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Tiwari V, Shandily S, Albert J, Mishra V, Dikkatwar M, Singh R, Sah SK, Chand S. Insights into medication-induced liver injury: Understanding and management strategies. Toxicol Rep 2025; 14:101976. [PMID: 40125297 PMCID: PMC11928981 DOI: 10.1016/j.toxrep.2025.101976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 02/10/2025] [Accepted: 02/23/2025] [Indexed: 03/25/2025] Open
Abstract
Drug-induced liver injury (DILI) has increasingly become a major concern in Western countries since the late 1960s, with an estimated annual incidence of 13.9-19.1 cases per 100,000 people. DILI is a significant cause of acute liver failure, exhibiting a high mortality rate of 10-50 %. Its etiology includes medications, herbal products, and dietary supplements, exacerbated by pre-existing liver conditions, sonorities, pregnancy, and nutritional deficiencies. It is categorized into intrinsic and idiosyncratic reactions. Intrinsic DILI, dose-dependent and predictable, is primarily caused by substances like paracetamol, which leads to liver toxicity through direct metabolic pathways. In contrast, idiosyncratic DILI is less common, unpredictable, and affects susceptible individuals, with non-steroidal anti-inflammatory drugs, antibiotics, and cardiovascular agents frequently implicated in hospitals. Oxidative stress, mitochondrial dysfunction, bile salt export inhibition, and stress on the endoplasmic reticulum are some DILI-related pathophysiology. Diagnosis relies on biochemical tests, serological markers, radiological investigations, and liver biopsy. Management strategies emphasize the identification and cessation of the offending drugs, supportive care, and specific treatment options targeted to the culprit drugs. Management depends on the severity and nature of the injury.
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Affiliation(s)
- Vatsalya Tiwari
- Amity Institute of Pharmacy, Amity University Uttar Pradesh, Noida, India
| | - Shrishti Shandily
- Amity Institute of Pharmacy, Amity University Uttar Pradesh, Noida, India
| | - Jessielina Albert
- Amity Institute of Pharmacy, Amity University Uttar Pradesh, Noida, India
| | - Vaibhav Mishra
- Amity Institute of Pharmacy, Amity University Uttar Pradesh, Noida, India
| | - Manoj Dikkatwar
- DY Patil University School of Pharmacy, DY Patil (Deemed to be University), Nerul, Navi Mumbai, Maharashtra 400706, India
| | - Rohit Singh
- Department of Pharmaceutical Sciences, School of Health Sciences and Technology, Dr. Vishwanath Karad MIT World Peace University, Pune, Maharashtra 411038, India
| | - Sujit Kumar Sah
- Department of Pharmaceutical Sciences, School of Health Sciences and Technology, Dr. Vishwanath Karad MIT World Peace University, Pune, Maharashtra 411038, India
| | - Sharad Chand
- Department of Pharmaceutical Sciences, School of Health Sciences and Technology, Dr. Vishwanath Karad MIT World Peace University, Pune, Maharashtra 411038, India
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Lucio-Rivera Z, Sanchez G, Gorski W. Amperometric determination of NADH and dehydrogenase enzymes at a redox-active nanocomposite. Talanta 2025; 286:127434. [PMID: 39732098 DOI: 10.1016/j.talanta.2024.127434] [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: 10/26/2024] [Revised: 12/15/2024] [Accepted: 12/18/2024] [Indexed: 12/30/2024]
Abstract
Aminated carbon nanotubes, CNTNH2, were covalently modified with glutardialdehyde (GDI) and the redox dye Azure to form a new electrode material CNTNH2-GDI-Azure (CGA). The nanocomposite of CGA and polysaccharide chitosan was used for the anodic determination of NADH. Compared to conventional carbon and metal electrodes, the CGA electrode drastically lowered the overpotential for NADH oxidation (by > 0.40 V), which minimized the interferences from the matrix of real-life samples (human serum). At -0.10 and 0.00 V, the CGA detected NADH and two NADH-dependent enzymes (lactate and malate dehydrogenase, LDH and MDH) down to 0.6 μM, 1.5 U L-1, and 0.5 U L-1, respectively. The activity of enzymes was quantified in 200-μL samples of human serum by the rapid (5 min) internally calibrated electrochemical continuous enzyme assay (ICECEA) at CGA within the clinically relevant linear ranges of 1.5-30 U L-1 (R2 = 0.994) for LDH and 0.5-8.1 U L-1 (R2 = 0.996) for MDH. Another attractive feature of CGA was that it maintained a stable NADH current (∼103 %) during a continuous 10-h long oxidation of 0.10 mM NADH, which sharply contrasted with a decaying NADH current observed at conventional electrodes. The CGA is a stable material that can be used in the form of a film or renewable paste electrode for the determination of NADH and hundreds of NADH-dependent dehydrogenases as biomarkers of human diseases.
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Affiliation(s)
| | - Gisela Sanchez
- Department of Chemistry, University of Texas at San Antonio, TX, 78249, USA
| | - Waldemar Gorski
- Department of Chemistry, University of Texas at San Antonio, TX, 78249, USA.
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3
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Aubrecht J, Potter D, Sauer JM, Warner R, Johnson KJ, McGill MR, Peron K, King NMP. Serum glutamate dehydrogenase activity enables sensitive and specific diagnosis of hepatocellular injury in humans. Toxicol Sci 2025; 203:171-180. [PMID: 39504457 PMCID: PMC11775418 DOI: 10.1093/toxsci/kfae143] [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] [Indexed: 11/08/2024] Open
Abstract
Serum activities of alanine- and aspartate aminotransferases (ALT and AST) are considered the "gold standard" biomarkers of hepatocyte injury in clinical practice and drug development. However, due to the expression of ALT and AST in myocytes, the diagnosis of hepatocellular injury in patients with underlying muscle diseases, including drug-induced muscle injury, is severely limited. Thus, we proposed glutamate dehydrogenase (GLDH) as a liver-specific alternative to serum ALT and AST. In fact, our exploratory studies showed that GLDH has comparable performance to ALT for detecting hepatocyte injury without interference from concomitant muscle injury. Here, we report the results of studies confirming the reference intervals in a healthy human population and the sensitivity and specificity of GLDH for the detection of hepatocyte injury in human subjects. In human subjects, we could not perform liver biopsies due to ethical reasons; we also confirmed the relationship of GLDH and histopathologic lesions using 32 model toxicants in rats. Furthermore, we have shown that injury to tissues that are known to express appreciable levels of GLDH does not affect serum GLDH measurements, indicating excellent liver specificity of serum GLDH. Finally, we observed faster elimination of GLDH than ALT in humans, indicating that decreasing GLDH values could be considered an early sign of recovery. This study provides comprehensive evidence of excellent sensitivity and liver specificity of GLDH for diagnosis of hepatocellular injury, including evaluation of reference intervals, which is essential for the interpretation of serum GLDH in human subjects.
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Affiliation(s)
- Jiri Aubrecht
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007, United States
| | - David Potter
- Nonclinical Statistics, Pfizer R&D, Cambridge, MA 02139, United States
| | - John Michael Sauer
- Predictive Safety Testing Consortium, PSTC, Critical Path Institute, Tucson, AZ 85718, United States
| | - Roscoe Warner
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, United States
| | - Kent J Johnson
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, United States
| | - Mitchell R McGill
- Department of Environmental Health Sciences, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States
| | - Katrina Peron
- Predictive Safety Testing Consortium, PSTC, Critical Path Institute, Tucson, AZ 85718, United States
| | - Nicholas M P King
- Predictive Safety Testing Consortium, PSTC, Critical Path Institute, Tucson, AZ 85718, United States
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Khalaf F, Touma D, Pappas A, Hatim L, Wojtowicz-Piotrowski S, Jeschke MG. Decoding burn trauma: biomarkers for early diagnosis of burn-induced pathologies. Biomark Res 2024; 12:160. [PMID: 39716257 DOI: 10.1186/s40364-024-00707-5] [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: 09/22/2024] [Accepted: 12/09/2024] [Indexed: 12/25/2024] Open
Abstract
Burn injuries represent a significant global challenge due to their multifaceted nature, characterized by a complex cascade of metabolic and immune dysfunction that can result in severe complications. If not identified and managed promptly, these complications can escalate, often leading to fatal outcomes. This underscores the critical importance of timely and precise diagnosis. Fortunately, biomarkers for burn-induced pathologies and outcomes have emerged as powerful diagnostic and prognostic tools. These biomarkers enable early diagnosis and intervention, facilitate risk assessment, support patient-specific treatment, monitoring of disease progression, and therapeutic efficacy, ultimately contributing to improved patient outcomes. However, while previous studies have provided valuable biomarkers for the detection of burn-induced pathologies, many of these were constrained by the techniques and sample sizes available at the time, which can limit the generalizability of the findings. This review highlights numerous biomarkers studied in the literature to date, underscoring the need to replicate these findings in more diverse and representative populations. It also emphasizes the importance of advancing research efforts to develop more efficient, accurate, and cost-effective approaches for integrating biomarkers into clinical practice.
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Affiliation(s)
- Fadi Khalaf
- David Braley Research Institute, Hamilton, ON, Canada
- Hamilton Health Sciences, Hamilton, ON, Canada
- Department of Biochemistry, McMaster University, Hamilton, ON, Canada
| | - Daniella Touma
- David Braley Research Institute, Hamilton, ON, Canada
- Hamilton Health Sciences, Hamilton, ON, Canada
| | - Alexandra Pappas
- David Braley Research Institute, Hamilton, ON, Canada
- Hamilton Health Sciences, Hamilton, ON, Canada
| | - Lareina Hatim
- David Braley Research Institute, Hamilton, ON, Canada
- Hamilton Health Sciences, Hamilton, ON, Canada
| | - Stephanie Wojtowicz-Piotrowski
- David Braley Research Institute, Hamilton, ON, Canada
- Hamilton Health Sciences, Hamilton, ON, Canada
- Department of Surgery, McMaster University, Hamilton, ON, Canada
| | - Marc G Jeschke
- David Braley Research Institute, Hamilton, ON, Canada.
- Hamilton Health Sciences, Hamilton, ON, Canada.
- Department of Biochemistry, McMaster University, Hamilton, ON, Canada.
- Department of Surgery, McMaster University, Hamilton, ON, Canada.
- David Braley Research Institute, C5-104, 20 Copeland Ave, Hamilton, ON, L8L 2X2, Canada.
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Lin CH, Cheng CF, Chiou YS, Wang I, Kuo CY. Molecular Biological Mechanisms of Action of Chrysophanol in Hepatic Stellate Cells Activated by Hepatic B Virus X Based on Network Pharmacology. Intervirology 2024; 67:119-135. [PMID: 39647471 PMCID: PMC11623962 DOI: 10.1159/000542355] [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: 05/05/2024] [Accepted: 10/28/2024] [Indexed: 12/10/2024] Open
Abstract
INTRODUCTION Chrysophanol (Cho) is a natural anthraquinone with biological effects such as inducing ferroptosis and anticancer activity. The hepatitis B virus X protein (HBx) is essential for HBV replication. We aimed to identify the key pathways in HBx-induced hepatic stellate cell (HSC) activation and to characterize the potential mechanisms of action of Cho against liver fibrosis. METHODS HSC-T6 cells were transfected with FLAG (control group) or FLAG-HBx (HBx group), and RNA sequencing and Western blotting analysis were conducted to assess the effects of HBx and Cho on specific molecular targets and signaling pathways. RESULTS Gene ontology and pathway analyses indicated that the genes targeted by HBx participate in immunological responses, chemokine and cytokine activity, cell-substrate adhesion, extracellular matrix organization, growth factor binding, defense responses, and antigen processing and presentation. RNA-seq and Western blotting data revealed that HBx-activated HSC-T6 cells exhibited upregulated expression of mammalian target of rapamycin (mTOR), phosphorylated mTOR (p-mTOR), S6, phosphorylated S6 (p-S6), peroxisome proliferator-activated receptor (PPAR-α), phosphorylated-PPAR-α (p-PPAR-α), CYP27, α-smooth muscle actin (α-SMA), connective tissue growth factor (CTGF), and Integrin-β1, which was reversed after treatment with Cho. These results were also verified in a HBx-activated HSC-T6 and LX-2 cell model and thioacetamide-induced liver fibrosis mouse model. CONCLUSIONS Thus, our findings indicate that Cho ameliorates HBx-induced HSC activation and liver fibrosis via inhibition of the mTOR and PPARs signaling pathways, suggesting that Cho is a potential therapeutic for chronic liver inflammation-mediated diseases.
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Affiliation(s)
- Chih-Hung Lin
- Department of Internal Medicine, Cathay General Hospital, Taipei, Taiwan
- School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei, Taiwan
- Ph.D. Program in Nutrition and Food Science, Fu Jen Catholic University, New Taipei, Taiwan
| | - Ching-Feng Cheng
- Department of Paediatrics, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan
- Department of Paediatrics, School of Medicine, Tzu Chi University, Hualien, Taiwan
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Yi-Shiou Chiou
- Master’s Degree Programme in Toxicology, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Inga Wang
- Department of Rehabilitation Sciences and Technology, University of Wisconsin- Milwaukee, Milwaukee, WI, USA
| | - Chan-Yen Kuo
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan
- Department of Medical Technology, Jenteh Junior College of Medicine, Nursing and Management, Miaoli, Taiwan
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Higareda MS, Pacumio L, Ammersbach M, Beaufrère H. BLOOD AND TISSUE ENZYME ACTIVITIES IN BEARDED DRAGONS ( POGONA VITTICEPS). J Zoo Wildl Med 2024; 55:983-993. [PMID: 39699144 DOI: 10.1638/2024-0058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/17/2024] [Indexed: 12/20/2024] Open
Abstract
Bearded dragons (Pogona vitticeps) are a common reptile species kept under human care and suffer from a wide range of diseases for which plasma biochemistry is used as a first-line diagnostic test. There is limited information available regarding tissue enzyme activities and origin that could assist in interpreting the bearded dragon plasma biochemistry enzymology profile. The aim of this study was to characterize the tissue activities of seven enzymes routinely used in the reptile biochemistry panel: alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), glutamate dehydrogenase (GLDH), lactate dehydrogenase (LDH), and creatine kinase (CK) in 12 adult inland bearded dragons in 13 tissues, plasma, and red blood cells. CK activity was highest in skeletal muscle followed by cardiac muscle; ALT and AST were distributed in several tissues and were relatively non-specific for all organs, additionally hepatic fat accumulation reduced AST hepatic activity on a weight per weight basis. ALP and GGT activities were mostly high in the kidneys; LDH activity was elevated in cardiac muscle and skeletal muscle followed by liver; and GLDH had primarily high enzyme activities in liver. Low red blood cell enzyme activities suggest that hemolysis is unlikely to artifactually increase AST or LDH plasma concentrations. These results provide a stepping stone to improve the interpretation of biochemistry results in bearded dragons, especially as it compares to other reptile species.
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Affiliation(s)
- Mariana Sosa Higareda
- Department of Veterinary Medicine and Epidemiology, UC Davis School of Veterinary Medicine
| | - Lisa Pacumio
- Department of Veterinary Medicine and Epidemiology, UC Davis School of Veterinary Medicine
| | - Mélanie Ammersbach
- Department of Pathology, Microbiology, and Immunology, UC Davis School of Veterinary Medicine
| | - Hugues Beaufrère
- Department of Veterinary Medicine and Epidemiology, UC Davis School of Veterinary Medicine,
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Alanazi ST, Salama SA, Althobaiti MM, Alotaibi RA, AlAbdullatif AA, Musa A, Harisa GI. Alleviation of Copper-Induced Hepatotoxicity by Bergenin: Diminution of Oxidative Stress, Inflammation, and Apoptosis via Targeting SIRT1/FOXO3a/NF-κB Axes and p38 MAPK Signaling. Biol Trace Elem Res 2024:10.1007/s12011-024-04401-3. [PMID: 39347884 DOI: 10.1007/s12011-024-04401-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Accepted: 09/26/2024] [Indexed: 10/01/2024]
Abstract
Despite its biological importance, excess copper induces organ damage, especially to the liver. Disruption of critical signaling cascades that control redox status, inflammatory responses, and cellular apoptosis significantly contributes to the copper-induced hepatotoxicity. The present work explored the hepatoprotective ability of bergenin against the copper-induced hepatotoxicity using male Wistar rats as a mammalian model. The results revealed that bergenin suppressed the copper-evoked histopathological changes and hepatocellular necrosis as indicated by decreased activity of the liver enzymes ALT and AST in the sera of the copper-intoxicated rats. It decreased hepatic copper content and the copper-induced oxidative stress as revealed by reduced lipid peroxidation and improved activity of the antioxidant enzymes thioredoxin reductase, glutathione peroxidase, catalase, and superoxide dismutase. Bergenin downregulated the inflammatory cytokines TNF-α and IL-6, and the inflammatory cell infiltration to the liver tissues. Additionally, it inhibited the copper-induced apoptosis as indicated by significant reduction in caspase-3 activity. At the molecular level, bergenin activated the antioxidant transcription factor FOXO3a, inhibited the nuclear translocation of the inflammatory transcription factor NF-κB, and suppressed the inflammatory signaling molecules p38 MAPK and c-Fos. Interestingly, bergenin improved the expression of the anti-apoptotic protein Bcl2 and reduced the pro-apoptotic protein BAX. Bergenin markedly enhanced the expression of the histone deacetylase protein SIRT1 that regulates activity of NF-κB and FOXO3a. Collectively, these findings highlight the alleviating activity of bergenin against the copper-induced hepatotoxicity via controlling oxidative stress, inflammation, and apoptosis potentially through upregulation of SIRT1, activation of FOXO3a along with suppression of NF-κB and p38 MAPK signaling.
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Affiliation(s)
- Samyah T Alanazi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, 11433, Riyadh, Saudi Arabia
| | - Samir A Salama
- Division of Biochemistry, Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, P.O. Box 11099, 21944, Taif, Saudi Arabia.
| | - Musaad M Althobaiti
- Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, P.O. Box 11099, 21944, Taif, Saudi Arabia
| | - Rana A Alotaibi
- College of Pharmacy, Taif University, P.O. Box 11099, 21944, Taif, Saudi Arabia
| | - Ammar A AlAbdullatif
- Pharmaceutical Care Services, Ministry of the National Guard-Health Affairs, P.O. Box 4616, 31412, Dammam, Saudi Arabia
| | - Arafa Musa
- Department of Pharmacognosy, College of Pharmacy, Jouf University, 72341, Sakaka, Aljouf, Saudi Arabia
| | - Gamaleldin I Harisa
- Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, 11451, Riyadh, Saudi Arabia
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Catumbela CSG, Morales R. Elderly mice with history of acetaminophen intoxication display worsened cognitive impairment and persistent elevation of astrocyte and microglia burden. Sci Rep 2024; 14:14205. [PMID: 38902507 PMCID: PMC11190293 DOI: 10.1038/s41598-024-65185-z] [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: 03/16/2024] [Accepted: 06/18/2024] [Indexed: 06/22/2024] Open
Abstract
Acetaminophen (APAP) is a leading cause of acute liver failure. The effect of APAP metabolite's effects in the periphery are well characterized; however, associated consequences in the brain remain poorly understood. Animal studies on this subject are few and reveal that frequent APAP intake can trigger cerebral abnormalities that vary depending on the subject's age. Alarmingly, experimental efforts have yet to examine associated consequences in elderly hosts, who correspond to the highest risk of medication overload, impaired drug clearance, and cognitive deficits. Here, we interrogated the cerebral and peripheral pathology of elderly mice submitted to monthly episodes of APAP intoxication since a young adult age. We found that weeks after the final episode of recurrent APAP exposure, mice exhibited worsened non-spatial memory deficit whereas spatial memory performance was unaltered. Interestingly, one month after the period of APAP intoxication, these mice showed increased glial burden without associated drivers, namely, blood-brain barrier disruption, cholesterol accumulation, and elevation of inflammatory molecules in the brain and/or periphery. Our experimental study reveals how recurrent APAP exposure affects the cognitive performance and cellular events in elderly brains. These data suggest that APAP-containing pharmacological interventions may foreshadow the elevated risk of neuropsychiatric disorders that afflict elderly populations.
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Affiliation(s)
- Celso S G Catumbela
- Department of Neurology, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Rodrigo Morales
- Department of Neurology, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
- Centro Integrativo de Biologia y Quimica Aplicada (CIBQA), Universidad Bernardo O'Higgins, Santiago, Chile.
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Yu SM, Zheng HC, Wang SC, Rong WY, Li P, Jing J, He TT, Li JH, Ding X, Wang RL. Salivary metabolites are promising noninvasive biomarkers of drug-induced liver injury. World J Gastroenterol 2024; 30:2454-2466. [PMID: 38764769 PMCID: PMC11099387 DOI: 10.3748/wjg.v30.i18.2454] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 04/05/2024] [Accepted: 04/18/2024] [Indexed: 05/11/2024] Open
Abstract
BACKGROUND Drug-induced liver injury (DILI) is one of the most common adverse events of medication use, and its incidence is increasing. However, early detection of DILI is a crucial challenge due to a lack of biomarkers and noninvasive tests. AIM To identify salivary metabolic biomarkers of DILI for the future development of noninvasive diagnostic tools. METHODS Saliva samples from 31 DILI patients and 35 healthy controls (HCs) were subjected to untargeted metabolomics using ultrahigh-pressure liquid chromatography coupled with tandem mass spectrometry. Subsequent analyses, including partial least squares-discriminant analysis modeling, t tests and weighted metabolite coexpression network analysis (WMCNA), were conducted to identify key differentially expressed metabolites (DEMs) and metabolite sets. Furthermore, we utilized least absolute shrinkage and selection operato and random fores analyses for biomarker prediction. The use of each metabolite and metabolite set to detect DILI was evaluated with area under the receiver operating characteristic curves. RESULTS We found 247 differentially expressed salivary metabolites between the DILI group and the HC group. Using WMCNA, we identified a set of 8 DEMs closely related to liver injury for further prediction testing. Interestingly, the distinct separation of DILI patients and HCs was achieved with five metabolites, namely, 12-hydroxydodecanoic acid, 3-hydroxydecanoic acid, tetradecanedioic acid, hypoxanthine, and inosine (area under the curve: 0.733-1). CONCLUSION Salivary metabolomics revealed previously unreported metabolic alterations and diagnostic biomarkers in the saliva of DILI patients. Our study may provide a potentially feasible and noninvasive diagnostic method for DILI, but further validation is needed.
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Affiliation(s)
- Si-Miao Yu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Hao-Cheng Zheng
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Si-Ci Wang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Wen-Ya Rong
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Ping Li
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Jing Jing
- Department of Hepatology of Traditional Chinese Medicine, The Fifth Medical Center of PLA General Hospital, Beijing 100039, China
| | - Ting-Ting He
- Department of Hepatology of Traditional Chinese Medicine, The Fifth Medical Center of PLA General Hospital, Beijing 100039, China
| | - Jia-Hui Li
- The First Clinical Medical College, Henan University of Traditional Chinese Medicine, Zhengzhou 450000, Henan Province, China
| | - Xia Ding
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Rui-Lin Wang
- Department of Hepatology of Traditional Chinese Medicine, The Fifth Medical Center of PLA General Hospital, Beijing 100039, China
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Eluu SC, Obayemi JD, Salifu AA, Yiporo D, Oko AO, Aina T, Oparah JC, Ezeala CC, Etinosa PO, Ugwu CM, Esimone CO, Soboyejo WO. In-vivo studies of targeted and localized cancer drug release from microporous poly-di-methyl-siloxane (PDMS) devices for the treatment of triple negative breast cancer. Sci Rep 2024; 14:31. [PMID: 38167999 PMCID: PMC10761815 DOI: 10.1038/s41598-023-50656-6] [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: 09/22/2023] [Accepted: 12/22/2023] [Indexed: 01/05/2024] Open
Abstract
Triple-negative breast cancer (TNBC) treatment is challenging and frequently characterized by an aggressive phenotype and low prognosis in comparison to other subtypes. This paper presents fabricated implantable drug-loaded microporous poly-di-methyl-siloxane (PDMS) devices for the delivery of targeted therapeutic agents [Luteinizing Hormone-Releasing Hormone conjugated paclitaxel (PTX-LHRH) and Luteinizing Hormone-Releasing Hormone conjugated prodigiosin (PG-LHRH)] for the treatment and possible prevention of triple-negative cancer recurrence. In vitro assessment using the Alamar blue assay demonstrated a significant reduction (p < 0.05) in percentage of cell growth in a time-dependent manner in the groups treated with PG, PG-LHRH, PTX, and PTX-LHRH. Subcutaneous triple-negative xenograft breast tumors were then induced in athymic female nude mice that were four weeks old. Two weeks later, the tumors were surgically but partially removed, and the device implanted. Mice were observed for tumor regrowth and organ toxicity. The animal study revealed that there was no tumor regrowth, six weeks post-treatment, when the LHRH targeted drugs (LHRH-PTX and LHRH-PGS) were used for the treatment. The possible cytotoxic effects of the released drugs on the liver, kidney, and lung are assessed using quantitative biochemical assay from blood samples of the treatment groups. Ex vivo histopathological results from organ tissues showed that the targeted cancer drugs released from the implantable drug-loaded device did not induce any adverse effect on the liver, kidneys, or lungs, based on the results of qualitative toxicity studies. The implications of the results are discussed for the targeted and localized treatment of triple negative breast cancer.
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Affiliation(s)
- S C Eluu
- Department of Pharmaceutical Microbiology and Biotechnology, Nnamdi Azikiwe University, Ifite Awka, 420110, Anambra State, Nigeria
| | - J D Obayemi
- Department of Mechanical Engineering, Higgins Lab, Worcester Polytechnic Institute (WPI), 100 Institute Road, Worcester, MA, 01609, USA
- Department of Biomedical Engineering, Gateway Park Life Sciences and Bioengineering Centre, Worcester Polytechnic Institute, 60 Prescott Street, Worcester, MA, 01609, USA
| | - A A Salifu
- Department of Engineering, Morrissey College of Arts and Science, Boston College, Boston, USA
| | - D Yiporo
- Department of Mechanical Engineering, Ashesi University, Berekuso, Ghana
| | - A O Oko
- Department of Biology and Biotechnology, David Umahi Federal, University of Health Sciences, Uburu, Nigeria
| | - T Aina
- Department of Material Science, African University of Science and Technology, Km 10 Airport Road, Abuja, Nigeria
| | - J C Oparah
- Department of Material Science, African University of Science and Technology, Km 10 Airport Road, Abuja, Nigeria
| | - C C Ezeala
- Department of Material Science, African University of Science and Technology, Km 10 Airport Road, Abuja, Nigeria
| | - P O Etinosa
- Department of Mechanical Engineering, Higgins Lab, Worcester Polytechnic Institute (WPI), 100 Institute Road, Worcester, MA, 01609, USA
| | - C M Ugwu
- Department of Pharmaceutical Microbiology and Biotechnology, Nnamdi Azikiwe University, Ifite Awka, 420110, Anambra State, Nigeria
| | - C O Esimone
- Department of Pharmaceutical Microbiology and Biotechnology, Nnamdi Azikiwe University, Ifite Awka, 420110, Anambra State, Nigeria
| | - W O Soboyejo
- Department of Mechanical Engineering, Higgins Lab, Worcester Polytechnic Institute (WPI), 100 Institute Road, Worcester, MA, 01609, USA.
- Department of Biomedical Engineering, Gateway Park Life Sciences and Bioengineering Centre, Worcester Polytechnic Institute, 60 Prescott Street, Worcester, MA, 01609, USA.
- Department of Engineering, SUNY Polytechnic Institute, 100 Seymour Rd, Utica, NY, 13502, USA.
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11
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Wang Y, She S, Li W, Zhu J, Li X, Yang F, Dai K. Inhibition of cGAS-STING pathway by stress granules after activation of M2 macrophages by human mesenchymal stem cells against drug induced liver injury. Mol Immunol 2024; 165:42-54. [PMID: 38150981 DOI: 10.1016/j.molimm.2023.12.005] [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: 07/08/2023] [Revised: 11/05/2023] [Accepted: 12/14/2023] [Indexed: 12/29/2023]
Abstract
OBJECTIVE Cells can produce stress granules (SGs) to protect itself from damage under stress. The cGAS-STING pathway is one of the important pattern recognition pathways in the natural immune system. This study was investigated whether human mesenchymal stem cells (hMSCs) could protect the liver by inducing M2 macrophages to produce SGs during acute drug induced liver injury (DILI) induced by acetaminophen (APAP). METHODS After intragastric administration of APAP in vivo to induce DILI mice model, hMSCs were injected into the tail vein. The co-culture system of hMSCs and M2 macrophages was established in vitro. It was further use SGs inhibitor anisomicin to intervene M2 macrophages. The liver histopathology, liver function, reactive oxygen species (ROS) level, apoptosis pathway, endoplasmic reticulum stress (ERS) level, SGs markers (G3BP1/TIA-1), cGAS-STING pathway, TNF-α, IL-6, IL-1β mRNA levels in liver tissue and M2 macrophages were observed. RESULTS In vivo experiments, it showed that hMSCs could alleviate liver injury, inhibite the level of ROS, apoptosis and ERS, protect liver function in DILI mice. The mount of M2 was increased in the liver. hMSCs could also induce the production of SGs, inhibit the cGAS-STING pathway and reduce TNF-α, IL-6, IL-1β mRNA expression. The results in vitro showed that hMSCs could induce the production of SGs in macrophages, inhibit the cGAS-STING pathway, promote the secretion of IL-4 and IL-13, and reduce TNF-α, IL-6, IL-1β mRNA level in cells. In the process of IL-4 inducing M2 macrophage activation, anisomycin could inhibit the production of SGs, activate the cGAS-STING pathway, and promote the inflammatory factor TNF-α, IL-6, IL-1β mRNA expression in cells. CONCLUSIONS HMSCs had a protective effect on acute DILI in mice induced by APAP. Its mechanism might involve in activating M2 type macrophages, promoting the production of SGs, inhibiting the cGAS-STING pathway, and reducing the expression of pro-inflammatory factors in macrophages, to reduce hepatocytes damage.
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Affiliation(s)
- Yao Wang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Sha She
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Wenyuan Li
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Jiling Zhu
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Xun Li
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Fan Yang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, China.
| | - Kai Dai
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, China.
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12
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McGill MR, Curry SC. The Evolution of Circulating Biomarkers for Use in Acetaminophen/Paracetamol-Induced Liver Injury in Humans: A Scoping Review. LIVERS 2023; 3:569-596. [PMID: 38434489 PMCID: PMC10906739 DOI: 10.3390/livers3040039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/05/2024] Open
Abstract
Acetaminophen (APAP) is a widely used drug, but overdose can cause severe acute liver injury. The first reports of APAP hepatotoxicity in humans were published in 1966, shortly after the development of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) as the first biomarkers of liver injury as opposed to liver function. Thus, the field of liver injury biomarkers has evolved alongside the growth in APAP hepatotoxicity incidence. Numerous biomarkers have been proposed for use in the management of APAP overdose patients in the intervening years. Here, we comprehensively review the development of these markers from the 1960s to the present day and briefly discuss possible future directions.
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Affiliation(s)
- Mitchell R McGill
- Dept. of Environmental Health Sciences, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, AR 72212, USA
- Dept. of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72212, USA
- Dept. of Pathology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72212, USA
| | - Steven C Curry
- Division of Clinical Data Analytics and Decision Support, University of Arizona College of Medicine-Phoenix, Phoenix, AZ 85006, USA
- Department of Medical Toxicology, Banner-University Medical Center Phoenix, Phoenix, AZ 85006, USA
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13
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Chinnappan R, Mir TA, Alsalameh S, Makhzoum T, Alzhrani A, Al-Kattan K, Yaqinuddin A. Low-Cost Point-of-Care Monitoring of ALT and AST Is Promising for Faster Decision Making and Diagnosis of Acute Liver Injury. Diagnostics (Basel) 2023; 13:2967. [PMID: 37761334 PMCID: PMC10529728 DOI: 10.3390/diagnostics13182967] [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: 06/05/2023] [Revised: 06/28/2023] [Accepted: 06/30/2023] [Indexed: 09/29/2023] Open
Abstract
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are important liver enzymes in clinical settings. Their levels are known to be elevated in individuals with underlying liver diseases and those consuming hepatotoxic drugs. Serum ALT and AST levels are crucial for diagnosing and assessing liver diseases. Serum ALT is considered the most reliable and specific candidate as a disease biomarker for liver diseases. ALT and AST levels are routinely analyzed in high-risk individuals for the bioanalysis of both liver function and complications associated with drug-induced liver injury. Typically, ALT and AST require blood sampling, serum separation, and testing. Traditional methods require expensive or sophisticated equipment and trained specialists, which is often time-consuming. Therefore, developing countries have limited or no access to these methods. To address the above issues, we hypothesize that low-cost biosensing methods (paper-based assays) can be applied to the analysis of ALT and AST levels in biological fluids. The paper-based biodetection technique can semi-quantitatively measure ALT and AST from capillary finger sticks, and it will pave the way for the development of an inexpensive and rapid alternative method for the early detection and diagnosis of liver diseases. This method is expected to significantly reduce the economic burden and aid routine clinical analysis in both developed and underdeveloped countries. The development of low-cost testing platforms and their diagnostic utility will be extremely beneficial in helping millions of patients with liver disorders.
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Affiliation(s)
- Raja Chinnappan
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (S.A.); (T.M.); (A.A.); (K.A.-K.)
- Tissue/Organ Bioengineering & BioMEMS Lab, Organ Transplant Centre of Excellence, Transplant Research & Innovation Department, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Tanveer Ahmad Mir
- Tissue/Organ Bioengineering & BioMEMS Lab, Organ Transplant Centre of Excellence, Transplant Research & Innovation Department, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Suliman Alsalameh
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (S.A.); (T.M.); (A.A.); (K.A.-K.)
| | - Tariq Makhzoum
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (S.A.); (T.M.); (A.A.); (K.A.-K.)
| | - Alaa Alzhrani
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (S.A.); (T.M.); (A.A.); (K.A.-K.)
- Tissue/Organ Bioengineering & BioMEMS Lab, Organ Transplant Centre of Excellence, Transplant Research & Innovation Department, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
- Medical Laboratory Technology Department, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Khaled Al-Kattan
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (S.A.); (T.M.); (A.A.); (K.A.-K.)
| | - Ahmed Yaqinuddin
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (S.A.); (T.M.); (A.A.); (K.A.-K.)
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14
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Lin CY, Omoscharka E, Liu Y, Cheng K. Establishment of a Rat Model of Alcoholic Liver Fibrosis with Simulated Human Drinking Patterns and Low-Dose Chemical Stimulation. Biomolecules 2023; 13:1293. [PMID: 37759693 PMCID: PMC10526499 DOI: 10.3390/biom13091293] [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: 07/12/2023] [Revised: 08/16/2023] [Accepted: 08/21/2023] [Indexed: 09/29/2023] Open
Abstract
Although alcohol is a well-known causal factor associated with liver diseases, challenges remain in inducing liver fibrosis in experimental rodent models. These challenges include rodents' natural aversion to high concentrations of alcohol, rapid alcohol metabolism, the need for a prolonged duration of alcohol administration, and technical difficulties. Therefore, it is crucial to establish an experimental model that can replicate the features of alcoholic liver fibrosis. The objective of this study was to develop a feasible rat model of alcoholic liver fibrosis that emulates human drinking patterns and combines low-dose chemicals within a relatively short time frame. We successfully developed an 8-week rat model of alcoholic liver fibrosis that mimics chronic and heavy drinking patterns. Rats were fed with a control liquid diet, an alcohol liquid diet, or alcohol liquid diet combined with multiple binges via oral gavage. To accelerate the progression of alcoholic liver fibrosis, we introduced low-dose carbon tetrachloride (CCl4) through intraperitoneal injection. This model allows researchers to efficiently evaluate potential therapeutics in preclinical studies of alcoholic liver fibrosis within a reasonable time frame.
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Affiliation(s)
- Chien-Yu Lin
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, USA
| | - Evanthia Omoscharka
- Department of Pathology, University Health/Truman Medical Center, School of Medicine, University of Missouri-Kansas City, 2301 Holmes Street, Kansas City, MO 64108, USA
| | - Yanli Liu
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, USA
| | - Kun Cheng
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, USA
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15
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Scott AM, Karlsson C, Mohanty T, Hartman E, Vaara ST, Linder A, Malmström J, Malmström L. Generalized precursor prediction boosts identification rates and accuracy in mass spectrometry based proteomics. Commun Biol 2023; 6:628. [PMID: 37301900 PMCID: PMC10257694 DOI: 10.1038/s42003-023-04977-x] [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: 12/19/2022] [Accepted: 05/24/2023] [Indexed: 06/12/2023] Open
Abstract
Data independent acquisition mass spectrometry (DIA-MS) has recently emerged as an important method for the identification of blood-based biomarkers. However, the large search space required to identify novel biomarkers from the plasma proteome can introduce a high rate of false positives that compromise the accuracy of false discovery rates (FDR) using existing validation methods. We developed a generalized precursor scoring (GPS) method trained on 2.75 million precursors that can confidently control FDR while increasing the number of identified proteins in DIA-MS independent of the search space. We demonstrate how GPS can generalize to new data, increase protein identification rates, and increase the overall quantitative accuracy. Finally, we apply GPS to the identification of blood-based biomarkers and identify a panel of proteins that are highly accurate in discriminating between subphenotypes of septic acute kidney injury from undepleted plasma to showcase the utility of GPS in discovery DIA-MS proteomics.
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Affiliation(s)
- Aaron M Scott
- Division of Infection Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden.
| | - Christofer Karlsson
- Division of Infection Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden
| | - Tirthankar Mohanty
- Division of Infection Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden
| | - Erik Hartman
- Division of Infection Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden
| | - Suvi T Vaara
- Division of Anaesthesia and Intensive Care Medicine Department of Surgery, Intensive Care Units, Helsinki University Central Hospital, Box 340, 00029 HUS, Helsinki, Finland
| | - Adam Linder
- Division of Infection Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden
| | - Johan Malmström
- Division of Infection Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden
| | - Lars Malmström
- Division of Infection Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden.
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16
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Floreani A, Bizzaro D, Shalaby S, Taliani G, Burra P. Sex disparity and drug-induced liver injury. Dig Liver Dis 2023; 55:21-28. [PMID: 35843842 DOI: 10.1016/j.dld.2022.06.025] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 06/03/2022] [Accepted: 06/21/2022] [Indexed: 12/31/2022]
Abstract
Drug-induced liver injury (DILI) is a potentially serious clinical condition that remains a major problem for patients, physicians and those involved in the development of new drugs. Population and hospital-based studies have reported incidences of DILI varying from 1.4 to 19.1/100.000. Overall, females have a 1.5- to 1.7-fold greater risk of developing adverse drug reactions and the female/male ratio increases after the age of 49 years, suggesting a clear susceptibility of DILI after menopause. Sex differences in pharmacokinetics and pharmacodynamic, sex-specific hormonal effects or interaction with signalling molecules that can influence drug efficacy and safety and differences in abnormal immune response following drug exposure are the main probable causes of the higher vulnerability observed among female patients. A novel phenotype of autoimmune-mediated DILI following the use of check-point inhibitors in oncology and haematology has been recently described. Finally, there have been increasing reports of DILI associated with use of herbal and dietary supplements that is more frequently reported in women.
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Affiliation(s)
- A Floreani
- Scientific Consultant Scientific Institute for Research, Hospitalization and Healthcare, Negrar, Verona, Italy; Senior Scholar, University of Padova, Padova, Italy.
| | - D Bizzaro
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - S Shalaby
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - G Taliani
- Department of Infectious and Tropical Diseases, La Sapienza University of Rome, Rome, Italy
| | - P Burra
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
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17
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Zajkowska M, Mroczko B. Chemokines in Primary Liver Cancer. Int J Mol Sci 2022; 23:ijms23168846. [PMID: 36012108 PMCID: PMC9408270 DOI: 10.3390/ijms23168846] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 08/04/2022] [Accepted: 08/08/2022] [Indexed: 11/16/2022] Open
Abstract
The liver is responsible for extremely important functions in the human body. In the liver’s structure, we distinguish between connective tissue (stroma) and parenchyma, the latter of which is formed from the basic structural and functional units of the liver—hepatocytes. There are many factors, that negatively affect the liver cells, contributing to their damage. This may lead to fibrosis, liver failure and, in consequence, primary liver cancer, which is the sixth most commonly diagnosed malignancy and the fourth leading cause of cancer death worldwide. Chemokines are a large family of secreted proteins. Their main role is to direct the recruitment and migration of cells to sites of inflammation or injury. Some authors suggest that these proteins might play a potential role in the development of many malignancies, including primary liver cancer. The aim of this study was to evaluate and summarize the knowledge regarding liver diseases, especially primary liver cancer (HCC) and the participation of chemokines in the development of this malignancy. Chemokines involved in the initiation of this type of tumor belong mainly to the CC and CXC chemokines. Their significant role in the course of hepatocellular carcinoma proves their usefulness in detecting and monitoring the course and treatment in patients with this disease.
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Affiliation(s)
- Monika Zajkowska
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland
- Correspondence: ; Tel.: +48-686-5168; Fax: +48-686-5169
| | - Barbara Mroczko
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland
- Department of Biochemical Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland
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18
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Vazquez JH, Kennon-McGill S, Byrum SD, Mackintosh SG, Jaeschke H, Williams DK, Lee WM, Dranoff JA, McGill MR. Proteomics Indicates Lactate Dehydrogenase Is Prognostic in Acetaminophen-Induced Acute Liver Failure Patients and Reveals Altered Signaling Pathways. Toxicol Sci 2022; 187:25-34. [PMID: 35172013 PMCID: PMC9216044 DOI: 10.1093/toxsci/kfac015] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/29/2023] Open
Abstract
Better biomarkers to predict death early in acute liver failure (ALF) are needed. To that end, we obtained early (study day 1) and later (day 3) serum samples from transplant-free survivors (n = 28) and nonsurvivors (n = 30) of acetaminophen-induced ALF from the NIH-sponsored Acute Liver Failure Study Group and from control volunteers (n = 10). To identify proteins that increase early in serum during ALF, we selected individuals from this cohort for whom alanine aminotransferase was lower on day 1 than day 3, indicating a time point before peak injury (n = 10/group). We then performed untargeted proteomics on their day 1 samples. Out of 1682 quantifiable proteins, 361 were ≥ 4-fold elevated or decreased in ALF patients versus controls and 16 of those were further elevated or decreased ≥ 4-fold in nonsurvivors versus survivors, indicating potential to predict death. Interestingly, 1 of the biomarkers was lactate dehydrogenase (LDH), which is already measured in most clinical laboratories. To validate our proteomics results and to confirm the prognostic potential of LDH, we measured LDH activity in all day 1 and 3 samples from all 58 ALF patients. LDH was elevated in the nonsurvivors versus survivors on both days. In addition, it had prognostic value similar to the model for end-stage liver disease and outperformed the King's College Criteria, while a combination of model for end-stage liver disease and LDH together outperformed either alone. Finally, bioinformatics analysis of our proteomics data revealed alteration of numerous signaling pathways that may be important in liver regeneration. Overall, we conclude LDH can predict death in APAP-induced ALF.
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Affiliation(s)
- Joel H Vazquez
- Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA
| | - Stefanie Kennon-McGill
- Department of Environmental and Occupational Health, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA
| | - Stephanie D Byrum
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA
| | - Samuel G Mackintosh
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
| | - D Keith Williams
- Department of Biostatistics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA
| | - William M Lee
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Med School, Dallas, Texas 75390, USA
| | - Jonathan A Dranoff
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA
| | - Mitchell R McGill
- Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA
- Department of Environmental and Occupational Health, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA
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19
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The Relationship between Plasma Alpha-1-Antitrypsin Polymers and Lung or Liver Function in ZZ Alpha-1-Antitrypsin-Deficient Patients. Biomolecules 2022; 12:biom12030380. [PMID: 35327571 PMCID: PMC8945708 DOI: 10.3390/biom12030380] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 02/21/2022] [Accepted: 02/25/2022] [Indexed: 12/14/2022] Open
Abstract
Alpha-1-Antitrypsin (AAT) is a protein of the SERPINA1 gene. A single amino acid mutation (Lys342Glu) results in an expression of misfolded Z-AAT protein, which has a high propensity to intra- and extra-cellular polymerization. Here, we asked whether levels of circulating Z-AAT polymers are associated with the severity of lung disease, liver disease, or both. We obtained cross sectional data from the Dutch part of the Alpha1 International Registry of 52 ZZ-AAT patients who performed a pulmonary function test and donated a blood sample on the same day. From the Alpha-1 Liver Aachen Registry, we obtained a cohort of 40 ZZ-AAT patients with available data on their liver function. The levels of plasma Z-AAT polymers were determined using a LG96 monoclonal antibody-based sandwich ELISA. In a Dutch cohort, the median plasma level of Z-AAT polymers of patients diagnosed for pulmonary disease was 947.5 µg/mL (733.6−1218 µg/mL (95% CI)), which did not correlate with airflow obstruction or gas transfer value. In the Alpha-1 liver patient cohort, the median polymer level was 1245.9 µg/mL (753−2034 µg/mL (95% CI)), which correlated with plasma gamma-glutamyl transferase (GGT, rs = 0.57, p = 0.001), glutamate dehydrogenase (GLDH, rs = 0.48, p = 0.002) and triglycerides (TG, rs = 0.48, p = 0.0046). A Wilcoxon rank test showed higher Z-AAT polymer values for the liver over the lung group (p < 0.0001). These correlations support a possible link between plasma Z-AAT polymers and the liver function.
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20
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Redrawing the map to novel DILI biomarkers in circulation: Where are we, where should we go, and how can we get there? LIVERS 2021; 1:286-293. [PMID: 34966905 DOI: 10.3390/livers1040022] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Circulating biomarkers of drug-induced liver injury (DILI) have been a focus of research in hepatology over the last decade, and several novel DILI biomarkers that hold promise for certain applications have been identified. For example, glutamate dehydrogenase holds promise as a specific biomarker of liver injury in patients with concomitant muscle damage. It may also be a specific indicator of mitochondrial damage. In addition, microRNA-122 is sensitive for early detection of liver injury in acetaminophen overdose patients. However, recent events in the field of DILI biomarker research have provided us with an opportunity to step back, consider how biomarker discovery has been done thus far, and determine how to move forward in a way that will optimize the discovery process. This is important because major challenges remain in the DILI field and related areas that could be overcome in part by new biomarkers. In this short review, we briefly describe recent progress in DILI biomarker discovery and development, identify current needs, and suggest a general approach to move forward.
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21
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Anselm V, Sommersdorf C, Carrasco-Triguero M, Katavolos P, Planatscher H, Steinhilber A, Joos T, Poetz O. Matrix and Sampling Effects on Quantification of Protein Biomarkers of Drug-Induced Liver Injury. J Proteome Res 2021; 20:4985-4994. [PMID: 34554759 DOI: 10.1021/acs.jproteome.1c00478] [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: 11/30/2022]
Abstract
Macrophage colony stimulating factor 1 receptor (MCSF1R), osteopontin (OPN), high-mobility group protein B1 (HMGB1), glutamate dehydrogenase (GLDH), keratin 18 (K18), and caspase-cleaved keratin 18 (ccK18) are considered promising mechanistic biomarkers for the diagnosis of drug-induced liver injury. Here, we aim to elucidate the impact of the sample matrix and handling on the quantification of these emerging protein biomarkers. We investigated effects such as time from collection to centrifugation during serum (± gel) or EDTA plasma preparation on two assay platforms: immunoaffinity liquid chromatography mass spectrometric assays and sandwich immunoassays. Furthermore, we measured GLDH activity with an enzymatic activity assay. Matrix effects were observed particularly for HMGB1 and MCSF1R. HMGB1 levels were higher in serum than in plasma, whereas higher concentrations of MCSF1R were observed in plasma than in serum. A comparison of sample collection to centrifugation time ranging from 15 to 60 min demonstrated increasing levels of HMGB1 in serum, while MCSF1R, OPN, GLDH, and ccK18 concentrations remained stable. Additionally, there was a poor correlation in HMGB1 and ccK18 levels between serum and plasma. Considering the observed matrix effects, we recommend plasma as a matrix of choice and cross-study comparison studies to be limited to those using the same matrix.
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Affiliation(s)
| | | | | | - Paula Katavolos
- Genentech, San Francisco, California 94080, United States.,Bristol-Myers Squibb, New Brunswick, New Jersey 08901, United States (at Genentech during the conduct of this study)
| | | | | | - Thomas Joos
- SIGNATOPE GmbH, Reutlingen 72770, Germany.,NMI Natural and Medical Sciences Institute at the University of Tuebingen, Reutlingen 72770, Germany
| | - Oliver Poetz
- SIGNATOPE GmbH, Reutlingen 72770, Germany.,NMI Natural and Medical Sciences Institute at the University of Tuebingen, Reutlingen 72770, Germany
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22
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Wagner KR, Guglieri M, Ramaiah SK, Charnas L, Marraffino S, Binks M, Vaidya VS, Palmer J, Goldstein R, Muntoni F. Safety and disease monitoring biomarkers in Duchenne muscular dystrophy: results from a Phase II trial. Biomark Med 2021; 15:1389-1396. [PMID: 34533053 DOI: 10.2217/bmm-2021-0222] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: Evaluate the utility of glutamate dehydrogenase (GLDH) and cardiac troponin I as safety biomarkers, and creatine kinase and muscle injury panel as muscle health biomarkers in Duchenne muscular dystrophy. Patients & methods: Data were collected during a Phase II trial of domagrozumab. Results: GLDH was a more specific biomarker for liver injury than alanine aminotransferase. Cardiac troponin I elevations were variable and not sustained, limiting its applicability as a biomarker. Muscle injury panel biomarkers were no more informative than creatine kinase as a muscle health biomarker. Conclusion: Results support the use of GLDH as a specific biomarker for liver injury in patients with Duchenne muscular dystrophy. Clinical trial registration: ClinicalTrials.gov, NCT02310763.
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Affiliation(s)
- Kathryn R Wagner
- Center for Genetic Muscle Disorders, Kennedy Krieger Institute, Departments of Neurology & Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| | - Michaela Guglieri
- The John Walton Muscular Dystrophy Research Centre, Newcastle University & Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | | | | | | | | | | | | | | | - Francesco Muntoni
- NIHR Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health, University College London, & Great Ormond Street Hospital Trust, London, UK
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23
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Abstract
The incidence rate of drug-induced liver injury has been high with the extensive use of drugs and the development and application of new drugs. The pathogenesis of drug-induced liver injury is not fully understood, so there is no significant breakthrough in its treatment. The diagnosis of drug-induced liver injury still depends on drug history, clinical manifestations, imaging, biochemical tests, and liver biopsy. This article reviews the recent progress in the understanding of the incidence rate, classification, risk factors, and serum markers of drug-induced liver injury.
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Affiliation(s)
- Zhao-Chun Chi
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao 266011, Shandong Province, China
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24
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Olivero-Verbel J, Harkema JR, Roth RA, Ganey PE. Fenofibrate, a peroxisome proliferator-activated receptor-alpha agonist, blocks steatosis and alters the inflammatory response in a mouse model of inflammation-dioxin interaction. Chem Biol Interact 2021; 345:109521. [PMID: 34052195 DOI: 10.1016/j.cbi.2021.109521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 04/07/2021] [Accepted: 05/14/2021] [Indexed: 12/01/2022]
Abstract
2,3,7,8-Tetrachlorodibenzo-p-dioxin (dioxin; TCDD) is an environmental contaminant that elicits a variety of toxic effects, many of which are mediated through activation of the aryl hydrocarbon receptor (AhR). Interaction between AhR and the peroxisome proliferator-activated receptor-alpha (PPAR-α), which regulates fatty acid metabolism, has been suggested. Furthermore, with recognition of the prevalence of inflammatory conditions, there is current interest in the potential for inflammatory stress to modulate the response to environmental agents. The aim of this work was to assess the interaction of TCDD with hepatic inflammation modulated by fenofibrate, a PPAR-α agonist. Female, C57BL/6 mice were treated orally with vehicle or fenofibrate (250 mg/kg) for 13 days, and then were given vehicle or 30 μg/kg TCDD. Four days later, the animals received an i.p. injection of lipopolysaccharide-galactosamine (LPS-GalN) (0.05x107 EU/kg and 500 mg/kg, respectively) to incite inflammation, or saline as vehicle control. After 4 h, the mice were euthanized, and blood and liver samples were collected for analysis. Livers of animals treated with TCDD with or without LPS-GalN had increased lipid deposition, and this effect was blocked by fenofibrate. In TCDD/LPS-GalN-treated mice, fenofibrate caused an increase in plasma activity of alanine aminotransferase, a marker of hepatocellular injury. TCDD reduced LPS-GalN-induced apoptosis, an effect that was prevented by fenofibrate pretreatment. LPS-GalN induced an increase in the concentration of interleukin-6 in plasma and accumulation of neutrophils in liver. TCDD exposure enhanced the former response and inhibited the latter one. These results suggest that fenofibrate counteracts the changes in lipid metabolism induced by TCDD but increases inflammation and liver injury in this model of inflammation-TCDD interaction.
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Affiliation(s)
- Jesus Olivero-Verbel
- Department of Pharmacology and Toxicology. Michigan State University, East Lansing, MI, USA; Environmental and Computational Chemistry Group, School of Pharmaceutical Sciences, University of Cartagena, Cartagena, 130014, Colombia
| | - Jack R Harkema
- Department of Pathobiology and Diagnostic Investigation, Institute for Integrative Toxicology, Michigan State University, USA
| | - Robert A Roth
- Department of Pharmacology and Toxicology. Michigan State University, East Lansing, MI, USA
| | - Patricia E Ganey
- Department of Pharmacology and Toxicology. Michigan State University, East Lansing, MI, USA.
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25
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Yevtodiyenko A, Bazhin A, Khodakivskyi P, Godinat A, Budin G, Maric T, Pietramaggiori G, Scherer SS, Kunchulia M, Eppeldauer G, Polyakov SV, Francis KP, Bryan JN, Goun EA. Portable bioluminescent platform for in vivo monitoring of biological processes in non-transgenic animals. Nat Commun 2021; 12:2680. [PMID: 33976191 PMCID: PMC8113525 DOI: 10.1038/s41467-021-22892-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 03/29/2021] [Indexed: 12/29/2022] Open
Abstract
Bioluminescent imaging (BLI) is one of the most powerful and widely used preclinical imaging modalities. However, the current technology relies on the use of transgenic luciferase-expressing cells and animals and therefore can only be applied to a limited number of existing animal models of human disease. Here, we report the development of a “portable bioluminescent” (PBL) technology that overcomes most of the major limitations of traditional BLI. We demonstrate that the PBL method is capable of noninvasive measuring the activity of both extracellular (e.g., dipeptidyl peptidase 4) and intracellular (e.g., cytochrome P450) enzymes in vivo in non-luciferase-expressing mice. Moreover, we successfully utilize PBL technology in dogs and human cadaver, paving the way for the translation of functional BLI to the noninvasive quantification of biological processes in large animals. The PBL methodology can be easily adapted for the noninvasive monitoring of a plethora of diseases across multiple species. Bioluminescence imaging tends to rely on transgenic luciferase-expressing cells and animals. Here the authors report a portable bioluminescent system to non-invasively measure intra- and extracellular enzymes in vivo in non-transgenic animals which do not express luciferase.
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Affiliation(s)
- Aleksey Yevtodiyenko
- Institute of Chemical Sciences and Engineering (ISIC), Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland.,Department of Chemistry, University of Missouri-Columbia, Columbia, MO, USA
| | - Arkadiy Bazhin
- Institute of Chemical Sciences and Engineering (ISIC), Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland
| | - Pavlo Khodakivskyi
- Institute of Chemical Sciences and Engineering (ISIC), Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland.,Department of Chemistry, University of Missouri-Columbia, Columbia, MO, USA
| | - Aurelien Godinat
- Institute of Chemical Sciences and Engineering (ISIC), Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland
| | - Ghyslain Budin
- Institute of Chemical Sciences and Engineering (ISIC), Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland
| | - Tamara Maric
- Institute of Chemical Sciences and Engineering (ISIC), Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland
| | - Giorgio Pietramaggiori
- Plastic and Reconstructive Surgery, Global Plastic Surgery, Lausanne, Switzerland.,Department of Neurosciences, University of Padova, Padova, Italy
| | - Sandra S Scherer
- Plastic and Reconstructive Surgery, Global Plastic Surgery, Lausanne, Switzerland.,Department of Neurosciences, University of Padova, Padova, Italy
| | - Marina Kunchulia
- Institute of Cognitive Neurosciences, Free University of Tbilisi, Tbilisi, Georgia
| | - George Eppeldauer
- National Institute of Standards and Technology (NIST), Gaithersburg, MD, USA
| | - Sergey V Polyakov
- National Institute of Standards and Technology (NIST), Gaithersburg, MD, USA.,Physics Department, University of Maryland, College Park, MD, USA
| | - Kevin P Francis
- Department of Orthopaedic Surgery, David Geffen School of Medicine at UCLA, Santa Monica, CA, USA
| | - Jeffrey N Bryan
- Department of Veterinary Medicine and Surgery, University of Missouri-Columbia, Columbia, MO, USA
| | - Elena A Goun
- Institute of Chemical Sciences and Engineering (ISIC), Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland. .,Department of Chemistry, University of Missouri-Columbia, Columbia, MO, USA.
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26
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Oda S, Yokoi T. Recent progress in the use of microRNAs as biomarkers for drug-induced toxicities in contrast to traditional biomarkers: A comparative review. Drug Metab Pharmacokinet 2021; 37:100372. [PMID: 33461055 DOI: 10.1016/j.dmpk.2020.11.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 11/19/2020] [Accepted: 11/23/2020] [Indexed: 02/09/2023]
Abstract
microRNAs (miRNAs) are small non-coding RNAs with 18-25 nucleotides. They play key regulatory roles in versatile biological process including development and apoptosis, and in disease pathogenesis, for example carcinogenesis, by negatively regulating gene expression. miRNAs often exhibit characteristics suitable for biomarkers such as tissue-specific expression patterns, high stability in serum/plasma, and change in abundance in circulation immediately after toxic injury. Since the discovery of circulating miRNAs in extracellular biological fluids in 2008, there have been many reports on the use of miRNAs as biomarkers for various diseases including cancer and organ injury in humans and experimental animals. In this review article, we have summarized the utility and limitation of circulating miRNAs as safety/toxicology biomarkers for specific tissue injuries including liver, skeletal muscle, heart, retina, and pancreas, by comparing them with conventional protein biomarkers. We have also covered the discovery of miRNAs in serum/plasma and their stability, the knowledge of which is essential for understanding the kinetics of miRNA biomarkers. Since numerous studies have reported the use of these circulating miRNAs as safety biomarkers with high sensitivity and specificity, we believe that circulating miRNAs can promote pre-clinical drug development and improve the monitoring of tissue injuries in clinical pharmacotherapy.
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Affiliation(s)
- Shingo Oda
- Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
| | - Tsuyoshi Yokoi
- Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan
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27
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Ascorbic acid coadministration with artesunate–amodiaquine, up-regulated antioxidant enzymes gene expression in bone marrow cells and elicited biochemical changes in Plasmodium berghei-infected mice. SN APPLIED SCIENCES 2021. [DOI: 10.1007/s42452-020-04063-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
AbstractOne of the hallmarks of malaria infection is oxidative stress. This study was aimed at investigating the potential effects of coadministering a therapeutic dose of artesunate–amodiaquine (AS/AQ) with Vitamin C (Vit C) orally on some biochemical parameters and antioxidant enzymes gene expression in bone marrow cells of Plasmodium berghei-infected mice. Thirty male Swiss albino mice were divided into five groups of six mice each as follows: Basal control (not infected with P. berghei), Untreated (P. berghei-infected without treatment), Vit C, AS/AQ and AS/AQ + Vit C combination treated mice. Treatment was done twice daily for three consecutive days. Complete parasite clearance was observed on the second day of treatment in AS/AQ and AS/AQ + Vit C combination treated P. berghei-infected mice. Serum albumin and bilirubin levels were higher in the AS/AQ + Vit C combination treated P. berghei-infected mice compared with those treated with AS/AQ only. Artesunate–amodiaquine + Vit C combination increased superoxide dismutase activity and reduced hydrogen peroxide and malondialdehyde levels in P. berghei-infected mice when compared with the mice treated with only AS/AQ. Furthermore, AS/AQ + Vit C combination significantly up-regulated catalase and glutathione peroxidase-1 (GPx-1) mRNA expression compared with the mice treated with only AS/AQ. This is the first report linking AS/AQ to antioxidant enzyme gene expression in bone marrow cells. Our findings showed that AS/AQ and Vit C coadministration may be beneficial as it ameliorated oxidative stress and up-regulated antioxidant enzyme gene expression in P. berghei-infected mice.
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28
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Vazquez JH, Clemens MM, Allard FD, Yee EU, Kennon-McGill S, Mackintosh SG, Jaeschke H, Hambuchen MD, McGill MR. Identification of Serum Biomarkers to Distinguish Hazardous and Benign Aminotransferase Elevations. Toxicol Sci 2020; 173:244-254. [PMID: 31651977 DOI: 10.1093/toxsci/kfz222] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
The standard circulating biomarker of liver injury in both clinical settings and drug safety testing is alanine aminotransferase (ALT). However, ALT elevations sometimes lack specificity for tissue damage. To identify novel serum biomarkers with greater specificity for injury, we combined unique animal models with untargeted proteomics, followed by confirmation with immunoblotting. Using proteomics, we identified 109 proteins in serum from mice with acetaminophen (APAP)-induced liver injury that were not detectable in serum from mice with benign ALT elevations due to high-dose dexamethasone (Dex). We selected 4 (alcohol dehydrogenase 1A1 [Aldh1a1], aldehyde dehydrogenase 1 [Adh1], argininosuccinate synthetase 1 [Ass1], and adenosylhomocysteinase [Ahcy]) with high levels for further evaluation. Importantly, all 4 were specific for injury when using immunoblots to compare serum from Dex-treated mice and mice with similar lower ALT elevations due to milder models of APAP or bromobenzene-induced liver injury. Immunoblotting for ALDH1A1, ADH1, and ASS1 in serum from APAP overdose patients without liver injury and APAP overdose patients with mild liver injury revealed that these candidate biomarkers can be detected in humans with moderate liver injury as well. Interestingly, further experiments with serum from rats with bile duct ligation-induced liver disease indicated that Aldh1a1 and Adh1 are not detectable in serum in cholestasis and may therefore be specific for hepatocellular injury and possibly even drug-induced liver injury, in particular. Overall, our results strongly indicate that ALDH1A1, ADH1, and ASS1 are promising specific biomarkers for liver injury. Adoption of these biomarkers could improve preapproval drug safety assessment.
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Affiliation(s)
- Joel H Vazquez
- Department of Pharmacology and Toxicology.,Graduate Program in Interdisciplinary Biomedical Sciences
| | - Melissa M Clemens
- Department of Pharmacology and Toxicology.,Graduate Program in Interdisciplinary Biomedical Sciences
| | - Felicia D Allard
- Department of Pathology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205
| | - Eric U Yee
- Department of Pathology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205
| | - Stefanie Kennon-McGill
- Department of Environmental and Occupational Health, Fay W. Boozman College of Public Health
| | - Samuel G Mackintosh
- Department of Biochemistry, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160
| | - Michael D Hambuchen
- Department of Pharmaceutical Sciences and Research, School of Pharmacy, Marshall University, Huntington, West Virginia 25701
| | - Mitchell R McGill
- Department of Pharmacology and Toxicology.,Department of Environmental and Occupational Health, Fay W. Boozman College of Public Health
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29
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López-Riera M, Conde I, Castell JV, Jover R. A Novel MicroRNA Signature for Cholestatic Drugs in Human Hepatocytes and Its Translation into Novel Circulating Biomarkers for Drug-Induced Liver Injury Patients. Toxicol Sci 2020; 173:229-243. [PMID: 31198949 DOI: 10.1093/toxsci/kfz138] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Drug-induced liver injury (DILI) diagnosis and classification (hepatocellular, cholestatic, and mixed) relies on traditional clinical biomarkers (eg ALT and ALP), despite limitations such as extrahepatic interferences, narrow dynamic ranges, and low mechanistic value. microRNAs may be very useful for complementing traditional DILI biomarkers but most studies in this direction have considered only paracetamol poisoning. Thus the value of microRNAs (miRNAs) as biomarkers for idiosyncratic DILI has not yet been demonstrated. In this study, we first examined the effect of model cholestatic drugs on the human hepatocyte miRNome by RNAseq and RT-qPCR. Results demonstrated that chlorpromazine, cyclosporin A, and ANIT induced (miR-21-3p, -21-5p, -22-3p, -27a-5p, -1260b, -34a-5p, and -98-5p) and repressed (-122-5p, -192-5p, -30c-5p, -424-5p, and -16-5p) specific miRNAs in sandwich-cultured upcyte hepatocytes. However, no common signature was found for cholestatic drugs. Next we investigated the levels of these miRNA in human serum and found that most were also significantly altered in cholestatic/mixed DILI patients upon hospital/ambulatory admission. However, miR-122-5p, -192-5p, -34a-5p, and -22-3p demonstrated a much more significant induction in patients with hepatocellular DILI, thus revealing better specificity for hepatocellular damage. Time-course analyses demonstrated that -1260b and -146 had a very similar profile to ALP, but with wider dynamic ranges, while -16-5p and -451a showed a negative correlation. Conversely, -122-5p and -192-5p correlated with ALT but with wider dynamic ranges and faster recoveries. Finally, the 122/451a and 122/16 ratios showed excellent prediction performances in both the study [area under the receiver operating characteristic curve (AUROC) >0.93] and the validation cohort (AUROC > 0.82), and can, therefore, be postulated for the first time as circulating miRNA biomarkers for idiosyncratic DILI.
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Affiliation(s)
- Mireia López-Riera
- *Unidad Mixta en Hepatología Experimental, IIS Hospital La Fe, 46026 Valencia, Spain
| | - Isabel Conde
- *Unidad Mixta en Hepatología Experimental, IIS Hospital La Fe, 46026 Valencia, Spain.,Medicina Digestiva, Sección Hepatología, Hospital La Fe, 46026 Valencia, Spain
| | - José V Castell
- *Unidad Mixta en Hepatología Experimental, IIS Hospital La Fe, 46026 Valencia, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain.,Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain
| | - Ramiro Jover
- *Unidad Mixta en Hepatología Experimental, IIS Hospital La Fe, 46026 Valencia, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain.,Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain
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30
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Dale JM, Hood SP, Bowen O, Bright H, Cutler KL, Berry N, Almond N, Goldin R, Karayiannis P, Rose NJ. Development of hepatic pathology in GBV-B-infected red-bellied tamarins (Saguinus labiatus). J Med Virol 2020; 92:3584-3595. [PMID: 32181899 DOI: 10.1002/jmv.25769] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 03/14/2020] [Indexed: 01/08/2023]
Abstract
GB virus B (GBV-B) is a new world monkey-associated flavivirus used to model acute hepatitis C virus (HCV) infection. Critical for evaluation of antiviral or vaccine approaches is an understanding of the effect of HCV on the liver at different stages of infection. In the absence of longitudinal human tissue samples at defined time points, we have characterized changes in tamarins. As early as 2 weeks post-infection histological changes were noticeable, and these were established in all animals by 6 weeks. Despite high levels of liver-associated viral RNA, there was reversal of hepatic damage on clearance of peripheral virus though fibrosis was demonstrated in four tamarins. Notably, viral RNA burden in the liver dropped to near undetectable or background levels in all animals which underwent a second viral challenge, highlighting the efficacy of the immune response in removing foci of replication in the liver. These data add to the knowledge of GBV-B infection in New World primates which can offer attractive systems for the testing of prophylactic and therapeutic treatments and the evaluation of their utility in preventing or reversing liver pathology.
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Affiliation(s)
- Jessica M Dale
- Division of Virology, National Institute for Biological Standards and Control, Medicine and Healthcare products Regulatory Agency, Blanche Lane, South Mimms, Potters Bar, Hertfordshire, UK
| | - Simon P Hood
- Division of Virology, National Institute for Biological Standards and Control, Medicine and Healthcare products Regulatory Agency, Blanche Lane, South Mimms, Potters Bar, Hertfordshire, UK
| | - Ori Bowen
- Division of Virology, National Institute for Biological Standards and Control, Medicine and Healthcare products Regulatory Agency, Blanche Lane, South Mimms, Potters Bar, Hertfordshire, UK
| | - Helen Bright
- Internal Medicine Research Unit, Pfizer Research and Development, Sandwich, Kent, UK
| | - Keith L Cutler
- Division of Virology, National Institute for Biological Standards and Control, Medicine and Healthcare products Regulatory Agency, Blanche Lane, South Mimms, Potters Bar, Hertfordshire, UK
| | - Neil Berry
- Division of Virology, National Institute for Biological Standards and Control, Medicine and Healthcare products Regulatory Agency, Blanche Lane, South Mimms, Potters Bar, Hertfordshire, UK
| | - Neil Almond
- Division of Virology, National Institute for Biological Standards and Control, Medicine and Healthcare products Regulatory Agency, Blanche Lane, South Mimms, Potters Bar, Hertfordshire, UK
| | - Robert Goldin
- Department of Cellular Pathology, Imperial College London, St. Mary's Campus, Norfolk Place, London, UK
| | - Peter Karayiannis
- Department of Medicine, Imperial College London, St. Mary's Campus, Norfolk Place, London, UK
| | - Nicola J Rose
- Division of Virology, National Institute for Biological Standards and Control, Medicine and Healthcare products Regulatory Agency, Blanche Lane, South Mimms, Potters Bar, Hertfordshire, UK
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31
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Church RJ, Schomaker SJ, Eaddy JS, Boucher GG, Kreeger JM, Aubrecht J, Watkins PB. Glutamate dehydrogenase as a biomarker for mitotoxicity; insights from furosemide hepatotoxicity in the mouse. PLoS One 2020; 15:e0240562. [PMID: 33035276 PMCID: PMC7546462 DOI: 10.1371/journal.pone.0240562] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 09/28/2020] [Indexed: 01/04/2023] Open
Abstract
Glutamate dehydrogenase (GLDH) is a liver-specific biomarker of hepatocellular damage currently undergoing qualification as a drug development tool. Since GLDH is located within the mitochondrial matrix, it has been hypothesized that it might also be useful in assessing mitotoxicity as an initiating event during drug-induced liver injury. According to this hypothesis, hepatocyte death that does not involve primary mitochondrial injury would result in release of intact mitochondria into circulation that could be removed by high speed centrifugation and result in lower GLDH activity measured in spun serum vs un-spun serum. A single prior study in mice has provided some support for this hypothesis. We sought to repeat and extend the findings of this study. Accordingly, mice were treated with the known mitochondrial toxicant, acetaminophen (APAP), or with furosemide (FS), a toxicant believed to cause hepatocyte death through mechanisms not involving mitotoxicity as initiating event. We measured GLDH levels in fresh plasma before and after high speed centrifugation to remove intact mitochondria. We found that both APAP and FS treatments caused substantial hepatocellular necrosis that correlated with plasma alanine aminotransferase (ALT) and GLDH elevations. The plasma GLDH activity in both the APAP- and FS- treated mice was not affected by high-speed centrifugation. Interestingly, the ratio of GLDH:ALT was 5-fold lower during FS compared to APAP hepatotoxicity. Electron microscopy confirmed that both APAP- and FS-treatments had resulted in mitochondrial injury. Mitochondria within vesicles were only observed in the FS-treated mice raising the possibility that mitophagy might account for reduced release of GLDH in the FS-treated mice. Although our results show that plasma GLDH is not clinically useful for evaluating mitotoxicity, the GLDH:ALT ratio as a measure of mitophagy needs to be further studied.
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Affiliation(s)
- Rachel J. Church
- Institute for Drug Safety Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
- Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
- * E-mail:
| | | | - J. Scott Eaddy
- Institute for Drug Safety Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | | | | | - Jiri Aubrecht
- Pfizer Inc., Groton, Connecticut, United States of America
| | - Paul B. Watkins
- Institute for Drug Safety Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
- Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
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32
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Dorsaf H, Sabrine M, Houda BL, Khémais BR, Mohsen S, Olfa T. Pecan pericarp extract protects against carbon tetrachloride-induced liver injury through oxidative mechanism in rats. Toxicol Res (Camb) 2020; 9:652-660. [PMID: 33178425 PMCID: PMC7640928 DOI: 10.1093/toxres/tfaa071] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 07/22/2020] [Accepted: 08/15/2020] [Indexed: 11/12/2022] Open
Abstract
The purpose of this study was to quantify the proanthocyanidin content of pecan (Carya illinoinensis) pericarp extract (PPE) and to assess its useful impacts against carbon tetrachloride (CCl4)-induced hepatotoxicity. Rats were randomly divided into four groups: Group 1: received intraperitoneal injection of saline solution, Group 2: was injected with PPE (25 mg/kg body weight) for 10 consecutive days, Group 3: received CCl4 (0.5 ml/kg, subcutaneous injection), Group 4: was coadministred with PPE + CCl4. The CCl4 was administered every 3 days during 10 days. Results revealed the presence of a high amount of total proanthocyanidins in the PPE (81.01 ± 0.21 mg TAE.g-1DW). CCl4 injection induced significant reductions in hepatic antioxidants but increased hepatic lipid peroxidation (LPO) as well as serum injury biomarkers. However, cotreatment with PPE significantly (P < 0.05) inverted CCl4-induced increase in plasma alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase activities, respectively to 74%, 77%, 60%, and 82% compared with CCl4 group. No significant toxic effects were observed following treatment with plant extract alone. PPE cotreatment also decreased significant (P < 0.05) the hepatic malondialdehyde formation (21%) and enhanced the liver catalase activity (107%) in CCl4-intoxicated rats. The histopathological examination showed inflammatory infiltration and degenerative changes in the hepatic tissue following CCl4 injection. The hepatoprotective activity of PPE against CCl4 exposure was supported by the maintenance of structural integrity of liver histopathology. In conclusion, the current study illustrated that PPE pretreatment significantly improved all examined parameters, restored the hepatic architecture and successfully alleviates oxidative damage induced by CCl4 intoxication.
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Affiliation(s)
- Hallegue Dorsaf
- Laboratory of Integrated Physiology, Faculty of Sciences of Bizerte, University of Carthage, Jarzouna, Bizerte 7021, Tunisia
| | - Moujahed Sabrine
- Laboratory of Integrated Physiology, Faculty of Sciences of Bizerte, University of Carthage, Jarzouna, Bizerte 7021, Tunisia
| | - Ben Lamine Houda
- Laboratory of Pathologic Anatomy, Menzel Bourguiba Hospital, 5 Palestina Road, Menzel Bourguiba, Bizerte 7050, Tunisia
| | - Ben Rhouma Khémais
- Laboratory of Integrated Physiology, Faculty of Sciences of Bizerte, University of Carthage, Jarzouna, Bizerte 7021, Tunisia
| | - Sakly Mohsen
- Laboratory of Integrated Physiology, Faculty of Sciences of Bizerte, University of Carthage, Jarzouna, Bizerte 7021, Tunisia
| | - Tebourbi Olfa
- Laboratory of Integrated Physiology, Faculty of Sciences of Bizerte, University of Carthage, Jarzouna, Bizerte 7021, Tunisia
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33
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Lin N, Zhou X, Geng X, Drewell C, Hübner J, Li Z, Zhang Y, Xue M, Marx U, Li B. Repeated dose multi-drug testing using a microfluidic chip-based coculture of human liver and kidney proximal tubules equivalents. Sci Rep 2020; 10:8879. [PMID: 32483208 PMCID: PMC7264205 DOI: 10.1038/s41598-020-65817-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Accepted: 04/15/2020] [Indexed: 11/28/2022] Open
Abstract
A microfluidic multi-organ chip emulates the tissue culture microenvironment, enables interconnection of organ equivalents and overcomes interspecies differences, making this technology a promising and powerful tool for preclinical drug screening. In this study, we established a microfluidic chip-based model that enabled non-contact cocultivation of liver spheroids and renal proximal tubule barriers in a connecting media circuit over 16 days. Meanwhile, a 14-day repeated-dose systemic administration of cyclosporine A (CsA) alone or in combination with rifampicin was performed. Toxicity profiles of the two different doses of CsA on different target organs could be discriminated and that concomitant treatment with rifampicin from day6 onwards decreased the CsA concentration and attenuated the toxicity compared with that after treatment with CsA for 14 consecutive days. The latter is manifested with the changes in cytotoxicity, cell viability and apoptosis, gene expression of metabolic enzymes and transporters, and noninvasive toxicity biomarkers. The on chip coculture of the liver and the proximal tubulus equivalents showed its potential as an effective and translational tool for repeated dose multi-drug toxicity screening in the preclinical stage of drug development.
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Affiliation(s)
- Ni Lin
- Key Laboratory of Beijing for Safety Evaluation of Drugs, National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, A8 Hongda Middle Street, Beijing Economic-Technological Development Area, Beijing, 100176, P. R. China.,Department of Pharmacology, Beijing Laboratory for Biomedical Detection Technology and Instrument, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.,Beijing Institute for Drug Control, 25 Science Park Road, Changping District, Beijing, 102206, China
| | - Xiaobing Zhou
- Key Laboratory of Beijing for Safety Evaluation of Drugs, National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, A8 Hongda Middle Street, Beijing Economic-Technological Development Area, Beijing, 100176, P. R. China
| | - Xingchao Geng
- Key Laboratory of Beijing for Safety Evaluation of Drugs, National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, A8 Hongda Middle Street, Beijing Economic-Technological Development Area, Beijing, 100176, P. R. China
| | - Christopher Drewell
- Technische Universitaet Berlin, Institute of Biotechnology, Department Medical Biotechnology, Gustav-Meyer-Allee 25, 13355, Berlin, Germany
| | - Juliane Hübner
- Technische Universitaet Berlin, Institute of Biotechnology, Department Medical Biotechnology, Gustav-Meyer-Allee 25, 13355, Berlin, Germany
| | - Zuogang Li
- Key Laboratory of Beijing for Safety Evaluation of Drugs, National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, A8 Hongda Middle Street, Beijing Economic-Technological Development Area, Beijing, 100176, P. R. China
| | - Yingli Zhang
- Key Laboratory of Beijing for Safety Evaluation of Drugs, National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, A8 Hongda Middle Street, Beijing Economic-Technological Development Area, Beijing, 100176, P. R. China
| | - Ming Xue
- Department of Pharmacology, Beijing Laboratory for Biomedical Detection Technology and Instrument, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
| | - Uwe Marx
- TissUse GmbH, Oudenarder Strasse 16, 13347, Berlin, Germany.
| | - Bo Li
- National Institutes for Food and Drug Control, 31 Hua Tuo road, Daxing district, Beijing, 102629, China.
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Serum glutamate dehydrogenase activity enables early detection of liver injury in subjects with underlying muscle impairments. PLoS One 2020; 15:e0229753. [PMID: 32407333 PMCID: PMC7224523 DOI: 10.1371/journal.pone.0229753] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Accepted: 02/11/2020] [Indexed: 12/18/2022] Open
Abstract
Serum activities of alanine and aspartate aminotransferases (ALT and AST) are used as gold standard biomarkers for the diagnosis of hepatocellular injury. Since ALT and AST lack liver specificity, the diagnosis of the onset of hepatocellular injury in patients with underlying muscle impairments is severely limited. Thus, we evaluated the potential of glutamate dehydrogenase (GLDH) as a liver specific alternative biomarker of hepatocellular injury. In our study, serum GLDH in subjects with Duchene muscular dystrophy (DMD) was equivalent to serum GLDH in age matched healthy subjects, while serum ALT was increased 20-fold in DMD subjects. Furthermore, serum GLDH in 131 subjects with variety of muscle impairments was similar to serum GLDH of healthy subjects while serum ALT corelated with serum creatine kinase, a widely accepted biomarker of muscle impairment. In addition, significant elevations of ALT, AST, and CK were observed in a case of a patient with rhabdomyolysis, while serum GLDH stayed within the normal range until the onset of hypoxia-induced liver injury. In a mouse model of DMD (DMDmdx), serum GLDH but not serum ALT clearly correlated with the degree of acetaminophen-induced liver injury. Taken together, our data support the utility of serum GLDH as a liver-specific biomarker of liver injury that has a potential to improve diagnosis of hepatocellular injury in patients with underlying muscle impairments. In drug development, GLDH may have utility as a biomarker of drug induced liver injury in clinical trials of new therapies to treat muscle diseases such as DMD.
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Laurent D, Semple F, Starkey Lewis PJ, Rose E, Black HA, Coe J, Forbes SJ, Arends MJ, Dear JW, Aitman TJ. Absolute measurement of the tissue origins of cell-free DNA in the healthy state and following paracetamol overdose. BMC Med Genomics 2020; 13:60. [PMID: 32252771 PMCID: PMC7133021 DOI: 10.1186/s12920-020-0705-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Accepted: 03/17/2020] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND Despite the emergence of cell-free DNA (cfDNA) as a clinical biomarker in cancer, the tissue origins of cfDNA in healthy individuals have to date been inferred only by indirect and relative measurement methods, such as tissue-specific methylation and nucleosomal profiling. METHODS We performed the first direct, absolute measurement of the tissue origins of cfDNA, using tissue-specific knockout mouse strains, in both healthy mice and following paracetamol (APAP) overdose. We then investigated the utility of total cfDNA and the percentage of liver-specific cfDNA as clinical biomarkers in patients presenting with APAP overdose. RESULTS Analysis of cfDNA from healthy tissue-specific knockout mice showed that cfDNA originates predominantly from white and red blood cell lineages, with minor contribution from hepatocytes, and no detectable contribution from skeletal and cardiac muscle. Following APAP overdose in mice, total plasma cfDNA and the percentage fraction originating from hepatocytes increased by ~ 100 and ~ 19-fold respectively. Total cfDNA increased by an average of more than 236-fold in clinical samples from APAP overdose patients with biochemical evidence of liver injury, and 18-fold in patients without biochemically apparent liver injury. Measurement of liver-specific cfDNA, using droplet digital PCR and methylation analysis, revealed that the contribution of liver to cfDNA was increased by an average of 175-fold in APAP overdose patients with biochemically apparent liver injury compared to healthy subjects, but was not increased in overdose patients with normal liver function tests. CONCLUSIONS We present a novel method for measurement of the tissue origins of cfDNA in healthy and disease states and demonstrate the potential of cfDNA as a clinical biomarker in APAP overdose.
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Affiliation(s)
- Danny Laurent
- Centre for Genomic and Experimental Medicine, Medical Research Council Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, UK
| | - Fiona Semple
- Centre for Genomic and Experimental Medicine, Medical Research Council Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, UK
| | - Philip J. Starkey Lewis
- Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
| | - Elaine Rose
- Centre for Genomic and Experimental Medicine, Medical Research Council Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, UK
| | - Holly A. Black
- Centre for Genomic and Experimental Medicine, Medical Research Council Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, UK
| | - Jennifer Coe
- Centre for Genomic and Experimental Medicine, Medical Research Council Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, UK
| | - Stuart J. Forbes
- Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
| | - Mark J. Arends
- Division of Pathology, Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, UK
| | - James W. Dear
- Pharmacology, Toxicology and Therapeutics, Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
| | - Timothy J. Aitman
- Centre for Genomic and Experimental Medicine, Medical Research Council Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, UK
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Bailey WJ, Barnum JE, Erdos Z, LaFranco-Scheuch L, Lane P, Vlasakova K, Sistare FD, Glaab WE. A Performance Evaluation of Liver and Skeletal Muscle-Specific miRNAs in Rat Plasma to Detect Drug-Induced Injury. Toxicol Sci 2020; 168:110-125. [PMID: 30496518 DOI: 10.1093/toxsci/kfy282] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Liver and skeletal muscle-specific microRNAs (miRNAs) are currently being evaluated as novel plasma biomarkers that may out-perform or add value to the conventional liver injury biomarkers alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and to the skeletal muscle injury biomarkers AST and creatine kinase (CK). A comprehensive evaluation was conducted to assess the relative performance of these miRNAs to detect and distinguish liver from muscle tissue injury. The performance of miR-122 and miR-192 for liver and miR-1, miR-133a, miR-133b, and miR-206 for skeletal muscle was compared with 10 enzymatic or protein biomarkers across 27 compounds causing specific types of tissue injury in rat. Receiver operator characteristic analyses were performed comparing the relative sensitivity and specificity of each of the biomarkers in individual animals with histopathology observations of necrosis and/or degeneration in various organs. All of the miRNAs outperformed ALT, AST, and/or CK in studies with either liver or skeletal muscle injury and demonstrated superior specificity in organs without type-specific injury (eg, liver biomarkers assessed with compounds that cause skeletal muscle injury). When additional protein biomarkers were included, glutamate dehydrogenase, arginase I, alpha-glutathione S-transferase for liver and skeletal troponin I, myosin light chain 3, fatty acid-binding protein 3, and creatine kinase M isoform for skeletal muscle, the miRNAs demonstrated equal or superior performance to the extended panel. Taken together, this comprehensive evaluation demonstrates that these novel miRNA toxicity biomarkers outperform and add value with respect to sensitivity and specificity over ALT, AST in monitoring the liver and over CK for monitoring skeletal muscle drug-induced injury.
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Affiliation(s)
- Wendy J Bailey
- Safety Assessment and Laboratory Animal Resources, Merck & Co., Inc., West Point, Pennsylvania 19486
| | - John E Barnum
- Safety Assessment and Laboratory Animal Resources, Merck & Co., Inc., West Point, Pennsylvania 19486
| | - Zoltan Erdos
- Safety Assessment and Laboratory Animal Resources, Merck & Co., Inc., West Point, Pennsylvania 19486
| | - Lisa LaFranco-Scheuch
- Safety Assessment and Laboratory Animal Resources, Merck & Co., Inc., West Point, Pennsylvania 19486
| | - Pamela Lane
- Safety Assessment and Laboratory Animal Resources, Merck & Co., Inc., West Point, Pennsylvania 19486
| | - Katerina Vlasakova
- Safety Assessment and Laboratory Animal Resources, Merck & Co., Inc., West Point, Pennsylvania 19486
| | - Frank D Sistare
- Safety Assessment and Laboratory Animal Resources, Merck & Co., Inc., West Point, Pennsylvania 19486
| | - Warren E Glaab
- Safety Assessment and Laboratory Animal Resources, Merck & Co., Inc., West Point, Pennsylvania 19486
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Abouelghar GE, El-Bermawy ZA, Salman HMS. Oxidative stress, hematological and biochemical alterations induced by sub-acute exposure to fipronil (COACH ®) in albino mice and ameliorative effect of selenium plus vitamin E. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2020; 27:7886-7900. [PMID: 31889272 DOI: 10.1007/s11356-019-06579-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Accepted: 09/23/2019] [Indexed: 06/10/2023]
Abstract
Fipronil (FIP) is a highly effective, broad-use insecticide that belongs to the phenylpyrazole chemical group. It is extensively used in the agriculture and veterinary medicine for controlling a wide variety of pests. Though FIP showed lower toxicity in vertebrates than in insects, it was recognized to have a variety of toxic effects in mammals. The present study was undertaken to evaluate FIP-induced alterations in the blood biochemical markers and oxidative stress parameters in male albino mice via oral sub-acute toxicity exposure. The possible ameliorative effect of the pretreatment with selenium plus α-tocopherol (vitamin E) against the harmful effects of FIP was also investigated. Mice in FIP-test groups were exposed to different sublethal doses, i.e., 1.43, 2.87, and 4.78 mg active ingredient (AI)/kg body weight (b.w.), equal to 1/100, 1/50, and 1/30 LD50 of FIP, respectively, for 28 days. Mice in the amelioration groups were orally administered with selenium + vitamin E (0.3 mg + 22.5 mg/kg b.w., respectively) 14 days prior to exposure to the higher dose (4.78 mg/kg) of FIP for another 14 days. Fipronil exposure at medium and high doses showed lowered values of red blood cell count (RBC), hematocrit (HCT), hemoglobin (HGB), white blood cell (WBC), and platelet (PLT) counts after 28-day exposure, compared to the control. All three doses caused significant increases in levels of liver-function biomarkers, i.e., aspartate amino transaminase (AST), alanine amino transaminase (ALT), alkaline phosphatase (ALP), cholesterol, and bilirubin levels compared to the control. Levels of biomarkers related to kidney functions, i.e., urea, uric acid, and creatinine, increased significantly than these of the control. Likewise, the oxidative stress indices, i.e., hydrogen peroxide (H2O2) and malondialdehyde (MDA), significantly increased at the higher and medium doses, while antioxidant enzymes, catalase (CAT) and superoxide dismutase (SOD), decreased significantly. On the other hand, prior administration of selenium + vitamin E in the FIP-exposed mice led to restore values of most hematological parameters nearly to these of the control. Also, the levels of AST, total protein, and creatinine seemed to be restored to the control values. Interestingly, pretreatment with selenium + vitamin E restored the levels of antioxidant enzymes, CAT and SOD, to the control values, whereas, oxidative stress indices, H2O2 and MDA, remained significantly high. It is our thought that the sublethal dose less than 1.43 mg/kg b.w. of commercial formulation of FIP (COACH® 200 SC) could be considered as no-observed-adverse-effect-level(NOAEL) under our present experimental conditions at short-term toxicity study. On the other hand, the higher sublethal doses, 4.78 and 2.87 mg/kg b.w., induced significant adverse effects in biomarkers and may be deleterious to human health following long-term exposure.
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Affiliation(s)
- Gamal E Abouelghar
- Department of Pesticides, Faculty of Agriculture, Menoufia University, Shebin Elkom, MNF, 32511, Egypt.
| | - Zeinab A El-Bermawy
- Department of Pesticides, Faculty of Agriculture, Menoufia University, Shebin Elkom, MNF, 32511, Egypt
| | - Hagar M S Salman
- Department of Pesticides, Faculty of Agriculture, Menoufia University, Shebin Elkom, MNF, 32511, Egypt
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Roth SE, Avigan MI, Bourdet D, Brott D, Church R, Dash A, Keller D, Sherratt P, Watkins PB, Westcott‐Baker L, Lentini S, Merz M, Ramaiah L, Ramaiah SK, Stanley AM, Marcinak J. Next-Generation DILI Biomarkers: Prioritization of Biomarkers for Qualification and Best Practices for Biospecimen Collection in Drug Development. Clin Pharmacol Ther 2020; 107:333-346. [PMID: 31314926 PMCID: PMC7006882 DOI: 10.1002/cpt.1571] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Accepted: 06/12/2019] [Indexed: 12/14/2022]
Abstract
The diagnosis and management of drug-induced liver injury (DILI) remains a challenge in clinical trials in drug development. The qualification of emerging biomarkers capable of predicting DILI soon after the initiation of treatment, differentiating DILI from underlying liver disease, identifying the causal entity, and assigning appropriate treatment options after DILI is diagnosed are needed. Qualification efforts have been hindered by lack of properly stored and consented biospecimens that are linked to clinical data relevant to a specific context of use. Recommendations are made for biospecimen collection procedures, with the focus on clinical trials, and for specific emerging biomarkers to focus qualification efforts.
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Affiliation(s)
| | | | - David Bourdet
- Theravance BiopharmaSouth San FranciscoCaliforniaUSA
| | | | - Rachel Church
- Department of Pharmacotherapy and Experimental TherapeuticsEshelman School of PharmacyUniversity of North CarolinaChapel HillNorth CarolinaUSA
| | - Ajit Dash
- GenentechSouth San FranciscoCaliforniaUSA
| | | | | | - Paul B. Watkins
- Department of Pharmacotherapy and Experimental TherapeuticsEshelman School of PharmacyUniversity of North CarolinaChapel HillNorth CarolinaUSA
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Fu S, Wu D, Jiang W, Li J, Long J, Jia C, Zhou T. Molecular Biomarkers in Drug-Induced Liver Injury: Challenges and Future Perspectives. Front Pharmacol 2020; 10:1667. [PMID: 32082163 PMCID: PMC7002317 DOI: 10.3389/fphar.2019.01667] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2019] [Accepted: 12/20/2019] [Indexed: 02/05/2023] Open
Abstract
Drug-induced liver injury (DILI) is one among the common adverse drug reactions and the leading causes of drug development attritions, black box warnings, and post-marketing withdrawals. Despite having relatively low clinical incidence, its potentially severe adverse events should be considered in the individual patients due to the high risk of acute liver failure. Although traditional liver parameters have been applied to the diagnosis of DILI, the lack of specific and sensitive biomarkers poses a major limitation, and thus accurate prediction of the subsequent clinical course remains a significant challenge. These drawbacks prompt the investigation and discovery of more effective biomarkers, which could lead to early detection of DILI, and improve its diagnosis and prognosis. Novel promising biomarkers include glutamate dehydrogenase, keratin 18, sorbitol dehydrogenase, glutathione S-transferase, bile acids, cytochrome P450, osteopontin, high mobility group box-1 protein, fatty acid binding protein 1, cadherin 5, miR-122, genetic testing, and omics technologies, among others. Furthermore, several clinical scoring systems have gradually emerged for the diagnosis of DILI including the Roussel Uclaf Causality Assessment Method (RUCAM), Clinical Diagnostic Scale (CDS), and Digestive Disease Week Japan (DDW-J) systems. However, currently their predictive value is limited with certain inherent deficiencies. Thus, perhaps the greatest benefit would be achieved by simultaneously combining the scoring systems and those biomarkers. Herein, we summarized the recent research progress on molecular biomarkers for DILI to improved approaches for its diagnosis and clinical management.
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Affiliation(s)
- Siyu Fu
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Dongbo Wu
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Wei Jiang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Juan Li
- Department of Infectious Diseases, Pidu District People's Hospital, Chengdu, China
| | - Jiang Long
- The Mental Health Center and the Psychiatric Laboratory, West China Hospital, Sichuan University, Chengdu, China
| | - Chengyao Jia
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Taoyou Zhou
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
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40
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Meunier L, Larrey D. Drug-Induced Liver Injury: Biomarkers, Requirements, Candidates, and Validation. Front Pharmacol 2019; 10:1482. [PMID: 31920666 PMCID: PMC6917655 DOI: 10.3389/fphar.2019.01482] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 11/15/2019] [Indexed: 12/12/2022] Open
Abstract
The hepatotoxicity of drugs is the main cause of drug withdrawal from the pharmaceutical market and interruption of the development of new molecules. Biomarkers are useful in several situations. In case of suspected drug-induced liver injury (DILI), biomarkers can be used to confirm liver damage, its severity, prognosis, confirm drug causality, or define the type of DILI. In this review, we will first present the currently used biomarkers and candidate biomarkers for the future. The current biomarkers are certainly very helpful including with the assistance of diagnostic method such the Roussel Uclaf Causality Assessment Method, but provide a limited information for the early detection of liver injury, the role of specific drug and the prediction of DILI. Some biomarkers are promising but they are not yet available for routine use. Studies are still needed to confirm their interest, particularly in comparison to Roussel Uclaf Causality Assessment Method.
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Affiliation(s)
| | - Dominique Larrey
- Liver and Transplantation Unit, Montpellier School of Medicine and IRB-INSERM-1183, Montpellier, France
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Danjuma MIM, Sajid J, Fatima H, Elzouki AN. Novel biomarkers for potential risk stratification of drug induced liver injury (DILI): A narrative perspective on current trends. Medicine (Baltimore) 2019; 98:e18322. [PMID: 31852121 PMCID: PMC6922486 DOI: 10.1097/md.0000000000018322] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 10/19/2019] [Accepted: 11/06/2019] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Drug induced liver injury (DILI) is an increasing cause of acute liver injury especially with increasing need for pharmacotherapy of widening comorbidities amongst our ever-aging population. Uncertainty however remains regarding both acceptable and widely agreeable diagnostic algorithms as well a clear understanding of mechanistic insights that most accurately underpins it. In this review, we have explored the potential role of emerging novel markers of DILI and how they could possibly be integrated into clinical care of patients. METHODS We explored PUBMED and all other relevant databases for scientific studies that explored potential utility of novel biomarkers of DILI, and subsequently carried out a narrative synthesis of this data. As this is a narrative review with no recourse to patient identifiable information, no ethics committee's approval was sought or required. RESULTS Novel biomarkers such as microRNA-122 (miR-122) profiles, high mobility group box-1 (HMGB1), glutamate dehydrogenase (GLDH), and cytokeratin-18 (K-18), amongst others do have the potential for reducing diagnostic uncertainties associated with DILI. CONCLUSION With the increasing validation of some of the novel liver biomarkers such as K-18, mir-122, HMGB-1, and GLDH, there is the potential for improvement in the diagnostic uncertainty commonly associated with cases of DILI.
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Affiliation(s)
| | - Jamal Sajid
- Hamad General Hospital, Hamad Medical Corporation (HMC)
| | - Haajra Fatima
- Internal Medicine Residency Program, Hamad Medical Corporation
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Zai JA, Khan MR, Mughal ZUN, Batool R, Naz I, Maryam S, Zahra Z. Methanol extract of Iphiona aucheri ameliorates CCl 4 induced hepatic injuries by regulation of genes in rats. Toxicol Res (Camb) 2019; 8:815-832. [PMID: 34055308 PMCID: PMC8142630 DOI: 10.1039/c9tx00157c] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 10/18/2019] [Indexed: 12/13/2022] Open
Abstract
We have investigated the protective potential of methanol extract of Iphiona aucheri (IAM) on the expression of endoplasmic reticulum (ER) stress associated genes and inflammatory genes on carbon tetrachloride (CCl4) induced hepatic toxicity in rats. Hepatic damage markers: aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and bilirubin were elevated while the content of antioxidants: catalase (CAT), superoxide dismutase (SOD), peroxidase (POD) and reduced glutathione (GSH) were decreased significantly (p < 0.05) in CCl4 treated rats as compared to the control group. The CCl4 intoxication induced a higher expression of glucose-regulated protein 78 kDa (GRP78), X-box-binding protein 1 total (XBP1t), spliced X-box-binding protein 1 (XBP1s), unspliced X-box-binding protein 1 (XBP1u), C/EBP homologous protein (CHOP) and genes involved in inflammation and fibrosis: tumor necrosis factor alpha (TNF-α), transforming growth factor-beta (TGF-β), mothers against DPP homolog 3 (SMAD3), alpha skeletal muscle actin (αSMA) and collagen type I alpha 1 chain (COL1A1). The intoxicated rats showed a low expression of the glutamate-cysteine ligase catalytic subunit (GCLC), protein disulfide isomerase (PDI) and nuclear factor (erythroid-derived 2) like-2 (Nrf2). The administration of IAM to intoxicated rats restored the expression of ER stress, inflammatory, fibrosis and antioxidant genes in a dose dependent manner. Our results indicated that IAM can impede the ER stress and inflammatory genes and it could be a complementary and alternative therapeutic agent for oxidative stress associated disorders.
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Affiliation(s)
- Jawaid Ahmed Zai
- Department of Biochemistry , Faculty of Biological Sciences , Quaid-i-azam University Islamabad , Islamabad , Pakistan . ; ; ; ; ; ;
| | - Muhammad Rashid Khan
- Department of Biochemistry , Faculty of Biological Sciences , Quaid-i-azam University Islamabad , Islamabad , Pakistan . ; ; ; ; ; ;
| | - Zaib Un Nisa Mughal
- Department of Biochemistry , Faculty of Biological Sciences , Quaid-i-azam University Islamabad , Islamabad , Pakistan . ; ; ; ; ; ;
| | - Riffat Batool
- Department of Biochemistry , Faculty of Biological Sciences , Quaid-i-azam University Islamabad , Islamabad , Pakistan . ; ; ; ; ; ;
| | - Irum Naz
- Department of Biochemistry , Faculty of Biological Sciences , Quaid-i-azam University Islamabad , Islamabad , Pakistan . ; ; ; ; ; ;
| | - Sonia Maryam
- Department of Biochemistry , Faculty of Biological Sciences , Quaid-i-azam University Islamabad , Islamabad , Pakistan . ; ; ; ; ; ;
| | - Zartash Zahra
- Department of Biochemistry , Faculty of Biological Sciences , Quaid-i-azam University Islamabad , Islamabad , Pakistan . ; ; ; ; ; ;
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Battista C, Yang K, Stahl SH, Mettetal JT, Watkins PB, Siler SQ, Howell BA. Using Quantitative Systems Toxicology to Investigate Observed Species Differences in CKA-Mediated Hepatotoxicity. Toxicol Sci 2019; 166:123-130. [PMID: 30060248 PMCID: PMC6204762 DOI: 10.1093/toxsci/kfy191] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
CKA, a chemokine receptor antagonist intended for treating inflammatory conditions, produced dose-dependent hepatotoxicity in rats but advanced into the clinic where single doses of CKA up to 600 mg appeared safe in humans. Because existing toxicological platforms used during drug development are not perfectly predictive, a quantitative systems toxicology model investigated the hepatotoxic potential of CKA in humans and rats through in vitro assessments of CKA on mitochondrial respiration, oxidative stress, and bile acid transporters. DILIsym predicted that single doses of CKA caused serum ALT >3xULN in a subset of the simulated rat population, while single doses in a simulated human population did not produce serum ALT elevations. Species differences were largely attributed to differences in liver exposure, but increased sensitivity to inhibition of mitochondrial respiration in the rat also contributed. We conclude that mechanistic modeling can elucidate species differences in the hepatotoxic potential of drug candidates.
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Affiliation(s)
- Christina Battista
- DILIsym Services, Inc., Research Triangle Park, North Carolina.,Division of Pharmacotherapy and Experimental Therapeutics, UNC Institute for Drug Safety Sciences, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Kyunghee Yang
- DILIsym Services, Inc., Research Triangle Park, North Carolina
| | - Simone H Stahl
- Safety and ADME Translational Sciences, Drug Safety and Metabolism, IMED Biotech Unit, Astra Zeneca R&D, Cambridge CB4 0WG, UK
| | - Jerome T Mettetal
- Safety and ADME Translational Sciences, Drug Safety and Metabolism, IMED Biotech Unit, Astra Zeneca R&D, Waltham, Massachusetts
| | - Paul B Watkins
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Institute for Drug Safety Sciences, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Scott Q Siler
- DILIsym Services, Inc., Research Triangle Park, North Carolina
| | - Brett A Howell
- DILIsym Services, Inc., Research Triangle Park, North Carolina.,DILIsym Services, Inc., Six Davis Drive, PO BOX 12317, Research Triangle Park, NC 27709
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Tajima S, Yamamoto N, Masuda S. Clinical prospects of biomarkers for the early detection and/or prediction of organ injury associated with pharmacotherapy. Biochem Pharmacol 2019; 170:113664. [PMID: 31606409 DOI: 10.1016/j.bcp.2019.113664] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Accepted: 10/08/2019] [Indexed: 12/31/2022]
Abstract
Several biomarkers are used to monitor organ damage caused by drug toxicity. Traditional markers of kidney function, such as serum creatinine and blood urea nitrogen are commonly used to estimate glomerular filtration rate. However, these markers have several limitations including poor specificity and sensitivity. A number of serum and urine biomarkers have recently been described to detect kidney damage caused by drugs such as cisplatin, gentamicin, vancomycin, and tacrolimus. Neutrophil gelatinase-associated lipocalin (NGAL), liver-type fatty acid-binding protein (L-FABP), kidney injury molecule-1 (KIM-1), monocyte chemotactic protein-1 (MCP-1), and cystatin C have been identified as biomarkers for early kidney damage. Hy's Law is widely used as to predict a high risk of severe drug-induced liver injury caused by drugs such as acetaminophen. Recent reports have indicated that glutamate dehydrogenase (GLDH), high-mobility group box 1 (HMGB-1), Keratin-18 (k18), MicroRNA-122 and ornithine carbamoyltransferase (OCT) are more sensitive markers of hepatotoxicity compared to the traditional markers including the blood levels of amiotransferases and total bilirubin. Additionally, the rapid development of proteomic technologies in biofluids and tissue provides a new multi-marker panel, leading to the discovery of more sensitive biomarkers. In this review, an update topics of biomarkers for the detection of kidney or liver injury associated with pharmacotherapy.
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Affiliation(s)
- Soichiro Tajima
- Department of Pharmacy, Kyushu University Hospital, Fukuoka 812-8582, Japan
| | - Nanae Yamamoto
- Department of Pharmacy, Kyushu University Hospital, Fukuoka 812-8582, Japan
| | - Satohiro Masuda
- Department of Pharmacy, Kyushu University Hospital, Fukuoka 812-8582, Japan; Department of Clinical Pharmacology and Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Department of Pharmacy, International University of Health and Welfare Narita Hospital, Japan; Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, International University of Health and Welfare Narita Hospital, Japan.
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Popović D, Kocić G, Katić V, Zarubica A, Janković Veličković L, Ničković VP, Jović A, Veljković A, Petrović V, Rakić V, Jović Z, Poklar Ulrih N, Sokolović D, Stojanović M, Stanković M, Radenković G, Nikolić GR, Lukač А, Milosavljević A, Sokolović D. Anthocyanins Protect Hepatocytes against CCl 4-Induced Acute Liver Injury in Rats by Inhibiting Pro-inflammatory mediators, Polyamine Catabolism, Lipocalin-2, and Excessive Proliferation of Kupffer Cells. Antioxidants (Basel) 2019; 8:antiox8100451. [PMID: 31590249 PMCID: PMC6826396 DOI: 10.3390/antiox8100451] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 08/29/2019] [Accepted: 08/31/2019] [Indexed: 12/31/2022] Open
Abstract
: This study examined the hepatoprotective and anti-inflammatory effects of anthocyanins from Vaccinim myrtillus (bilberry) fruit extract on the acute liver failure caused by carbon tetrachloride-CCl4 (3 mL/kg, i.p.). The preventive treatment of the bilberry extract (200 mg anthocyanins/kg, orally, 7 days) prior to the exposure to the CCl4 resulted in an evident decrease in markers of liver damage (glutamate dehydrogenase, sorbitol dehydrogenase, malate dehydrogenase), and reduced pro-oxidative (conjugated dienes, lipid hydroperoxide, thiobarbituric acid reactive substances, advanced oxidation protein products, NADPH oxidase, hydrogen peroxide, oxidized glutathione), and pro-inflammatory markers (tumor necrosis factor-alpha, interleukin-6, nitrite, myeloperoxidase, inducible nitric oxide synthase, cyclooxygenase-2, CD68, lipocalin-2), and also caused a significant decrease in the dissipation of the liver antioxidative defence capacities (reduced glutathione, glutathione S-transferase, and quinone reductase) in comparison to the results detected in the animals treated with CCl4 exclusively. The administration of the anthocyanins prevented the arginine metabolism's diversion towards the citrulline, decreased the catabolism of polyamines (the activity of putrescine oxidase and spermine oxidase), and significantly reduced the excessive activation and hyperplasia of the Kupffer cells. There was also an absence of necrosis, in regard to the toxic effect of CCl4 alone. The hepatoprotective mechanisms of bilberry extract are based on the inhibition of pro-oxidative mediators, strong anti-inflammatory properties, inducing of hepatic phase II antioxidant enzymes (glutathione S-transferase, quinone reductase) and reduced glutathione, hypoplasia of Kupffer cells, and a decrease in the catabolism of polyamines.
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Affiliation(s)
- Dejan Popović
- Department of Biochemistry, Faculty of Medicine, University of Niš, Bulevar dr Zorana Đinđića 81, 18000 Niš, Serbia; (G.K.); (A.V.); (D.S.)
- Correspondence: ; Tel.: +00-381-637-195-951
| | - Gordana Kocić
- Department of Biochemistry, Faculty of Medicine, University of Niš, Bulevar dr Zorana Đinđića 81, 18000 Niš, Serbia; (G.K.); (A.V.); (D.S.)
| | - Vuka Katić
- Department of Pathology, Faculty of Medicine, University of Niš, Bulevar dr Zorana Đinđića 81, 18000 Niš, Serbia; (V.K.); (L.J.V.)
| | - Aleksandra Zarubica
- Department of Chemistry, Faculty of Science and Mathematics, University of Niš, Višegradska 33, 18000 Niš, Serbia;
| | - Ljubinka Janković Veličković
- Department of Pathology, Faculty of Medicine, University of Niš, Bulevar dr Zorana Đinđića 81, 18000 Niš, Serbia; (V.K.); (L.J.V.)
| | | | - Andrija Jović
- Clinic of Skin and Venereal Diseases, Clinical Center of Niš, Bulevar dr Zorana Đinđića 48, 18000 Niš, Serbia;
| | - Andrej Veljković
- Department of Biochemistry, Faculty of Medicine, University of Niš, Bulevar dr Zorana Đinđića 81, 18000 Niš, Serbia; (G.K.); (A.V.); (D.S.)
| | - Vladimir Petrović
- Department of Histology and Embryology, Faculty of Medicine, University of Niš, Bulevar dr Zorana Đinđića 81, 18000 Niš, Serbia; (V.P.); (G.R.)
| | - Violeta Rakić
- College of Agriculture and Food Technology, Ćirila i Metodija 1, 18400 Prokuplje, Serbia;
| | - Zorica Jović
- Department of Pharmacology and Toxicology, Faculty of Medicine, University of Niš, Bulevar dr Zorana Đinđića 81, 18000 Niš, Serbia;
| | - Nataša Poklar Ulrih
- Department of Food Science and Technology, Biotechnical Faculty, University of Ljubljana, Jamnikarjeva 101, 1000 Ljubljana, Slovenia;
| | - Danka Sokolović
- Institute for Blood Transfusion in Nis, Bulevar dr Zorana Đinđića 48, 18000 Niš, Serbia;
| | - Marko Stojanović
- Faculty of Medicine, University of Niš, Bulevar dr Zorana Đinđića 81, 18000 Niš, Serbia; (M.S.); (M.S.); (A.M.)
| | - Marko Stanković
- Faculty of Medicine, University of Niš, Bulevar dr Zorana Đinđića 81, 18000 Niš, Serbia; (M.S.); (M.S.); (A.M.)
| | - Goran Radenković
- Department of Histology and Embryology, Faculty of Medicine, University of Niš, Bulevar dr Zorana Đinđića 81, 18000 Niš, Serbia; (V.P.); (G.R.)
| | - Gordana R. Nikolić
- Medical Faculty, University of Priština, 38220 Kosovska Mitrovica, Serbia;
| | - Аzra Lukač
- Health Center Rožaje, 84310 Rožaje, Montenegro;
| | - Aleksandar Milosavljević
- Faculty of Medicine, University of Niš, Bulevar dr Zorana Đinđića 81, 18000 Niš, Serbia; (M.S.); (M.S.); (A.M.)
| | - Dušan Sokolović
- Department of Biochemistry, Faculty of Medicine, University of Niš, Bulevar dr Zorana Đinđića 81, 18000 Niš, Serbia; (G.K.); (A.V.); (D.S.)
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Variance component analysis of circulating miR-122 in serum from healthy human volunteers. PLoS One 2019; 14:e0220406. [PMID: 31348817 PMCID: PMC6660082 DOI: 10.1371/journal.pone.0220406] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Accepted: 07/15/2019] [Indexed: 12/25/2022] Open
Abstract
Micro-RNA (miR)-122 is a promising exploratory biomarker for detecting liver injury in preclinical and clinical studies. Elevations in serum or plasma have been associated with viral and autoimmune hepatitis, non-alcoholic steatohepatitis (NASH), hepatocellular carcinoma, and drug-induced liver injury (DILI). However, these associations were primarily based upon population differences between the disease state and the controls. Thus, little is known about the variability and subsequent variance components of circulating miR-122 in healthy humans, which has implications for the practical use of the biomarker clinically. To address this, we set out to perform variance components analysis of miR-122 in a cohort of 40 healthy volunteers. Employing a quantitative real-time polymerase chain reaction (qRT-PCR) assay to detect miR-122 and other circulating miRNAs in human serum, the relative expression of miR-122 was determined using two different normalization approaches: to the mean expression of a panel of several endogenous miRNAs identified using an adaptive algorithm (miRA-Norm) and to the expression of an exogenous miRNA control (Caenorhabditis elegans miR-39). Results from a longitudinal study in healthy volunteers (N = 40) demonstrated high variability with 117- and 111-fold 95% confidence reference interval, respectively. This high variability of miR-122 in serum appeared to be due in part to ethnicity, as 95% confidence reference intervals were approximately three-fold lower in volunteers that identified as Caucasian relative to those that identified as Non-Caucasian. Variance analysis revealed equivalent contributions of intra- and inter-donor variability to miR-122. Surprisingly, miR-122 exhibited the highest variability compared to other 36 abundant miRNAs in circulation; the next variable miRNA, miR-133a, demonstrated a 45- to 62-fold reference interval depending on normalization approaches. In contrast, alanine aminotransferase (ALT) activity levels in this population exhibited a 5-fold total variance, with 80% of this variance due to inter-donor sources. In conclusion, miR-122 demonstrated higher than expected variability in serum from healthy volunteers, which has implications for its potential utility as a prospective biomarker of liver damage or injury.
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Di Lenardo D, Silva FRPD, de Carvalho França LF, Carvalho JDS, Alves EHP, Vasconcelos DFP. Evaluation of Biochemical Parameters Present in the Saliva of Patients with Chronic Periodontitis: Results from a Meta-Analysis. Genet Test Mol Biomarkers 2019; 23:255-263. [PMID: 30986096 DOI: 10.1089/gtmb.2017.0272] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIMS Periodontitis results from the presence of periodontopathogenic bacterial activity in the region of the gingival sulcus promoting tissue degradation and alveolar bone resorption. Biochemical analysis of the saliva can be used as a less invasive method for disease prognosis. This study aimed to evaluate the relationship between biochemical protein levels in the saliva sample of patients with chronic periodontitis and healthy patients. MATERIALS AND METHODS A literature review was performed using electronic databases (Cochrane Library, Google Scholar, MEDLINE, PubMed, and Web of Science) for studies published before July 2, 2016. The abstracts were evaluated, and the data extraction was performed by two calibrated examiners. The mean difference, and heterogeneity were calculated, and funnel plots were produced. RESULTS Twenty case-control studies were selected with 2436 patients with chronic periodontitis and 1787 controls. The meta-analysis showed that increased levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatine kinase (CK), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), and acid phosphatase (ACP) were all associated with periodontitis (p < 0.05), while blood urea nitrogen (BUN) and osteoprotegerin (OPG) levels did not show statistical differences between cases and controls (p > 0.05). CONCLUSIONS This meta-analysis evidenced that increased levels of AST, ALT, CK, gama glutamil transferase (GGT), LDH, ALP, and ACP are associated in patients with chronic periodontitis, while BUN and OPG level in saliva did not present differences between groups.
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Affiliation(s)
- David Di Lenardo
- Laboratory of Histological Analysis and Preparation (LAPHIS), Federal University of Piauí, Parnaíba, Brazil
| | | | | | | | - Even Herlany Pereira Alves
- Laboratory of Histological Analysis and Preparation (LAPHIS), Federal University of Piauí, Parnaíba, Brazil
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Abstract
Drug-induced liver injury (DILI) is a major clinical and regulatory challenge. As a result, interest in DILI biomarkers is growing. So far, considerable progress has been made in identification of biomarkers for diagnosis (acetaminophen-cysteine protein adducts), prediction (genetic biomarkers), and prognosis (microRNA-122, high mobility group box 1 protein, keratin-18, glutamate dehydrogenase, mitochondrial DNA). Many of those biomarkers also provide mechanistic insight. The purpose of this chapter is to review major advances in DILI biomarker research over the last decade, and to highlight some of the challenges involved in implementation. Although much work has been done, more liver-specific biomarkers, more DILI-specific biomarkers, and better prognostic biomarkers for survival are all still needed. Furthermore, more work is needed to define reference intervals and medical decision limits.
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Affiliation(s)
- Mitchell R McGill
- Department of Environmental and Occupational Health, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, AR, United States; Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR, United States.
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS, United States
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Church RJ, Kullak-Ublick GA, Aubrecht J, Bonkovsky HL, Chalasani N, Fontana RJ, Goepfert JC, Hackman F, King NMP, Kirby S, Kirby P, Marcinak J, Ormarsdottir S, Schomaker SJ, Schuppe-Koistinen I, Wolenski F, Arber N, Merz M, Sauer JM, Andrade RJ, van Bömmel F, Poynard T, Watkins PB. Candidate biomarkers for the diagnosis and prognosis of drug-induced liver injury: An international collaborative effort. Hepatology 2019; 69:760-773. [PMID: 29357190 PMCID: PMC6054900 DOI: 10.1002/hep.29802] [Citation(s) in RCA: 158] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Accepted: 01/19/2018] [Indexed: 02/06/2023]
Abstract
Current blood biomarkers are suboptimal in detecting drug-induced liver injury (DILI) and predicting its outcome. We sought to characterize the natural variabilty and performance characteristics of 14 promising DILI biomarker candidates. Serum or plasma from multiple cohorts of healthy volunteers (n = 192 and n = 81), subjects who safely took potentially hepatotoxic drugs without adverse effects (n = 55 and n = 92) and DILI patients (n = 98, n = 28, and n = 143) were assayed for microRNA-122 (miR-122), glutamate dehydrogenase (GLDH), total cytokeratin 18 (K18), caspase cleaved K18, glutathione S-transferase α, alpha-fetoprotein, arginase-1, osteopontin (OPN), sorbitol dehydrogenase, fatty acid binding protein, cadherin-5, macrophage colony-stimulating factor receptor (MCSFR), paraoxonase 1 (normalized to prothrombin protein), and leukocyte cell-derived chemotaxin-2. Most candidate biomarkers were significantly altered in DILI cases compared with healthy volunteers. GLDH correlated more closely with gold standard alanine aminotransferase than miR-122, and there was a surprisingly wide inter- and intra-individual variability of miR-122 levels among healthy volunteers. Serum K18, OPN, and MCSFR levels were most strongly associated with liver-related death or transplantation within 6 months of DILI onset. Prediction of prognosis among DILI patients using the Model for End-Stage Liver Disease was improved by incorporation of K18 and MCSFR levels. Conclusion: GLDH appears to be more useful than miR-122 in identifying DILI patients, and K18, OPN, and MCSFR are promising candidates for prediction of prognosis during an acute DILI event. Serial assessment of these biomarkers in large prospective studies will help further delineate their role in DILI diagnosis and management.
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Affiliation(s)
- Rachel J. Church
- Institute for Drug Safety Sciences, University of North Carolina at Chapel Hill, Research Triangle Park, NC,Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, North Carolina
| | - Gerd A. Kullak-Ublick
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Switzerland,Mechanistic Safety, Novartis Global Drug Development, Basel, Switzerland
| | | | | | - Naga Chalasani
- School of Medicine, Indiana University, Indianapolis, IN
| | | | | | | | | | | | | | | | | | | | - Ina Schuppe-Koistinen
- Science for Life Laboratory, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | | | - Nadir Arber
- Tel Aviv Sourasky Medical Center, Tel Aviv University, Israel
| | - Michael Merz
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Switzerland,Discovery and Investigative Safety, Novartis Institutes for Biomedical Research, Basel, Switzerland
| | | | - Raul J. Andrade
- Unidad de Gestión Clínica de Aparato Digestivo, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Málaga, Spain
| | - Florian van Bömmel
- Section of Hepatology, Clinic of Gastroenterology and Hepatology, University Hospital Leipzig, Leipzig, Germany
| | - Thierry Poynard
- Department of Hepatology, Groupe Hospitalier Pitié Salpêtrière, University Pierre et Marie Curie, INSERM UMR 938, Paris, France
| | - Paul B. Watkins
- Institute for Drug Safety Sciences, University of North Carolina at Chapel Hill, Research Triangle Park, NC,Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, North Carolina
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Schomaker S, Ramaiah S, Khan N, Burkhardt J. Safety biomarker applications in drug development. J Toxicol Sci 2019; 44:225-235. [DOI: 10.2131/jts.44.225] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
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