenation, and circulation, is the mainstay of treatment. Basic treatment principles include limiting the amount of toxin absorbed, enhancing the elimination of ingested toxin, and preventing the conversion of non-toxic compounds to toxic metabolites. Drugs or poisons, where specific antidotes or effective therapies exist (especially acetaminophen, salicylates, methanol, ethylene glycol, and digitalis), should be aggressively sought and treated after initial stabilization has been accomplished. For those drugs or poisons where specific quantitative tests are available, levels should be obtained before treatment and may be repeated as clinically indicated.
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Affiliation(s)
- Syed Azharuddin
- Division of Pulmonary and Critical Care Medicine, (Drs Azharuddin, Ogbebor, Arshad, and Cheema and Ms Smith), Division of Infectious Disease (Dr Ogbebor), Allegheny Health Network, Pittsburgh, Pennsylvania and Department of Pharmacy, Allegheny General Hospital, Pittsburgh, Pennsylvania (Dr Shuster)
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27
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Chacón FJ, Cayuela ML, Sánchez-Monedero MA. Paracetamol degradation pathways in soil after biochar addition. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2022; 307:119546. [PMID: 35644431 DOI: 10.1016/j.envpol.2022.119546] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 05/06/2022] [Accepted: 05/24/2022] [Indexed: 06/15/2023]
Abstract
Little is known about the effect of biochar on the degradation of paracetamol in soil, considering the ubiquity of this pollutant in the environment. Given the importance of the electrochemical properties of biochar for contaminant remediation, we investigated the influence of raw and designer redox-active biochars on paracetamol degradation in soil. Metabolite quantification indicated that a minimum of 53% of the spiked paracetamol was transformed in biochar-amended soil, resulting in the accumulation of different degradation products. The identification of these products allowed us to chart paracetamol degradation pathways in soil with and without biochar amendment. Some of the major degradation routes were observed to proceed via catechol and phenol, despite being previously described as having only a minor role in paracetamol metabolism. Additionally, a new transformation route from paracetamol to NAPQI was discovered in anaerobic soil originating from direct redox reactions on the surface of the designer biochars. These results may contribute to change our understanding of the environmental fate of paracetamol in soil and the role of biochar in its biodegradation.
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Affiliation(s)
- Francisco J Chacón
- Department of Soil and Water Conservation and Organic Waste Management, CEBAS-CSIC, Box 164 Espinardo, 30100, Murcia, Spain.
| | - Maria L Cayuela
- Department of Soil and Water Conservation and Organic Waste Management, CEBAS-CSIC, Box 164 Espinardo, 30100, Murcia, Spain
| | - Miguel A Sánchez-Monedero
- Department of Soil and Water Conservation and Organic Waste Management, CEBAS-CSIC, Box 164 Espinardo, 30100, Murcia, Spain
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Mehrpour O, Hoyte C, Goss F, Shirazi FM, Nakhaee S. Decision tree algorithm can determine the outcome of repeated supratherapeutic ingestion (RSTI) exposure to acetaminophen: review of 4500 national poison data system cases. Drug Chem Toxicol 2022:1-7. [DOI: 10.1080/01480545.2022.2083149] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Omid Mehrpour
- Data Science Institute, Southern Methodist University, Dallas, TX, USA
- Denver Health and Hospital Authority, Denver, CO, USA
| | - Christopher Hoyte
- Department of Emergency Medicine, University of Colorado Hospital, Aurora, Colorado
| | - Foster Goss
- Department of Emergency Medicine, University of Colorado Hospital, Aurora, Colorado
| | - Farshad M. Shirazi
- Arizona Poison & Drug Information Center, University of Arizona, College of Pharmacy and University of Arizona, College of Medicine, Tucson, AZ, USA
| | - Samaneh Nakhaee
- Medical Toxicology and Drug Abuse Research Center (MTDRC), Birjand University of Medical Sciences (BUMS), Birjand, Iran
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29
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Xu Q, Deng Y, Ming J, Luo Z, Chen X, Chen T, Wang Y, Yan S, Zhou J, Mao L, Sun W, Zhou Q, Ren H, Zhang Y. Methyl 6-O-cinnamoyl-α-d-glucopyranoside Ameliorates Acute Liver Injury by Inhibiting Oxidative Stress Through the Activation of Nrf2 Signaling Pathway. Front Pharmacol 2022; 13:873938. [PMID: 35559264 PMCID: PMC9086595 DOI: 10.3389/fphar.2022.873938] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 03/18/2022] [Indexed: 12/19/2022] Open
Abstract
Excessive stimulation of hepatotoxins and drugs often lead to acute liver injury, while treatment strategies for acute liver injury have been limited. Methyl 6-O-cinnamoyl-α-d-glucopyranoside (MCGP) is a structure modified compound from cinnamic acid, a key chemical found in plants with significant antioxidant, anti-inflammatory, and antidiabetic effects. In this study, we investigated the effects and underlying mechanisms of MCGP on acetaminophen (APAP)- or carbon tetrachloride (CCl4)-induced acute liver injury. As a result, MCGP inhibited cell death and apoptosis induced by APAP or CCl4, and suppressed the reactive oxygen species (ROS) generation stimulated by H2O2 in liver AML12 cells. In vivo, MCGP alleviated APAP/CCl4-induced hepatic necrosis and resumed abnormal aminotransferase activities and liver antioxidase activities. In addition, MCGP depressed APAP- or CCl4-induced oxidative stress through the suppression of CYP2E1 and activation of nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. MCGP also enhanced the number of PCNA-positive hepatocytes, increased hepatic PCNA and Bcl-XL, and decreased BAX expression in APAP-/CCl4-intoxicated mice. Furthermore, MCGP activated the GSDMD-N/cleaved caspase 1 pathway. In summary, MCGP might act as a potential therapeutic drug against drug-induced and chemical-induced acute liver injuries, and its underlying mechanisms might engage on the pressing of oxidative stress, refraining of hepatocyte apoptosis, and facilitating of liver regeneration.
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Affiliation(s)
- Qianqian Xu
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yanfang Deng
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiaxiong Ming
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zengwei Luo
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xia Chen
- Hubei Key Laboratory of Biotechnology of Chinese Traditional Medicine, National & Local Joint Engineering Research Center of High-throughput Drug Screening Technology, School of Life Sciences, Hubei University, Wuhan, China
| | - Tianqi Chen
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yafen Wang
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shan Yan
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiajun Zhou
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lina Mao
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Weiguang Sun
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qun Zhou
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hong Ren
- Biobank, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yonghui Zhang
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Purohit B, Kumar A, Mahato K, Srivastava A, Chandra P. Engineered three-dimensional Au-Cu bimetallic dendritic nanosensor for ultrasensitive drug detection in urine samples and in vitro human embryonic kidney cells model. Microchem J 2022. [DOI: 10.1016/j.microc.2022.107239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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Drug-Induced Liver Injury: Clinical Evidence of N-Acetyl Cysteine Protective Effects. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:3320325. [PMID: 34912495 PMCID: PMC8668310 DOI: 10.1155/2021/3320325] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 11/12/2021] [Accepted: 11/22/2021] [Indexed: 12/29/2022]
Abstract
Oxidative stress is a key pathological feature implicated in both acute and chronic liver diseases, including drug-induced liver injury (DILI). The latter describes hepatic injury arising as a direct toxic effect of administered drugs or their metabolites. Although still underreported, DILI remains a significant cause of liver failure, especially in developed nations. Currently, it is understood that mitochondrial-generated oxidative stress and abnormalities in phase I/II metabolism, leading to glutathione (GSH) suppression, drive the onset of DILI. N-Acetyl cysteine (NAC) has attracted a lot of interest as a therapeutic agent against DILI because of its strong antioxidant properties, especially in relation to enhancing endogenous GSH content to counteract oxidative stress. Thus, in addition to updating information on the pathophysiological mechanisms implicated in oxidative-induced hepatic injury, the current review critically discusses clinical evidence on the protective effects of NAC against DILI, including the reduction of patient mortality. Besides injury caused by paracetamol, NAC can also improve liver function in relation to other forms of liver injury such as those induced by excessive alcohol intake. The implicated therapeutic mechanisms of NAC extend from enhancing hepatic GSH levels to reducing biomarkers of paracetamol toxicity such as keratin-18 and circulating caspase-cleaved cytokeratin-18. However, there is still lack of evidence confirming the benefits of using NAC in combination with other therapies in patients with DILI.
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Li R, Liu J, Ma J, Sun X, Wang Y, Yan J, Yu Q, Diao J, Yang C, Reid LM, Wang Y. Fibrinogen improves liver function via promoting cell aggregation and fibronectin assembly in hepatic spheroids. Biomaterials 2021; 280:121266. [PMID: 34875515 DOI: 10.1016/j.biomaterials.2021.121266] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 10/10/2021] [Accepted: 11/17/2021] [Indexed: 12/17/2022]
Abstract
Many key functions performed by the liver depend on the interaction between parenchymal cells and the microenvironment comprised of neighboring cells and extracellular matrix. The biological macromolecules in the matrix, which are dynamically changing, participate in various physiological processes through interactions with cell surface receptors, antigens, and ion channels. We found the rat liver biomatrix scaffold (LBS) prepared from adult rats is more effective in enhancing the function of hepatic spheroids than those derived from newborn or senile rats. Combined with matrisome and bioinformatics analyses, we further found that the glycoproteins, fibronectin and fibrinogen may have special potential for improving hepatocyte function. Human primary hepatocyte organoids and HepaRG spheroids showed more mature hepatocyte phenotype after adding fibronectin and fibrinogen to the culture system. During the cultivation of hepatic spheroids, fibrinogen resulted in an increase in cell-cell junction by promoting cell aggregation and helping fibronectin to assemble on cell surface, which resulted in activation of Wnt/β-catenin pathway. Fibronectin-integrin αVβ1-Wnt/β-catenin may be the axis of signal transduction in parenchymal cell microenvironment. Importantly, fibrinogen enhances the signal transduction. These results suggest that the addition of fibronectin and fibrinogen to the 3D culture system is a new strategy for inducing parenchymal cell functional maturation.
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Affiliation(s)
- Ruihong Li
- Stem Cell and Tissue Engineering Lab, Beijing Institute of Health Service and Transfusion Medicine, Beijing, 100850, China
| | - Juan Liu
- Hepato-pancreato-biliary Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, 102218, China
| | - Jie Ma
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Life Omics, Beijing, 102206, China
| | - Xuer Sun
- Stem Cell and Tissue Engineering Lab, Beijing Institute of Health Service and Transfusion Medicine, Beijing, 100850, China
| | - Yi Wang
- Stem Cell and Tissue Engineering Lab, Beijing Institute of Health Service and Transfusion Medicine, Beijing, 100850, China
| | - Jiexin Yan
- Stem Cell and Tissue Engineering Lab, Beijing Institute of Health Service and Transfusion Medicine, Beijing, 100850, China
| | - Qunfang Yu
- Stem Cell and Tissue Engineering Lab, Beijing Institute of Health Service and Transfusion Medicine, Beijing, 100850, China
| | - Jinmei Diao
- Hepato-pancreato-biliary Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, 102218, China
| | - Chun Yang
- Institute of Biomechanics and Medical Engineering, School of Aerospace, Tsinghua University, Beijing, 100084, China
| | - Lola M Reid
- Biology and Biotechnology, Lineberger Cancer Center, University of North Carolina School of Medicine, Chapel Hill, 27599, USA
| | - Yunfang Wang
- Stem Cell and Tissue Engineering Lab, Beijing Institute of Health Service and Transfusion Medicine, Beijing, 100850, China; Hepato-pancreato-biliary Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, 102218, China.
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Nishie A, Ushijima Y, Takayama Y, Fujita N, Kubo Y, Ishimatsu K, Tsurumaru D, Kohjima M, Ishigami K. Hemodynamic Alteration in the Liver in Acute Hepatitis: A Quantitative Evaluation Using Computed Tomographic Perfusion. In Vivo 2021; 35:3537-3545. [PMID: 34697192 DOI: 10.21873/invivo.12656] [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: 09/12/2021] [Revised: 09/29/2021] [Accepted: 09/30/2021] [Indexed: 11/10/2022]
Abstract
BACKGROUND/AIM We aimed to elucidate the hemodynamic alterations in the liver of patients with acute hepatitis (AH) using computed tomography perfusion imaging. PATIENTS AND METHODS For 14 patients with AH and nine patients with no disease (ND group), we compared the mean arterial blood flow (AF), portal blood flow (PF) and perfusion index (%) [PI=AF/(AF+PF) ×100] of the right and left liver lobes and investigated their relationship with clinical factors. RESULTS The mean PI of the right lobe in the AH group (30.5±10.0%) was significantly higher than that in the ND group (20.8±9.7%) (p=0.031). For all patients of the AH and ND groups, the PI of the right lobe was increased as the prothrombin time decreased (R=-0.56, p=0.006) and as the prothrombin time-international normalized ratio increased (R=0.48, p=0.02). CONCLUSION The PI of the right liver lobe may increase in AH and may be a predictive parameter for the severity of hepatic failure.
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Affiliation(s)
- Akihiro Nishie
- Department of Radiology, Graduate School of Medical Science, University of the Ryukyus, Okinawa, Japan; .,Department of Advanced Imaging and Interventional Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yasuhiro Ushijima
- Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yukihisa Takayama
- Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Nobuhiro Fujita
- Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yuichiro Kubo
- Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Keisuke Ishimatsu
- Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Daisuke Tsurumaru
- Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Motoyuki Kohjima
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kousei Ishigami
- Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Crocin Possesses Excellent Hepatoprotective Effects Against Acetaminophen-Induced Hepatotoxicity in Mice. Jundishapur J Nat Pharm Prod 2021. [DOI: 10.5812/jjnpp.115165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Background: Acetaminophen (APAP) is a common analgesic and antipyretic medicine that can lead to acute liver injury at high doses. Crocin, a Crocus sativus’ ingredient, has potent antioxidant effects. Objectives: This study examined the protective effects of crocin against APAP-induced oxidative stress in mice. Methods: In this study, 56 mice were randomly divided into seven groups (n = 8 per group), including the negative (normal saline, 10 mL/kg) and positive (oral normal saline for five days + a single dose of APAP (300 mg/kg) on day 6th) control groups. The third group (NAC) received normal saline for up to five days, and on the 6th day, immediately after the administration of acetaminophen, received NAC (50 mg/kg). Groups fourth to sixth received respectively 12.5, 25, and 50 mg/kg of crocin (orally for six days), followed by a single dose of APAP (300 mg/kg) on 6th day. The last group received crocin (50 mg/kg) for six days. Then 24 h after the last injection, the animals were sacrificed, and samples were collected for biochemical and histopathological evaluations. Results: The levels of ALT, AST, and MDA increased, and the activity of CAT, GSH, and GPX decreased in the APAP-treated group compared to the control group. In APAP-treated groups, the administration of crocin decreased the serum levels of AST, ALT, and MDA and increased the activity of CAT, GSH, and GPX. Histopathological evaluations confirmed the above findings. Conclusions: According to our results, it seems that crocin has a protective effect against acetaminophen-induced liver toxicity and can be used as a therapeutic agent to treat APAP-induced hepatotoxicity.
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Mehrpour O, Saeedi F, Hoyte C. Decision tree outcome prediction of acute acetaminophen exposure in the United States: A study of 30,000 cases from the National Poison Data System. Basic Clin Pharmacol Toxicol 2021; 130:191-199. [PMID: 34649297 DOI: 10.1111/bcpt.13674] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 10/08/2021] [Accepted: 10/12/2021] [Indexed: 12/25/2022]
Abstract
Acetaminophen is one of the most commonly used analgesic drugs in the United States. However, the outcomes of acute acetaminophen overdose might be very serious in some cases. Therefore, prediction of the outcomes of acute acetaminophen exposure is crucial. This study is a 6-year retrospective cohort study using National Poison Data System (NPDS) data. A decision tree algorithm was used to determine the risk predictors of acetaminophen exposure. The decision tree model had an accuracy of 0.839, an accuracy of 0.836, a recall of 0.72, a specificity of 0.86 and an F1_score of 0.76 for the test group and an accuracy of 0.848, a recall of 0.85, a recall of 0.74, a specificity of 0.87 and an F1_score of 0.78 for the training group. Our results showed that elevated serum levels of liver enzymes, other liver function test abnormality, anorexia, acidosis, electrolyte abnormality, increased bilirubin, coagulopathy, abdominal pain, coma, increased anion gap, tachycardia and hypotension were the most important factors in determining the outcome of acute acetaminophen exposure. Therefore, the decision tree model is a reliable approach in determining the prognosis of acetaminophen exposure cases and can be used in an emergency room or during hospitalization.
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Affiliation(s)
- Omid Mehrpour
- Data Science Institute, Southern Methodist University, Dallas, Texas, USA.,Rocky Mountain Poison and Drug Safety, Denver Health and Hospital Authority, Denver, Colorado, USA
| | - Farhad Saeedi
- Student Research Committee, Birjand University of Medical Sciences, Birjand, Iran.,Medical Toxicology and Drug Abuse Research Center (MTDRC), Birjand University of Medical Sciences (BUMS), Birjand, Iran
| | - Christopher Hoyte
- University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.,University of Colorado Hospital, Aurora, Colorado, USA
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Vitrone M, Mele F, Durante-Mangoni E, Zampino R. Drugs and liver injury: a not to be overlooked binomial in COVID-19. J Chemother 2021; 34:207-220. [PMID: 34644236 DOI: 10.1080/1120009x.2021.1988203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
SARS-CoV-2 infection (COVID-19) results predominantly in pulmonary involvement but a direct, virus-induced liver damage may also occur, whose mechanisms are being actively investigated. Accordingly, it appears of utmost importance to monitor liver function and carefully evaluate hepatic safety of the various drugs administered during COVID-19. In this respect, many drugs, biological agents and novel molecules, whose efficacy in COVID-19 is under scrutiny, have also been shown to potentially cause or worsen liver damage. In this article, we review safety data of established as well as promising agents for COVID-19.
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Affiliation(s)
- M Vitrone
- Department of Advanced Medical & Surgical Sciences, University of Campania "L. Vanvitelli", Naples, Italy
| | - F Mele
- Department of Advanced Medical & Surgical Sciences, University of Campania "L. Vanvitelli", Naples, Italy
| | - E Durante-Mangoni
- Department of Precision Medicine, University of Campania "L. Vanvitelli", Naples, Italy.,Unit of Infectious and Transplant Medicine, AORN Ospedali dei Colli - Monaldi Hospital, Naples, Italy
| | - R Zampino
- Department of Advanced Medical & Surgical Sciences, University of Campania "L. Vanvitelli", Naples, Italy.,Unit of Infectious and Transplant Medicine, AORN Ospedali dei Colli - Monaldi Hospital, Naples, Italy
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Shen P, Han L, Chen G, Cheng Z, Liu Q. Emodin Attenuates Acetaminophen-Induced Hepatotoxicity via the cGAS-STING Pathway. Inflammation 2021; 45:74-87. [PMID: 34409550 DOI: 10.1007/s10753-021-01529-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 07/27/2021] [Indexed: 01/24/2023]
Abstract
Emodin is a natural bioactive compound from traditional Chinese herbs that exerts anti-inflammatory, antioxidant, anticancer, hepatoprotective, and neuroprotective effects. However, the protective effects of emodin in acetaminophen (APAP)-induced hepatotoxicity are not clear. The present study examined the effects of emodin on APAP-induced hepatotoxicity and investigated the potential molecular mechanisms. C57BL/6 mice were pretreated with emodin (15 and 30 mg/kg) for 5 consecutive days and then given APAP (300 mg/kg) to establish an APAP-induced liver injury model. Mice were sacrificed to detect the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and albumin (ALB) and the liver tissue levels of glutathione (GSH), malondialdehyde (MDA), and superoxide dismutase (SOD). Histological assessment, Western blotting, and ELISA were performed. Emodin pretreatment significantly reduced the levels of ALT, AST, and ALP; increased the levels of ALB; alleviated hepatocellular damage and apoptosis; attenuated the exhaustion of GSH and SOD and the accumulation of MDA; and increased the expression of antioxidative enzymes, including nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), and NAD(P)H quinone dehydrogenase 1 (NQO1). Emodin also inhibited the expression of NLRP3 and reduced the levels of pro-inflammatory factors, including interleukin-1 beta (IL-1β), IL-6, and tumor necrosis factor-alpha (TNF-α). Emodin inhibited interferon (IFN)-α, cyclic GMP-AMP synthase (cGAS), and its downstream signaling effector stimulator of interferon genes (STING) expression to protect the liver against APAP-induced inflammatory responses and apoptosis. These results suggest that emodin protected hepatocytes from APAP-induced liver injury via the upregulation of the Nrf2-mediated antioxidative stress pathway, the inhibition of the NLRP3 inflammasome, and the downregulation of the cGAS-STING signaling pathway.
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Affiliation(s)
- Pan Shen
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan, 430030, China
| | - Liang Han
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan, 430030, China
| | - Guang Chen
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan, 430030, China
| | - Zhe Cheng
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan, 430030, China
| | - Qiong Liu
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan, 430030, China.
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan, 430030, China.
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Abstract
OBJECTIVE A narrative review of randomized, blinded, controlled studies assessing the antipyretic effect of ibuprofen versus acetaminophen or combined or alternating treatment in children was conducted. METHODS Searches of the PubMed and Embase literature databases were conducted to identify relevant articles. Selected articles were limited to studies published in English that investigated OTC oral tablet and syrup formulations of acetaminophen and ibuprofen; there were no publication date limits. Open-label studies, nonrandomized studies, and those evaluating intravenous or suppository formulations of acetaminophen or ibuprofen were excluded. Variations in designs, endpoints, methods, and patient populations precluded our ability to conduct a formal systematic review. RESULTS At physician-directed dosing (acetaminophen 15 mg/kg vs ibuprofen 10 mg/kg), no significant differences in antipyretic effects from 0‒6 h and between 0‒6, ‒12, ‒24, or ‒48 h, with single or multiple-doses, respectively, were observed. Tolerability profiles at physician dosing were similar. In 14 over-the-counter dose comparisons (acetaminophen, 10-15 mg/kg; ibuprofen, 2.5-10 mg/kg), antipyresis favored ibuprofen in 6, was similar between groups in 7, and favored acetaminophen (15 mg/kg vs ibuprofen 5 mg/kg) in 1 comparison. Both medications were well tolerated. Efficacy favored combination over individual components in 3 of 4 studies; alternating use results were mixed. All combination or alternating treatments were well tolerated. CONCLUSIONS Antipyretic effects of ibuprofen and acetaminophen are similar at physician-directed doses; ibuprofen may be modestly superior at over-the-counter doses.
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Affiliation(s)
- Ian M Paul
- Pediatrics and Public Health Sciences, Penn State College of Medicine, Hershey, PA, USA
| | - Philip D Walson
- Department of Clinical Pharmacology, University Medical Center at Georg-August-Universität, Göttingen, Germany
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Labib AY, Ammar RM, El-Naga RN, El-Bahy AAZ, Tadros MG, Michel HE. Mechanistic insights into the protective effect of paracetamol against rotenone-induced Parkinson's disease in rats: Possible role of endocannabinoid system modulation. Int Immunopharmacol 2021; 94:107431. [PMID: 33578261 DOI: 10.1016/j.intimp.2021.107431] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 01/21/2021] [Accepted: 01/22/2021] [Indexed: 12/17/2022]
Abstract
Parkinson's disease (PD) is a disabling progressive neurodegenerative disease. So far, PD's treatment remains symptomatic with no curative effects. Aside from its blatant analgesic and antipyretic efficacy, recent studies highlighted the endowed neuroprotective potentials of paracetamol (PCM). To this end: the present study investigated: (1) Possible protective role of PCM against rotenone-induced PD-like neurotoxicity in rats, and (2) the mechanisms underlying its neuroprotective actions including cannabinoid receptors' modulation. A dose-response study was conducted using three doses of PCM (25, 50, and 100 mg/kg/day, i.p.) and their effects on body weight changes, spontaneous locomotor activity, rotarod test, tyrosine hydroxylase (TH) and α-synuclein expression, and striatal dopamine (DA) content were evaluated. Results revealed that PCM (100 mg/kg/day, i.p.) halted PD motor impairment, prevented rotenone-induced weight loss, restored normal histological tissue structure, reversed rotenone-induced reduction in TH expression and striatal DA content, and markedly decreased midbrain and striatal α-synuclein expression in rotenone-treated rats. Accordingly, PCM (100 mg/kg/day, i.p.) was selected for further mechanistic investigations, where it ameliorated rotenone-induced oxidative stress, neuro-inflammation, apoptosis, and disturbed cannabinoid receptors' expression. In conclusion, our findings imply a multi-target neuroprotective effect of PCM in PD which could be attributed to its antioxidant, anti-inflammatory and anti-apoptotic activities, in addition to cannabinoid receptors' modulation.
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Affiliation(s)
- Aya Yassin Labib
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Heliopolis University for Sustainable Development, Cairo, Egypt
| | - Ramy M Ammar
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Kafrelsheikh University, Kafr El-Sheikh, Egypt
| | - Reem N El-Naga
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Alshaymaa Amin Zaki El-Bahy
- Department of Pharmacology and Toxicology, School of Pharmaceutical Science, University of Hertfordshire, Hosted by Global Academic Foundation, New Administrative City, Egypt
| | - Mariane G Tadros
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Haidy E Michel
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
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Comparative Studies on the Hepatoprotective Effect of White and Coloured Rice Bran Oil against Acetaminophen-Induced Oxidative Stress in Mice through Antioxidant- and Xenobiotic-Metabolizing Systems. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:5510230. [PMID: 33995822 PMCID: PMC8096545 DOI: 10.1155/2021/5510230] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 04/09/2021] [Accepted: 04/15/2021] [Indexed: 12/14/2022]
Abstract
Rice bran oil (RBO) comprises various nutrients and phytochemicals which exhibit several health benefits. There are no studies regarding the functional effects of different colours of RBO. This study was aimed to compare the constituents and antioxidant activities of white rice bran oil (WRBO) and coloured rice bran oil (CRBO). Each RBO showed similar free fatty acid profiles. However, greater amounts of vitamin E, phytosterols, carotenoids, and chlorophylls were found in CRBO, which had lower γ-oryzanol content than WRBO. Oxidative stress was induced in male mice by an overdose of acetaminophen (APAP) at 300 mg/kg body weight. The mice were then fed with RBO at the equivalent dose to 100 mg/kg body weight of γ-oryzanol three hours later and sacrificed six hours after APAP treatment. The administration of 100 mg γ-oryzanol equivalent in CRBO ameliorated APAP-induced hepatotoxicity in mice more strongly than 100 mg γ-oryzanol equivalent in WRBO, as evidenced by the significant reduction of serum ALT, hepatocellular necrosis, and hepatic lipid peroxidation. CRBO could improve xenobiotic-metabolizing and antioxidant enzyme activities, including glutathione S-transferase, superoxide dismutase, glutathione peroxidase, and glutathione reductase, and also increase mRNA expression of various antioxidant-responsive genes. Vitamin E, phytosterols, carotenoids, and chlorophyll might be the protective compounds in CRBO that alleviate APAP-induced hepatotoxicity through the interruption of APAP metabolism and the activation of antioxidant systems at both transcriptional and enzymatic levels. These findings might provide a protective role of CRBO on oxidative stress associated with several degenerative diseases.
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Zhao J, Kim JW, Zhou Z, Qi J, Tian W, Lim CW, Han KM, Kim B. Macrophage-Inducible C-Type Lectin Signaling Exacerbates Acetaminophen-Induced Liver Injury by Promoting Kupffer Cell Activation in Mice. Mol Pharmacol 2021; 99:92-103. [PMID: 33262251 DOI: 10.1124/molpharm.120.000043] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 11/18/2020] [Indexed: 02/06/2023] Open
Abstract
Overdose of acetaminophen (APAP) has become one of the most frequent causes of acute liver failure. Macrophage-inducible C-type lectin (Mincle) acts as a key moderator in immune responses by recognizing spliceosome-associated protein 130 (SAP130), which is an endogenous ligand released by necrotic cells. This study aims to explore the function of Mincle in APAP-induced hepatotoxicity. Wild-type (WT) and Mincle knockout (KO) mice were used to induce acute liver injury by injection of APAP. The hepatic expressions of Mincle, SAP130, and Mincle signaling intermediate (Syk) were markedly upregulated after the APAP challenge. Mincle KO mice showed attenuated injury in the liver, as shown by reduced pathologic lesions, decreased alanine aminotransferase and aspartate aminotransferase levels, downregulated levels of inflammatory cytokines, and decreased neutrophil infiltration. Consistently, inhibition of Syk signaling by GS9973 alleviated APAP hepatotoxicity. Most importantly, Kupffer cells (KCs) were found as the major cellular source of Mincle. The depletion of KCs abolished the detrimental role of Mincle, and the adoptive transfer of WT KC to Mincle KO mice partially reversed the hyporesponsiveness to hepatotoxicity induced by APAP. Furthermore, the expression levels of interleukin (IL)-1β and neutrophil-attractant CXC chemokines were substantially lower in KCs isolated from APAP-treated Mincle KO mice compared with those from WT mice. Similar results were found in primary Mincle KO KCs treated with a ligand of Mincle (trehalose-6,6-dibehenate) or in conditioned media obtained from APAP-treated hepatocytes. Collectively, Mincle can regulate the inflammatory response of KCs, which is necessary for the complete progression of hepatotoxicity induced by APAP. SIGNIFICANCE STATEMENT: Acetaminophen (APAP) overdose is becoming a main cause of drug-induced acute liver damage in the developed world. This study showed that macrophage-inducible C-type lectin (Mincle) deletion or inhibition of Mincle downstream signaling attenuates APAP hepatotoxicity. Furthermore, Mincle as a modulator of Kupffer cell activation contributes to the full process of hepatotoxicity induced by APAP. This mechanism will offer valuable insights to overcome the limitation of APAP hepatotoxicity treatment.
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Affiliation(s)
- Jing Zhao
- Biosafety Research Institute and College of Veterinary Medicine, Jeonbuk National University, Iksan, Jeonbuk, Republic of Korea (J.Z., J.-W.K., Z.Z., J.Q., W.T., C.W.L., B.K.); Department of Pathology, Dongguk University Ilsan Hospital, Goyang, Republic of Korea (K.M.H.); and College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan, People's Republic of China (J.Z.)
| | - Jong-Won Kim
- Biosafety Research Institute and College of Veterinary Medicine, Jeonbuk National University, Iksan, Jeonbuk, Republic of Korea (J.Z., J.-W.K., Z.Z., J.Q., W.T., C.W.L., B.K.); Department of Pathology, Dongguk University Ilsan Hospital, Goyang, Republic of Korea (K.M.H.); and College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan, People's Republic of China (J.Z.)
| | - Zixiong Zhou
- Biosafety Research Institute and College of Veterinary Medicine, Jeonbuk National University, Iksan, Jeonbuk, Republic of Korea (J.Z., J.-W.K., Z.Z., J.Q., W.T., C.W.L., B.K.); Department of Pathology, Dongguk University Ilsan Hospital, Goyang, Republic of Korea (K.M.H.); and College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan, People's Republic of China (J.Z.)
| | - Jing Qi
- Biosafety Research Institute and College of Veterinary Medicine, Jeonbuk National University, Iksan, Jeonbuk, Republic of Korea (J.Z., J.-W.K., Z.Z., J.Q., W.T., C.W.L., B.K.); Department of Pathology, Dongguk University Ilsan Hospital, Goyang, Republic of Korea (K.M.H.); and College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan, People's Republic of China (J.Z.)
| | - Weishun Tian
- Biosafety Research Institute and College of Veterinary Medicine, Jeonbuk National University, Iksan, Jeonbuk, Republic of Korea (J.Z., J.-W.K., Z.Z., J.Q., W.T., C.W.L., B.K.); Department of Pathology, Dongguk University Ilsan Hospital, Goyang, Republic of Korea (K.M.H.); and College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan, People's Republic of China (J.Z.)
| | - Chae Woong Lim
- Biosafety Research Institute and College of Veterinary Medicine, Jeonbuk National University, Iksan, Jeonbuk, Republic of Korea (J.Z., J.-W.K., Z.Z., J.Q., W.T., C.W.L., B.K.); Department of Pathology, Dongguk University Ilsan Hospital, Goyang, Republic of Korea (K.M.H.); and College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan, People's Republic of China (J.Z.)
| | - Kang Min Han
- Biosafety Research Institute and College of Veterinary Medicine, Jeonbuk National University, Iksan, Jeonbuk, Republic of Korea (J.Z., J.-W.K., Z.Z., J.Q., W.T., C.W.L., B.K.); Department of Pathology, Dongguk University Ilsan Hospital, Goyang, Republic of Korea (K.M.H.); and College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan, People's Republic of China (J.Z.)
| | - Bumseok Kim
- Biosafety Research Institute and College of Veterinary Medicine, Jeonbuk National University, Iksan, Jeonbuk, Republic of Korea (J.Z., J.-W.K., Z.Z., J.Q., W.T., C.W.L., B.K.); Department of Pathology, Dongguk University Ilsan Hospital, Goyang, Republic of Korea (K.M.H.); and College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan, People's Republic of China (J.Z.)
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Liao Y, Yang Y, Pan D, Ding Y, Zhang H, Ye Y, Li J, Zhao L. HSP90α Mediates Sorafenib Resistance in Human Hepatocellular Carcinoma by Necroptosis Inhibition under Hypoxia. Cancers (Basel) 2021; 13:cancers13020243. [PMID: 33440739 PMCID: PMC7827218 DOI: 10.3390/cancers13020243] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 12/30/2020] [Accepted: 01/04/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Hypoxia is one of the characteristics of most solid tumors and induces cell resistant to chemotherapy. In this paper, we established a hypoxia model in both in vitro and in vivo to investigate the mechanisms of Sorafenib resistance in Hepatocellular carcinoma (HCC). Here, we observed that necroptosis could be an important target of Sorafenib in liver cancer and necroptosis blocking might be important in Sorafenib resistance under hypoxia. Mechanistically, our work suggests that HSP90α plays a pivotal role in Sorafenib-induced necroptosis by binding with necrosome. HSP90α could promote MLKL chaperone-mediated autophagy degradation in hypoxia, which subsequently decreased necroptosis. Consequently, the inhibition of necroptosis contributes to Sorafenib resistant. The Sorafenib resistance was reversed by HSP90α inhibitor-Demethoxygeldanamycin (17-AAG) in vivo and in vitro. This study highlights the important role of HSP90α in Sorafenib resistance under hypoxia microenvironment, and provides a potential therapy target for liver cancer. Abstract As one of the most common malignancies worldwide, Hepatocellular carcinoma (HCC) has been treated by Sorafenib, which is the first approved target drug by FDA for advanced HCC. However, drug resistance is one of the obstacles to its application. As a typical characteristic of most solid tumors, hypoxia has become a key cause of resistance to chemotherapy and radiotherapy. It is important to elucidate the underlying mechanisms of Sorafenib resistance under hypoxia. In this study, the morphological changes of hepatocellular carcinoma cells were observed by Live Cell Imaging System and Transmission Electron Microscope; Sorafenib was found to induce necroptosis in liver cancer. Under hypoxia, the distribution of necroptosis related proteins was changed, which contributed to Sorafenib resistance. HSP90α binds with the necrosome complex and promotes chaperone-mediated autophagy (CMA) degradation, which leads necroptosis blocking and results in Sorafenib resistance. The patient-derived tumor xenograft (PDX) model has been established to investigate the potential therapeutic strategies to overcome Sorafenib resistance. 17-AAG inhibited HSP90α and presented obvious reversal effects of Sorafenib resistance in vivo and in vitro. All the results emphasized that HSP90α plays a critical role in Sorafenib resistance under hypoxia and 17-AAG combined with Sorafenib is a promising therapy for hepatocellular carcinoma.
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Affiliation(s)
- Yan Liao
- School of Basic Medicine and Clinical Pharmacology, China Pharmaceutical University, Nanjing 211100, China; (Y.L.); (Y.Y.); (D.P.); (Y.D.); (H.Z.)
| | - Yue Yang
- School of Basic Medicine and Clinical Pharmacology, China Pharmaceutical University, Nanjing 211100, China; (Y.L.); (Y.Y.); (D.P.); (Y.D.); (H.Z.)
| | - Di Pan
- School of Basic Medicine and Clinical Pharmacology, China Pharmaceutical University, Nanjing 211100, China; (Y.L.); (Y.Y.); (D.P.); (Y.D.); (H.Z.)
| | - Youxiang Ding
- School of Basic Medicine and Clinical Pharmacology, China Pharmaceutical University, Nanjing 211100, China; (Y.L.); (Y.Y.); (D.P.); (Y.D.); (H.Z.)
| | - Heng Zhang
- School of Basic Medicine and Clinical Pharmacology, China Pharmaceutical University, Nanjing 211100, China; (Y.L.); (Y.Y.); (D.P.); (Y.D.); (H.Z.)
| | - Yuting Ye
- Pathology and PDX Efficacy Center, China Pharmaceutical University, Nanjing 211100, China; (Y.Y.); (J.L.)
| | - Jia Li
- Pathology and PDX Efficacy Center, China Pharmaceutical University, Nanjing 211100, China; (Y.Y.); (J.L.)
| | - Li Zhao
- School of Basic Medicine and Clinical Pharmacology, China Pharmaceutical University, Nanjing 211100, China; (Y.L.); (Y.Y.); (D.P.); (Y.D.); (H.Z.)
- Correspondence:
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Reza MS, Shuvo MSR, Hassan MM, Basher MA, Islam MA, Naznin NE, Jafrin S, Ahmed KS, Hossain H, Daula AFMSU. Antidiabetic and hepatoprotective potential of whole plant extract and isolated compounds of Aeginetia indica. Biomed Pharmacother 2020; 132:110942. [DOI: 10.1016/j.biopha.2020.110942] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 10/19/2020] [Accepted: 10/25/2020] [Indexed: 02/06/2023] Open
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Zhan C, Lin G, Huang Y, Wang Z, Zeng F, Wu S. A dopamine-precursor-based nanoprodrug for in-situ drug release and treatment of acute liver failure by inhibiting NLRP3 inflammasome and facilitating liver regeneration. Biomaterials 2020; 268:120573. [PMID: 33260093 DOI: 10.1016/j.biomaterials.2020.120573] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 11/18/2020] [Accepted: 11/22/2020] [Indexed: 02/06/2023]
Abstract
Acute liver failure (ALF) is a severe liver disease with high mortality rate. Inflammasome is a newly-found and promising target for effective treatment of immunity-associated diseases including liver disease, and dopamine has recently been proved as an inhibitor for NLRP3 inflammasome. This work demonstrates a diselenide-based nanodrug for ALF treatment through inhibiting NLRP3 inflammasome activation and enhancing liver regeneration. A diselenide-containing molecule (DSeSeD) has been synthesized via covalently linking two l-Dopa molecules to a diselenide linker, and the resultant molecules form stable nanoparticles in aqueous media and encapsulate SW033291 (an inhibitor of prostaglandin-degrading enzyme that hampers liver regeneration) to produce the nanodrug (SW@DSeSeD). As a nanoscale prodrug, SW@DSeSeD protects its payloads from decomposition in bloodstream upon administration, accumulates in liver of ALF mice, then responds to the overexpressed ROS and thereby releases SW033291 as well as a stable dopamine precursor that can transform into dopamine in hepatic cells, thus achieving significant therapeutic efficacy against ALF through inhibiting NLRP3 inflammasome activation and enhancing hepatic regeneration. Moreover, multiple contrast agents have been loaded onto the nanodrug to achieve fluorescence, optoacoustic and magnetic resonance imaging for nanodrug location and disease evaluation.
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Affiliation(s)
- Chenyue Zhan
- Biomedical Division, State Key Laboratory of Luminescent Materials and Devices, Guangdong Provincial Key Laboratory of Luminescence from Molecular Aggregates, College of Materials Science and Engineering, South China University of Technology, Wushan Road 381, Guangzhou, 510640, China
| | - Guifang Lin
- Biomedical Division, State Key Laboratory of Luminescent Materials and Devices, Guangdong Provincial Key Laboratory of Luminescence from Molecular Aggregates, College of Materials Science and Engineering, South China University of Technology, Wushan Road 381, Guangzhou, 510640, China
| | - Yong Huang
- Biomedical Division, State Key Laboratory of Luminescent Materials and Devices, Guangdong Provincial Key Laboratory of Luminescence from Molecular Aggregates, College of Materials Science and Engineering, South China University of Technology, Wushan Road 381, Guangzhou, 510640, China
| | - Ziqian Wang
- Biomedical Division, State Key Laboratory of Luminescent Materials and Devices, Guangdong Provincial Key Laboratory of Luminescence from Molecular Aggregates, College of Materials Science and Engineering, South China University of Technology, Wushan Road 381, Guangzhou, 510640, China
| | - Fang Zeng
- Biomedical Division, State Key Laboratory of Luminescent Materials and Devices, Guangdong Provincial Key Laboratory of Luminescence from Molecular Aggregates, College of Materials Science and Engineering, South China University of Technology, Wushan Road 381, Guangzhou, 510640, China.
| | - Shuizhu Wu
- Biomedical Division, State Key Laboratory of Luminescent Materials and Devices, Guangdong Provincial Key Laboratory of Luminescence from Molecular Aggregates, College of Materials Science and Engineering, South China University of Technology, Wushan Road 381, Guangzhou, 510640, China.
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Schneider KM, Elfers C, Ghallab A, Schneider CV, Galvez EJC, Mohs A, Gui W, Candels LS, Wirtz TH, Zuehlke S, Spiteller M, Myllys M, Roulet A, Ouzerdine A, Lelouvier B, Kilic K, Liao L, Nier A, Latz E, Bergheim I, Thaiss CA, Hengstler JG, Strowig T, Trautwein C. Intestinal Dysbiosis Amplifies Acetaminophen-Induced Acute Liver Injury. Cell Mol Gastroenterol Hepatol 2020; 11:909-933. [PMID: 33189892 PMCID: PMC7900526 DOI: 10.1016/j.jcmgh.2020.11.002] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 10/31/2020] [Accepted: 11/02/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Acute liver failure (ALF) represents an unmet medical need in Western countries. Although the link between intestinal dysbiosis and chronic liver disease is well-established, there is little evidence for a functional role of gut-liver interaction during ALF. Here we hypothesized that intestinal dysbiosis may affect ALF. METHODS To test this hypothesis, we assessed the association of proton pump inhibitor (PPI) or long-term antibiotics (ABx) intake, which have both been linked to intestinal dysbiosis, and occurrence of ALF in the 500,000 participants of the UK BioBank population-based cohort. For functional studies, male Nlrp6-/- mice were used as a dysbiotic mouse model and injected with a sublethal dose of acetaminophen (APAP) or lipopolysaccharide (LPS) to induce ALF. RESULTS Multivariate Cox regression analyses revealed a significantly increased risk (odds ratio, 2.3-3) for developing ALF in UK BioBank participants with PPI or ABx. Similarly, dysbiotic Nlrp6-/- mice displayed exacerbated APAP- and LPS-induced liver injury, which was linked to significantly reduced gut and liver tissue microbiota diversity and correlated with increased intestinal permeability at baseline. Fecal microbiota transfer (FMT) from Nlrp6-/- mice into wild-type (WT) mice augmented liver injury on APAP treatment in recipient WT mice, resembling the inflammatory phenotype of Nlrp6-/- mice. Specifically, FMT skewed monocyte polarization in WT mice toward a Ly6Chi inflammatory phenotype, suggesting a critical function of these cells as sensors of gut-derived signals orchestrating the inflammatory response. CONCLUSIONS Our data show an important yet unknown function of intestinal microbiota during ALF. Intestinal dysbiosis was transferrable to healthy WT mice via FMT and aggravated liver injury. Our study highlights intestinal microbiota as a targetable risk factor for ALF.
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Affiliation(s)
- Kai Markus Schneider
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany; Department of Microbiology; Institute for Immunology; and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Carsten Elfers
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Ahmed Ghallab
- Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany; Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt
| | | | - Eric J C Galvez
- Helmholtz Centre for Infection Research, Braunschweig, Germany; and Hannover Medical School, Hannover, Germany
| | - Antje Mohs
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Wenfang Gui
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | | | | | - Sebastian Zuehlke
- Department of Chemistry and Chemical Biology, Institute of Experimental Research (INFU), TU Dortmund University, Dortmund, Germany
| | - Michael Spiteller
- Department of Chemistry and Chemical Biology, Institute of Experimental Research (INFU), TU Dortmund University, Dortmund, Germany
| | - Maiju Myllys
- Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany
| | | | | | | | - Konrad Kilic
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Lijun Liao
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany; Department of Anesthesiology and Pain Management, Shanghai East Hospital, Tongji University, Shanghai, China
| | - Anika Nier
- Department of Nutritional Sciences, R.F. Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Eicke Latz
- Institute for Innate Immunity, University of Bonn, Bonn, Germany
| | - Ina Bergheim
- Department of Nutritional Sciences, R.F. Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Christoph A Thaiss
- Department of Microbiology; Institute for Immunology; and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Jan G Hengstler
- Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany
| | - Till Strowig
- Helmholtz Centre for Infection Research, Braunschweig, Germany; and Hannover Medical School, Hannover, Germany
| | - Christian Trautwein
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
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Shen M, Chen M, Liang T, Wang S, Xue Y, Bertz R, Xie XQ, Feng Z. Pain Chemogenomics Knowledgebase (Pain-CKB) for Systems Pharmacology Target Mapping and Physiologically Based Pharmacokinetic Modeling Investigation of Opioid Drug-Drug Interactions. ACS Chem Neurosci 2020; 11:3245-3258. [PMID: 32966035 DOI: 10.1021/acschemneuro.0c00372] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
More than 50 million adults in America suffer from chronic pain. Opioids are commonly prescribed for their effectiveness in relieving many types of pain. However, excessive prescribing of opioids can lead to abuse, addiction, and death. Non-steroidal anti-inflammatory drugs (NSAIDs), another major class of analgesic, also have many problematic side effects including headache, dizziness, vomiting, diarrhea, nausea, constipation, reduced appetite, and drowsiness. There is an urgent need for the understanding of molecular mechanisms that underlie drug abuse and addiction to aid in the design of new preventive or therapeutic agents for pain management. To facilitate pain related small-molecule signaling pathway studies and the prediction of potential therapeutic target(s) for the treatment of pain, we have constructed a comprehensive platform of a pain domain-specific chemogenomics knowledgebase (Pain-CKB) with integrated data mining computing tools. Our new computing platform describes the chemical molecules, genes, proteins, and signaling pathways involved in pain regulation. Pain-CKB is implemented with a friendly user interface for the prediction of the relevant protein targets and analysis and visualization of the outputs, including HTDocking, TargetHunter, BBB predictor, and Spider Plot. Combining these with other novel tools, we performed three case studies to systematically demonstrate how further studies can be conducted based on the data generated from Pain-CKB and its algorithms and tools. First, systems pharmacology target mapping was carried out for four FDA approved analgesics in order to identify the known target and predict off-target interactions. Subsequently, the target mapping outcomes were applied to build physiologically based pharmacokinetic (PBPK) models for acetaminophen and fentanyl to explore the drug-drug interaction (DDI) between this pair of drugs. Finally, pharmaco-analytics was conducted to explore the detailed interaction pattern of acetaminophen reactive metabolite and its hepatotoxicity target, thioredoxin reductase.
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Affiliation(s)
- Mingzhe Shen
- Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, National Center of Excellence for Computational Drug Abuse Research, Drug Discovery Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States
| | - Maozi Chen
- Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, National Center of Excellence for Computational Drug Abuse Research, Drug Discovery Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States
| | - Tianjian Liang
- Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, National Center of Excellence for Computational Drug Abuse Research, Drug Discovery Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States
| | - Siyi Wang
- Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, National Center of Excellence for Computational Drug Abuse Research, Drug Discovery Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States
| | - Ying Xue
- Department of Pharmacy and Therapeutics, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States
| | - Richard Bertz
- Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, National Center of Excellence for Computational Drug Abuse Research, Drug Discovery Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States
| | - Xiang-Qun Xie
- Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, National Center of Excellence for Computational Drug Abuse Research, Drug Discovery Institute, and Departments of Computational Biology and Structural Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States
| | - Zhiwei Feng
- Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, National Center of Excellence for Computational Drug Abuse Research, Drug Discovery Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States
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Minsart C, Rorive S, Lemmers A, Quertinmont E, Gustot T. N-acetylcysteine and glycyrrhizin combination: Benefit outcome in a murine model of acetaminophen-induced liver failure. World J Hepatol 2020; 12:596-618. [PMID: 33033567 PMCID: PMC7522565 DOI: 10.4254/wjh.v12.i9.596] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 06/29/2020] [Accepted: 08/26/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Acetaminophen overdose is the most frequent cause of drug-induced liver failure in developed countries. Substantial progress has been made in understanding the mechanism of hepatocellular injury, but N-acetylcysteine remains the only effective treatment despite its short therapeutic window. Thus, other hepatoprotective drugs are needed for the delayed treatment of acetaminophen-induced hepatotoxicity. Our interest focused on glycyrrhizin for its role as an inhibitor of high mobility group box 1 (HMGB1) protein, a member of the family of damage-associated molecular pattern, known to play an important pathological role in various diseases.
AIM To investigate the efficacy of the N-acetylcysteine/glycyrrhizin combination compared to N-acetylcysteine alone in the prevention of liver toxicity.
METHODS Eight-week-old C57BL/6J wild-type female mice were used for all our experiments. Mice fasted for 15 h were treated with acetaminophen (500 mg/kg) or vehicle (phosphate-buffered saline) by intraperitoneal injection and separated into the following groups: Glycyrrhizin (200 mg/kg); N-acetylcysteine (150 mg/kg); and N-acetylcysteine/glycyrrhizin. In all groups, mice were sacrificed 12 h following acetaminophen administration. The assessment of hepatotoxicity was performed by measuring plasma levels of alanine aminotransferase, aspartate aminotransferase and lactate dehydrogenase. Hepatotoxicity was also evaluated by histological examination of hematoxylin and eosin-stained tissues sections. Survival rates were compared between various groups using Kaplan-Meier curves.
RESULTS Consistent with data published in the literature, we confirmed that intraperitoneal administration of acetaminophen (500 mg/kg) in mice induced severe liver injury as evidenced by increases in alanine aminotransferase, aspartate aminotransferase and lactate dehydrogenase but also by liver necrosis score. Glycyrrhizin administration was shown to reduce the release of HMGB1 and significantly decreased the severity of liver injury. Thus, the co-administration of glycyrrhizin and N-acetylcysteine was investigated. Administered concomitantly with acetaminophen, the combination significantly reduced the severity of liver injury. Delayed administration of the combination of drugs, 2 h or 6 h after acetaminophen, also induced a significant decrease in hepatocyte necrosis compared to mice treated with N-acetylcysteine alone. In addition, administration of N-acetylcysteine/glycyrrhizin combination was associated with an improved survival rate compared to mice treated with only N-acetylcysteine.
CONCLUSION We demonstrate that, compared to N-acetylcysteine alone, co-administration of glycyrrhizin decreases the liver necrosis score and improves survival in a murine model of acetaminophen-induced liver injury. Our study opens a potential new therapeutic pathway in the prevention of acetaminophen hepatotoxicity.
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Affiliation(s)
- Charlotte Minsart
- Laboratory of Experimental Gastroenterology, Erasme Hospital, Université Libre de Bruxelles, Brussels 1070, Belgium
| | - Sandrine Rorive
- Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, Brussels 1070, Belgium
- DIAPATH-Center for Microscopy and Molecular Imaging, Université Libre de Bruxelles, Gosselies 6041, Belgium
| | - Arnaud Lemmers
- Laboratory of Experimental Gastroenterology, Erasme Hospital, Université Libre de Bruxelles, Brussels 1070, Belgium
- Department of Gastroenterology, Hepato Pancreatology and Digestive Oncology, Erasme Hospital, Université Libre de Bruxelles, Brussels 1070, Belgium
| | - Eric Quertinmont
- Laboratory of Experimental Gastroenterology, Erasme Hospital, Université Libre de Bruxelles, Brussels 1070, Belgium
| | - Thierry Gustot
- Laboratory of Experimental Gastroenterology, Erasme Hospital, Université Libre de Bruxelles, Brussels 1070, Belgium
- Department of Gastroenterology, Hepato Pancreatology and Digestive Oncology, Erasme Hospital, Université Libre de Bruxelles, Brussels 1070, Belgium
- Inserm Unité 1149, Centre de Recherche sur l’inflammation, Paris 75006, France
- UMR S_1149, Université Paris Diderot, Paris 75006, France
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Shabat Y, Lichtenstein Y, Ilan Y. Short-Term Cohousing of Sick with Healthy or Treated Mice Alleviates the Inflammatory Response and Liver Damage. Inflammation 2020; 44:518-525. [PMID: 32978699 DOI: 10.1007/s10753-020-01348-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 08/19/2020] [Accepted: 09/22/2020] [Indexed: 01/08/2023]
Abstract
Cohousing of sick with healthy or treated animals is based on the concept of sharing an intestinal ecosystem and coprophagy, the consumption of feces, which includes sharing of the microbiome and of active drug metabolites secreted in the feces or urine. To develop a model for short-term cohousing, enabling the study of the effect of sharing an ecosystem on inflammatory states. To determine the impact of cohousing of sick and healthy mice on the immune-mediated disorders, mice injected with concanavalin A (ConA) were cohoused with healthy or sick mice or with steroid-treated or untreated mice. To determine the effect of cohousing on acetaminophen (APAP)-induced liver damage, APAP-injected mice were cohoused with N-acetyl-cysteine (NAC)-treated or untreated mice. In the ConA-induced immune-mediated hepatitis model, cohousing of sick with healthy mice was associated with the alleviation of liver damage in sick animals. Similarly, a significant decrease in serum ALT was noted in ConA-injected mice kept in the same cage as ConA-injected mice treated with steroids. A trend for reduction in liver enzymes in APAP-injected mice was observed upon cohousing with NAC-treated animals. Cohousing of sick mice with healthy or treated mice ameliorated the immune-mediated inflammatory state induced by ConA and APAP. These models for liver damage can serve as biological systems for determining the effects of alterations in the ecosystem on the immune system.
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Affiliation(s)
- Yehudit Shabat
- Gastroenterology and Liver Units, Department of Medicine, Hebrew University-Hadassah Medical Center, Ein-Kerem, POB 1200, IL91120, Jerusalem, Israel
| | - Yoav Lichtenstein
- Gastroenterology and Liver Units, Department of Medicine, Hebrew University-Hadassah Medical Center, Ein-Kerem, POB 1200, IL91120, Jerusalem, Israel
| | - Yaron Ilan
- Gastroenterology and Liver Units, Department of Medicine, Hebrew University-Hadassah Medical Center, Ein-Kerem, POB 1200, IL91120, Jerusalem, Israel.
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Liao Y, Yang Y, Wang X, Wei M, Guo Q, Zhao L. Oroxyloside ameliorates acetaminophen-induced hepatotoxicity by inhibiting JNK related apoptosis and necroptosis. JOURNAL OF ETHNOPHARMACOLOGY 2020; 258:112917. [PMID: 32360799 DOI: 10.1016/j.jep.2020.112917] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Revised: 04/23/2020] [Accepted: 04/23/2020] [Indexed: 06/11/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Oroxyloside is a natural flavonoid isolated from Scutellaria baicalensis Georgi (Lamiaceae) which is a Chinese herb widely used for liver diseases. However, its mechanisms on protecting against drug induced liver injury has not been investigated yet. AIM OF THE STUDY To investigate the protecting effects and the primary mechanisms of oroxyloside on acetaminophen (APAP)-induced liver injury. MATERIALS AND METHODS After a 12 h fasting period with free access to water, C57BL/6 mice were injected with APAP (300 mg/kg) intragastrically (i.g.) and 1 h later with oroxyloside (100 mg/kg, i.g.). When mice sacrificed, blood samples were collected from fundus venous plexus and liver tissues were collected. In addition, cells were incubated with 10 mM APAP alone and 10 mM APAP combined with 100 μM oroxyloside for 24 h. ELISA, TUNEL assay, qRT-PCR et al. were used to assess the effect of oroxyloside on ameliorating APAP-induced hepatotoxicity in vitro and in vivo. Western bolt and immunohistochemistry were used in the signaling pathway analysis. RESULTS Oroxyloside administration significantly decreased the accumulations of CYP2E1, CYP1A2, IL-6, IL-1β, ALT and AST induced by APAP in vivo. In addition, oroxyloside inhibited the APAP-induced JNK related apoptosis by enhancing the antioxidant defenses, reversing ER-stress and keeping the mito-balance of liver cells in vivo and in vitro. Furthermore, oroxyloside protected the liver cells from necroptosis by affecting JNK pathway. CONCLUSION Oroxyloside acted as a protective agent against APAP-induced liver injury through inhibiting JNK-related apoptosis and necroptosis.
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Affiliation(s)
- Yan Liao
- School of Basic Medicine and Clinical Pharmacology, China Pharmaceutical University, Nanjing, 211100, China
| | - Yue Yang
- School of Basic Medicine and Clinical Pharmacology, China Pharmaceutical University, Nanjing, 211100, China
| | - Xiaoping Wang
- School of Basic Medicine and Clinical Pharmacology, China Pharmaceutical University, Nanjing, 211100, China
| | - Mian Wei
- School of Basic Medicine and Clinical Pharmacology, China Pharmaceutical University, Nanjing, 211100, China
| | - Qinglong Guo
- School of Basic Medicine and Clinical Pharmacology, China Pharmaceutical University, Nanjing, 211100, China
| | - Li Zhao
- School of Basic Medicine and Clinical Pharmacology, China Pharmaceutical University, Nanjing, 211100, China.
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Britza SM, Musgrave IF, Byard RW. Paracetamol (acetaminophen) hepatotoxicity increases in the presence of an added herbal compound. Leg Med (Tokyo) 2020; 47:101740. [PMID: 32634765 DOI: 10.1016/j.legalmed.2020.101740] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 06/10/2020] [Accepted: 06/20/2020] [Indexed: 02/07/2023]
Abstract
Hepatotoxicity from paracetamol/acetaminophen has occasionally been reported at lower than expected doses. As herbal preparations may interact with pharmaceutical drugs the following in vitro study was undertaken to determine whether the toxic effects of paracetamol on liver cell growth in culture would be exacerbated by the addition of psoralen, a furanocoumarin compound that is present in Psoralea corylifolia, a common Chinese herb. The following study utilising a liver carcinoma cell line (HepG2) showed that Psoralea corylifolia was significantly toxic from 0.3 mg/ml to 5 mg/ml (p < 0.05), whereas paracetamol was not toxic below 50 mM (p = 0.0026). Interactions between previously non-toxic levels of 0.1 mg/ml of Psoralea corylifolia and increasing concentrations of paracetamol (0-50 mM), however, were observed, with a significant increase in toxicity compared to paracetamol alone (30% cell death vs. 72% cell death with Psoralea corylifolia). A significant synergistic interaction was observed at 40 mM paracetamol with 0.1 mg/ml of Psoralea (p = 0.038). This study has, therefore, shown significantly increased hepatotoxicity in cell cultures exposed to paracetamol when herbal compounds containing furanocoumarins were added. Fulminant acute liver failure occurring after the ingestion of low doses of paracetamol may not, therefore, always be due to an occult idiosyncratic response to paracetamol, but instead possibly to the combined effects of paracetamol and herbal preparations. Given the widespread use of both paracetamol and herbal preparations this possibility should be considered in cases of unexplained hepatic necrosis and liver failure that present for medicolegal investigation.
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Affiliation(s)
- Susan M Britza
- Adelaide Medical School, The University of Adelaide, Adelaide 5005, South Australia, Australia
| | - Ian F Musgrave
- Adelaide Medical School, The University of Adelaide, Adelaide 5005, South Australia, Australia
| | - Roger W Byard
- Adelaide Medical School, The University of Adelaide, Adelaide 5005, South Australia, Australia; Forensic Science South Australia, Adelaide, South Australia 5000, Australia.
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