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Wang Z, Guo Z, Wang W, Zhang Q, Song S, Xue Y, Zhang Z, Wang J. Prediction of tuberculosis treatment outcomes using biochemical makers with machine learning. BMC Infect Dis 2025; 25:229. [PMID: 39962412 PMCID: PMC11834319 DOI: 10.1186/s12879-025-10609-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Accepted: 02/06/2025] [Indexed: 02/20/2025] Open
Abstract
BACKGROUND Tuberculosis (TB) continues to pose a significant threat to global public health. Enhancing patient prognosis is essential for alleviating the disease burden. OBJECTIVE This study aims to evaluate TB prognosis by incorporating treatment discontinuation into the assessment framework, expanding beyond mortality and drug resistance. METHODS Seven feature selection methods and twelve machine learning algorithms were utilized to analyze admission test data from TB patients, identifying predictive features and building prognostic models. SHapley Additive exPlanations (SHAP) were applied to evaluate feature importance in top-performing models. RESULTS Analysis of 1,086 TB cases showed that a K-Nearest Neighbor classifier with Mutual Information feature selection achieved an area under the receiver operation curve (AUC) of 0.87 (95% CI: 0.83-0.92). Key predictors of treatment failure included elevated levels of 5'-nucleotidase, uric acid, globulin, creatinine, cystatin C, and aspartate transaminase. SHAP analysis highlighted 5'-nucleotidase, uric acid, and globulin as having the most significant influence on predicting treatment discontinuation. CONCLUSION Our model provides valuable insights into TB outcomes based on initial patient tests, potentially guiding prevention and control strategies. Elevated biomarker levels before therapy are associated with increased risk of treatment discontinuation, indicating their potential as early warning indicators.
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Affiliation(s)
- Zheyue Wang
- Department of Epidemiology, Center for Global Health, School of Public Health, National Vaccine Innovation Platform, Nanjing Medical University, Nanjing, 211166, China
- Changzhou Medical Center, Nanjing Medical University, Changzhou, 213004, China
- Department of Epidemiology, Gusu School, Nanjing Medical University, Nanjing, 211166, China
| | - Zhenpeng Guo
- Department of Epidemiology, Center for Global Health, School of Public Health, National Vaccine Innovation Platform, Nanjing Medical University, Nanjing, 211166, China
- Changzhou Medical Center, Nanjing Medical University, Changzhou, 213004, China
| | - Weijia Wang
- School of Information and Software, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Qiang Zhang
- Department of Epidemiology, Center for Global Health, School of Public Health, National Vaccine Innovation Platform, Nanjing Medical University, Nanjing, 211166, China
| | - Suya Song
- Changzhou Medical Center, Nanjing Medical University, Changzhou, 213004, China
- Department of Pulmonary Diseases, The Third People's Hospital of Changzhou, Changzhou, 213001, China
| | - Yuan Xue
- Changzhou Medical Center, Nanjing Medical University, Changzhou, 213004, China
| | - Zhixin Zhang
- Changzhou Medical Center, Nanjing Medical University, Changzhou, 213004, China.
- Department of Pulmonary Diseases, The Third People's Hospital of Changzhou, Changzhou, 213001, China.
| | - Jianming Wang
- Department of Epidemiology, Center for Global Health, School of Public Health, National Vaccine Innovation Platform, Nanjing Medical University, Nanjing, 211166, China.
- Changzhou Medical Center, Nanjing Medical University, Changzhou, 213004, China.
- Department of Epidemiology, Gusu School, Nanjing Medical University, Nanjing, 211166, China.
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Shang S, Yang H, Qu L, Fan D, Deng J. Ginsenoside, a potential natural product against liver diseases: a comprehensive review from molecular mechanisms to application. Crit Rev Food Sci Nutr 2025:1-25. [PMID: 39810734 DOI: 10.1080/10408398.2025.2451761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2025]
Abstract
Liver disease constitutes a significant cause of global mortality, with its pathogenesis being multifaceted. Identifying effective pharmacological and preventive strategies is imperative for liver protection. Ginsenosides, the major bioactive compounds found in ginseng, exhibit multiple pharmacological activities including protection against liver-related diseases by mitigating liver fat accumulation and inflammation, preventing hepatic fibrosis, and exerting anti-hepatocarcinogenic effects. However, a comprehensive overview elucidating the regulatory pathways associated with ginsenosides in liver disease remains elusive. This review aims to consolidate the molecular mechanisms through which different ginsenosides ameliorate distinct liver diseases, alongside the pathogenic factors underlying liver ailments. Notably, ginsenosides Rb1 and Rg1 demonstrate significantly effective in treating fatty liver, hepatitis, and liver fibrosis, and ginsenosides CK and Rh2 exhibit potent anti-hepatocellular carcinogenic effects. Their molecular mechanisms underlying these effects primarily involve the modulation of AMPK, NF-κB, TGF-β, NFR2, JNK, and other pathways, thereby attenuating hepatic fat accumulation, inflammation, inhibition of hepatic stellate cell activation, and promoting apoptosis in hepatocellular carcinoma cells. Furthermore, it provides insights into the safety profile and current applications of ginsenosides, thereby facilitating their clinical development. Consequently, ginsenosides present promising prospects for liver disease management, underscoring their potential as valuable therapeutic agents in this context.
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Affiliation(s)
- Shiyan Shang
- Shaanxi Key Laboratory of Degradable Biomedical Materials, Shaanxi R&D Center of Biomaterials and Fermentation Engineering, Biotech & Biomed Research Institute, School of Chemical Engineering, Northwest University, Xi'an, China
| | - Haixia Yang
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Linlin Qu
- Shaanxi Key Laboratory of Degradable Biomedical Materials, Shaanxi R&D Center of Biomaterials and Fermentation Engineering, Biotech & Biomed Research Institute, School of Chemical Engineering, Northwest University, Xi'an, China
| | - Daidi Fan
- Shaanxi Key Laboratory of Degradable Biomedical Materials, Shaanxi R&D Center of Biomaterials and Fermentation Engineering, Biotech & Biomed Research Institute, School of Chemical Engineering, Northwest University, Xi'an, China
| | - Jianjun Deng
- Shaanxi Key Laboratory of Degradable Biomedical Materials, Shaanxi R&D Center of Biomaterials and Fermentation Engineering, Biotech & Biomed Research Institute, School of Chemical Engineering, Northwest University, Xi'an, China
- State Key Laboratory of Vegetable Biobreeding, Institute of Vegetables and Flowers, Chinese Academy of Agricultural Sciences, Beijing, China
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Liu Z, Ren J, Qiu C, Wang Y, Zhang T. Application of mesenchymal stem cells in liver fibrosis and regeneration. LIVER RESEARCH 2024; 8:246-258. [PMID: 39958916 PMCID: PMC11771278 DOI: 10.1016/j.livres.2024.11.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 11/20/2024] [Accepted: 11/22/2024] [Indexed: 02/18/2025]
Abstract
Liver transplantation remains the most effective treatment for end-stage liver disease (ESLD), but it is fraught with challenges such as immunosuppression, high risk and cost, and donor shortage. In recent years, stem cell transplantation has emerged as a promising new strategy for ESLD treatment, with mesenchymal stem cells (MSCs) gaining significant attention because of their unique properties. MSCs can regulate signaling pathways, including hepatocyte growth factor/c-Met, Wnt/beta (β)-catenin, Notch, transforming growth factor-β1/Smad, interleukin-6/Janus kinase/signal transducer and activator of transcription 3, and phosphatidylinositol 3-kinase/PDK/Akt, thereby influencing the progression of liver fibrosis and regeneration. As a promising stem cell type, MSCs offer numerous advantages in liver disease treatment, including low immunogenicity; ease of acquisition; unlimited proliferative ability; pluripotent differentiation potential; immunomodulatory function; and anti-inflammatory, antifibrotic, and antiapoptotic biological characteristics. This review outlines the mechanisms by which MSCs reverse liver fibrosis and promote liver regeneration. MSCs are crucial in reversing liver fibrosis and repairing liver damage through the secretion of growth factors, regulation of signaling pathways, and modulation of immune responses. MSCs have shown good therapeutic effects in preclinical and clinical studies, providing new strategies for liver disease treatment. However, challenges still exist in the clinical application of MSCs, including low differentiation efficiency and limited sources. This review provides a reference for MSC application in liver disease treatment. With the continuous progress in MSC research, MSCs are expected to achieve breakthroughs in liver disease treatment, thereby improving patient treatment outcomes.
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Affiliation(s)
- Zhenyu Liu
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of General Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
- Organ Transplantation Institute of Xiamen University, Xiamen Human Organ Transplantation Quality Control Center, Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Junkai Ren
- Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Cheng Qiu
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of General Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
- Organ Transplantation Institute of Xiamen University, Xiamen Human Organ Transplantation Quality Control Center, Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Ying Wang
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of General Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Tong Zhang
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of General Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
- Organ Transplantation Institute of Xiamen University, Xiamen Human Organ Transplantation Quality Control Center, Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, Fujian, China
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Yutani R, Venketaraman V, Sheren N. Treatment of Acute and Long-COVID, Diabetes, Myocardial Infarction, and Alzheimer's Disease: The Potential Role of a Novel Nano-Compound-The Transdermal Glutathione-Cyclodextrin Complex. Antioxidants (Basel) 2024; 13:1106. [PMID: 39334765 PMCID: PMC11429141 DOI: 10.3390/antiox13091106] [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: 06/23/2024] [Revised: 08/21/2024] [Accepted: 08/26/2024] [Indexed: 09/30/2024] Open
Abstract
Oxidative stress (OS) occurs from excessive reactive oxygen species or a deficiency of antioxidants-primarily endogenous glutathione (GSH). There are many illnesses, from acute and post-COVID-19, diabetes, myocardial infarction to Alzheimer's disease, that are associated with OS. These dissimilar illnesses are, in order, viral infections, metabolic disorders, ischemic events, and neurodegenerative disorders. Evidence is presented that in many illnesses, (1) OS is an early initiator and significant promotor of their progressive pathophysiologic processes, (2) early reduction of OS may prevent later serious and irreversible complications, (3) GSH deficiency is associated with OS, (4) GSH can likely reduce OS and restore adaptive physiology, (5) effective administration of GSH can be accomplished with a novel nano-product, the GSH/cyclodextrin (GC) complex. OS is an overlooked pathological process of many illnesses. Significantly, with the GSH/cyclodextrin (GC) complex, therapeutic administration of GSH is now available to reduce OS. Finally, rigorous prospective studies are needed to confirm the efficacy of this therapeutic approach.
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Affiliation(s)
- Ray Yutani
- Department of Family Medicine, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
| | - Vishwanath Venketaraman
- Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
| | - Nisar Sheren
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
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Wang T, Lu Z, Sun GF, He KY, Chen ZP, Qu XH, Han XJ. Natural Products in Liver Fibrosis Management: A Five-year Review. Curr Med Chem 2024; 31:5061-5082. [PMID: 38362686 DOI: 10.2174/0109298673288458240203064112] [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: 10/26/2023] [Revised: 01/11/2024] [Accepted: 01/23/2024] [Indexed: 02/17/2024]
Abstract
Liver fibrosis, characterized by the overproduction of extracellular matrix proteins within liver tissue, poses a rising global health concern. However, no approved antifibrotic drugs are currently available, highlighting the critical need for understanding the molecular mechanisms of liver fibrosis. This knowledge could not only aid in developing therapies but also enable early intervention, enhance disease prediction, and improve our understanding of the interaction between various underlying conditions and the liver. Notably, natural products used in traditional medicine systems worldwide and demonstrating diverse biochemical and pharmacological activities are increasingly recognized for their potential in treating liver fibrosis. This review aims to comprehensively understand liver fibrosis, emphasizing the molecular mechanisms and advancements in exploring natural products' antifibrotic potential over the past five years. It also acknowledges the challenges in their development and seeks to underscore their potency in enhancing patient prognosis and reducing the global burden of liver disease.
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Affiliation(s)
- Tao Wang
- Institute of Geriatrics, Jiangxi Provincial People's Hospital, the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, P.R. China
| | - Zhuo Lu
- Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, P.R. China
| | - Gui-Feng Sun
- Institute of Geriatrics, Jiangxi Provincial People's Hospital, the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, P.R. China
| | - Kai-Yi He
- Institute of Geriatrics, Jiangxi Provincial People's Hospital, the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, P.R. China
| | - Zhi-Ping Chen
- Department of Critical Care Medicine, Jiangxi Provincial People's Hospital, the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, P.R. China
| | - Xin-Hui Qu
- The Second Department of Neurology, Jiangxi Provincial People's Hospital, the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, P.R. China
| | - Xiao-Jian Han
- Institute of Geriatrics, Jiangxi Provincial People's Hospital, the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, P.R. China
- The Second Department of Neurology, Jiangxi Provincial People's Hospital, the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, P.R. China
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Kainat KM, Ansari MI, Bano N, Jagdale PR, Ayanur A, Kumar M, Sharma PK. Rifampicin-induced ER stress and excessive cytoplasmic vacuolization instigate hepatotoxicity via alternate programmed cell death paraptosis in vitro and in vivo. Life Sci 2023; 333:122164. [PMID: 37827230 DOI: 10.1016/j.lfs.2023.122164] [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: 08/06/2023] [Revised: 09/29/2023] [Accepted: 10/07/2023] [Indexed: 10/14/2023]
Abstract
AIMS Rifampicin-induced hepatotoxicity is a primary cause of drug-induced liver injury (DILI), posing a significant challenge to its continued clinical application. Moreover, the mechanism underlying rifampicin-induced hepatotoxicity remains unclear. MAIN METHODS Human hepatocyte line-17 (HHL-17) cells were treated with an increasing dose of rifampicin for 24 h, and male Wistar rats were given rifampicin [150 mg/kg body weight (bw)] orally for 28 days. Viability assay, protein expression, and cell death assays were analyzed in vitro. Moreover, liver serum markers, body/organ weight, H&E staining, protein expression, etc., were assayed in vivo. KEY FINDINGS Rifampicin induced a dose-dependent hepatotoxicity in HHL-17 cells (IC50; 600 μM), and increased the serum levels of liver injury markers, e.g., alanine transaminase (ALT) and aspartate transaminase (AST) in rats. Rifampicin-induced cell death was non-apoptotic and non-necroptotic both in vitro and in vivo. Further, excessive cellular vacuolization and reduced expression of Alix protein confirmed the induction of paraptosis both in vitro and in vivo. In addition, a significant increase in the endoplasmic reticulum (ER) stress markers (e.g., BiP, CHOP, and total polyubiquitinated proteins) was detected, demonstrating the induction of ER stress and altered protein homeostasis. Interestingly, rifampicin-induced hepatotoxicity was associated with the inhibition of autophagy and enhanced reactive oxygen species (ROS) generation in HHL-17 cells. Furthermore, inhibition of protein synthesis by cycloheximide (CHX) suppressed paraptosis by alleviating rifampicin-induced ER stress and ROS generation. SIGNIFICANCE Rifampicin-induced hepatotoxicity involves ER stress-driven paraptosis as a novel mechanism of its toxicity that may be targeted to protect liver cells from rifampicin toxicity.
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Affiliation(s)
- K M Kainat
- Food Drug and Chemical Toxicology Group, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Mohammad Imran Ansari
- Food Drug and Chemical Toxicology Group, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Nuzhat Bano
- Food Drug and Chemical Toxicology Group, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Pankaj Ramji Jagdale
- Regulatory Toxicology Group, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India
| | - Anjaneya Ayanur
- Regulatory Toxicology Group, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India
| | - Mahadeo Kumar
- Regulatory Toxicology Group, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India
| | - Pradeep Kumar Sharma
- Food Drug and Chemical Toxicology Group, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
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Hao Z, Zhang M, Chen X, Zhu M, Han B, He Y, Yi H, Tang S. Genetic variants of the nuclear factor erythroid 2-related factor 2/antioxidant reaction element pathway on the risk of antituberculosis drug-induced liver injury: a systematic review. Pharmacogenomics 2023; 24:345-357. [PMID: 37166414 DOI: 10.2217/pgs-2023-0040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/12/2023] Open
Abstract
Aim: To evaluate the effects of genetic variants in the nuclear factor erythroid 2-related factor 2/antioxidant reaction element signaling pathway on antituberculosis drug-induced liver injury (AT-DILI) susceptibility. Methods: The PubMed, Embase, Cochrane, Web of Science, China National Knowledge Infrastructure and Wanfang databases were searched from inception to April 2022. Results: Seven case-control studies with 4676 patients were included. Six genes with 35 SNPs in the pathway have been reported. Among 17 SNPs reported in two or more studies, the meta-analysis indicated that only one SNP (rs3735656 in MAFK) was significantly associated with a decreased risk for AT-DILI under the dominant model (odds ratio: 0.636; 95% CI: 0.519-0.780; p < 0.001). Conclusion: SNP rs3735656 in the MAFK gene was significantly associated with the risk of AT-DILI.
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Affiliation(s)
- Zhuolu Hao
- Department of Epidemiology & Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Meiling Zhang
- Department of Infectious Disease, The Jurong Hospital Affiliated to Jiangsu University, Jurong, 212400, China
| | - Xinyu Chen
- Department of Epidemiology & Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Min Zhu
- Department of Epidemiology & Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Bing Han
- Department of Epidemiology & Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Yiwen He
- Department of Epidemiology & Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Honggang Yi
- Department of Epidemiology & Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Shaowen Tang
- Department of Epidemiology & Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
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Sahu N, Rakshit S, Nirala SK, Bhadauria M. Naringenin protects hepato-renal tissues against antituberculosis drugs induced toxic manifestations by modulating interleukin-6, insulin like growth factor-1, biochemical and ultra-structural integrity. Mol Biol Rep 2023; 50:1019-1031. [PMID: 36383336 DOI: 10.1007/s11033-022-07799-y] [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: 02/04/2022] [Revised: 07/13/2022] [Accepted: 07/14/2022] [Indexed: 11/17/2022]
Abstract
BACKGROUND The antituberculosis drugs (ATDs), isoniazid, rifampicin, pyrazinamide and ethambutol prompt extreme hepatic and renal damage during treatment of tuberculosis. The present study aimed to investigate protective potential of naringenin against ATDs induced hepato-renal injury. METHODS Rats were administered with ATDs (pyrazinamide; 210, ethambutol; 170, isoniazid; 85, rifampicin; 65 mg/kg b.wt) orally for 8 weeks (3 days/week) followed by naringenin at three different doses (10, 20 and 40 mg/kg b.wt) conjointly for 8 weeks (3 days/week alternately to ATDs administration) and silymarin (50 mg/kg b.wt) as positive control. RESULTS Exposure to ATDs caused significant increase in interleukin-6 (IL-6), triglycerides, cholesterol, bilirubin whereas depletion in insulin like growth factor-1 (IGF-1), albumin and glucose in serum. Endogenous antioxidant enzymes glutathione reductase (GR), glutathione peroxidase (GPx) and glucose-6-phosphate-dehydrogenase (G-6-PDH) were diminished in liver and kidney tissues with parallel increase in triglycerides, cholesterol, microsomal LPO and aniline hydroxylase (CYP2E1 enzyme). Ultra-structural observations of liver and kidney showed marked deviation in plasma membranes of various cellular and sub-cellular organelles after 8 weeks of exposure to ATDs. CONCLUSIONS Conjoint treatment of naringenin counteracted ATDs induced toxic manifestations by regulating IL-6, IGF-1, CYP2E1, biochemical and ultra-structural integrity in a dose dependent manner. Naringenin has excellent potential to protect ATDs induced hepato-renal injury by altering oxidative stress, modulation of antioxidant enzymes, serum cytokines and ultra-structural changes.
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Affiliation(s)
- Nisha Sahu
- Toxicology and Pharmacology Laboratory, Department of Zoology, Guru Ghasidas University, 495009, Bilaspur, CG, India
| | - Samrat Rakshit
- Toxicology and Pharmacology Laboratory, Department of Zoology, Guru Ghasidas University, 495009, Bilaspur, CG, India
| | - Satendra Kumar Nirala
- Laboratory of Natural Products, Department of Rural Technology and Social Development, Guru Ghasidas University, 495009, Bilaspur, CG, India
| | - Monika Bhadauria
- Toxicology and Pharmacology Laboratory, Department of Zoology, Guru Ghasidas University, 495009, Bilaspur, CG, India.
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Zhuang X, Li L, Liu T, Zhang R, Yang P, Wang X, Dai L. Mechanisms of isoniazid and rifampicin-induced liver injury and the effects of natural medicinal ingredients: A review. Front Pharmacol 2022; 13:1037814. [PMID: 36299895 PMCID: PMC9589499 DOI: 10.3389/fphar.2022.1037814] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 09/29/2022] [Indexed: 11/28/2022] Open
Abstract
Isoniazid (INH) and rifampicin (RFP) are the first-line medications for tuberculosis treatment, and liver injury is the major adverse effect. Natural medicinal ingredients provide distinct benefits in alleviating patients’ symptoms, lowering the liver injury risk, delaying disease progression, and strengthening the body’s ability to heal. This paper summarises the recent research on the mechanisms of INH and RFP-induced liver injury and the effects of natural medicinal ingredients. It is believed that INH-induced liver injury may be attributed to oxidative stress, mitochondrial dysfunction, drug metabolic enzymes, protoporphyrin IX accumulation, endoplasmic reticulum stress, bile transport imbalance, and immune response. RFP-induced liver injury is mainly related to cholestasis, endoplasmic reticulum stress, and liver lipid accumulation. However, the combined effect of INH and RFP on liver injury risk is still uncertain. RFP can increase INH-induced hepatotoxicity by regulating the expression of drug-metabolizing enzymes and transporters. In contrast, INH can antagonize RFP-induced liver injury by reducing the total bilirubin level in the blood. Sagittaria sagittifolia polysaccharide, quercetin, gallic acid, and other natural medicinal ingredients play protective roles on INH and RFP-induced liver injury by enhancing the body’s antioxidant capacity, regulating metabolism, inhibiting cell apoptosis, and reducing the inflammatory response. There are still many gaps in the literature on INH and RFP-induced liver injury mechanisms and the effects of natural medicinal ingredients. Thus, further research should be carried out from the perspectives of liver injury phenotype, injury markers, in vitro and in vivo liver injury model construction, and liver-gut axis. This paper comprehensively reviewed the literature on mechanisms involved in INH and RFP-induced liver injury and the status of developing new drugs against INH and RFP-induced liver injury. In addition, this review also highlighted the uses and advantages of natural medicinal ingredients in treating drug-induced liver injury.
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Affiliation(s)
- Xiuping Zhuang
- School of Pharmacy, Binzhou Medical University, Yantai, China
- School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Li Li
- Department of Pediatrics, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Tianyi Liu
- Grade Three Laboratory of Traditional Chinese Medicine Preparation of the National Administration of Traditional Chinese Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Rui Zhang
- School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Peimin Yang
- Grade Three Laboratory of Traditional Chinese Medicine Preparation of the National Administration of Traditional Chinese Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xin Wang
- Grade Three Laboratory of Traditional Chinese Medicine Preparation of the National Administration of Traditional Chinese Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
- *Correspondence: Xin Wang, ; Long Dai,
| | - Long Dai
- School of Pharmacy, Binzhou Medical University, Yantai, China
- *Correspondence: Xin Wang, ; Long Dai,
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10
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Guo YQ, Zhang YJ, Pan YZ, Wu MY, Liu J, Yang W. Recent advances in research of modes of hepatocyte death in anti-tuberculosis drug-induced liver injury. Shijie Huaren Xiaohua Zazhi 2022; 30:817-822. [DOI: 10.11569/wcjd.v30.i18.817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Antituberculosis drug-induced liver injury (ATB-DILI) is the most common and most serious side effect of antituberculous drug therapy, which brings great challenges to drug treatment of tuberculosis. Isoniazid and rifampicin as first-line anti-tuberculosis drugs produce a variety of toxic metabolites that directly cause liver cell necrosis, and a large amount of free radicals that induce oxidative stress, leading to programmed death of liver cells such as apoptosis, ferroptosis, and autophagy. Iron death is a recently discovered mode of cell death, and its role in ATB-DILI has not been fully elucidated. Blocking the pathway of hepatocyte death is an important means to treat ATB-DILI. In this paper, we discuss the mechanism and characteristics of different cell death modes in order to help identify new diagnostic markers and therapeutic drug targets.
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Affiliation(s)
- Yu-Qing Guo
- Department of Pharmacy, Hospital for Infectious Diseases, Soochow University, Suzhou 215131, Jiangsu Province, China
| | - Yi-Jie Zhang
- Department of Pharmacy, Hospital for Infectious Diseases, Soochow University, Suzhou 215131, Jiangsu Province, China
| | - Yun-Zhi Pan
- Department of Pharmacy, Hospital for Infectious Diseases, Soochow University, Suzhou 215131, Jiangsu Province, China
| | - Mei-Ying Wu
- Department of Pharmacy, Hospital for Infectious Diseases, Soochow University, Suzhou 215131, Jiangsu Province, China
| | - Jia Liu
- Department of Pharmacy, Hospital for Infectious Diseases, Soochow University, Suzhou 215131, Jiangsu Province, China
| | - Wei Yang
- Department of Pharmacy, Hospital for Infectious Diseases, Soochow University, Suzhou 215131, Jiangsu Province, China
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11
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Georgiev T, Hadzhibozheva P, Karamalakova Y, Georgieva E, Perinkadakatt F, Ilinov Z, Petkov K, Ananiev J. Therapeutic approach of glutathione/glutathione peroxidase-4 axis modulation in the light of ferroptosis. PHARMACIA 2022. [DOI: 10.3897/pharmacia.69.e87716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
In the 21st century beginning, the evidence of a new type of programmed cell death, different from apoptosis, began to accumulate. In 2012, the ferroptosis concept was officially introduced. It refers to a kind of cell death that is associated with iron accumulation in the cell, impaired redox potential, and ROS increment with concomitant lipid peroxidation. Ferroptosis plays an important role in the pathophysiology of several organ damages such as tumors, neurodegenerative, ischemia-reperfusion, inflammatory diseases, and others. In ferroptosis, the leading mechanism is the glutathione (GSH) depletion and inactivation of Glutathione peroxidase-4 (GPX4), which strongly shifts the oxidative balance in the cell, leading to the activation of certain signalling pathways to induce oxidative death. The article aims to focus attention on the modulation of the GSH/GPX axis as a key factor in the treatment of these diseases.
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12
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Merchant SA, Shaikh MJS, Nadkarni P. Tuberculosis conundrum - current and future scenarios: A proposed comprehensive approach combining laboratory, imaging, and computing advances. World J Radiol 2022; 14:114-136. [PMID: 35978978 PMCID: PMC9258306 DOI: 10.4329/wjr.v14.i6.114] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 04/17/2022] [Accepted: 05/28/2022] [Indexed: 02/06/2023] Open
Abstract
Tuberculosis (TB) remains a global threat, with the rise of multiple and extensively drug resistant TB posing additional challenges. The International health community has set various 5-yearly targets for TB elimination: mathematical modelling suggests that a 2050 target is feasible with a strategy combining better diagnostics, drugs, and vaccines to detect and treat both latent and active infection. The availability of rapid and highly sensitive diagnostic tools (Gene-Xpert, TB-Quick) will vastly facilitate population-level identification of TB (including rifampicin resistance and through it, multi-drug-resistant TB). Basic-research advances have illuminated molecular mechanisms in TB, including the protective role of Vitamin D. Also, Mycobacterium tuberculosis impairs the host immune response through epigenetic mechanisms (histone-binding modulation). Imaging will continue to be key, both for initial diagnosis and follow-up. We discuss advances in multiple imaging modalities to evaluate TB tissue changes, such as molecular imaging techniques (including pathogen-specific positron emission tomography imaging agents), non-invasive temporal monitoring, and computing enhancements to improve data acquisition and reduce scan times. Big data analysis and Artificial Intelligence (AI) algorithms, notably in the AI sub-field called “Deep Learning”, can potentially increase the speed and accuracy of diagnosis. Additionally, Federated learning makes multi-institutional/multi-city AI-based collaborations possible without sharing identifiable patient data. More powerful hardware designs - e.g., Edge and Quantum Computing- will facilitate the role of computing applications in TB. However, “Artificial Intelligence needs real Intelligence to guide it!” To have maximal impact, AI must use a holistic approach that incorporates time tested human wisdom gained over decades from the full gamut of TB, i.e., key imaging and clinical parameters, including prognostic indicators, plus bacterial and epidemiologic data. We propose a similar holistic approach at the level of national/international policy formulation and implementation, to enable effective culmination of TB’s endgame, summarizing it with the acronym “TB - REVISITED”.
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Affiliation(s)
- Suleman Adam Merchant
- Lokmanya Tilak Municipal Medical College and General Hospital, Mumbai 400022, Maharashtra, India
| | - Mohd Javed Saifullah Shaikh
- Department of Radiology, North Bengal Neuro Centre, Jupiter magnetic resonance imaging, Diagnostic Centre, Siliguri 734003, West Bengal, India
| | - Prakash Nadkarni
- College of Nursing, University of Iowa, Iowa 52242, IA, United States
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13
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Liu F, Tang J, Ye L, Tan J, Qiu Y, Hu F, He J, Chen B, He Y, Zeng Z, Mao R, Cao Q, Gao X, Chen M. Prophylactic Antitubercular Therapy Is Associated With Accelerated Disease Progression in Patients With Crohn's Disease Receiving Anti-TNF Therapy: A Retrospective Multicenter Study. Clin Transl Gastroenterol 2022; 13:e00493. [PMID: 35758823 PMCID: PMC9236600 DOI: 10.14309/ctg.0000000000000493] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 04/05/2022] [Indexed: 11/23/2022] Open
Abstract
INTRODUCTION Prophylactic antitubercular therapy (ATT) is widely prescribed in patients with Crohn's disease (CD) receiving antitumor necrosis factor (anti-TNF) treatment. However, antitubercular agents have been demonstrated to possess profibrotic effects. We aimed to evaluate whether ATT accelerated disease progression in patients with CD receiving anti-TNF treatment. METHODS A retrospective, multicenter study was performed in CD patients presented with inflammatory behavior (B1) and treated with anti-TNF agents. Disease progression was defined as the development of a stricturing (B2) or penetrating (B3) phenotype. ATT users were propensity score-matched with non-ATT users. Survival and multivariable Cox analyses were used to identify factors associated with disease progression. RESULTS We enrolled 441 patients, including 295 ATT users and 146 non-ATT users, with a median follow-up of 3.15 years (interquartile range: 1.6-4.7). The cumulative rates of disease progression in the ATT group were constantly higher than those in the non-ATT group after 1-, 3-, 5-, and 10-year follow-ups, respectively (P = 0.031). Multivariable Cox analysis identified ATT as an independent risk factor for disease progression using both the whole (hazard ratio = 2.22; 95% confidence interval: 1.11-4.48; P = 0.025) and propensity score-matched cohorts (hazard ratio = 2.35; 95% confidence interval: 1.07-5.14; P = 0.033). In subgroup analysis, patients receiving ATT ≥4.5 months had a significantly higher rate of disease progression compared with patients receiving ATT <4.5 months (P = 0.005) and non-ATT treatment (P = 0.036). DISCUSSION Prophylactic ATT with duration over 4.5 months was associated with disease progression in patients with CD receiving anti-TNF treatment.
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Affiliation(s)
- Fen Liu
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jian Tang
- Department of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Lingna Ye
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jinyu Tan
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yun Qiu
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Fan Hu
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jinshen He
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Baili Chen
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yao He
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Zhirong Zeng
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Ren Mao
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Qian Cao
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiang Gao
- Department of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Minhu Chen
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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14
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Gillessen A, Angelico F, Chen J, Lu L, Lucena MI, Fu Q, Xie Q, Andrade RJ, Xie W, Xu X, Yu Y, Mao YM, Nan Y. Silymarin for Treating Toxic Liver Disease: International Consensus Recommendations. GASTRO HEP ADVANCES 2022; 1:882-893. [PMID: 39131840 PMCID: PMC11307908 DOI: 10.1016/j.gastha.2022.05.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 05/09/2022] [Indexed: 08/13/2024]
Abstract
Chronic liver disease (CLD) is a leading health problem impacting the quality of life globally. China shares a major global burden of CLD-including alcoholic liver disease, nonalcoholic fatty liver disease/metabolic dysfunction-associated fatty liver disease, and drug-induced liver injury, except for chronic viral hepatitis. Several exogenous toxins or endogenous metabolic insults trigger hepatic pathology toward steatosis, inflammation, and fibrosis, which, if left untreated, may culminate in liver cirrhosis. Oxidative stress is a common pathomechanism underlying all phenotypes of toxic liver injury; thus, these may be brought under a unified entity, viz. toxic liver disease (TLD). Therefore, a common strategy to treat TLD is to use antioxidants as hepatoprotective agents. The cornerstone for treating fatty liver disease is lifestyle modification, diet, exercise, and behavioral therapy, along with the limited use of pharmacological agents. Available preclinical and clinical evidence indicates that silymarin is a hepatoprotective agent with established antioxidant, anti-inflammatory, antifibrotic effects. An international expert panel of clinicians was convened to discuss combining alcoholic liver disease, nonalcoholic fatty liver disease/metabolic dysfunction-associated fatty liver disease, drug-induced liver injury, and liver cirrhosis under the single definition of TLD, based on the shared pathologic mechanism of oxidative stress. The panel highlighted the significance of silymarin as an antioxidant treatment for TLD.
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Affiliation(s)
- Anton Gillessen
- Department of Internal Medicine, Herz-Jesu-Hospital, Muenster, Germany
| | - Francesco Angelico
- Department of Public Health and Infectious Diseases, Sapienza University School of Medicine, Rome, Italy
| | - Jun Chen
- Department of Liver Disease Medical Center/Head of the Fourth Department of Liver Disease, Shenzhen Third People's Hospital, Shenzhen, China
| | - Lungen Lu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai, China
| | - Maria Isabel Lucena
- Department of Pharmacology, School of Medicine, University of Málaga, Málaga, Spain
| | - Qingchun Fu
- Department of Liver Disease, Centre of Shanghai Public Health Clinical Centre, Shanghai, China
| | - Qing Xie
- Department of Infectious Diseases, Ruijin Hospital, Shanghai, China
| | - Raul J. Andrade
- Services of Gastroenterology & Clinical Pharmacology, Málaga Biomedical Research Institute, IBIMA, University Hospital, University of Málaga, Málaga, Spain
| | - Wen Xie
- Liver Disease Centre, Beijing Ditan Hospital Capital Medical University, Beijing, China
| | - Xiaoyuan Xu
- Department of Infectious Diseases, Peking University Health Science Centre, Beijing, China
| | - Yanyan Yu
- Department of Infectious Disease, Peking University First Hospital, Beijing, China
| | - Yi-min Mao
- Department of Gastroenterology, Renji Hospital, Shanghai, China
| | - Yuemin Nan
- Department of Liver Diseases, The Third Hospital of Hebei Medical University, Shijiazhuang, China
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15
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Sen A, Anakk S. Jekyll and Hyde: nuclear receptors ignite and extinguish hepatic oxidative milieu. Trends Endocrinol Metab 2021; 32:790-802. [PMID: 34481730 PMCID: PMC8464172 DOI: 10.1016/j.tem.2021.07.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 07/26/2021] [Accepted: 07/27/2021] [Indexed: 12/21/2022]
Abstract
Nuclear receptors (NRs) are ligand-binding transcription factors that regulate gene networks and physiological responses. Often oxidative stress precedes the onset of liver diseases, and Nrf2 is a key regulator of antioxidant pathways. NRs crosstalk with Nrf2, since NR activation can influence the oxidative milieu by modulating reductive cellular processes. Diet and xenobiotics also regulate NR expression and activity, suggesting a feedback loop. Depending on the tissue context and cues, NRs either increase or decrease toxicity and oxidative damage. Many FDA-approved drugs target NRs, and one could potentially repurpose them to ameliorate reactive oxygen species (ROS). Here, we discuss how several NRs modulate oxidative stress subsequent to diet, organic pollutants, and drug-induced injury to the liver.
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Affiliation(s)
- Anushna Sen
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Sayeepriyadarshini Anakk
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
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Aristianti A, Nurkhaeri N, Tandiarrang VY, Awaluddin A, Muslimin L. Formulation and Pharmacological Studies of Leaves of Moringa (Moringa oleifera), a Novel Hepatoprotection in Oral Drug Formulations. Open Access Maced J Med Sci 2021. [DOI: 10.3889/oamjms.2021.5839] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
BACKGROUND: Moringa oleifera, Moringaceae, is a tree that is native to South East Asia. Various parts of this tree are commonly used in traditional medicine to treat inflammation, hepatitis, gastric ulcer, and other ailments.
AIM: M. oleifera leaves extract was formulated into stable suspensions, characterized, and then evaluated for hepatoprotection activity against isoniazid.
MATERIALS AND METHODS: The leaves were extracted using cold maceration, and suspensions of extract were prepared using sodium carboxymethyl cellulose (Na-CMC) as suspension agent at various concentrations (0.1, 0.5, and 1.0%). The formulations were analyzed by their appearance, color, odor, and taste. Density, pH, viscosity, re-dispersibility test, and sedimentation volume were observed. The stability of oral suspensions was analyzed in accelerated studies (5°C ± 2°C and 35°C ± 2°C for 12 h for 7 cycles) to find stable formulation, while the hepatoprotection activity was analyzed using an in vivo isoniazid-induced model.
RESULTS: The appearance, color, odor, and taste of the suspensions were shown to be characteristic of the extract. Na-CMC at concentration 0.5% showed good physical properties. Stable suspension at dose 400 mg/kg BW per oral for 28 days exhibited a significant (p < 0.05) decrease in the serum glutamate oxaloacetate transaminase and serum glutamate pyruvate transaminase.
CONCLUSION: Suspension containing M. oleifera leaves extract at 50 mg/5 mL was successfully obtained and showed physical properties that were appropriate and characteristic of this dosage form, suitable for hepatoprotection (400 mg/kg BW), making this an alternative to tablets.
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An Evaluation of the In Vitro Roles and Mechanisms of Silibinin in Reducing Pyrazinamide- and Isoniazid-Induced Hepatocellular Damage. Int J Mol Sci 2020; 21:ijms21103714. [PMID: 32466226 PMCID: PMC7279482 DOI: 10.3390/ijms21103714] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 05/19/2020] [Accepted: 05/22/2020] [Indexed: 02/06/2023] Open
Abstract
Tuberculosis remains a significant infectious lung disease that affects millions of patients worldwide. Despite numerous existing drug regimens for tuberculosis, drug-induced liver injury is a major challenge that limits the effectiveness of these therapeutics. Two drugs that form the backbone of the commonly administered quadruple antitubercular regimen, that is, pyrazinamide (PZA) and isoniazid (INH), are associated with such hepatotoxicity. Yet, we lack safe and effective alternatives to the antitubercular regimen. Consequently, current research largely focuses on exploiting the hepatoprotective effect of nutraceutical compounds as complementary therapy. Silibinin, a herbal product widely believed to protect against various liver diseases, potentially provides a useful solution given its hepatoprotective mechanisms. In our study, we identified silibinin’s role in mitigating PZA- and INH-induced hepatotoxicity and elucidated a deeper mechanistic understanding of silibinin’s hepatoprotective ability. Silibinin preserved the viability of human foetal hepatocyte line LO2 when co-administered with 80 mM INH and decreased apoptosis induced by a combination of 40 mM INH and 10 mM PZA by reducing oxidative damage to mitochondria, proteins, and lipids. Taken together, this proof-of-concept forms the rational basis for the further investigation of silibinin’s hepatoprotective effect in subsequent preclinical studies and clinical trials.
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