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Wang Y, Peng X, Qian B, Wang L, Wang J. The integration of metabolites from Forsythia suspensa and gut microbiota ameliorates drug-induced liver injury: network pharmacology and molecular docking studies. ARTIFICIAL CELLS, NANOMEDICINE, AND BIOTECHNOLOGY 2025; 53:105-121. [PMID: 40055878 DOI: 10.1080/21691401.2025.2475088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 02/19/2025] [Accepted: 02/24/2025] [Indexed: 05/13/2025]
Abstract
This study integrates metabolites from Forsythia suspensa (FS) and gut microbiota GM to assess combined therapeutic efficacy against drug-induced liver injury (DILI) using network pharmacology and molecular docking. Metabolites of FS and GM were retrieved from the NPASS and gutMGene databases, respectively. Relevant targets for metabolites and DILI-related targets were identified through public databases. The PPI network and KEGG pathway analysis were employed to identify hub targets and key signalling pathways. Furthermore, we performed a molecular docking assay on the active metabolites and targets to verify the network pharmacological concept. The physicochemical properties and toxicity of identified key metabolites were assessed using in silico platforms. 19 final targets were recognized as key proteins responsible for the alleviation of DILI by FS and GM metabolites, with ESR1 emerging as a central target in the PPI network. The estrogen signalling pathway, particularly involving ESR1, ESR2 and JUN genes, was identified as a key mediator in the therapeutic effects. Four GM metabolites (baicalein, luteolin, lunularin and 2,3-bis(3,4-dihydroxybenzyl)butyrolactone) and two FS metabolites (pinoresinol and isolariciresinol) were identified as non-toxic, promising candidates. In conclusion, metabolites from FS and GM may exert a potent synergistic effect on DILI through modulation of the estrogen signalling pathway.
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Affiliation(s)
- Yanni Wang
- Department of Pharmacy, The Third Affiliated Hospital of Wenzhou Medical University, Ruian, China
| | - Xiangxiang Peng
- Department of Pharmacy, The Third Affiliated Hospital of Wenzhou Medical University, Ruian, China
| | - Bingjie Qian
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Wenzhou Medical University, Ruian, China
| | - Libo Wang
- Department of Pharmacy, XianJu People's Hospital, Zhejiang Southeast Campus of Zhejiang Provincial People's Hospital, Affiliated Xianju's Hospital, Hangzhou Medical College, Xianju, China
| | - Jiabing Wang
- Department of Pharmacy, Municipal Hospital Affiliated to Taizhou University, Taizhou, China
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2
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Yang J, Yang Y, Tan X, Du H, Zhou Z, Chen L, Tian X, Zheng G, Hu J, Zhang C, Qiu Z. Unlocking the potential of the ACE2/Ang-(1-7)/Mas Axis in liver diseases: From molecular mechanisms to translational applications. Diabetes Obes Metab 2025. [PMID: 40344459 DOI: 10.1111/dom.16435] [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: 01/25/2025] [Revised: 04/11/2025] [Accepted: 04/21/2025] [Indexed: 05/11/2025]
Abstract
Over the past two decades, the identification of new functions within the renin-angiotensin system (RAS) has extended beyond its traditional roles, with the emergence of the angiotensin-converting enzyme 2 (ACE2)/Ang-(1-7)/Mas axis being particularly significant. This axis is hypothesized to balance or modulate the effects of the traditional ACE/Ang II/AT1 axis in various physiological and pathological contexts. ACE2, a membrane-bound carboxypeptidase and an ancient homologue of ACE converts Angiotensin II (Ang II) into Angiotensin 1-7 (Ang-(1-7)). The Mas receptor is a G-protein-coupled receptor that specifically binds Ang-(1-7). Recent research has increasingly focused on the local expression of RAS in different tissues. Ang-(1-7) produces a variety of biological effects by binding to the Mas receptor, including anti-inflammatory, antioxidant, anti-apoptotic and anti-fibrotic actions, thereby influencing a range of mechanisms in the heart, kidneys, brain and other tissues. Preclinical animal model studies indicate that manipulating the protective RAS can significantly alter the progression of multiple liver diseases. Hepatic overexpression of ACE2 or administration of Ang-(1-7) and its analogues has been shown to be therapeutically effective against drug-induced liver injury, metabolic-associated fatty liver disease, liver fibrosis and hepatocellular carcinoma progression. These effects are achieved through various pathways, including the regulation of lipid metabolism, inhibition of epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) production, as well as suppression of aerobic glycolysis. In current clinical trials, while recombinant human ACE2 (Rh-ACE2) has demonstrated safety and good tolerance in most studies, research on the relevance of activating the ACE2/Ang-(1-7) axis in the mechanisms and evolution of human diseases remains in its early stages. Therefore, further elucidation of the complex interactions between the classical and counter-regulatory RAS axes in clinical settings is crucial. This review will summarize the roles of selective activation of the ACE2/Ang-(1-7)/Mas axis, with a focus on its mechanisms in the treatment of liver diseases. Additionally, we will discuss the safety concerns regarding selective activation of the ACE2/Ang-(1-7)/Mas axis in clinical applications and the challenges of tissue-specific activation of this axis, providing effective therapeutic strategies for targeted activation of the hepatic ACE2/Ang-(1-7)/Mas axis in clinical practice.
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Affiliation(s)
- Jun Yang
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, People's Republic of China
| | - Yuan Yang
- Institute of Maternal and Child Health, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Xiangyun Tan
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, People's Republic of China
| | - Hongzhi Du
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, People's Republic of China
| | - Zhongshi Zhou
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, People's Republic of China
| | - Liang Chen
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, People's Republic of China
| | - Xianxiang Tian
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, People's Republic of China
| | - Guohua Zheng
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, People's Republic of China
| | - Junjie Hu
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, People's Republic of China
| | - Cong Zhang
- College of Basic Medical Sciences, China Three Gorges University, Yichang, China
| | - Zhenpeng Qiu
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, People's Republic of China
- Hubei Key Laboratory of Resources and Chemistry of Chinese Medicine, Hubei University of Chinese Medicine, Wuhan, People's Republic of China
- Center of Traditional Chinese Medicine Modernization for Liver Diseases, Hubei University of Chinese Medicine, Wuhan, People's Republic of China
- Hubei Shizhen Laboratory, Wuhan, People's Republic of China
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3
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Moustafa PE, Farouk H, Khattab MS, El-Marasy SA. Diacerein counteracts amiodarone‑induced hepatotoxicity in rats via targeting TLR4/NF-kB/NLRP3 pathways. Toxicol Mech Methods 2025:1-13. [PMID: 40331897 DOI: 10.1080/15376516.2025.2499024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 04/14/2025] [Accepted: 04/23/2025] [Indexed: 05/08/2025]
Abstract
This study investigates the protective effects of diacerein (DCN) against amiodarone (AMIO)-induced hepatotoxicity in a rat model. AMIO administration resulted in significant elevations of liver enzymes, ALT and AST, indicating hepatocellular membrane disruption and oxidative stress, as demonstrated by elevated levels of malondialdehyde (MDA) and decreased glutathione (GSH). Additionally, pro-inflammatory cytokines including TNF-α and IL-1β were expressed more when AMIO triggered the Toll-like receptor 4/nuclear factor kappa B/inflammasome 3 (TLR4/NF-κB/NLRP3) inflammatory pathway, along with elevated caspase-1 (CASP1) levels, which promoted apoptosis. In contrast, oral administration of DCN for two weeks effectively mitigated these effects by reducing liver enzyme levels and improving histopathological alterations. DCN also demonstrated anti-oxidant properties by decreasing MDA levels and increasing nuclear factor erythroid 2-related factor 2 (Nrf2) and GSH content. Furthermore, DCN downregulated the hepatic content of TLR4, NF-κB p65, NLRP3, CASP1, and pro-inflammatory cytokines, thereby inhibiting the activation of the inflammatory cascade. Moreover, DCN reduced protein expression of caspase 3. Those findings suggest that DCN exerts its hepatoprotective effects through its anti-oxidant activity, modulation of TLR4/NF-κB/NLRP3 inflammatory pathways, and reduction of apoptosis. These results provide new insights into potential therapeutic strategies for managing AMIO-induced hepatotoxicity, warranting further investigation into the underlying molecular mechanisms of DCN's protective effects.
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Affiliation(s)
- Passant E Moustafa
- Department of Pharmacology, Medical Research and Clinical Studies Institute, National Research Centre, Giza, Egypt
| | - Hadir Farouk
- Department of Pharmacology, Medical Research and Clinical Studies Institute, National Research Centre, Giza, Egypt
| | - Marwa S Khattab
- Department of Pathology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
| | - Salma A El-Marasy
- Department of Pharmacology, Medical Research and Clinical Studies Institute, National Research Centre, Giza, Egypt
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4
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Cheng Y, Yang Y, Su Y, Chen R, Qian D, Xu J. FAERS based disproportionality analysis and network pharmacology investigation of taxanes associated drug induced liver injury. Sci Rep 2025; 15:15137. [PMID: 40307389 PMCID: PMC12043806 DOI: 10.1038/s41598-025-99669-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Accepted: 04/22/2025] [Indexed: 05/02/2025] Open
Abstract
Taxanes play a crucial role in cancer treatment, particularly for non-small cell lung cancer and breast cancer. However, real-world studies examining drug-induced liver injury (DILI) associated with these drugs remain limited. Our study investigates the association between taxanes and DILI through analysis of the Food and Drug Administration Adverse Event Reporting System (FAERS) database, alongside an exploration of potential hepatotoxicity mechanisms via network pharmacology. We collected DILI reports related to taxanes from the FAERS database between January 2004 and March 2024, employing disproportionality analyses with the reporting odds ratio (ROR) and 95% confidence intervals. Our findings revealed a significant association between paclitaxel (ROR = 2.35) and nab-paclitaxel (ROR = 3.14) with DILI, while docetaxel demonstrated no significant correlation (ROR = 0.68), although it was linked to higher mortality rates and earlier onset. Network pharmacology analysis uncovered that the mechanisms of liver injury induced by these two drugs may not be entirely congruent. Unique targets for docetaxel included BCL2, CNR2, and MAPK1, while the 'Regulation of lipolysis in adipocytes' pathway was specifically associated with docetaxel-induced DILI. Our findings indicate that taxanes exhibit differential hepatotoxic risks and hepatotoxicity mechanisms, emphasizing the need for enhanced drug safety monitoring strategies for cancer patients.
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Affiliation(s)
- Yijie Cheng
- Pharmacy Department, Changshu Hospital Affiliated to Soochow University, Changshu No.1 People's Hospital, Changshu, China
- Central Laboratory, Changshu Hospital Affiliated to Soochow University, Changshu No.1 People's Hospital, Changshu, China
- School of Biology and Food Engineering, Changshu Institute of Technology, Changshu, China
| | - Yuxin Yang
- School of Biology and Food Engineering, Changshu Institute of Technology, Changshu, China
| | - Yan Su
- School of Biology and Food Engineering, Changshu Institute of Technology, Changshu, China
| | - Ruihuan Chen
- Pharmacy Department, Changshu Hospital Affiliated to Soochow University, Changshu No.1 People's Hospital, Changshu, China
| | - Da Qian
- Central Laboratory, Changshu Hospital Affiliated to Soochow University, Changshu No.1 People's Hospital, Changshu, China.
| | - Jingyuan Xu
- Central Laboratory, Changshu Hospital Affiliated to Soochow University, Changshu No.1 People's Hospital, Changshu, China.
- School of Biology and Food Engineering, Changshu Institute of Technology, Changshu, China.
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5
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Reinhart JM. Drug-Induced Liver Injury. Vet Clin North Am Small Anim Pract 2025:S0195-5616(25)00029-4. [PMID: 40280782 DOI: 10.1016/j.cvsm.2025.03.003] [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: 04/29/2025]
Abstract
Drug-induced liver injury (DILI) is an underrecognized cause of hepatic disease in dogs and cats. Successful identification of cases requires an initial suspicion by the practitioner, a thorough drug exposure history, and knowledge of the toxic potential for common veterinary drugs. This article reviews the pathogenesis, classification, and diagnosis of DILI in small animals. It also discusses the clinical presentation, prevalence, and outcomes of DILI for several drugs important in veterinary medicine including azathioprine, azole antifungals, carprofen, diazepam, doxycycline, lomustine, methimazole, phenobarbital, rifampin, sulfonamide antibiotics, and zonisamide, as well as the toxic potential for nutraceuticals and herbal preparations.
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Affiliation(s)
- Jennifer M Reinhart
- Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois Urbana-Champaign, 1008 West Hazelwood Drive, Urbana, IL 61802, USA.
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6
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Kaito S, Sato K, Sasaki T, Hosaka T, Shizu R, Takeshita JI, Yoshinari K. Association between drug-induced heart failure and CYP1A1, CYP1B1, and CYP3A4 inhibition: Utility of cytochrome P450 inhibition assay for evaluating cardiotoxicity of drug candidates. Toxicol In Vitro 2025; 107:106075. [PMID: 40258480 DOI: 10.1016/j.tiv.2025.106075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 04/04/2025] [Accepted: 04/15/2025] [Indexed: 04/23/2025]
Abstract
Unpredictable adverse drug reactions (ADRs) present a significant challenge in drug development and require advanced prediction systems for ADRs. Previously, we identified a connection between drug-induced liver injury (DILI) and the inhibition of CYP1A1 or CYP1B1, reporting the usefulness of this inhibition data from these cytochrome P450s (P450s) for predicting DILI. This study aimed to investigate the utility of P450 inhibition data in predicting drug-induced organ toxicities beyond DILI. We selected 364 drugs with ADR information as test drugs from the public database SIDER (Side Effect Resource). Our focus was on 10 groups of ADRs affecting the liver, kidney, heart, blood/hematopoietic system, intestines, muscle, and lungs, as classified by MedDRA. The inhibitory activities of 10 human P450s were evaluated in vitro using recombinant enzymes and luminescent substrates. Our analyses revealed notable associations between heart failure and the inhibition of CYP1A1, CYP1B1, and CYP3A4. Heart failure-positive drugs tended to exhibit strong inhibition of these P450s compared to heart failure-negative drugs. Furthermore, most drugs that inhibited two or three of the three P450 forms were found to be heart failure-positive. These results suggest that the inhibition assay data for CYP1A1, CYP1B1, and CYP3A4 help assess drug-induced cardiotoxicity during drug development.
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Affiliation(s)
- Shunnosuke Kaito
- School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Kiyomi Sato
- School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Takamitsu Sasaki
- School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Takuomi Hosaka
- School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Ryota Shizu
- School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Jun-Ichi Takeshita
- School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan; Research Institute of Science for Safety and Sustainability, National Institute of Advanced Industrial Science and Technology, Tsukuba, Japan
| | - Kouichi Yoshinari
- School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
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7
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Hionides-Gutierrez A, Goikoetxea-Usandizaga N, Sanz-García C, Martínez-Chantar ML, Cubero FJ. Novel Emerging Mechanisms in Acetaminophen (APAP) Hepatotoxicity. Liver Int 2025; 45:e16167. [PMID: 39548712 DOI: 10.1111/liv.16167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Revised: 10/31/2024] [Accepted: 11/01/2024] [Indexed: 11/18/2024]
Abstract
BACKGROUND Drug-induced liver injury represents a critical public health issue, marked by unpredictable and potentially severe adverse reactions to medications, herbal products or dietary supplements. AIMS Acetaminophen is notably a leading cause of hepatotoxicity, impacting over one million individuals worldwide. MATERIALS & METHODS Extensive research has elucidated the intricate mechanisms driving APAP-induced liver injury, emphasising the significant roles of endoplasmic reticulum stress, oxidative stress, mitochondrial dysfunction and cell death. RESULTS These insights pave the way for innovative therapeutic strategies, including the use of magnesium, bile acids, microbiota modulation and mesenchymal stem cells. DISCUSSION & CONCLUSION This review explores into these pathological mechanisms, proposing viable therapeutic interventions for patients suffering from APAP-induced liver injury.
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Affiliation(s)
| | - Naroa Goikoetxea-Usandizaga
- Liver Disease Lab, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), Derio, Bizkaia, Spain
- Centre for Biomedical Research, Network on Liver and Digestive Diseases (CIBEREHD), Madrid, Spain
| | - Carlos Sanz-García
- Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, Spain
| | - María L Martínez-Chantar
- Liver Disease Lab, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), Derio, Bizkaia, Spain
- Centre for Biomedical Research, Network on Liver and Digestive Diseases (CIBEREHD), Madrid, Spain
| | - Francisco Javier Cubero
- Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, Spain
- Centre for Biomedical Research, Network on Liver and Digestive Diseases (CIBEREHD), Madrid, Spain
- Health Research Institute Gregorio Marañón (IiSGM), Madrid, Spain
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8
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Church RJ, Anchang B, Bennett BD, Bushel PR, Watkins PB. Blood toxicogenomics reveals potential biomarkers for management of idiosyncratic drug-induced liver injury. Front Genet 2025; 16:1524433. [PMID: 40201567 PMCID: PMC11975945 DOI: 10.3389/fgene.2025.1524433] [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: 11/07/2024] [Accepted: 03/04/2025] [Indexed: 04/10/2025] Open
Abstract
Introduction: Accurate diagnosis, assessment, and prognosis of idiosyncratic drug-induced liver injury (IDILI) is problematic, in part due to the shortcomings of traditional blood biomarkers. Studies in rodents and healthy volunteers have supported that RNA transcript changes in whole blood may address some of these shortcomings. Methods: In this study, we conducted RNA-Seq analysis on peripheral blood samples collected from 55 patients with acute IDILI and 17 patients with liver injuries not attributed to IDILI. Results and discussion: Three differentially expressed genes (DEGs; CFD, SQLE, and INKA1) were identified as significantly associated with IDILI vs. other liver injuries. No DEGs were identified comparing IDILI patients to the 5 patients with autoimmune hepatitis, suggesting possible common underlying mechanisms. Two genes (VMO1 and EFNA1) were significantly associated with hepatocellular injury compared to mixed/cholestatic injury. When patients with severe vs. milder IDILI were compared, we identified over 500 DEGs. The top pathways identified from these DEGs had in common down regulation of multiple T-cell specific genes. Further analyses confirmed that these changes could largely be accounted for by a fall in the concentration of circulating T-cells during severe DILI, perhaps due to exhaustion or sequestration of these cells in the liver. Exploration of DEGs specific for the individual causal agents was largely unsuccessful, but isoniazid-induced IDILI demonstrated 25 DEGs compared to other non-isoniazid IDILI cases. Finally, among the 14 IDILI patients that had hepatocellular jaundice (i.e., Hy's Law cases), we identified 39 DEGs between the 4 patients with fatal or liver transplantation outcomes compared to those that recovered. These findings suggest the potential for blood-based transcriptomic biomarkers to aid in the diagnosis and prognostic stratification of IDILI.
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Affiliation(s)
- Rachel J. Church
- Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina Eshelman School of Pharmacy, Chapel Hill, NC, United States
| | - Benedict Anchang
- Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, United States
| | - Brian D. Bennett
- Integrative Bioinformatics Group, National Institute of Environmental Health Sciences, Research Triangle Park, NC, United States
| | - Pierre R. Bushel
- Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, United States
| | - Paul B. Watkins
- Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina Eshelman School of Pharmacy, Chapel Hill, NC, United States
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9
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Ashfaq MA, Malik HZ, Patel L, Moreno C. Cefdinir-Induced Liver Injury: A Case Report. Cureus 2025; 17:e81523. [PMID: 40308432 PMCID: PMC12043275 DOI: 10.7759/cureus.81523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/31/2025] [Indexed: 05/02/2025] Open
Abstract
Cephalosporins are very rarely known to cause drug-induced liver injury (DILI). We present the case of a healthy 40-year-old female who developed DILI after completing a course of cefdinir, a third-generation cephalosporin, to treat a urinary tract infection. A 40-year-old female with no past medical history presented to the emergency department with a chief complaint of epigastric pain and jaundice for the last four days. A workup at an urgent care revealed hyperbilirubinemia and elevated liver enzymes, prompting this visit. She had completed a five-day course of cefdinir for a urinary tract infection three weeks prior to her visit. Physical examination revealed a vitally stable patient with scleral icterus and no other positive findings. Laboratory workup was significant for total bilirubin 4.3 mg/dL, direct bilirubin 0.7 mg/dL, ALP 130 unit/L, ALT 546 unit/L, and AST 213 unit/L. Serum hepatitis panel, ferritin, ceruloplasmin, alpha-1 antitrypsin, and autoimmune workup were within normal limits. Ultrasound and CT of the abdomen and magnetic resonance cholangiopancreatography did not reveal any pathology. Liver biopsy demonstrated hepatocellular adaptive changes and mild bile duct epithelial damage, suggestive of DILI. This case highlights the importance of obtaining a thorough medical history, including recent medication use, drug dose, and time of symptom onset, for a patient presenting with elevated liver enzymes. This case also emphasizes keeping a broad list of differential diagnoses when managing patients with elevated liver enzymes.
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Affiliation(s)
| | | | - Leena Patel
- Internal Medicine, University of South Alabama, Mobile, USA
| | - Cesar Moreno
- Gastroenterology, University of South Alabama, Mobile, USA
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10
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Halegoua‐DeMarzio D, Navarro V. Challenges in herbal-induced liver injury identification and prevention. Liver Int 2025; 45:e16071. [PMID: 39136211 PMCID: PMC11815602 DOI: 10.1111/liv.16071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Revised: 07/15/2024] [Accepted: 08/05/2024] [Indexed: 02/13/2025]
Abstract
Herbal and dietary supplements (HDS) are being used worldwide at an increasing rate. Mirroring this trend, HDS-induced liver injury, also known as HDS-induced liver injury (HILI), has increased significantly over the past three decades in the Drug-Induced Liver Injury Network (DILIN), now accounting for 20% of cases of drug-induced liver injury (DILI). There are significant challenges in the identification and prevention of HILI due to varying presentations, ability to make clear diagnosis, identification of the responsible ingredient, lack of treatment, and lack of regulatory oversight of HDS products to confirm their ingredients and ensure safety. The major implicated agents include anabolic steroids, green tea extract, garcinia cambogia, kratom, ashwagandha, turmeric and multi-ingredient nutritional supplements. Fortunately, with the formation of major DILI consortiums across the world, the last decade has seen advances in the identification of at-risk genetic phenotypes, the use of chemical analysis on multi-ingredient nutritional supplements, and the publication of data/injury patterns of potentially risky HDS.
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Affiliation(s)
- Dina Halegoua‐DeMarzio
- Division of Gastroenterology and Hepatology, Department of MedicineSidney Kimmel Medical College at Thomas Jefferson University HospitalPhiladelphiaPennsylvaniaUSA
| | - Victor Navarro
- Department of HepatologyJefferson Health‐Einstein HospitalPhiladelphiaPennsylvaniaUSA
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11
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Gu Z, Deng M, Luo Q, Lin S, Yu J, Li C, Wang X, Chen L, Liu T, Li Y, He B. Harnessing HDAC-targeted oleanolic acid derivatives for combined anti-cancer and hepatoprotective effects. Int J Biol Macromol 2025; 297:139761. [PMID: 39800013 DOI: 10.1016/j.ijbiomac.2025.139761] [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: 12/03/2024] [Revised: 01/03/2025] [Accepted: 01/09/2025] [Indexed: 01/15/2025]
Abstract
The development of anti-tumor drugs with hepatoprotective properties has always been highly valued due to their dual capabilities of safeguarding the liver and combating tumors. Moreover, when used in conjunction with specific chemotherapy drugs, they can enhance the efficacy of cancer treatment while simultaneously reducing liver damage caused by chemotherapeutic agents. Our research focused on oleanolic acid (OA), a natural compound known for its liver-protective effects. By incorporating an HDAC-targeting pharmacophore at the 28-COOH site of OA, we aimed to identify compounds that offer dual benefits of liver protection and anti-tumor activity. Compound 2c demonstrated significant inhibitory effects on the growth of RS4;11, K562, and RPMI8226 cells, showed cytotoxicity against HepG2 liver cancer cells, and exhibited favorable selectivity towards normal liver cells. Moreover, compound 2c induced apoptosis in HepG2 cells and arrested cell cycle progression at the G2 phase. Further investigations revealed that compound 2c could alleviate cisplatin-induced liver cell damage and animal liver injury by activating the NRF2/HO-1 pathway. In a HepG2 xenograft model, intravenous administration of compound 2c effectively suppressed tumor growth without eliciting adverse reactions, while enhanced NRF2 and HO-1 expression was observed in the liver tissues of mice treated with compound 2c. Besides, co-administration of cisplatin with compound 2c could significantly enhance the anti-tumor efficacy of cisplatin but minimize liver injury caused by the treatment of cisplatin. Our study provides a lead compound possessing hepatoprotective and antitumor activity, offering a novel strategy to avoid pharmacological liver injury.
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Affiliation(s)
- Zhicheng Gu
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, Guizhou Medical University, Guiyang 550004, China
| | - Mingzhenglong Deng
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, Guizhou Medical University, Guiyang 550004, China
| | - Qinggen Luo
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, Guizhou Medical University, Guiyang 550004, China
| | - Shuxian Lin
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, Guizhou Medical University, Guiyang 550004, China
| | - Junhui Yu
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, Guizhou Medical University, Guiyang 550004, China
| | - Cunjiang Li
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, Guizhou Medical University, Guiyang 550004, China
| | - Xingyu Wang
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, Guizhou Medical University, Guiyang 550004, China
| | - Lei Chen
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, Guizhou Medical University, Guiyang 550004, China
| | - Ting Liu
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, Guizhou Medical University, Guiyang 550004, China
| | - Yan Li
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, Guizhou Medical University, Guiyang 550004, China
| | - Bin He
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, Guizhou Medical University, Guiyang 550004, China.
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12
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Ye W, Ding Y, Li M, Tian Z, Wang S, Liu Z. Drug-induced autoimmune-like hepatitis: A disproportionality analysis based on the FAERS database. PLoS One 2025; 20:e0317680. [PMID: 39913410 PMCID: PMC11801597 DOI: 10.1371/journal.pone.0317680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Accepted: 01/02/2025] [Indexed: 02/09/2025] Open
Abstract
BACKGROUND Drug-induced autoimmune-like hepatitis (DI-ALH) is a potentially life-threatening condition that can lead to acute liver failure and necessitate liver transplantation. While the association between certain drugs and DI-ALH has been documented, a comprehensive analysis of drug-related signals in a large, real-world pharmacovigilance database is lacking. This study aimed to systematically identify drugs linked to DI-ALH by analyzing adverse event reports from the U.S. Food and Drug Administration's (FDA) Adverse Event Reporting System (FAERS) database. METHODS We searched the FAERS database for the term "autoimmune hepatitis" and extracted DI-ALH reports from the first quarter of 2004 to the first quarter of 2024. Positive signal drugs were identified using Proportional Reporting Ratio (PRR), Reporting Odds Ratio (ROR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayesian Geometric Mean (EBGM). To confirm a significant drug-adverse event association, each method had to meet predefined thresholds: for PRR and ROR, values were considered significant if the lower 95% confidence interval (CI) was greater than 1 and at least three reports were identified; for BCPNN, an Information Component (IC025) greater than 0 indicated a signal; for EBGM, a value greater than 2 for the lower 95% confidence interval (EBGM05) was used to denote a positive signal. RESULTS A total of 5,723 DI-ALH reports were extracted from the FAERS database. Disproportionality analysis identified 50 drugs with strong associations to DI-ALH, with biologics, statins, antibiotics, and antiviral drugs representing the most common categories. Among these, nitrofurantoin (ROR 94.79, CI 78.53-114.41), minocycline (ROR 77.82, CI 65.09-93.05), and nivolumab (ROR 47.12, CI 15.06-147.39) exhibited the strongest signals. Additionally, several previously unreported drugs, including mesalazine, aldesleukin, onasemnogene abeparvovec-xioi, and nefazodone, were identified as having strong associations with DI-ALH. These findings were consistent across all four signal detection methods, further validating the robustness of the associations. CONCLUSION This study provides a comprehensive assessment of drugs associated with DI-ALH through a rigorous analysis of the FAERS database using multiple signal detection methods. By identifying both well-known and previously underreported drugs, this study contributes to a more complete understanding of drug-induced liver injury. The findings have important implications for pharmacovigilance strategies and clinical risk assessment. However, limitations inherent in the FAERS database, such as underreporting and the potential for reporting bias, should be considered. Further clinical validation is warranted to confirm these associations.
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Affiliation(s)
- Wangyu Ye
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yuan Ding
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Meng Li
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zhihua Tian
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Shaoli Wang
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zhen Liu
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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13
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Parlatan U, Boudreau L, Torun H, Fan L, Aygun U, Gokaltun AA, Akin D, Usta OB, Demirci U. SHINE: SERS-based Hepatotoxicity detection using Inference from Nanoscale Extracellular vesicle content. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.30.635446. [PMID: 39974950 PMCID: PMC11838255 DOI: 10.1101/2025.01.30.635446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
Extracellular vesicles (EV) are becoming crucial tools in liquid biopsy, diagnostics, and therapeutic applications, yet their nanoscale characterization remains challenging. In this context, the detection of drug-induced liver injury, i.e., hepatotoxicity, through extracellular vesicle molecular content remains an unexplored frontier. To this end, we present a label-free surface-enhanced Raman (SERS) spectroscopy approach, which provides rapid EV content analysis under ten minutes and requires only 1.3 microliters of sample. Using hepatic cultures as a model, our platform captures distinct and reproducible EV molecular changes in response to acetaminophen-induced hepatoxicity. Our platform achieves exceptional accuracy with root mean squared error values as low as 3.80%, establishing strong correlations between EV spectra and conventional toxicity biomarkers. Unlike previous EV-SERS studies limited to vesicle identification and disease markers, this approach reveals EV drug-response signatures strongly correlated with conventional toxicity markers. These findings establish EVs as dynamic reporters of cellular drug responses and demonstrate use of SERS-based EV detection of hepatotoxicity.
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Affiliation(s)
- Ugur Parlatan
- Bio-Acoustic MEMS in Medicine (BAMM) Lab, Canary Center at Stanford, Department of Radiology, School of Medicine, Stanford University, California, CA, 94304, USA
| | - Luke Boudreau
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
- Shriners Hospitals for Children, Boston, MA 02114, USA
| | - Hulya Torun
- Bio-Acoustic MEMS in Medicine (BAMM) Lab, Canary Center at Stanford, Department of Radiology, School of Medicine, Stanford University, California, CA, 94304, USA
| | - Letao Fan
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
- Shriners Hospitals for Children, Boston, MA 02114, USA
| | - Ugur Aygun
- Bio-Acoustic MEMS in Medicine (BAMM) Lab, Canary Center at Stanford, Department of Radiology, School of Medicine, Stanford University, California, CA, 94304, USA
- Department of Electrical and Electronics Engineering, Koç University, Istanbul, 34450, Turkiye
| | - Ayse Aslihan Gokaltun
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
- Shriners Hospitals for Children, Boston, MA 02114, USA
| | - Demir Akin
- Bio-Acoustic MEMS in Medicine (BAMM) Lab, Canary Center at Stanford, Department of Radiology, School of Medicine, Stanford University, California, CA, 94304, USA
| | - O Berk Usta
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
- Shriners Hospitals for Children, Boston, MA 02114, USA
| | - Utkan Demirci
- Bio-Acoustic MEMS in Medicine (BAMM) Lab, Canary Center at Stanford, Department of Radiology, School of Medicine, Stanford University, California, CA, 94304, USA
- Department of Electrical Engineering (by courtesy), Stanford University, Stanford, CA, 94305, USA
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14
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Guan J, Dong D, Xie P, Zhao Z, Guo Y, Lee TY, Yao L, Chiang YC. StackDILI: Enhancing Drug-Induced Liver Injury Prediction through Stacking Strategy with Effective Molecular Representations. J Chem Inf Model 2025; 65:1027-1039. [PMID: 39786982 DOI: 10.1021/acs.jcim.4c02079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2025]
Abstract
Drug-induced liver injury (DILI) is a major challenge in drug development, often leading to clinical trial failures and market withdrawals due to liver toxicity. This study presents StackDILI, a computational framework designed to accelerate toxicity assessment by predicting DILI risk. StackDILI integrates multiple molecular descriptors to extract structural and physicochemical features, including the constitution, pharmacophore, MACCS, and E-state descriptors. Additionally, a genetic algorithm is employed for feature selection and optimization, ensuring that the most relevant features are used. These optimized features are processed through a stacking ensemble model comprising multiple tree-based machine learning models, improving prediction accuracy and interpretability. Notably, StackDILI demonstrates a strong performance on the DILIrank test set and maintains robustness across cross-validation. Moreover, interpretability analysis reveals key molecular features associated with DILI risks, providing valuable insights into toxicity prediction. To further improve accessibility, a user-friendly web interface is developed, allowing users to input SMILES strings and receive rapid predictions with ease. The StackDILI model provides a powerful tool for efficient DILI assessment, supporting safer drug development. The web interface is accessible at https://awi.cuhk.edu.cn/biosequence/StackDILI/.
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Affiliation(s)
- Jiahui Guan
- Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Road, 518172 Shenzhen, China
| | - Danhong Dong
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Road, 518172 Shenzhen, China
| | - Peilin Xie
- Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Road, 518172 Shenzhen, China
- School of Science and Engineering, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Road, 518172 Shenzhen, China
| | - Zhihao Zhao
- Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Road, 518172 Shenzhen, China
| | - Yilin Guo
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Road, 518172 Shenzhen, China
| | - Tzong-Yi Lee
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu 300093, Taiwan
- Center for Intelligent Drug Systems and Smart Bio-Devices (IDS2B), National Yang Ming Chiao Tung University, Hsinchu 300093, Taiwan
| | - Lantian Yao
- Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Road, 518172 Shenzhen, China
- School of Science and Engineering, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Road, 518172 Shenzhen, China
| | - Ying-Chih Chiang
- Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Road, 518172 Shenzhen, China
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Road, 518172 Shenzhen, China
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15
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Zhong YH, Wu XW, Zhang XY, Zhang SW, Feng Y, Zhang XM, Xu BB, Zhong GY, Huang HL, He JW, Zeng JX, Liang J. Intestinal microbiota-mediated serum pharmacochemistry reveals hepatoprotective metabolites of Platycodonis Radix against APAP-induced liver injury. J Chromatogr B Analyt Technol Biomed Life Sci 2025; 1251:124395. [PMID: 39644824 DOI: 10.1016/j.jchromb.2024.124395] [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: 09/04/2024] [Revised: 11/09/2024] [Accepted: 11/19/2024] [Indexed: 12/09/2024]
Abstract
The urgent need for new medications that regulate CYP2E1, CASP3, Nrf2, HO-1, TLR2, TLR4, STAT3, and NF-κB activities is paramount for the treatment of drug-induced liver injury (DILI), particularly from acetaminophen (APAP). Previous studies have suggested that platycosides of Platycodonis Radix exhibits hepatoprotective properties against APAP-induced liver injury (AILI), and their serum metabolites may be the effective agents. As the identify the serum metabolites of platycosides is a huge challenge, the mechanism whether platycosides exert effects through the serum metabolites regulating those targets still remain unclear. In this study, we propose a novel method termed intestinal microbiota-mediated serum pharmacochemistry (IMSP) to identify the serum metabolite profile of platycosides, using deglycosylated platycosides as template molecules. Our results identified a total of 44 prototype platycosides in the total platycosides fraction of Platycodonis Radix (PF). In rat serum, we identified 12 prototype platycosides and 45 metabolites derived from the 44 platycosides. Furthermore, our findings indicate that all 44 platycosides can enter the serum in the form of metabolites. The presence of these metabolites in serum is closely related to their oral bioavailability and the content of the prototypes. The in vivo animal experiments showed that the PF possessed significant anti-AILI effects and CYP2E1, CASP3, Nrf2, HO-1, TLR2, TLR4, STAT3, and NF-κB p65 regulation activities. And the in vitro cell experiments and molecular docking analyses further demonstrated that the hepatoprotective effects were mainly ascribed to the serum metabolites, which regulating targets of CYP2E1, CASP3, Nrf2, HO-1, TLR2, TLR4, STAT3, and NF-κB p65. Additionally, the activities of these metabolites are closely associated with their structures. In summary, the IMSP method significantly enhances the ability to identify platycoside metabolites in serum, reveals that all platycosides may contribute to anti-AILI activity through their metabolites, PF and some of these metabolites are promising candidate compounds for developing new medications with anti-AILI effects for the first time.
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Affiliation(s)
- Yuan-Han Zhong
- Research Center for Traditional Chinese Medicine Resources and Ethnic Minority Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China
| | - Xi-Wa Wu
- Research Center for Traditional Chinese Medicine Resources and Ethnic Minority Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China
| | - Xin-Yu Zhang
- Research Center for Traditional Chinese Medicine Resources and Ethnic Minority Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China
| | - Shou-Wen Zhang
- Research Center for Traditional Chinese Medicine Resources and Ethnic Minority Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China
| | - Yan Feng
- Research Center for Traditional Chinese Medicine Resources and Ethnic Minority Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China
| | - Xue-Mei Zhang
- Research Center for Traditional Chinese Medicine Resources and Ethnic Minority Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China
| | - Bing-Bing Xu
- Jiangxi Provincial Institute of Traditional Chinese Medicine, Nanchang 330046, China
| | - Guo-Yue Zhong
- Research Center for Traditional Chinese Medicine Resources and Ethnic Minority Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China
| | - Hui-Liang Huang
- Research Center for Traditional Chinese Medicine Resources and Ethnic Minority Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China
| | - Jun-Wei He
- Research Center for Traditional Chinese Medicine Resources and Ethnic Minority Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China
| | - Jin-Xiang Zeng
- Research Center for Traditional Chinese Medicine Resources and Ethnic Minority Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China.
| | - Jian Liang
- Research Center for Traditional Chinese Medicine Resources and Ethnic Minority Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China.
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16
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Nakakuni M, Nakano K, Inui A, Kobayashi S, Deguchi N, Mitsui S, Kuriyama T, Miyazaki S. Liver function trends in children with suspected drug-induced hepatocellular injury: A survey using an electronic medical records database. Pediatr Int 2025; 67:e15847. [PMID: 39966880 DOI: 10.1111/ped.15847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Revised: 06/05/2024] [Accepted: 08/05/2024] [Indexed: 02/20/2025]
Abstract
BACKGROUND Drug-induced liver injury (DILI) is a common adverse drug event with limited pediatric data in the literature. This study aimed to use pediatric electronic medical records to assess hepatocellular DILI in pediatric patients who were prescribed liver-injury-inducing drugs. METHODS The Pediatric Medical Information Collection System (P-MICS) is a centralized database integrating electronic medical records from over 40 medical pediatric centers. Pediatric patients in the P-MICS with serum alanine aminotransferase (ALT) levels five or more times the upper limit of normal and who were below 15 years of age were selected. Those with liver diseases unrelated to drug-induced causes were excluded. We identified drugs prescribed 2 to 90 days before the first elevated ALT reading. High-risk liver-injury-causing drugs were determined based on the LiverTox score. We analyzed post-event ALT and total bilirubin levels (TB) and DILI management. RESULTS Of the 817 patients with suspected DILI, 251 were prescribed four drugs identified as high-risk drugs for hepatocellular DILI: methotrexate (n = 129), aspirin (n = 82), vancomycin (n = 58), and cyclophosphamide (n = 51). The median ALT level at the first event was 245 U/L. Approximately 35% of methotrexate users and cyclophosphamide users experienced recurrent ALT elevation. Some methotrexate users also showed TB elevation. Discontinuation of high-risk drugs resulted in fewer relapses and TB elevations than pharmacotherapy. CONCLUSIONS The P-MICS effectively identifies pediatric patients with potential liver injury and tracks liver function in those prescribed liver-injury-causing drugs. This study underscores liver injury risks in pediatric anticancer drug users, highlighting the utility of the P-MICS in monitoring off-label drug safety in children.
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Affiliation(s)
- Masayoshi Nakakuni
- Center for Clinical Research and Development, National Center for Child Health and Development, Tokyo, Japan
- Social Pharmacy and Regulatory Science, Showa Pharmaceutical University, Tokyo, Japan
| | - Kosuke Nakano
- Center for Clinical Research and Development, National Center for Child Health and Development, Tokyo, Japan
| | - Ayano Inui
- Department Pediatric Hepatology and Gastroenterology, Saiseikai Yokohamashi Tobu Hospital, Kanagawa, Japan
| | | | - Naoko Deguchi
- Center for Clinical Research and Development, National Center for Child Health and Development, Tokyo, Japan
| | - Seiji Mitsui
- Center for Clinical Research and Development, National Center for Child Health and Development, Tokyo, Japan
| | - Takeshi Kuriyama
- Center for Clinical Research and Development, National Center for Child Health and Development, Tokyo, Japan
| | - Seiko Miyazaki
- Center for Clinical Research and Development, National Center for Child Health and Development, Tokyo, Japan
- Social Pharmacy and Regulatory Science, Showa Pharmaceutical University, Tokyo, Japan
- Pharmacoepidemiology, Faculty of Pharmaceutical Sciences, Teikyo Heisei University, Tokyo, Japan
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17
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Alfwuaires MA. Rosmarinic acid protects against cyclophosphamide-induced hepatotoxicity via inhibition of oxidative stress, inflammation, and apoptosis and upregulation of Nrf2 in mice. J Mol Histol 2024; 56:49. [PMID: 39702535 DOI: 10.1007/s10735-024-10290-6] [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: 09/17/2024] [Accepted: 10/29/2024] [Indexed: 12/21/2024]
Abstract
Cyclophosphamide (CP) is widely used in chemotherapy to treat various types of cancer. However, it is toxic to the liver and other organs. Rosmarinic acid (RA) possesses anti-inflammatory, antioxidant, and cytoprotective properties. This study investigated the protective effects of RA against CP-induced liver injury in mice. Mice were treated with RA (25, 50, and 100 mg/kg) for 15 days and followed by a single injection of CP on day 16th. CP injection resulted in an elevation in serum AST, ALT, and ALP, along with multiple histopathological alterations in the liver. CP also induced increased levels of MDA and NO, associated with declined GSH, SOD and CAT. RA pretreatment prevented liver injury, alleviated the enhanced levels of MDA and NO, and restored antioxidants defenses, hence avoiding the oxidative injury in the liver. Moreover, RA pretreatment attenuated NF-κB p65 and proinflammatory cytokines levels. Liver of CP-injected mice also showed a decrease in Bcl2, accompanied with elevated BAX and caspase-3 expression, an effect that RA pretreatment alleviated. In addition, pretreatment of CP-administrated mice with RA restored the Nrf2 expression in the liver. Taken together, this study suggests a potential application value of RA in preventing CP hepatotoxicity and sheds light on the possible mechanism.
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Affiliation(s)
- Manal A Alfwuaires
- Department of Biological Sciences, Faculty of Science, King Faisal University, 31982, Al Hofuf, Al-Ahsa, Saudi Arabia.
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18
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Wang R, Li Y, Xia X. Severe liver injury induced by minocycline in hepatitis B patient: a Case Report. Front Pharmacol 2024; 15:1516217. [PMID: 39749206 PMCID: PMC11693611 DOI: 10.3389/fphar.2024.1516217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Accepted: 12/06/2024] [Indexed: 01/04/2025] Open
Abstract
Physical liver injury is an acute and potentially serious adverse event that may result in acute liver failure or even death. Diagnosis is often challenging. Minocycline, a semi-synthetic second-generation tetracycline, has high fat solubility and good tissue permeability. It is widely used for acne treatment. This report presents a 32-year-old female hepatitis B carrier who took minocycline (50 mg twice daily) for acne. After 1 week, she experienced fatigue, jaundice, abdominal bloating, and discomfort. Upon admission, laboratory tests revealed significantly elevated transaminase levels, ascites on abdominal ultrasonography, positive hepatitis B markers, impaired coagulation function, and a final diagnosis of subacute liver failure with chronic hepatitis B. Following discontinuation of minocycline and initiation of liver enzyme protection therapy, the patient's liver and coagulation functions improved after undergoing artificial liver therapy combined with CRRT. This case highlights a rare occurrence of minocycline-induced liver injury in a hepatitis B carrier, emphasizing that acute liver injury is a potential and serious adverse effect of minocycline, particularly in patients with pre-existing liver disease.
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Affiliation(s)
| | | | - Xue Xia
- Pharmacy Department Nanjing Lishui People’s Hospital, Zhongda Hospital Lishui Branch, Southeast University, Nanjing, Jiangsu Province, China
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19
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Chang E, Shi YF, Liu JF, Wei W. Post-marketing safety concerns with elagolix: a disproportionality analysis of the FDA adverse event reporting system. Expert Opin Drug Saf 2024; 23:1545-1552. [PMID: 38700323 DOI: 10.1080/14740338.2024.2351451] [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: 11/17/2023] [Accepted: 03/01/2024] [Indexed: 05/05/2024]
Abstract
OBJECTIVE Elagolix is approved for the treatment of moderate-to-severe pain associated with endometriosis. However, the long-term safety of elagolix in a large sample of real-world patients is unknown. METHODS The U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) reports were collected and analyzed from January 2019 to June 2023. Disproportionality analyses, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS) algorithms, were employed in data mining to quantify the signals of elagolix-related adverse events (AEs). RESULTS After removing the non-drug-related AE signals, we detected several AE signals such as hot flushes, bone pain, suicidal ideation, depression, and increased liver enzymes, which were known during the clinical trial phase. In addition to this, we detected several unexpected important AEs that were not mentioned in the drug insert, including cystitis interstitial, parosmia, and epiploic appendagitis. The median onset time of elagolix-associated AEs was 28.5 days. CONCLUSION Our study provides a comprehensive picture of the safety of elagolix in the post-marketing setting, while also identifying potential new AE signals. These findings emphasize the importance of continued monitoring of the potential risks of elagolix.
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Affiliation(s)
- En Chang
- Department of Pharmacy, People's Hospital of Zhongjiang County, Deyang, Sichuan, China
| | - Yong-Fang Shi
- College of Pharmacy, Heze University, Heze, Shandong, China
| | - Jin-Feng Liu
- Department of Pharmacy, People's Hospital of Zhongjiang County, Deyang, Sichuan, China
| | - Wei Wei
- Department of Pharmacy, People's Hospital of Zhongjiang County, Deyang, Sichuan, China
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20
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Saleh RO, Hamad HA, Najim MA, Menon SV, Kaur M, Sivaprasad GV, Abohassan M, Juan WT, Husseen B, Mustafa YF. Exosome-mediated Transfer of lncRNA in Liver Associated Diseases; Uncovered Truths. Cell Biochem Biophys 2024:10.1007/s12013-024-01617-x. [PMID: 39567423 DOI: 10.1007/s12013-024-01617-x] [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] [Accepted: 11/08/2024] [Indexed: 11/22/2024]
Abstract
Exosomes are extracellular vesicles with a diameter ranging from 40 to 160 nm. They are produced by hepatocytes, cholangiocytes, hepatic stellate cells (HSCs), liver sinusoidal endothelial cells (LSECs) and Kupffer cells in liver tissue. The secretion of exosomes might vary in quantity and composition in reaction to multiple triggers and various stages of disease. They transport various payloads, such as proteins, DNAs, and RNAs, and enable cell interaction to regulate myriad physiological and pathological processes in liver tissue. Long non-coding RNAs (lncRNAs) are a crucial component of exosomes with an excellent capability to regulate multiple cellular activities such as differentiation, development, metabolism, proliferation, apoptosis, and activation. With the advancements in transcriptomic and genomic study methods and database management technology, the functions and mechanisms of exosomal lncRNAs in liver diseases have been well-studied. This article delves into the detailed role of exosomal lncRNAs in liver disease onset and progression, ranging from hepatocellular carcinoma (HCC) to liver fibrosis drug-induced liver damage (DILI) and steatotic liver diseases.
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Affiliation(s)
- Raed Obaid Saleh
- Medical Laboratory Techniques Department, College of Health and Medical Technology, University of Al Maarif, Anbar, Iraq.
| | - Hamad Ali Hamad
- Department of Pathological Analysis, Collage of Applied Sciences, University of Fallujah, Fallujah, Iraq
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University Putra Malaysia, Serdang, Malaysia
| | | | - Soumya V Menon
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Mandeep Kaur
- Department of Sciences, Vivekananda Global University, Jaipur, Rajasthan, India
| | - G V Sivaprasad
- Department of Basic Science & Humanities, Raghu Engineering College, Visakhapatnam, India
| | - Mohammad Abohassan
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Wen-Tau Juan
- Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
| | - Beneen Husseen
- Medical Laboratory Technique college, The Islamic University, Najaf, Iraq
- Medical Laboratory Technique college, The Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- Medical Laboratory Technique college, The Islamic University of Babylon, Babylon, Iraq
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, Iraq
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21
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Guo K, van den Beucken T. Advances in drug-induced liver injury research: in vitro models, mechanisms, omics and gene modulation techniques. Cell Biosci 2024; 14:134. [PMID: 39488681 PMCID: PMC11531151 DOI: 10.1186/s13578-024-01317-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Accepted: 10/21/2024] [Indexed: 11/04/2024] Open
Abstract
Drug-induced liver injury (DILI) refers to drug-mediated damage to the structure and function of the liver, ranging from mild elevation of liver enzymes to severe hepatic insufficiency, and in some cases, progressing to liver failure. The mechanisms and clinical symptoms of DILI are diverse due to the varying combination of drugs, making clinical treatment and prevention complex. DILI has significant public health implications and is the primary reason for post-marketing drug withdrawals. The search for reliable preclinical models and validated biomarkers to predict and investigate DILI can contribute to a more comprehensive understanding of adverse effects and drug safety. In this review, we examine the progress of research on DILI, enumerate in vitro models with potential benefits, and highlight cellular molecular perturbations that may serve as biomarkers. Additionally, we discuss omics approaches frequently used to gather comprehensive datasets on molecular events in response to drug exposure. Finally, three commonly used gene modulation techniques are described, highlighting their application in identifying causal relationships in DILI. Altogether, this review provides a thorough overview of ongoing work and approaches in the field of DILI.
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Affiliation(s)
- Kaidi Guo
- Department of Toxicogenomics, GROW - Research Institute for Oncology & Reproduction, Maastricht University, Maastricht, 6200, MD, The Netherlands.
| | - Twan van den Beucken
- Department of Toxicogenomics, GROW - Research Institute for Oncology & Reproduction, Maastricht University, Maastricht, 6200, MD, The Netherlands
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Yang Z, Chan YM, Chan DSH, Wu C, Wang Z, Jiang Y, Liu D, Xia Z, Zhang L, Cai Y, Wong CY. A Biomineralized Bifunctional Patient-Friendly Nanosystem for Sustained Glucose Monitoring and Control in Diabetes. SMALL METHODS 2024; 8:e2400159. [PMID: 38697928 DOI: 10.1002/smtd.202400159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 04/04/2024] [Indexed: 05/05/2024]
Abstract
Regular blood glucose monitoring and control is necessary for people with type 1 or advanced type 2 diabetes, yet diagnosing and treating patients with diabetes in an accurate, sustained and patient-friendly manner remains limited. Here, a glucose-responsive bifunctional nanosystem (PGOxMns) is constructed via one-pot biomineralisation of manganese dioxide with glucose oxidase and ε-poly-L-lysine. Under hyperglycaemic conditions, the cascade reactions that occur when glucose interacts with PGOxMns can trigger the production of Mn(II), which enhances the magnetic resonance imaging signal. Simultaneously, manganese dioxide catalyses the decomposition of toxic hydrogen peroxide into oxygen, which also maintains glucose oxidase (GOx) activity. In an in vivo model of diabetes, PGOxMns is used to monitor glucose levels (0-20 mm) and allowed identification of diabetic mice via T1-weighted MRI. Furthermore, PGOxMns is found to have a high insulin-loading capacity (83.6%), likely due to its positive charge. A single subcutaneous injection of insulin-loaded nanosystem (Ins-PGOxMns) into diabetic mice resulted in a rapid and efficient response to a glucose challenge and prolonged blood glucose level control (< 200 mg dL-1) for up to 50 h. Overall, this proof-of-concept study demonstrates the feasibility of using biomineralised nanosystems to develop patient-friendly strategies for glucose monitoring and control.
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Affiliation(s)
- Zhe Yang
- Department of Chemistry, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong SAR, 999077, China
| | - Yuen-Man Chan
- Department of Chemistry, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong SAR, 999077, China
| | - Daniel Shiu-Hin Chan
- Department of Chemistry, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong SAR, 999077, China
| | - Chengnan Wu
- Department of Chemistry, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong SAR, 999077, China
| | - Zimeng Wang
- Department of Mathematics and Information Technology, Education University of Hong Kong, Tai Po, New Territories, Hong Kong SAR, 999077, China
| | - Yuxin Jiang
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Guangdong, 524023, China
| | - Danyong Liu
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Guangdong, 524023, China
| | - Zhengyuan Xia
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Guangdong, 524023, China
- Department of Anesthesiology, The First Affiliated Hospital of Jinan University, Guangdong, 510632, China
| | - Li Zhang
- Department of Chemistry, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong SAR, 999077, China
| | - Yin Cai
- Department of Health Technology and Informatics, Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, 999077, China
| | - Chun-Yuen Wong
- Department of Chemistry, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong SAR, 999077, China
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Hamdy NM, El-Sisi MG, Ibrahim SM, ElNokoudy H, Hady AA, Abd-Ellatef GEF, Sallam AAM, Barakat BM. In silico analysis and comprehensive review of circular-RNA regulatory roles in breast diseases; a step-toward non-coding RNA precision. Pathol Res Pract 2024; 263:155651. [PMID: 39454476 DOI: 10.1016/j.prp.2024.155651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 10/10/2024] [Accepted: 10/11/2024] [Indexed: 10/28/2024]
Abstract
In the current comprehensive review, we first highlighted circRNAs, which are key ncRNAs. Next, we discussed the relationships among circRNAs and breast cancer subtypes via in silico databases analysis and extensive literature search. CircRNAs, that sponge miRNA axes or act as silencers of oncogenic mRNAs, have been extensively addressed in the context of this review. During BC pathogenesis, the circRNA/microRNA/messenger RNA (mRNA) axis plays a major role in disease growth, progression, and survival/resistance and could be targeted for improved treatment options. This review also aimed to address oncogenic and tumor suppressor mRNAs, which are regulated by various circRNAs in BC. Moreover, we mentioned the relation of different circRNAs with cancer hallmarks, patient survival together with drug resistance. Additionally, we discussed circRNAs as vaccines and biomarkers in BC. Finally, we studied exosomal circRNAs as a hot interesting area in the research. REVIEW SIGNIFICANCE: Via using in silico databases, bioinformatics analysis, and a thorough literature search to first highlight circRNA as a crucial ncRNA and its biogenesis, and then we explored the connection between circRNA and breast illnesses. In the framework of the review, circRNA sponged-miRNAs axis or as silencers to oncogenic mRNAs were extensively discussed. In the pathophysiology of BC, the circular RNA/microRNA/messenger RNA axis is crucial for the propagation of the disease and resistance that may be targeted for more effective treatment options, in order to confront tumor suppressor and oncogenic mRNAs that are presently regulated by circRNAs in BC. For better patient results, we advised further mechanistic research to elucidate additional ncRNA axis that may be targeted for the therapy of BC and for prognosis/ or early diagnosis.
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Affiliation(s)
- Nadia M Hamdy
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt.
| | - Mona G El-Sisi
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt
| | - Sherine M Ibrahim
- Biochemistry Department, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), Giza, Egypt
| | - Heba ElNokoudy
- Medication Management & Pharmacy Affairs, Egypt Healthcare Authority, Cairo, Egypt
| | - Ahmad A Hady
- Clinical Oncology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Gamal Eldein Fathy Abd-Ellatef
- Therapeutic Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre, 33 El Bohouth St., Dokki, Giza 12622, Egypt
| | - Al-Aliaa M Sallam
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt; Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Bassant Mohamed Barakat
- Department of Clinical Pharmacy, Faculty of Pharmacy, Al Baha University, Al Baha 1988, Saudi Arabia; Department of Pharmacology and Toxicology, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr City, Cairo 11651, Egypt
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Reis TSA, Siqueira VDS, Ferreira SRR, Domann N, Rodrigues BA, Fleury ACC, de Souza IMFNB, Cardoso LPV, Siqueira CS, Rezende HHA. Evaluation of nitazoxanide in the treatment of experimental murine neurotoxoplasmosis. Rev Inst Med Trop Sao Paulo 2024; 66:e61. [PMID: 39417497 PMCID: PMC11469426 DOI: 10.1590/s1678-9946202466061] [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: 05/27/2024] [Accepted: 08/26/2024] [Indexed: 10/19/2024] Open
Abstract
Toxoplasmosis is a widespread zoonotic disease that poses significant public health concern globally, with neurotoxoplasmosis being a severe complication associated with high mortality rates. The standard therapy for neurotoxoplasmosis involves a combination of sulfadiazine and pyrimethamine, which, despite its efficacy, is often limited by adverse effects leading to treatment discontinuation. This study aimed to evaluate the in vivo efficacy of nitazoxanide in treating neurotoxoplasmosis in mice infected with the Me49 strain. The study comprised two groups: Group I, including subgroups of uninfected, infected and treated with saline, and infected and untreated mice; and Group II, comprising infected mice treated with nitazoxanide at 100 mg/kg/day, nitazoxanide at 150 mg/kg/day, and pyrimethamine combined with sulfadiazine. After 14 days of treatment, the mice were euthanized for organ collection. Histopathological examination of the brains revealed that the highest dose of nitazoxanide reduced parasitic load and cerebral hemorrhages. Biochemical and histopathological analyses of liver and kidney tissues demonstrated toxicological profiles comparable to pyrimethamine and sulfadiazine. However, despite showing efficacy and similar toxicity levels, nitazoxanide treatment was less effective regimen in controlling neurotoxoplasmosis in this experimental model compared to the pyrimethamine and sulfadiazine. Thus, while nitazoxanide presents potential in neurotoxoplasmosis treatment, pyrimethamine combined with sulfadiazine remains the preferred therapeutic choice based on better efficacy observed in this study.
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Affiliation(s)
- Thaís Santos Anjo Reis
- Universidade Federal de Jataí, Instituto de Ciências da Saúde, Programa de Pós-Graduação em Ciências Aplicadas à Saúde, Jataí, Goiás, Brazil
| | - Victor da Silva Siqueira
- Universidade Federal de Jataí, Instituto de Ciências da Saúde, Programa de Pós-Graduação em Ciências Aplicadas à Saúde, Jataí, Goiás, Brazil
| | - Stéfanne Rodrigues Rezende Ferreira
- Universidade Federal de Jataí, Instituto de Ciências da Saúde, Programa de Pós-Graduação em Ciências Aplicadas à Saúde, Jataí, Goiás, Brazil
| | - Natália Domann
- Universidade Federal de Jataí, Instituto de Ciências da Saúde, Programa de Pós-Graduação em Ciências Aplicadas à Saúde, Jataí, Goiás, Brazil
| | - Benílton Alves Rodrigues
- Universidade Federal de Jataí, Instituto de Ciências da Saúde, Curso de Biomedicina, Jataí, Goiás, Brazil
| | | | | | - Ludimila Paula Vaz Cardoso
- Universidade Federal de Jataí, Instituto de Ciências da Saúde, Programa de Pós-Graduação em Ciências Aplicadas à Saúde, Jataí, Goiás, Brazil
| | - Carla Silva Siqueira
- Universidade Federal de Jataí, Instituto de Ciências da Saúde, Programa de Pós-Graduação em Ciências Aplicadas à Saúde, Jataí, Goiás, Brazil
| | - Hanstter Hallison Alves Rezende
- Universidade Federal de Jataí, Instituto de Ciências da Saúde, Programa de Pós-Graduação em Ciências Aplicadas à Saúde, Jataí, Goiás, Brazil
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Xun T, Zhang M, Wei S, Zhao C, Lin Z, Feng H, Wang X, Zhao J, Yang X. CYP2E1 mediated advanced oxidation protein products exacerbate acetaminophen induced drug-derived liver injury in vitro and in vivo. Eur J Pharm Sci 2024; 200:106829. [PMID: 38866111 DOI: 10.1016/j.ejps.2024.106829] [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: 10/08/2023] [Revised: 05/22/2024] [Accepted: 06/10/2024] [Indexed: 06/14/2024]
Abstract
Drug-induced liver injury (DILI) is prevalent in the treatment of chronic kidney disease (CKD). Advanced oxidation protein products (AOPPs) are markers of CKD progression and participate in the occurrence and development of liver diseases. However, the mechanisms underlying the regulation of DILI in CKD have not been established. Herein, we demonstrate the involvement of Cytochrome p450 2E1 (CYP2E1) in DILI induced by AOPPs is exacerbated by exposure to acetaminophen (APAP). We used a adenine-induced CKD model, a model of DILI induced by APAP, and the AOPPs model was generated by intraperitoneal injection. The decline in renal function was associated with a significantly increased concentration of Scr, BUN and AOPPs, and renal tissue fibrosis. The ALT, AST, and AOPPs levels and liver tissue necrosis increased significantly in CKD model group compared with the sodium carboxymethyl cellulose (CMCNa) group. In the AOPPs model, compared to the PBS controls, ALT, AST, and AOPP levels, and liver tissue necrosis increased significantly. In HepG2 or L0-2 cell lines, cell survival was significantly reduced in the AOPP + APAP treatment and CYP2E1 protein expression was increased. FPS-ZM1 or NAC attenuated the hepatocyte toxicity induced by AOPP + APAP and suppression of CYP2E1 expression. AOPPs exacerbated APAP-induced DILI through CYP2E1 signaling pathways. Protein uremic toxins, such as AOPPs, can modify drug toxicity in patients with CKD. This study provides new a rationale to reduce the generation of DILIs in clinical treatment in patients with CKD. AOPPs targeting may present a novel approach to reduce the occurrence of DILI.
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Affiliation(s)
- Tianrong Xun
- Department of Pharmacy, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Mimi Zhang
- Department of Pharmacy, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Sui Wei
- Department of Pharmacy, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Chenyu Zhao
- Department of Pharmacy, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Zhufen Lin
- Department of Pharmacy, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Haixing Feng
- Department of Neurology, Shenzhen Institute of Translational Medicine, Shenzhen Second People's Hospital. Shenzhen University, Shenzhen, China
| | - Xiaokang Wang
- Department of Pharmacy, Shenzhen Longhua District Central Hospital, Shenzhen, China
| | - Jingqian Zhao
- Department of Pharmacy, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Xixiao Yang
- Department of Pharmacy, Shenzhen Hospital, Southern Medical University, Shenzhen, China.
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Feng CX, Ye WY, Shan QW. Clinical and biochemical characteristics, and outcome in 33 patients with ceftriaxone-induced liver injury. Eur J Clin Pharmacol 2024; 80:1317-1324. [PMID: 38809311 DOI: 10.1007/s00228-024-03701-w] [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: 01/08/2024] [Accepted: 05/10/2024] [Indexed: 05/30/2024]
Abstract
PURPOSE To summarize the clinical and biochemical characteristics of patients with ceftriaxone-induced liver injury and guide the selection of safe medication. METHODS Retrieved domestic and foreign databases from inception to October 2023, collected case data conforming to ceftriaxone-induced liver injury, and statistically analyzed the data. RESULTS A total of 617 articles were retrieved, and 16 articles with 33 cases (10 children, 23 adults) were included. Males represented 60% (18/30), with a male-to-female ratio of 1.5:1. The age of onset ranged from 2 days to 96 years, with 15 of 23 adults (65%) over 55 years old. The time from ceftriaxone use to liver injury fluctuated between 0.5 and 47 days. Only 9 patients (27.3%, 9/33) had clinical symptoms, and the clinical classification was dominated by cholestatic injury (46.2%, 12/26). There was a significant difference in the clinical classification of ceftriaxone-induced liver injury between children and adults (P = 0.0126), with hepatocellular injury predominating in children and cholestatic injury predominating in adults. The severity of liver injury was mainly mild (66.7%, 12/18). Peak values of alanine aminotransferase ranging from 228.5 to 8098 U/L, aspartate aminotransferase ranging from 86.7 to 21575 U/L, alkaline phosphatase ranging from 143 to 2434 U/L, and total bilirubin ranging from 3.35 to 66.1 mg/dL. There was a significant difference in peak values of alkaline phosphatase between children and adults (P = 0.027), with a higher peak value of alkaline phosphatase in adults (1039 ± 716.4 U/L vs. 257 ± 134.9 U/L). Patients with normal imaging examinations accounted for the majority (61.5%, 7/13). The prognosis of 32 patients (97%, 32/33) was good, and one child with sickle cell anemia who developed immune hemolysis, progressive renal failure, and acute liver injury after using ceftriaxone died in the end. CONCLUSION Ceftriaxone-induced liver injury can occur at any age, with a higher risk in the elderly, and age may be related to the clinical classification. Although the clinical manifestations are not specific, close monitoring of liver biochemical indicators during the use can detect liver injury early. Most cases have a good prognosis, but for people with concomitant sickle cell anemia, it is necessary to be vigilant about the occurrence of severe hemolytic anemia.
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Affiliation(s)
- Cai-Xia Feng
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Difficult and Critical illness Center, Pediatric Clinical Medical Research Center of Guangxi, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Wen-Yu Ye
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Difficult and Critical illness Center, Pediatric Clinical Medical Research Center of Guangxi, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Qing-Wen Shan
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Difficult and Critical illness Center, Pediatric Clinical Medical Research Center of Guangxi, Nanning, Guangxi Zhuang Autonomous Region, China.
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Yu S, Li J, He T, Zheng H, Wang S, Sun Y, Wang L, Jing J, Wang R. Age-related differences in drug-induced liver injury: a retrospective single-center study from a large liver disease specialty hospital in China, 2002-2022. Hepatol Int 2024; 18:1202-1213. [PMID: 38898191 PMCID: PMC11297843 DOI: 10.1007/s12072-024-10679-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 04/06/2024] [Indexed: 06/21/2024]
Abstract
BACKGROUND AND AIMS Drug-induced liver injury (DILI) is a prevalent adverse reaction in clinical settings. However, there is limited research on age-related differences in DILI. We performed a large-scale retrospective study to delineate the characteristics of DILI across different age groups. METHODS We collected data on a total of 17,946 patients with confirmed DILI hospitalized at the Fifth Medical Center of the People's Liberation Army (PLA) General Hospital in Beijing, China, from January 1, 2002, to December 31, 2022. The patients were stratified based on age into the following groups: children (< 18 years), young adults (18-44 years), middle-aged individuals (45-64 years), and elderly individuals (≥ 65 years). We gathered demographic information, medical histories, laboratory results, disease severity assessments, and mortality statistics for all patients. RESULTS Overall, the distribution of DILI cases across different age groups was as follows: 6.57% were children, 24.82% were young adults, 49.06% were middle-aged individuals, and 19.54% were elderly individuals. The percentage of females increased with age, rising from 36.47% in the pediatric group to 60.51% in the elderly group. Notably, central nervous system agents (15.44%) and anti-infectious agents (21.80%) were more commonly associated with DILI in children, while cardiovascular agents (10.58%) and herbal dietary supplements or traditional medicines (H/TMs) (26.29%) were more prevalent among elderly people with DILI. Among all age groups, hepatocellular-type DILI was more common in the pediatric group (p < 0.001), whereas cholestatic-type DILI and chronic DILI were more prevalent in the elderly group (p < 0.001). Acute liver failure (ALF) and fatal outcomes were more prevalent in the pediatric and elderly groups, particularly in the pediatric group (2.04%, p = 0.041; 0.85%, p = 0.007, respectively). CONCLUSIONS Children and elderly individuals face a higher risk of adverse outcomes following DILI.
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Affiliation(s)
- Simiao Yu
- Department of Hepatology and Traditional Chinese Medicine, The Fifth Medical Center, PLA General Hospital, 100 West Fourth Ring Middle Road, Fengtai District, Beijing, 100039, China.
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Jiahui Li
- Department of Hepatology and Traditional Chinese Medicine, The Fifth Medical Center, PLA General Hospital, 100 West Fourth Ring Middle Road, Fengtai District, Beijing, 100039, China
| | - Tingting He
- Department of Hepatology and Traditional Chinese Medicine, The Fifth Medical Center, PLA General Hospital, 100 West Fourth Ring Middle Road, Fengtai District, Beijing, 100039, China
| | - Haocheng Zheng
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Sici Wang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Yongqiang Sun
- Department of Hepatology and Traditional Chinese Medicine, The Fifth Medical Center, PLA General Hospital, 100 West Fourth Ring Middle Road, Fengtai District, Beijing, 100039, China
| | - Liping Wang
- Department of Hepatology and Traditional Chinese Medicine, The Fifth Medical Center, PLA General Hospital, 100 West Fourth Ring Middle Road, Fengtai District, Beijing, 100039, China
| | - Jing Jing
- Department of Hepatology and Traditional Chinese Medicine, The Fifth Medical Center, PLA General Hospital, 100 West Fourth Ring Middle Road, Fengtai District, Beijing, 100039, China.
| | - Ruilin Wang
- Department of Hepatology and Traditional Chinese Medicine, The Fifth Medical Center, PLA General Hospital, 100 West Fourth Ring Middle Road, Fengtai District, Beijing, 100039, China.
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Zhu L, Yang X, Wu S, Dong R, Yan Y, Lin N, Zhang B, Tan B. Hepatotoxicity of epidermal growth factor receptor - tyrosine kinase inhibitors (EGFR-TKIs). Drug Metab Rev 2024; 56:302-317. [PMID: 39120430 DOI: 10.1080/03602532.2024.2388203] [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: 03/27/2024] [Accepted: 07/30/2024] [Indexed: 08/10/2024]
Abstract
Drug-induced liver injury (DILI) is one of the most frequently adverse reactions in clinical drug use, usually caused by drugs or herbal compounds. Compared with other populations, cancer patients are more prone to abnormal liver function due to primary or secondary liver malignant tumor, radiation-induced liver injury and other reasons, making potential adverse reactions from liver damage caused by anticancer drugs of particular concernduring clinical treatment process. In recent years, the application of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has changed the treatment status of a series of solid malignant tumors. Unfortunately, the increasing incidence of hepatotoxicitylimits the clinical application of EGFR-TKIs. The mechanisms of liver injury caused by EGFR-TKIs were complex. Despite more than a decade of research, other than direct damage to hepatocytes caused by inhibition of cellular DNA synthesis and resulting in hepatocyte necrosis, the rest of the specific mechanisms remain unclear, and few effective solutions are available. This review focuses on the clinical feature, incidence rates and the recent advances on the discovery of mechanism of hepatotoxicity in EGFR-TKIs, as well as rechallenge and therapeutic strategies underlying hepatotoxicity of EGFR-TKIs.
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Affiliation(s)
- Lulin Zhu
- Department of Pharmacy, Key Laboratory of Clinical CancerPharmacology andToxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China
| | - Xinxin Yang
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Shanshan Wu
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Rong Dong
- Department of Pharmacy, Key Laboratory of Clinical CancerPharmacology andToxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China
| | - Youyou Yan
- Department of Pharmacy, Key Laboratory of Clinical CancerPharmacology andToxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China
| | - Nengming Lin
- Department of Pharmacy, Key Laboratory of Clinical CancerPharmacology andToxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
- Westlake Laboratory of Life Sciences and Biomedicine of Zhejiang Province, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Bo Zhang
- Department of Pharmacy, Key Laboratory of Clinical CancerPharmacology andToxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
- Westlake Laboratory of Life Sciences and Biomedicine of Zhejiang Province, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Biqin Tan
- Department of Pharmacy, Key Laboratory of Clinical CancerPharmacology andToxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
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Song S, Qiu R, Huang Y, Zhou Z, Yan J, Ou Q, Wei D, He J, Liang Y, Du X, Yao W, Lu T. Study on the mechanism of hepatotoxicity of Aucklandiae radix through liver metabolomics and network pharmacology. Toxicol Res (Camb) 2024; 13:tfae123. [PMID: 39119266 PMCID: PMC11303830 DOI: 10.1093/toxres/tfae123] [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: 02/08/2024] [Revised: 07/15/2024] [Accepted: 08/02/2024] [Indexed: 08/10/2024] Open
Abstract
Background Aucklandiae Radix (CAR) and its roasted processed products (PAR) are extensively used in various Chinese patent medicines due to their diverse pharmacological activities. However, numerous side effects of CAR have been reported and the hepatotoxicity and the corresponding mechanisms have not been thoroughly investigated. Our study aims to explore the underlying mechanism of the hepatotoxic impacts of CAR. Methods In this study, metabolomic analysis was performed using liver tissue from the mice administered with different dosages of CAR/PAR extracts to examine the hepatotoxic impacts of CAR and elucidate the underlying mechanism. Network pharmacology was employed to predict the potential molecular targets and associated signaling pathways based on the distinctive compounds between CAR and PAR. A composition-target-GO-Bio process-metabolic pathway network was constructed by integrating the hepatotoxicity-related metabolic pathways. Finally, the target proteins related with the hepatotoxic effect of CAR were identified and validated in vivo. Results The metabolomics analysis revealed that 33 related metabolic pathways were significantly altered in the high-dose CAR group, four of which were associated with the hepatotoxicity and could be alleviated by PAR. The network identified NQO1 as the primary target of the hepatotoxic effect induced by CAR exposure, which was subsequently verified by Western Blotting. Further evidence in vivo demonstrated that Nrf2 and HO-1, closely related to NQO1, were also the main targets through which CAR induced the liver injury, and that oxidative stress should be the primary mechanism for the CAR-induced hepatotoxicity. Conclusions This preliminary study on the hepatic toxic injury of CAR provides a theoretical basis for the rational and safe use of CAR rationally and safely in clinical settings.
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Affiliation(s)
- Shen Song
- School of Pharmacy, Nanjing University of Chinese Medicine, Xianlin Road 138, Nanjing 210023, China
| | - Rongli Qiu
- School of Pharmacy, Nanjing University of Chinese Medicine, Xianlin Road 138, Nanjing 210023, China
| | - Yan Huang
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Xianlin Road 138, Nanjing 210023, China
| | - Zhuxiu Zhou
- School of Pharmacy, Nanjing University of Chinese Medicine, Xianlin Road 138, Nanjing 210023, China
| | - Jin Yan
- School of Pharmacy, Nanjing University of Chinese Medicine, Xianlin Road 138, Nanjing 210023, China
| | - Qiaochan Ou
- School of Pharmacy, Nanjing University of Chinese Medicine, Xianlin Road 138, Nanjing 210023, China
| | - Donghui Wei
- School of Pharmacy, Nanjing University of Chinese Medicine, Xianlin Road 138, Nanjing 210023, China
| | - Jingxuan He
- School of Pharmacy, Nanjing University of Chinese Medicine, Xianlin Road 138, Nanjing 210023, China
| | - Yi Liang
- School of Pharmacy, Nanjing University of Chinese Medicine, Xianlin Road 138, Nanjing 210023, China
| | - Xingyue Du
- School of Pharmacy, Nanjing University of Chinese Medicine, Xianlin Road 138, Nanjing 210023, China
| | - Weifeng Yao
- School of Pharmacy, Nanjing University of Chinese Medicine, Xianlin Road 138, Nanjing 210023, China
| | - Tulin Lu
- School of Pharmacy, Nanjing University of Chinese Medicine, Xianlin Road 138, Nanjing 210023, China
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Kaito S, Takeshita JI, Iwata M, Sasaki T, Hosaka T, Shizu R, Yoshinari K. Utility of human cytochrome P450 inhibition data in the assessment of drug-induced liver injury. Xenobiotica 2024; 54:411-419. [PMID: 38315106 DOI: 10.1080/00498254.2024.2312505] [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: 12/13/2023] [Accepted: 01/28/2024] [Indexed: 02/07/2024]
Abstract
Drug-induced liver injury (DILI) is a major cause of drug development discontinuation and drug withdrawal from the market, but there are no golden standard methods for DILI risk evaluation. Since we had found the association between DILI and CYP1A1 or CYP1B1 inhibition, we further evaluated the utility of cytochrome P450 (P450) inhibition assay data for DILI risk evaluation using decision tree analysis.The inhibitory activity of drugs with DILI concern (DILI drugs) and no DILI concern (no-DILI drugs) against 10 human P450s was assessed using recombinant enzymes and luminescent substrates. The drugs were also subjected to cytotoxicity assays and high-content analysis using HepG2 cells. Molecular descriptors were calculated by alvaDesc.Decision tree analysis was performed with the data obtained as variables with or without P450-inhibitory activity to discriminate between DILI drugs and no-DILI drugs. The accuracy was significantly higher when P450-inhibitory activity was included. After the decision tree discrimination, the drugs were further discriminated with the P450-inhibitory activity. The results demonstrated that many false-positive and false-negative drugs were correctly discriminated by using the P450 inhibition data.These results suggest that P450 inhibition assay data are useful for DILI risk evaluation.
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Affiliation(s)
- Shunnosuke Kaito
- School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Jun-Ichi Takeshita
- School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
- Research Institute of Science for Safety and Sustainability, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Japan
| | - Misaki Iwata
- School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Takamitsu Sasaki
- School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Takuomi Hosaka
- School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Ryota Shizu
- School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Kouichi Yoshinari
- School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
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Zarei MH, Akbulut S, Zafari M, Saghaei E, Lorigooini Z, Khoei HA, Khosravi S, Bijad E. Black radish root extract alleviates sodium valproate-induced liver damage via inhibiting mitochondrial membrane potential collapse and oxidative stress in mice. Asian Pac J Trop Biomed 2024; 14:298-306. [DOI: 10.4103/apjtb.apjtb_195_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 07/17/2024] [Indexed: 11/12/2024] Open
Abstract
Objective:
To explore the effect of black radish (Raphanus sativus L. var niger) root extract on liver enzymes, oxidative stress, and histopathological alterations in mice with sodium valproate-induced hepatotoxicity.
Methods:
Thirty-two mice were divided into four groups: the control group received drinking water by gavage, the second group was administered with 100 mg/kg of sodium valproate, the third group received 300 mg/kg of black radish root extract, and the fourth group was given both sodium valproate (100 mg/kg) and black radish root extract (300 mg/kg). After 28 days, the mice were euthanized, and serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP), along with liver malondialdehyde (MDA), reactive oxygen species (ROS), mitochondrial parameters, tumor necrosis factor-alpha (TNF-α) gene expression, and histopathological changes were assessed.
Results:
Sodium valproate caused hepatic damage in mice, characterized by elevated serum levels of liver enzymes, increased MDA and ROS levels and TNF-α gene expression, as well as histopathological alterations. The black radish root extract significantly alleviated sodium valproate-caused hepatic injury by decreasing the serum levels of ALT and AST, MDA, ROS, TNF-α gene expression, as well as mitochondrial impairment, but did not have a significant effect on sodium valproate-induced histopathological changes.
Conclusions:
The black radish root extract demonstrates protective effects against sodium valproate-induced liver injury, possibly through mitigating oxidative stress, mitochondrial impairment, and inflammatory mediator expression.
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Affiliation(s)
- Mohammad Hadi Zarei
- Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Sami Akbulut
- Department of Liver Transplant Institute and Biostatistics, Inonu University Faculty of Medicine, 44280, Malatya, Turkey
| | - Maryam Zafari
- Student Research Committee, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Elham Saghaei
- Physiology and Pharmacology Department, School of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Zahra Lorigooini
- Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Hossein Amini Khoei
- Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Somaye Khosravi
- Department of Anatomical Sciences, School of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Elham Bijad
- Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
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Román-Sagüillo S, Quiñones Castro R, Juárez-Fernández M, Soluyanova P, Stephens C, Robles-Díaz M, Jorquera Plaza F, González-Gallego J, Martínez-Flórez S, García-Mediavilla MV, Nistal E, Jover R, Sánchez-Campos S. Idiosyncratic Drug-Induced Liver Injury and Amoxicillin-Clavulanate: Spotlight on Gut Microbiota, Fecal Metabolome and Bile Acid Profile in Patients. Int J Mol Sci 2024; 25:6863. [PMID: 38999973 PMCID: PMC11241776 DOI: 10.3390/ijms25136863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 06/18/2024] [Accepted: 06/20/2024] [Indexed: 07/14/2024] Open
Abstract
Several hepatic disorders are influenced by gut microbiota, but its role in idiosyncratic drug-induced liver injury (iDILI), whose main causative agent is amoxicillin-clavulanate, remains unknown. This pioneering study aims to unravel particular patterns of gut microbiota composition and associated metabolites in iDILI and iDILI patients by amoxicillin-clavulanate (iDILI-AC). Thus, serum and fecal samples from 46 patients were divided into three study groups: healthy controls (n = 10), non-iDILI acute hepatitis (n = 12) and iDILI patients (n = 24). To evaluate the amoxicillin-clavulanate effect, iDILI patients were separated into two subgroups: iDILI non-caused by amoxicillin-clavulanate (iDILI-nonAC) (n = 18) and iDILI-AC patients (n = 6). Gut microbiota composition and fecal metabolome plus serum and fecal bile acid (BA) analyses were performed, along with correlation analyses. iDILI patients presented a particular microbiome profile associated with reduced fecal secondary BAs and fecal metabolites linked to lower inflammation, such as dodecanedioic acid and pyridoxamine. Moreover, certain taxa like Barnesiella, Clostridia UCG-014 and Eubacterium spp. correlated with significant metabolites and BAs. Additionally, comparisons between iDILI-nonAC and iDILI-AC groups unraveled unique features associated with iDILI when caused by amoxicillin-clavulanate. In conclusion, specific gut microbiota profiles in iDILI and iDILI-AC patients were associated with particular metabolic and BA status, which could affect disease onset and progression.
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Affiliation(s)
- Sara Román-Sagüillo
- Instituto Universitario de Biomedicina (IBIOMED), Universidad de León, 24071 León, Spain
| | - Raisa Quiñones Castro
- Servicio de Aparato Digestivo, Complejo Asistencial Universitario de León, 24008 León, Spain
| | - María Juárez-Fernández
- Instituto Universitario de Biomedicina (IBIOMED), Universidad de León, 24071 León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Polina Soluyanova
- Unidad Mixta de Investigación en Hepatología Experimental, IIS Hospital La Fe, 46026 Valencia, Spain
- Departamento de Bioquímica y Biología Molecular, Universidad de Valencia, 46010 Valencia, Spain
| | - Camilla Stephens
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Unidad de Gestión Clínica de Aparato Digestivo y Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA Plataforma BIONAND, Hospital Universitario Virgen de la Victoria, Facultad de Medicina, Universidad de Málaga, 29010 Málaga, Spain
| | - Mercedes Robles-Díaz
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Unidad de Gestión Clínica de Aparato Digestivo y Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA Plataforma BIONAND, Hospital Universitario Virgen de la Victoria, Facultad de Medicina, Universidad de Málaga, 29010 Málaga, Spain
| | - Francisco Jorquera Plaza
- Instituto Universitario de Biomedicina (IBIOMED), Universidad de León, 24071 León, Spain
- Servicio de Aparato Digestivo, Complejo Asistencial Universitario de León, 24008 León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Javier González-Gallego
- Instituto Universitario de Biomedicina (IBIOMED), Universidad de León, 24071 León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Susana Martínez-Flórez
- Instituto Universitario de Biomedicina (IBIOMED), Universidad de León, 24071 León, Spain
| | - María Victoria García-Mediavilla
- Instituto Universitario de Biomedicina (IBIOMED), Universidad de León, 24071 León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Esther Nistal
- Instituto Universitario de Biomedicina (IBIOMED), Universidad de León, 24071 León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Ramiro Jover
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Unidad Mixta de Investigación en Hepatología Experimental, IIS Hospital La Fe, 46026 Valencia, Spain
- Departamento de Bioquímica y Biología Molecular, Universidad de Valencia, 46010 Valencia, Spain
| | - Sonia Sánchez-Campos
- Instituto Universitario de Biomedicina (IBIOMED), Universidad de León, 24071 León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
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Huang Y, Zhang Y, Wu K, Tan X, Lan T, Wang G. Role of Gut Microecology in the Pathogenesis of Drug-Induced Liver Injury and Emerging Therapeutic Strategies. Molecules 2024; 29:2663. [PMID: 38893536 PMCID: PMC11173750 DOI: 10.3390/molecules29112663] [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: 04/28/2024] [Revised: 06/01/2024] [Accepted: 06/01/2024] [Indexed: 06/21/2024] Open
Abstract
Drug-induced liver injury (DILI) is a common clinical pharmacogenic disease. In the United States and Europe, DILI is the most common cause of acute liver failure. Drugs can cause hepatic damage either directly through inherent hepatotoxic properties or indirectly by inducing oxidative stress, immune responses, and inflammatory processes. These pathways can culminate in hepatocyte necrosis. The role of the gut microecology in human health and diseases is well recognized. Recent studies have revealed that the imbalance in the gut microecology is closely related to the occurrence and development of DILI. The gut microecology plays an important role in liver injury caused by different drugs. Recent research has revealed significant changes in the composition, relative abundance, and distribution of gut microbiota in both patients and animal models with DILI. Imbalance in the gut microecology causes intestinal barrier destruction and microorganism translocation; the alteration in microbial metabolites may initiate or aggravate DILI, and regulation and control of intestinal microbiota can effectively mitigate drug-induced liver injury. In this paper, we provide an overview on the present knowledge of the mechanisms by which DILI occurs, the common drugs that cause DILI, the gut microbiota and gut barrier composition, and the effects of the gut microbiota and gut barrier on DILI, emphasizing the contribution of the gut microecology to DILI.
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Affiliation(s)
- Yuqiao Huang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Yu Zhang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Kaireng Wu
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Xinxin Tan
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Tian Lan
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150086, China
| | - Guixiang Wang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
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Jin SF, Pan Q, Zhou JP, Pan XP. Mechanisms of liver injuries caused by traditional Chinese medicines. Hepatobiliary Pancreat Dis Int 2024; 23:310-312. [PMID: 37217410 DOI: 10.1016/j.hbpd.2023.05.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 05/03/2023] [Indexed: 05/24/2023]
Affiliation(s)
- Shui-Fang Jin
- Intensive Care Unit, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310006, China
| | - Qi Pan
- Institute of Liver Diseases, College of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Jin-Peng Zhou
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou 310056, China
| | - Xiao-Ping Pan
- Institute of Liver Diseases, College of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
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Wiese J, Derian NA, Ghimire S, Bambhroliya Z, Joshi T. Glecaprevir-Pibrentasvir and Ethinyl Estradiol-Induced Liver Injury in a Patient Without Cirrhosis. Cureus 2024; 16:e61980. [PMID: 38983976 PMCID: PMC11232366 DOI: 10.7759/cureus.61980] [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] [Accepted: 05/30/2024] [Indexed: 07/11/2024] Open
Abstract
Most drug liver injury cases are the result of an unexpected interaction with medications. We present a 33-year-old woman, four months postpartum, on ethinyl estradiol/norgestrel, who presented in the ED with nausea, vomiting, abdominal pain, and severe pruritus six weeks after starting glecaprevir-pibrentasvir (GP) treatment. The patient was suspected to have a drug-induced liver injury (DILI), and GP was discontinued. Other potential causes of liver injury were ruled out via labs, imaging, and liver biopsy. The patient's liver function significantly improved after discontinuing GP. Few cases of DILI secondary to GP have been reported. However, to the best of our knowledge, DILI from the interaction of ethinyl estradiol and GP does not exist in published literature. In our case, DILI was likely due to the effect of GP and ethinyl estradiol on the liver's cytochrome 450 (CYP 450) system. The aim of this report is to raise awareness and improve pharmacovigilance, especially in patients receiving medications that are metabolized by the liver's CYP 450 system. Early detection of DILI secondary to drug-interaction and discontinuation of the culprit medication is the mainstay of treatment. However, there is a lack of evidence-based management strategies for premature discontinuation of GP in the setting of DILI while treating chronic hepatitis C virus (HCV) infection. Further investigations are warranted.
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Affiliation(s)
- Jennifer Wiese
- Internal Medicine, Marshall University Joan C. Edwards School of Medicine, Huntington, USA
| | - Nayiri A Derian
- Internal Medicine, Marshall University Joan C. Edwards School of Medicine, Huntington, USA
| | - Shristee Ghimire
- Internal Medicine, University of Science & Technology Chattogram, Chattogram, BGD
| | - Zarna Bambhroliya
- Internal Medicine, Marshall University Joan C. Edwards School of Medicine, Huntington, USA
| | - Tejas Joshi
- Gastroenterology and Hepatology, Marshall University Joan C. Edwards School of Medicine, Huntington, USA
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36
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Matusak M, Aljabban J, Wirtz M, Agni R, Spengler E. Cholestasis Linked to Bodybuilding Supplements: Exploring the Risks of Contamination. Case Reports Hepatol 2024; 2024:5112461. [PMID: 38826497 PMCID: PMC11142851 DOI: 10.1155/2024/5112461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 10/26/2023] [Accepted: 04/22/2024] [Indexed: 06/04/2024] Open
Abstract
Drug-induced liver injury resulting from herbal and dietary supplement use is increasingly common and underrecognized. We report a case of a 34-year-old male recreational bodybuilder who presented with muscle cramping, fatigue, and diffuse itching in the setting of bodybuilding supplement use. Labs showed cholestatic liver injury, and liver biopsy revealed bland cholestasis and sinusoidal dilation. He was diagnosed with anabolic-androgenic steroid-induced liver injury. He was symptomatically managed with plasmapheresis for debilitating pruritus. This case highlights drug-induced liver injury as a complication of bodybuilding supplement use containing unlabeled anabolic-androgenic steroids. Sports medicine providers should inquire on herbal and dietary supplement use and be aware of potential contaminants.
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Affiliation(s)
- Mark Matusak
- Department of Family Medicine, University of Wisconsin Hospital and Clinics, Madison, USA
| | - Jihad Aljabban
- Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, USA
| | - Mark Wirtz
- Department of Family Medicine, University of Wisconsin Hospital and Clinics, Madison, USA
| | - Rashmi Agni
- Department of Pathology, University of Wisconsin Hospital and Clinics, Madison, USA
| | - Erin Spengler
- Department of Gastroenterology and Hepatology, University of Wisconsin Hospital and Clinics, Madison, USA
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37
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Li G, Hou Y, Zhang C, Zhou X, Bao F, Yang Y, Chen L, Yu D. Interplay Between Drug-Induced Liver Injury and Gut Microbiota: A Comprehensive Overview. Cell Mol Gastroenterol Hepatol 2024; 18:101355. [PMID: 38729523 PMCID: PMC11260867 DOI: 10.1016/j.jcmgh.2024.05.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 05/02/2024] [Accepted: 05/03/2024] [Indexed: 05/12/2024]
Abstract
Drug-induced liver injury is a prevalent severe adverse event in clinical settings, leading to increased medical burdens for patients and presenting challenges for the development and commercialization of novel pharmaceuticals. Research has revealed a close association between gut microbiota and drug-induced liver injury in recent years. However, there has yet to be a consensus on the specific mechanism by which gut microbiota is involved in drug-induced liver injury. Gut microbiota may contribute to drug-induced liver injury by increasing intestinal permeability, disrupting intestinal metabolite homeostasis, and promoting inflammation and oxidative stress. Alterations in gut microbiota were found in drug-induced liver injury caused by antibiotics, psychotropic drugs, acetaminophen, antituberculosis drugs, and antithyroid drugs. Specific gut microbiota and their abundance are associated closely with the severity of drug-induced liver injury. Therefore, gut microbiota is expected to be a new target for the treatment of drug-induced liver injury. This review focuses on the association of gut microbiota with common hepatotoxic drugs and the potential mechanisms by which gut microbiota may contribute to the pathogenesis of drug-induced liver injury, providing a more comprehensive reference for the interaction between drug-induced liver injury and gut microbiota.
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Affiliation(s)
- Guolin Li
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China; Department of Pharmacy, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yifu Hou
- Department of Organ Transplantation, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China; Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province and Organ Transplantation Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Changji Zhang
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China; Department of Pharmacy, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Xiaoshi Zhou
- Department of Pharmacy, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Furong Bao
- Department of Nursing, Guanghan People's Hospital, Guanghan, China
| | - Yong Yang
- Department of Pharmacy, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China; Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
| | - Lu Chen
- Department of Pharmacy, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China; Department of Organ Transplantation, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
| | - Dongke Yu
- Department of Pharmacy, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China; Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
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Nikolajevic N, Nikolajevic M, Pantic I, Korica B, Kotseva M, Alempijevic T, Jevtic D, Madrid CI, Dumic I. Drug-Induced Liver Injury Due to Doxycycline: A Case Report and Review of Literature. Cureus 2024; 16:e59687. [PMID: 38836151 PMCID: PMC11150051 DOI: 10.7759/cureus.59687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/03/2024] [Indexed: 06/06/2024] Open
Abstract
Antibiotics are among the most common causes of drug-induced liver injury worldwide. Amoxicillin/clavulanic acid and nitrofurantoin are the most common culprits while tetracyclines are a rare cause of liver injury. Among tetracyclines, minocycline has been reported more frequently than doxycycline, which is an extremely rare cause of drug-induced liver injury. We present a healthy 28-year-old male patient from rural United States who was taking doxycycline for Lyme disease. After five days of therapy, he developed nausea, vomiting, fatigue, and significant transaminitis consistent with a hepatocellular pattern of liver injury. After a thorough workup which ruled out other causes such as infection, autoimmune diseases, liver malignancy, and vascular, structural, and metabolic disorders, his liver injury was attributed to doxycycline. We reached the diagnosis also by demonstrating a consistent temporal association between doxycycline intake and liver injury and the patient recovered completely with the cessation of doxycycline. Recognition of doxycycline as a cause of drug-induced liver injury should be considered in patients utilizing this antibiotic. Doxycycline, unlike minocycline, has a short latency period. Early recognition and discontinuation of doxycycline in our patient resulted in the complete resolution of symptoms and transaminitis preventing further morbidity and mortality.
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Affiliation(s)
- Nikola Nikolajevic
- Internal Medicine, University of Belgrade, Faculty of Medicine, Belgrade, SRB
| | - Milan Nikolajevic
- Internal Medicine, University of Belgrade, Faculty of Medicine, Belgrade, SRB
| | - Ivana Pantic
- Gastroenterology and Hepatology, Clinic for Gastroenterology, University Clinical Center of Serbia, Belgrade, SRB
| | - Bojan Korica
- Gastroenterology and Hepatology, Clinic for Gastroenterology, University Clinical Center of Serbia, Belgrade, SRB
| | | | - Tamara Alempijevic
- Gastroenterology and Hepatology, Clinic for Gastroenterology, University Clinical Center of Serbia, Belgrade, SRB
| | - Dorde Jevtic
- Internal Medicine, NYC Health + Hospitals/Elmhurst, Queens, USA
| | | | - Igor Dumic
- Hospital Medicine, Mayo Clinic Health System, Eau Claire, USA
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Shaheen M, Lei GS, Relich RF, Jarasvaraparn C, Tolliver KM, Molleston JP, González IA. Granulomas in Pediatric Liver Biopsies: Single Center Experience. Pediatr Dev Pathol 2024; 27:218-227. [PMID: 38221675 DOI: 10.1177/10935266231221908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/16/2024]
Abstract
BACKGROUND Granulomas in pediatric liver biopsies (GPLB) are rare with the largest pediatric cohort reported over 25 years ago. METHODS Single-center retrospective study of GPLB. RESULTS Seventeen liver biopsies from 16 patients with granulomas were identified (9 boys, 56%) with a median age of 13 years (range: 1-18) for which the most common indication was the presence of a nodule/mass (47%). Significant comorbidities were seen in 13 patients (81%) and included: liver transplant (25%), history of a neoplasm (25%), autoimmune hepatitis (6%), Crohn disease (6%), bipolar disorder (6%), severe combined immunodeficiency (6%), and sickle cell disease (6%). Eleven patients were taking multiple medications at the time of biopsy. Granulomas were more commonly pan-acinar (11 cases) followed by subcapsular (4 cases), portal (1 case), and periportal (1 case). Necrosis was seen in 10 cases (59%). GMS stain was positive in 2 cases for Histoplasma-like yeast; microbiological cultures were negative in all cases (no: 4). A 18S and 16S rRNA gene sequencing performed in 15 cases revealed only 1 with a pathogenic microorganism, Mycobacterium angelicum. CONCLUSION In our experience, GPLB are heterogenous with only 3 cases having an identifiable infectious etiology and many of the remaining cases being associated to multiple medications, suggesting drug-induced liver injury as possible etiology.
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Affiliation(s)
- Muhammad Shaheen
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Guang-Sheng Lei
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Ryan F Relich
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Chaowapong Jarasvaraparn
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Kyla M Tolliver
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Jean P Molleston
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Iván A González
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
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Saleh AK, El-Mahdy NA, El-Masry TA, El-Kadem AH. Trifluoperazine mitigates cyclophosphamide-induced hepatic oxidative stress, inflammation, and apoptosis in mice by modulating the AKT/mTOR-driven autophagy and Nrf2/HO-1 signaling cascades. Life Sci 2024; 344:122566. [PMID: 38499285 DOI: 10.1016/j.lfs.2024.122566] [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: 10/27/2023] [Revised: 02/26/2024] [Accepted: 03/12/2024] [Indexed: 03/20/2024]
Abstract
AIM This study aims to investigate the hepatoprotective effect of the antipsychotic drug trifluoperazine (TFP) against cyclophosphamide (CPA)-induced hepatic injury by exploring its effect on autophagy and the Nrf2/HO-1 signaling pathway. MAIN METHODS The hepatotoxicity of CPA was assessed by biochemical analysis of the serum hepatotoxicity markers (ALT, AST, and direct bilirubin), histopathological examination, and ultrastructure analysis by transmission electron microscopy (TEM). The ELISA technique was used to assess the hepatic content of oxidative stress (MDA and SOD) and inflammatory markers (IL-1β and TNF-α). Immunohistochemical assessment was used to investigate the hepatic expression of NF-κB, Nrf2, caspase-3, as well as autophagy flux markers (p62 and LC3B). The mRNA expression of HO-1 was assessed using RT-qPCR. Western blot assay was used to determine the expression of p-AKT and p-mTOR. KEY FINDINGS TFP improved CPA-induced hepatotoxicity by reducing the elevated hepatotoxicity markers, and alleviating the histopathological changes with improving ultrastructure alterations. It also reduced oxidative stress by reducing MDA content and upregulating SOD activity. In addition, it exhibited anti-inflammatory and anti-apoptotic effects by decreasing NF-κB expression, IL-1β, TNF-α levels, and caspase-3 expression. Furthermore, TFP-induced hepatoprotection was mediated by favoring Nrf2 expression and increasing the mRNA level of HO-1. As well, it improved autophagy by increasing LC3B expression concurrently with reducing p62 expression. Moreover, TFP modulated the AKT/mTOR pathway by reducing the expression of p-AKT and p-mTOR. SIGNIFICANCE TFP significantly protected against CPA-induced hepatotoxicity by upregulating Nrf2/HO-1 signaling along with enhancement of protective autophagy via inhibition of the AKT/mTOR signaling pathway.
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Affiliation(s)
- Ahmed K Saleh
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt.
| | - Nageh A El-Mahdy
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt.
| | - Thanaa A El-Masry
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt.
| | - Aya H El-Kadem
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt.
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Kmail A. Mitigating digestive disorders: Action mechanisms of Mediterranean herbal active compounds. Open Life Sci 2024; 19:20220857. [PMID: 38645751 PMCID: PMC11032100 DOI: 10.1515/biol-2022-0857] [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: 11/11/2023] [Revised: 03/06/2024] [Accepted: 03/07/2024] [Indexed: 04/23/2024] Open
Abstract
This study explores the effects of the Mediterranean diet, herbal remedies, and their phytochemicals on various gastrointestinal conditions and reviews the global use of medicinal plants for common digestive problems. The review highlights key plants and their mechanisms of action and summarizes the latest findings on how plant-based products influence the digestive system and how they work. We searched various sources of literature and databases, including Google Scholar, PubMed, Science Direct, and MedlinePlus. Our focus was on gathering relevant papers published between 2013 and August 2023. Certain plants exhibit potential in preventing or treating digestive diseases and cancers. Notable examples include Curcuma longa, Zingiber officinale, Aloe vera, Calendula officinalis, Lavandula angustifolia, Thymus vulgaris, Rosmarinus officinalis, Ginkgo biloba, Cynodon dactylon, and Vaccinium myrtillus. The phytochemical analysis of the plants showed that compounds such as quercetin, anthocyanins, curcumin, phenolics, isoflavones glycosides, flavonoids, and saponins constitute the main active substances within these plants. These natural remedies have the potential to enhance the digestive system and alleviate pain and discomfort in patients. However, further research is imperative to comprehensively evaluate the benefits and safety of herbal medicines to use their active ingredients for the development of natural and effective drugs.
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Affiliation(s)
- Abdalsalam Kmail
- Faculty of Sciences, Arab American University Jenin, P. O. Box 240, Jenin, Palestine
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Huang CK, Huang JY, Chang CH, Tsai SJ, Shu CC, Wang HC, Chien KL. The effect of statins on the risk of anti-tuberculosis drug-induced liver injury among patients with active tuberculosis: A cohort study. JOURNAL OF MICROBIOLOGY, IMMUNOLOGY, AND INFECTION = WEI MIAN YU GAN RAN ZA ZHI 2024:S1684-1182(24)00069-0. [PMID: 38632021 DOI: 10.1016/j.jmii.2024.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 03/18/2024] [Accepted: 04/02/2024] [Indexed: 04/19/2024]
Abstract
BACKGROUND Tuberculosis (TB) remains prevalent worldwide, and anti-TB drugs are associated with drug-induced liver injury (DILI). Statins have pleiotropic effects which may decrease inflammation and achieve immunomodulation. However, few studies have investigated the pleiotropic effects of statins on the risk of DILI. The purpose of this study was to investigate whether statins prevent anti-tuberculosis DILI among active TB patients on standard anti-TB drug therapy. METHODS We conducted a hospital-based retrospective cohort study using claims data from the Integrated Medical Database of National Taiwan University Hospital (NTUH-iMD). Patients with a positive TB culture were included. The use of statins was defined as a daily equivalent dose >0.5 mg of pitavastatin. Deterioration in liver function was evaluated according to elevated liver enzyme levels. The primary and secondary endpoints were the DILI and the severe DILI. The prognostic value of statins was evaluated by Kaplan-Meier analysis, and Cox proportional hazards models. RESULTS A total of 1312 patients with a diagnosis of TB and receiving anti-TB treatment were included. During the study period, 193 patients had the DILI and 140 patients had the severe DILI. Kaplan-Meier analysis showed a significant difference between the usual statin users and controls in the DILI. In multivariable Cox proportional hazards analysis, statins showed a protective effect against the primary and secondary endpoints. In addition, the protective effect of statins showed a dose-response relationship against the DILI. CONCLUSION Statin treatment had a protective effect against the risk of anti-TB DILI with a positive dose-response relationship.
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Affiliation(s)
- Chun-Kai Huang
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Institute of Epidemiology & Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
| | - Jei-Yie Huang
- Institute of Epidemiology & Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan; Department of Nuclear Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chin-Hao Chang
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Shang-Jie Tsai
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Chin-Chung Shu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
| | - Hao-Chien Wang
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; The National Taiwan University Cancer Center, Taipei, Taiwan
| | - Kuo-Liong Chien
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Institute of Epidemiology & Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
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Stauffer WT, Bobardt M, Ure DR, Foster RT, Gallay P. Cyclophilin D knockout significantly prevents HCC development in a streptozotocin-induced mouse model of diabetes-linked NASH. PLoS One 2024; 19:e0301711. [PMID: 38573968 PMCID: PMC10994289 DOI: 10.1371/journal.pone.0301711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Accepted: 03/20/2024] [Indexed: 04/06/2024] Open
Abstract
A family of Peptidyl-prolyl isomerases (PPIases), called Cyclophilins, localize to numerous intracellular and extracellular locations where they contribute to a variety of essential functions. We previously reported that non-immunosuppressive pan-cyclophilin inhibitor drugs like reconfilstat (CRV431) or NV556 decreased multiple aspects of non-alcoholic fatty liver disease (NAFLD) in mice under two different non-alcoholic steatohepatitis (NASH) mouse models. Both CRV431 and NV556 inhibit several cyclophilin isoforms, among which cyclophilin D (CypD) has not been previously investigated in this context. It is unknown whether it is necessary to simultaneously inhibit multiple cyclophilin family members to achieve therapeutic benefits or if loss-of-function of one is sufficient. Furthermore, narrowing down the isoform most responsible for a particular aspect of NAFLD/NASH, such as hepatocellular carcinoma (HCC), would allow for more precise future therapies. Features of human diabetes-linked NAFLD/NASH can be reliably replicated in mice by administering a single high dose of streptozotocin to disrupt pancreatic beta cells, in conjunction with a high sugar, high fat, high cholesterol western diet over the course of 30 weeks. Here we show that while both wild-type (WT) and Ppif-/- CypD KO mice develop multipe severe NASH disease features under this model, the formation of HCC nodules was significantly blunted only in the CypD KO mice. Furthermore, of differentially expressed transcripts in a qPCR panel of select HCC-related genes, nearly all were downregulated in the CypD KO background. Cyclophilin inhibition is a promising and novel avenue of treatment for diet-induced NAFLD/NASH. This study highlights the impact of CypD loss-of-function on the development of HCC, one of the most severe disease outcomes.
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Affiliation(s)
- Winston T. Stauffer
- Department of Immunology & Microbiology, Scripps Research, La Jolla, California, United States of America
| | - Michael Bobardt
- Department of Immunology & Microbiology, Scripps Research, La Jolla, California, United States of America
| | - Daren R. Ure
- Hepion Pharmaceuticals, Edison, New Jersey, United States of America
| | - Robert T. Foster
- Hepion Pharmaceuticals, Edison, New Jersey, United States of America
| | - Philippe Gallay
- Department of Immunology & Microbiology, Scripps Research, La Jolla, California, United States of America
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Wang Z, Jiang L, Lv X, Yin H, Wang Z, Li W, Liu Y. Higher risk of hepatotoxicity associated with cabozantinib in cancer patients. Crit Rev Oncol Hematol 2024; 196:104298. [PMID: 38364886 DOI: 10.1016/j.critrevonc.2024.104298] [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: 10/10/2023] [Revised: 02/05/2024] [Accepted: 02/12/2024] [Indexed: 02/18/2024] Open
Abstract
BACKGROUND The efficacy of cabozantinib has attracted interest in various solid tumors. The primary aim of this study was to evaluate the risk of hepatotoxicity associated with cabozantinib in the patients with cancer. METHODS PubMed, Cochrane, and EMBASE databases were searched for published randomized controlled trials (RCTs) from inception to September 9, 2023. The mainly outcomes were all-grade and grade ≥3 elevation of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), expressed as relative risk (RR) and 95% confidence interval (CI). All data were pooled using fixed-effect or random-effects models according to the heterogeneity of the included RCTs. RESULTS Among the 922 records identified, 8 RCTs incorporating 2613 patients with cancer were included. For patients receiving cabozantinib, the relative risks of all-grade AST elevation (RR, 2.63; 95% CI, 2.16-3.20, P < 0.001), all-grade ALT elevation (RR, 2.89; 95% CI, 2.31-3.60, P < 0.001), grade ≥3 AST elevation (RR, 2.26; 95% CI, 1.34-3.83, P = 0.002), and grade ≥3 ALT elevation (RR, 3.40; 95% CI, 1.65-7.01, P < 0.001) were higher than those of patients who did not receive cabozantinib group. Further subgroup analysis showed that the relative risk of hepatotoxicity associated with cabozantinib was higher than that in the other TKIs (erlotinib, sunitinib, and sorafenib) and the non-TKI drug groups (everolimus, prednisone, mitoxantrone, and paclitaxel). CONCLUSIONS Compared with other solid tumor drugs, such as everolimus, sorafenib, sunitinib, paclitaxel, mitoxantrone-prednisone et al., cabozantinib has a higher risk of hepatotoxicity.
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Affiliation(s)
- Zhen Wang
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin 124221, China
| | - Lili Jiang
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin 124221, China
| | - Xin Lv
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin 124221, China
| | - Hang Yin
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin 124221, China
| | - Zhe Wang
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Wenli Li
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin 124221, China
| | - Yong Liu
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin 124221, China.
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Abegg VF, Panajatovic MV, Mancuso RV, Allard JA, Duthaler U, Odermatt A, Krähenbühl S, Bouitbir J. Mechanisms of hepatocellular toxicity associated with the components of St. John's Wort extract hypericin and hyperforin in HepG2 and HepaRG cells. Toxicol Lett 2024; 393:1-13. [PMID: 38219807 DOI: 10.1016/j.toxlet.2024.01.008] [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: 10/16/2023] [Revised: 12/19/2023] [Accepted: 01/10/2024] [Indexed: 01/16/2024]
Abstract
St. John's Wort preparations are used for the treatment of mild to moderate depression. They are usually well tolerated but can cause adverse reactions including liver toxicity in rare cases. To date, the mechanism(s) underlying the hepatotoxicity of St. John's Wort extracts are poorly investigated. We studied the hepatocellular toxicity of hypericin and hyperforin as the two main ingredients of St. John's Wort extracts in HepG2 and HepaRG cells and compared the effects to citalopram (a synthetic serotonin uptake inhibitor) with a special focus on mitochondrial toxicity and oxidative stress. In HepG2 cells, hypericin was membrane-toxic at 100 µM and depleted ATP at 20 µM. In HepaRG cells, ATP depletion started at 5 µM. In comparison, hyperforin and citalopram were not toxic up to 100 µM. In HepG2 cells, hypericin decreased maximal respiration starting at 2 µM and mitochondrial ATP formation starting at 10 µM but did not affect glycolytic ATP production. Hypericin inhibited the activity of complex I, II and IV of the electron transfer system and caused mitochondrial superoxide accumulation in cells. The protein expression of mitochondrial superoxide dismutase 2 (SOD2) and thioredoxin 2 (TRX2) and total and reduced glutathione decreased in cells exposed to hypericin. Finally, hypericin diminished the mitochondrial DNA copy number and caused cell necrosis but not apoptosis. In conclusion, hypericin, but not hyperforin or citalopram, is a mitochondrial toxicant at low micromolar concentrations. This mechanism may contribute to the hepatotoxicity occasionally observed in susceptible patients treated with St. John's Wort preparations.
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Affiliation(s)
- Vanessa Fabienne Abegg
- Division of Pharmaceutical Biology, Department of Pharmaceutical Sciences, University of Basel, Switzerland
| | | | | | - Julien Arthur Allard
- Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Switzerland
| | - Urs Duthaler
- Division of Clinical Pharmacology & Toxicology, University Hospital, Basel, Switzerland
| | - Alex Odermatt
- Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Switzerland
| | - Stephan Krähenbühl
- Division of Clinical Pharmacology & Toxicology, University Hospital, Basel, Switzerland
| | - Jamal Bouitbir
- Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Switzerland.
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Yang K, Kong R, Spiegel R, Baird JD, O'Keefe K, Howell BA, Watkins PB. Quantitative Systems Toxicology Modeling Informed Safe Dose Selection of Emvododstat in Acute Myeloid Leukemia Patients. Clin Pharmacol Ther 2024; 115:525-534. [PMID: 38065572 DOI: 10.1002/cpt.3136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Accepted: 12/03/2023] [Indexed: 12/23/2023]
Abstract
Clinical investigation of emvododstat for the treatment of solid tumors was halted after two patients who were heavily treated with other anticancer therapies experienced drug-induced liver failure. However, preclinical investigations supported that emvododstat at lower doses might be effective in treating acute myeloid leukemia (AML) and against severe acute respiratory syndrome-coronavirus 2 as a dihydroorotate dehydrogenase inhibitor. Therefore, a quantitative systems toxicology model, DILIsym, was used to predict liver safety of the proposed dosing of emvododstat in AML clinical trials. In vitro mechanistic toxicity data of emvododstat and its desmethyl metabolite were integrated with in vivo exposure within DILIsym to predict hepatotoxicity responses in a simulated human population. DILIsym simulations predicted alanine aminotransferase elevations observed in prior emvododstat clinical trials in patients with solid tumors, but not in the prospective AML clinical trial with the proposed dosing regimens. Exposure predictions based on physiologically-based pharmacokinetic modeling suggested that reduced doses of emvododstat would produce clinical exposures that would be efficacious to treat AML. In the AML clinical trial, only eight patients experienced aminotransferase elevations, all of which were mild (grade 1), all resolving within a short period of time, and no patient showed symptoms of hepatotoxicity, confirming the prospective prediction of liver safety. Overall, retrospective DILIsym simulations adequately predicted the liver safety liabilities of emvododstat in solid tumor trials and prospective simulations predicted the liver safety of reduced doses in an AML clinical trial. The modeling was critical to enabling regulatory approval to proceed with the AML clinical trial wherein the predicted liver safety was confirmed.
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Affiliation(s)
- Kyunghee Yang
- Quantitative Systems Pharmacology Solutions, Simulations Plus Inc., Research Triangle Park, North Carolina, USA
| | - Ronald Kong
- PTC Therapeutics, Inc., South Plainfield, New Jersey, USA
| | - Robert Spiegel
- PTC Therapeutics, Inc., South Plainfield, New Jersey, USA
| | - John D Baird
- PTC Therapeutics, Inc., South Plainfield, New Jersey, USA
| | - Kylie O'Keefe
- PTC Therapeutics, Inc., South Plainfield, New Jersey, USA
| | - Brett A Howell
- Quantitative Systems Pharmacology Solutions, Simulations Plus Inc., Research Triangle Park, North Carolina, USA
| | - Paul B Watkins
- UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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Tao W, Fan Q, Wei J. Gut-Liver Axis as a Therapeutic Target for Drug-Induced Liver Injury. Curr Issues Mol Biol 2024; 46:1219-1236. [PMID: 38392196 PMCID: PMC10887627 DOI: 10.3390/cimb46020078] [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: 12/19/2023] [Revised: 01/27/2024] [Accepted: 01/30/2024] [Indexed: 02/24/2024] Open
Abstract
Drug-induced liver injury (DILI) is a liver disease that remains difficult to predict and diagnose, and the underlying mechanisms are yet to be fully clarified. The gut-liver axis refers to the reciprocal interactions between the gut and the liver, and its homeostasis plays a prominent role in maintaining liver health. It has been recently reported that patients and animals with DILI have a disrupted gut-liver axis, involving altered gut microbiota composition, increased intestinal permeability and lipopolysaccharide translocation, decreased short-chain fatty acids production, and impaired bile acid metabolism homeostasis. The present review will summarize the evidence from both clinical and preclinical studies about the role of the gut-liver axis in the pathogenesis of DILI. Moreover, we will focus attention on the potential therapeutic strategies for DILI based on improving gut-liver axis function, including herbs and phytochemicals, probiotics, fecal microbial transplantation, postbiotics, bile acids, and Farnesoid X receptor agonists.
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Affiliation(s)
- Wenjing Tao
- Hubei Key Laboratory of Animal Embryo and Molecular Breeding, Institute of Animal Husbandry and Veterinary, Hubei Academy of Agricultural Sciences, Wuhan 430064, China
| | - Qiwen Fan
- Hubei Key Laboratory of Animal Embryo and Molecular Breeding, Institute of Animal Husbandry and Veterinary, Hubei Academy of Agricultural Sciences, Wuhan 430064, China
| | - Jintao Wei
- Hubei Key Laboratory of Animal Embryo and Molecular Breeding, Institute of Animal Husbandry and Veterinary, Hubei Academy of Agricultural Sciences, Wuhan 430064, China
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Lucena MI, Villanueva-Paz M, Alvarez-Alvarez I, Aithal GP, Björnsson ES, Cakan-Akdogan G, Cubero FJ, Esteves F, Falcon-Perez JM, Fromenty B, Garcia-Ruiz C, Grove JI, Konu O, Kranendonk M, Kullak-Ublick GA, Miranda JP, Remesal-Doblado A, Sancho-Bru P, Nelson L, Andrade RJ, Daly AK, Fernandez-Checa JC. Roadmap to DILI research in Europe. A proposal from COST action ProEuroDILINet. Pharmacol Res 2024; 200:107046. [PMID: 38159783 PMCID: PMC7617395 DOI: 10.1016/j.phrs.2023.107046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 12/19/2023] [Accepted: 12/20/2023] [Indexed: 01/03/2024]
Abstract
In the current article the aims for a constructive way forward in Drug-Induced Liver Injury (DILI) are to highlight the most important priorities in research and clinical science, therefore supporting a more informed, focused, and better funded future for European DILI research. This Roadmap aims to identify key challenges, define a shared vision across all stakeholders for the opportunities to overcome these challenges and propose a high-quality research program to achieve progress on the prediction, prevention, diagnosis and management of this condition and impact on healthcare practice in the field of DILI. This will involve 1. Creation of a database encompassing optimised case report form for prospectively identified DILI cases with well-characterised controls with competing diagnoses, biological samples, and imaging data; 2. Establishing of preclinical models to improve the assessment and prediction of hepatotoxicity in humans to guide future drug safety testing; 3. Emphasis on implementation science and 4. Enhanced collaboration between drug-developers, clinicians and regulatory scientists. This proposed operational framework will advance DILI research and may bring together basic, applied, translational and clinical research in DILI.
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Affiliation(s)
- M I Lucena
- Servicios de Aparato Digestivo y Farmacología Clínica, Hospital Universitario Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, Universidad de Málaga, Málaga, Spain; Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain; Plataforma de Investigación Clínica y Ensayos Clínicos UICEC-IBIMA, Plataforma ISCIII de Investigación Clínica, Madrid, Spain.
| | - M Villanueva-Paz
- Servicios de Aparato Digestivo y Farmacología Clínica, Hospital Universitario Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, Universidad de Málaga, Málaga, Spain; Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - I Alvarez-Alvarez
- Servicios de Aparato Digestivo y Farmacología Clínica, Hospital Universitario Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, Universidad de Málaga, Málaga, Spain; Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - G P Aithal
- Nottingham Digestive Diseases Centre, Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, United Kingdom; NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, United Kingdom
| | - E S Björnsson
- Faculty of Medicine, University of Iceland, Department of Gastroenterology and Hepatology, Landspitali University Hospital, Reykjavik, Iceland
| | - G Cakan-Akdogan
- Izmir Biomedicine and Genome Center, Izmir, Turkey. Department of Medical Biology, Faculty of Medicine, Dokuz Eylül University, Izmir, Turkey
| | - F J Cubero
- Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain; Department of Immunology, Ophthalmology and ORL, Complutense University School of Medicine, Madrid, Spain; Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - F Esteves
- Center for Toxicogenomics and Human Health (ToxOmics), NMS | FCM, Universidade NOVA de Lisboa, Lisbon, Portugal
| | - J M Falcon-Perez
- Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain; Exosomes Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Bizkaia, 48160, Spain. IKERBASQUE, Basque Foundation for Science, Bilbao, Bizkaia 48009, Spain
| | - B Fromenty
- INSERM, Univ Rennes, INRAE, Institut NUMECAN (Nutrition Metabolisms and Cancer) UMR_A 1341, UMR_S 1317, F-35000 Rennes, France
| | - C Garcia-Ruiz
- Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. University of Barcelona, Barcelona, Spain; Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain
| | - J I Grove
- Nottingham Digestive Diseases Centre, Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, United Kingdom; NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, United Kingdom
| | - O Konu
- Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, Ankara, Turkey; Interdisciplinary Neuroscience Program, Bilkent University, Ankara, Turkey; UNAM-Institute of Materials Science and Nanotechnology, Bilkent University, Ankara, Turkey
| | - M Kranendonk
- Center for Toxicogenomics and Human Health (ToxOmics), NMS | FCM, Universidade NOVA de Lisboa, Lisbon, Portugal
| | - G A Kullak-Ublick
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland; CMO & Patient Safety, Global Drug Development, Novartis Pharma, Basel, Switzerland
| | - J P Miranda
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - A Remesal-Doblado
- Servicios de Aparato Digestivo y Farmacología Clínica, Hospital Universitario Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, Universidad de Málaga, Málaga, Spain
| | - P Sancho-Bru
- Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. University of Barcelona, Barcelona, Spain
| | - L Nelson
- Institute for Bioengineering, School of Engineering, Faraday Building, The University of Edinburgh, Scotland, UK
| | - R J Andrade
- Servicios de Aparato Digestivo y Farmacología Clínica, Hospital Universitario Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, Universidad de Málaga, Málaga, Spain; Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - A K Daly
- Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - J C Fernandez-Checa
- Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. University of Barcelona, Barcelona, Spain; Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
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49
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Mao J, Tan L, Tian C, Wang W, Zhang H, Zhu Z, Li Y. Research progress on rodent models and its mechanisms of liver injury. Life Sci 2024; 337:122343. [PMID: 38104860 DOI: 10.1016/j.lfs.2023.122343] [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: 09/21/2023] [Revised: 11/22/2023] [Accepted: 12/06/2023] [Indexed: 12/19/2023]
Abstract
The liver is the most important organ for biological transformation in the body and is crucial for maintaining the body's vital activities. Liver injury is a serious pathological condition that is commonly found in many liver diseases. It has a high incidence rate, is difficult to cure, and is prone to recurrence. Liver injury can cause serious harm to the body, ranging from mild to severe fatty liver disease. If the condition continues to worsen, it can lead to liver fibrosis and cirrhosis, ultimately resulting in liver failure or liver cancer, which can seriously endanger human life and health. Therefore, establishing an rodent model that mimics the pathogenesis and severity of clinical liver injury is of great significance for better understanding the pathogenesis of liver injury patients and developing more effective clinical treatment methods. The author of this article summarizes common chemical liver injury models, immune liver injury models, alcoholic liver injury models, drug-induced liver injury models, and systematically elaborates on the modeling methods, mechanisms of action, pathways of action, and advantages or disadvantages of each type of model. The aim of this study is to establish reliable rodent models for researchers to use in exploring anti-liver injury and hepatoprotective drugs. By creating more accurate theoretical frameworks, we hope to provide new insights into the treatment of clinical liver injury diseases.
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Affiliation(s)
- Jingxin Mao
- Chongqing Medical and Pharmaceutical College, Chongqing 400030, China; College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China
| | - Lihong Tan
- Chongqing Medical and Pharmaceutical College, Chongqing 400030, China; Chongqing Key Laboratory of High Active Traditional Chinese Drug Delivery System, Chongqing 400030, China
| | - Cheng Tian
- Chongqing Medical and Pharmaceutical College, Chongqing 400030, China; Chongqing Key Laboratory of High Active Traditional Chinese Drug Delivery System, Chongqing 400030, China
| | - Wenxiang Wang
- Chongqing Three Gorges Medical College, Chongqing 404120, China
| | - Hao Zhang
- Chongqing Medical and Pharmaceutical College, Chongqing 400030, China; Chongqing Key Laboratory of High Active Traditional Chinese Drug Delivery System, Chongqing 400030, China
| | - Zhaojing Zhu
- Chongqing Medical and Pharmaceutical College, Chongqing 400030, China; Chongqing Key Laboratory of High Active Traditional Chinese Drug Delivery System, Chongqing 400030, China
| | - Yan Li
- Chongqing Medical and Pharmaceutical College, Chongqing 400030, China; Chongqing Key Laboratory of High Active Traditional Chinese Drug Delivery System, Chongqing 400030, China.
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50
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Leal F, Zeiringer S, Jeitler R, Costa PF, Roblegg E. A comprehensive overview of advanced dynamic in vitro intestinal and hepatic cell culture models. Tissue Barriers 2024; 12:2163820. [PMID: 36680530 PMCID: PMC10832944 DOI: 10.1080/21688370.2022.2163820] [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: 08/23/2022] [Accepted: 12/22/2022] [Indexed: 01/22/2023] Open
Abstract
Orally administered drugs pass through the gastrointestinal tract before being absorbed in the small intestine and metabolised in the liver. To test the efficacy and toxicity of drugs, animal models are often employed; however, they are not suitable for investigating drug-tissue interactions and making reliable predictions, since the human organism differs drastically from animals in terms of absorption, distribution, metabolism and excretion of substances. Likewise, simple static in vitro cell culture systems currently used in preclinical drug screening often do not resemble the native characteristics of biological barriers. Dynamic models, on the other hand, provide in vivo-like cell phenotypes and functionalities that offer great potential for safety and efficacy prediction. Herein, current microfluidic in vitro intestinal and hepatic models are reviewed, namely single- and multi-tissue micro-bioreactors, which are associated with different methods of cell cultivation, i.e., scaffold-based versus scaffold-free.
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Affiliation(s)
- Filipa Leal
- BIOFABICS, Rua Alfredo Allen 455, 4200-135 Porto, Portugal
| | - Scarlett Zeiringer
- Department of Pharmaceutical Technology and Biopharmacy, University of Graz, Institute of Pharmaceutical Sciences, Universitaetsplatz 1, Graz, Austria
| | - Ramona Jeitler
- Department of Pharmaceutical Technology and Biopharmacy, University of Graz, Institute of Pharmaceutical Sciences, Universitaetsplatz 1, Graz, Austria
| | - Pedro F. Costa
- BIOFABICS, Rua Alfredo Allen 455, 4200-135 Porto, Portugal
| | - Eva Roblegg
- Department of Pharmaceutical Technology and Biopharmacy, University of Graz, Institute of Pharmaceutical Sciences, Universitaetsplatz 1, Graz, Austria
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