Lesión hepática inducida por Phyllanthus niruri (chancapiedra), un remedio natural para urolitiasis / Liver injury induced by Phyllanthus niruri (chancapiedra), a natural remedy for urolithiasis

Tanto la lesión hepática inducida por drogas (DILI), así como la lesión hepática inducida por hierbas (HILI), son una preocupación creciente en la atención sanitaria contemporánea que plantea importantes desafíos clínicos debido a sus variadas etiologías, presentaciones clínicas y posibles resultados potencialmente mortales. Presentamos el caso de un paciente masculino de 38 años con antecedentes de cálculos renales que consultó por dolor lumbar y hematuria. Al ingreso presentó ictericia, hepatomegalia, dolor a la palpación en fosa ilíaca derecha y no tenía signos de hepatopatía crónica, con pruebas de función hepática anormales, que mostraron un patrón hepatocelular asociado con hiperbilirrubinemia. Se descartó obstrucción biliar, trombosis portal, hepatitis autoinmune y viral, con panel autoinmune negativo. El paciente refirió haber consumido un remedio herbario para los cálculos renales llamado "vino rompe cálculos (chancapiedra)", que se supone contiene Phyllanthus niruri, cinco días antes del inicio de los síntomas. Una biopsia hepática reveló hepatitis aguda con infiltrado inflamatorio mixto. Debido al empeoramiento de las pruebas de función hepática y la sospecha de DILI idiosincrásico, se inició un ensayo terapéutico con corticosteroides, que resultó en una mejoría clínica y del perfil hepático. La gravedad de este caso nos recuerda la necesidad de incrementar el seguimiento por parte de las autoridades reguladoras de medicamentos, implementar campañas educativas para los pacientes e informar a la comunidad sobre productos con alertas activas.

Both drug-induced liver injury (DILI) and herb-induced liver injury (HILI) are a growing concern in contemporary healthcare that poses significant clinical challenges due to their varied etiology, clinical presentations, and potential life-threatening outcomes. We present the case of a 38-year-old male patient with a history of kidney stones who consulted for low back pain and hematuria. On admission he presented with jaundice, hepatomegaly, pain on palpation in the right iliac fossa and no signs of chronic liver disease, with abnormal liver function tests, which showed a hepatocellular pattern associated with hyperbilirubinemia. Biliary obstruction, portal thrombosis, autoimmune and viral hepatitis were ruled out, with negative autoimmune panel. The patient reported consuming an herbal remedy for kidney stones called "stone-breaking wine (chancapiedra)", presumed to contain Phyllanthus niruri, five days before the onset of symptoms. A liver biopsy revealedacute hepatitis with mixed inflammatory infiltrate. Due to worsening liver function tests and suspicion of idiosyncratic DILI, a therapeutic trial with corticosteroids was initiated, which resulted in clinical and liver profile improvement. The severity of this case reminds us of the need to increase follow-up by drug regulatory authorities, implement educational campaigns for patients, and inform the community about products with active alerts.

[An analysis on clinical characteristics and prognosis-related risk factors in patients with drug-induced liver injury].

Objective: To explore the drugs and clinical characteristics causing drug-induced liver injury (DILI) in recent years, as well as identify drug-induced liver failure, and chronic DILI risk factors, in order to better manage them timely. Methods: A retrospective investigation and analysis was conducted on 224 cases diagnosed with DILI and followed up for at least six months between January 2018 and December 2020. Univariate and multivariate logistic regression analyses were used to identify risk factors for drug-induced liver failure and chronic DILI. Results: Traditional Chinese medicine (accounting for 62.5%), herbal medicine (accounting for 84.3% of traditional Chinese medicine), and some Chinese patent medicines were the main causes of DILI found in this study. Severe and chronic DILI was associated with cholestatic type. Preexisting gallbladder disease, initial total bilirubin, initial prothrombin time, and initial antinuclear antibody titer were independent risk factors for DILI. Prolonged time interval between alkaline phosphatase (ALP) and alanine aminotransferase (ALT) falling from the peak to half of the peak (T(0.5ALP) and T(0.5ALT)) was an independent risk factor for chronic DILI [area under the receiver operating characteristic curve (AUC) = 0.787, 95%CI: 0.697~0.878, P < 0.001], with cutoff values of 12.5d and 9.5d, respectively. Conclusion: Traditional Chinese medicine is the main contributing cause of DILI. The occurrence risk of severe DILI is related to preexisting gallbladder disease, initial total bilirubin, prothrombin time, and antinuclear antibodies. T(0.5ALP) and T(0.5ALT) can be used as indicators to predict chronic DILI.

Multi-omics reveals that 5-O-methylvisammioside prevention acute liver injury in mice by regulating the TNF/MAPK/NF-κB/arachidonic acid pathway.

BACKGROUND: The pathogenesis of acute liver injury (ALI) has been a pressing issue in the medical scientific community. We previously found that 5-O-methylvisammioside (MeV) from Saposhnikovia divaricata (Turcz.) Schischk has excellent anti-inflammatory properties. However, the mechanism by which MeV protects against ALI still needs to be deeply investigated. PURPOSE: In the present study, we established an acetaminophen (APAP) -induced ALI mouse model and pre-protected the mice with MeV. METHODS & RESULTS: Our findings indicate that MeV (5 and 10 mg/kg) lowered the blood levels of alanine aminotransferase and aspartate aminotransferase and reduced the infiltration of inflammatory cells in the liver. MeV initially showed an inhibitory effect on ALI. We then analyzed the molecular mechanisms underlying the effects of MeV by transcriptomic and metabolomic analyzes. Through transcriptomic analysis, we identified 4675 differentially expressed genes between the APAP+MeV group and the APAP-induced ALI group, which were mainly enriched in the MAPK pathway, the TNF pathway, and the NF-κB pathway. Through metabolomic analysis, we found that 249 metabolites in the liver were differentially regulated between the APAP+MeV group and the APAP- induced ALI group, which were mainly enriched in the arachidonic acid pathway. The mRNA expression levels of key genes (encoding TNF-α, p38, AP-1, RelB, IL-1ß, and Ptges), as determined by RT-PCR analysis, were consistent with the RNA-seq data. The ELISA results indicate that MeV markedly decreased the serum levels of TNF-α and IL-1ß in mice. Finally, the key proteins in the NF-κB and MAPK pathways were examined using immunoblotting. The results showed that MeV decreased IκB-α phosphorylation and inhibited the nuclear translocation of NF-κB. In addition, MeV reduced the hepatic inflammatory burst mainly by inhibiting the phosphorylation of p38 and JNK in the MAPK pathway. CONCLUSION: The present study demonstrated (i) that MeV could ameliorate APAP-induced ALI by inhibiting arachidonic acid metabolism and the TNF, MAPK, and NF-κB pathways, and (ii) that MeV is a promising drug candidate for the prevention of ALI.

2,3,5,4'- tetrahydroxystilbene-2-O-ß-D- glucopyranoside (TSG)-Driven immune response in the hepatotoxicity of Polygonum multiflorum.

ETHNOPHARMACOLOGICAL RELEVANCE: 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucopyranoside (TSG) as the primary constituent of Polygonum multiflorum Thumb. (PM) possesses anti-oxidative, antihypercholesterolemic, anti-tumor and many more biological activities. The root of PM has been used as a tonic medicine for thousands of years. However, cases of PM-induced liver injury are occasionally reported, and considered to be related to the host immune status. AIM OF THE STUDY: The primary toxic elements and specific mechanisms PM causing liver damage are still not thoroughly clear. Our study aimed to investigate the influences of TSG on the immune response in idiosyncratic hepatotoxicity of PM. MATERIALS AND METHODS: The male C57BL/6 mice were treated with different doses of TSG and the alterations in liver histology, serum liver enzyme levels, proportions of T cells and cytokines secretion were evaluated by hematoxylin and eosin (HE), RNA sequencing, quantitative real time polymerase chain reaction (qRT-PCR), Flow cytometry (FCM), and enzyme-linked immunosorbent assay (ELISA), respectively. Then, primary spleen cells from drug-naive mice were isolated and cultured with TSG in vitro. T cell subsets proliferation and cytokines secretion after treated with TSG were assessed by CCK8, FCM and ELISA. In addition, mice were pre-treated with anti-CD25 for depleting regulatory T cells (Tregs), and then administered with TSG. Liver functions and immunological alterations were analyzed to evaluate liver injury. RESULTS: Data showed that TSG induced liver damage, and immune cells infiltration in the liver tissues. FCM results showed that TSG could activate CD4+T and CD8+T in the liver. Results further confirmed that TSG notably up-regulated the levels of inflammatory cytokines including TNF-α, IFN-γ, IL-18, perforin and granzyme B in the liver tissues. Furthermore, based on transcriptomics profiles, some immune system-related pathways including leukocyte activation involved in inflammatory response, leukocyte cell-cell adhesion, regulation of interleukin-1 beta production, mononuclear cell migration, antigen processing and presentation were altered in TSG treated mice. CD8+T/CD4+T cells were also stimulated by TSG in vitro. Interestingly, increased proportion of Tregs was observed after TSG treatment in vitro and in vivo. Foxp3 and TGF-ß1 mRNA expressions were up-regulated in the liver tissues. Depletion of Tregs moderately enhanced TSG induced the secretion of inflammatory cytokines in serum. CONCLUSIONS: Our findings showed that TSG could trigger CD4+T and CD8+T cells proliferation, promote cytokines secretion, which revealed that adaptive immune response associated with the mild liver injury cause by TSG administration. Regulatory T cells (Tregs) mainly sustain immunological tolerance, and in this study, the progression of TSG induced liver injury was limited by Tregs. The results of our investigations allow us to preliminarily understand the mechanisms of PM related idiosyncratic hepatotoxicity.

Xanthohumol ameliorates drug-induced hepatic ferroptosis via activating Nrf2/xCT/GPX4 signaling pathway.

BACKGROUND: As a canonical iron-dependent form of regulated cell death (RCD), ferroptosis plays a crucial role in chemical-induced liver injuries. Previous studies have demonstrated that xanthohumol (Xh), a natural prenylflavonoid isolated from hops, exhibits anti-inflammatory, anti-antioxidative and hepatoprotective properties. However, the regulatory effects of Xh on hepatic ferroptosis and the underlying mechanism have not yet been fully elucidated. PURPOSE: To investigate the hepatoprotective effects of Xh against drug-induced liver injury (DILI) and the regulatory effects of Xh on hepatic ferroptosis, as well as to reveal the underlying molecular mechanisms. METHODS/STUDY DESIGN: The hepatoprotective benefits of Xh were investigated in APAP-induced liver injury (AILI) mice and HepaRG cells. Xh was administered intraperitoneally to assess its in vivo effects. Histological and biochemical studies were carried out to evaluate liver damage. A series of ferroptosis-related markers, including intracellular Fe2+ levels, ROS and GSH levels, the levels of MDA, LPO and 4-HNE, as well as the expression levels of ferroptosis-related proteins and modulators were quantified both in vivo and in vitro. The modified peptides of Keap1 by Xh were characterized utilizing nano LC-MS/MS. RESULTS: Xh remarkably suppresses hepatic ferroptosis and ameliorates AILI both in vitro and in vivo, via suppressing Fe2+ accumulation, ROS formation, MDA generation and GSH depletion, these observations could be considerably mitigated by the ferroptosis inhibitor ferrostatin-1 (Fer-1). Mechanistically, Xh could significantly activate the Nrf2/xCT/GPX4 signaling pathway to counteract AILI-induced hepatocyte ferroptosis. Further investigations showed that Xh could covalently modify three functional cysteine residues (cys151, 273, 288) of Keap1, which in turn, reduced the ubiquitination rates of Nrf2 and prolonged its degradation half-life. CONCLUSIONS: Xh evidently suppresses hepatic ferroptosis and ameliorates AILI via covalent modifying three key cysteines of Keap1 and activating Nrf2/xCT/GPX4 signaling pathway.

The Hepatoprotective Effects of Ginsenoside from Ginseng: A Review of Molecular Mechanisms and Therapeutic Potentials.

Treatment of hepatic diseases presents a significant challenge due to their diverse nature. Ginsenosides, bioactive compounds derived from the root of Panax ginseng and widely used in traditional Chinese medicine, offer multifaceted protection to various organs in the body. Their versatile effects, including antioxidant, anti-inflammatory, anti-apoptotic and more, make them a promising approach for addressing hepatic disorders. This review explores the intricate molecular mechanisms and properties of ginsenosides in the prevention and treatment of liver ailments, from mild conditions to severe damage and liver fibrosis. Given the increasing prevalence of hepatic disorders, this article sheds light on the significant pharmaceutical potential of ginsenosides in the realm of hepatic disease management.

Group 1 innate lymphoid cell activation via recognition of NKG2D and liver resident macrophage MULT-1: Collaborated roles in triptolide induced hepatic immunotoxicity in mice.

Triptolide (TP) is the major bioactive component of traditional Chinese medicine Tripterygium wilfordii Hook. F., a traditional Chinese medicinal plant categorized within the Tripterygium genus of the Celastraceae family. It is recognized for its therapeutic potential in addressing a multitude of diseases. Nonetheless, TP is known to exhibit multi-organ toxicity, notably hepatotoxicity, which poses a significant concern for the well-being of patients undergoing treatment. The precise mechanisms responsible for TP-induced hepatotoxicity remain unresolved. In our previous investigation, it was determined that TP induces heightened hepatic responsiveness to exogenous lipopolysaccharide (LPS). Additionally, natural killer (NK) cells were identified as a crucial effector responsible for mediating hepatocellular damage in this context. However, associated activating receptors and the underlying mechanisms governing NK cell represented innate lymphoid cell (ILC) activation remained subjects of inquiry and were not yet investigated. Herein, activating receptor Killer cell lectin like receptor K1 (NKG2D) of group 1 ILCs was specifically upregulated in TP- and LPS-induced acute liver failure (ALF), and in vivo blockade of NKG2D significantly reduced group 1 ILC mediated cytotoxicity and mitigated TP- and LPS-induced ALF. NKG2D ligand UL16-binding protein-like transcript 1 (MULT-1) was found upregulated in liver resident macrophages (LRMs) after TP administration, and LRMs did exhibit NK cell activating effect. Furthermore, M1 polarization of LRMs cells was observed, along with an elevation in intracellular tumor necrosis factor (TNF)-α levels. In vivo neutralization of TNF-α significantly alleviated TP- and LPS-induced ALF. In conclusion, the collaborative role of group 1 ILCs and LRMs in mediating hepatotoxicity was confirmed in TP- and LPS-induced ALF. TP-induced MULT-1 expression in LRMs was the crucial mechanism in the activation of group 1 ILCs via MULT-1-NKG2D signal upon LPS stimulation, emphasizing the importance of infection control after TP administration.

Safety of herbal decoctions: A scoping review of clinical studies in South Korea focusing on liver and kidney functions.

ETHNOPHARMACOLOGICAL RELEVANCE: Approximately 27% of individuals seeking Korean medicine (KM) services in South Korea are prescribed herbal decoctions. The South Korean government has considered the validity of providing National Health Insurance coverage for herbal decoctions. Therefore, it is important to investigate their safety. AIM OF THE STUDY: To investigate the safety of herbal decoctions commonly prescribed by KM doctors and to assess their effects on liver and kidney function by comprehensively analyzing Korean clinical studies in a scoping review. MATERIALS AND METHODS: The Arksey and O'Malley framework and modified methods were applied in this scoping review. A comprehensive search of seven electronic health databases was conducted, and relevant clinical studies published between 2000 and 2022 were identified. Subsequently, only clinical studies reporting the results of liver and/or renal function tests in patient prescribed herbal decoctions by KM doctors were included. The characteristics of the included clinical studies and the reported proportion of each liver and/or renal function indicator were analyzed. Meta-analyses of the effects of herbal decoction on liver and/or renal function reported in prospective cohort studies were also performed. RESULTS: Fifty-nine clinical studies were included in this review. The proportion of prospective cohort studies markedly decreased in the 2010s compared to the 2000s, while there was no noticeable change in the number of relevant clinical studies. Herbal decoctions were prescribed for less than one month in most included studies. Abnormal changes in liver or renal function indicators were identified in a small number of studies (3.70% and 7.69%, respectively). In a meta-analysis of 15 prospective cohort studies, no statistically significant changes in four liver function indices and two renal function indices were observed before and after the prescription of herbal decoctions. CONCLUSIONS: Qualitative and quantitative analyses demonstrated favorable safety profiles for herbal decoctions. This scoping review includes the gaps noted between clinical application and research regarding the safety profiles of herbal decoctions. These findings could be used as evidence to support the inclusion of herbal decoction prescriptions in the National Health Insurance coverage in South Korea.

Protective effect of Tibetan medicine Qiwei Tiexie pills on liver injury induced by acetaminophen overdose: An integrated strategy of network pharmacology, metabolomics and transcriptomics.

BACKGROUND: Drug-induced liver injury, particularly from acetaminophen (APAP), has emerged as a significant public health concern. Unfortunately, there is currently no effective treatment strategy available. Qiwei Tiexie pills (QWTX), a traditional Tibetan medicine, have demonstrated considerable clinical efficacy in treating various liver diseases. Nevertheless, the protective effect of QWTX against drug-induced liver injury and its underlying mechanism remains poorly understood. PURPOSE: This study aimed to assess the therapeutic potential of QWTX, a Tibetan medicine, in an animal model of APAP-induced liver injury. Additionally, we sought to investigate the molecular mechanism through which QWTX exerts its effects. METHODS: We employed LC-MS and network pharmacology to predict the potential targets of QWTX in drug-induced liver injury. Subsequently, we employed HE staining, transcriptomics, metabolomics, and qRT-PCR to analyze the mechanism underlying QWTX treatment in drug-induced liver injury. RESULTS: Network pharmacology analysis revealed that the active components of QWTX are involved in inflammatory and drug metabolism-related pathways. In mouse models, pretreatment with QWTX effectively mitigated the elevated levels of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and inflammatory factors (IL-1ß, IL-6, and TNF-α) induced by APAP overdose. Moreover, APAP inhibited 1459 differentially expressed genes (DEGs) and 874 differential accumulation metabolites (DAMs), while QWTX promoted their expression. Conversely, APAP promoted 874 genes and 119 metabolites, which were inhibited by QWTX. Further analysis demonstrated that QWTX ameliorated the metabolic disorders induced by APAP overdose and potentially exerted a protective effect by inhibiting the expression of critical genes in crucial inflammatory pathways. QWTX also up-regulated antioxidant enzymes, thereby mitigating the oxidative stress resulting from APAP overdose. CONCLUSION: QWTX treatment effectively protects against APAP-induced liver damage in mice. Transcriptomic and metabolomic analyses further revealed that QWTX ameliorated hepatic metabolic disorders induced by APAP overdose while significantly suppressing the inflammatory response and oxidative stress associated with drug-induced liver injury. This study provides a new insight into the treatment of drug-induced liver injury by the TCM system and provides a basis for the development of new therapies for drug-induced liver injury by QWTX and its active ingredients.

Clinical characteristics and prognosis of non-APAP drug-induced acute liver failure: a large multicenter cohort study.

BACKGROUND: There is growing recognition of natural history, complications, and outcomes of patients who develop non-acetaminophen (APAP) drug-induced acute liver failure (ALF). To clarify high-risk factors and develop a nomogram model to predict transplant-free survival (TFS) in patients with non-APAP drug-induced ALF. METHODS: Patients with non-APAP drug-induced ALF from 5 participating centers were retrospectively analyzed. The primary endpoint was 21-day TFS. Total sample size was 482 patients. RESULTS: Regarding causative agents, the most common implicated drugs were herbal and dietary supplements (HDS) (57.0%). The hepatocellular type (R ≥ 5) was the main liver injury pattern (69.0%). International normalized ratio, hepatic encephalopathy grades, the use of vasopressor, N-acetylcysteine, or artificial liver support system were associated with TFS and incorporated to construct a nomogram model (drug-induced acute liver failure-5, DIALF-5). The AUROC of DIALF-5 for 7-day, 21-day, 60-day, and 90-day TFS in the internal cohort were 0.886, 0.915, 0.920, and 0.912, respectively. Moreover, the AUROC of DIALF-5 for 21-day TFS had the highest AUROC, which was significantly higher than 0.725 of MELD and 0.519 of KCC (p < 0.05), numerically higher than 0.905 of ALFSG-PI but without statistical difference (p > 0.05). These results were successfully validated in the external cohort (147 patients). CONCLUSIONS: Based on easily identifiable clinical data, the novel DIALF-5 model was developed to predict transplant-free survival in non-APAP drug-induced ALF, which was superior to KCC, MELD and had a similar prediction performance to ALFSG-PI but is more convenient, which can directly calculate TFS at multiple time points.

[Identification of Q-markers for Schisandrae Sphenantherae Fructus in treating drug-induced liver injury based on network pharmacology, fingerprint and quantitative analysis].

This study aims to establish the ultra-performance liquid chromatography(UPLC) fingerprint and multi-indicator quantitative analysis method for Schisandrae Sphenantherae Fructus(SSF) and to screen out the potential quality markers(Q-markers) of hepatoprotection based on network pharmacology. The similarity analysis was performed using the Chinese Medicine Chromatographic Fingerprint Similarity Evaluation System, which showed that the similarity of the fingerprints of 15 samples from different regions ranged from 0.981 to 0.998. Eighteen common components were identified, from which 3 differential components were selected by cluster analysis and principal component analysis. The "component-target-pathway" network was built to predict the core components related to the hepatoprotective effects. Fourteen core components were screened by network pharmacology. They acted on the targets such as AKT1, CCND1, CYP1A1, CYP3A4, MAPK1, MAPK3, NOS2, NQO1, and PTGS2 to regulate the signaling pathways of lipid metabolism and atherosclerosis, hepatitis B, interleukin-17, and tumor necrosis factor. Considering the chemical measurability, characteristics, and validity, schisantherin A, anwulignan, and schisandrin A were identified as the Q-markers. The content of schisantherin A, anwulignan, and schisandrin A in the test samples were 0.20%-0.57%, 0.13%-0.33%, and 0.42%-0.70%, respectively. Combining the fingerprint, network pharmacology, and content determination, this study predicted that schisantherin A, anwulignan, and schisandrin A were the Q-markers for the hepatoprotective effect of SSF. The results can provide reference for improving the quality evaluation standard and exploring the hepatoprotective mechanism of SSF.

[Drug-induced liver injury: diagnosis of exclusion].

Drug-induced liver injury (DILI) is a relevant issue in clinical practice and is still a diagnosis of exclusion. Despite the low incidence in the general population, DILI is the cause of most cases of acute hepatic injury and has a mortality rate of up to 50%. Despite many reports in the medical literature about the DILI mechanisms, a clear causal relationship between them, drugs, and risk factors has not been established. Current clinical practice is based on a combination of a thorough study of a history of risk factors, the timing of drug and dietary supplements' administration, and the analysis of laboratory and instrumental tests. It aligns with the international criteria of the Rousell Uclaf Causality Assessment Method (RUCAM), which is considered one of the main diagnostic algorithms for DILI. The article addresses current DILI classification, risk factors, diagnostic algorithms, causalities, clinical evaluation, promising liver function biomarkers, and specific treatment.

Nutritional intervention is promising in alleviating liver injury during tuberculosis treatment: a review.

Liver injury is a main adverse effect of first-line tuberculosis drugs. Current management of tuberculosis-drug-induced liver injury (TBLI) mainly relies on withdrawing tuberculosis drugs when necessary. No effective treatment exists. Various nutrients and functional food ingredients may play a protective role in TBLI. However, a comprehensive review has not been conducted to compare the effects of these nutrients and functional food ingredients. We searched Pubmed and Web of Science databases from the earliest date of the database to March 2023. All available in-vitro, animal and clinical studies that examined the effects of nutritional intervention on TBLI were included. The underlying mechanism was briefly reviewed. Folic acid, quercetin, curcumin, Lactobacillus casei, spirulina and Moringa oleifera possessed moderate evidence to have a beneficial effect on alleviating TBLI mostly based on animal studies. The evidence of other nutritional interventions on TBLI was weak. Alleviating oxidative stress and apoptosis were the leading mechanisms for the beneficial effects of nutritional intervention on TBLI. In conclusion, a few nutritional interventions are promising for alleviating TBLI including folic acid, quercetin, curcumin, L. casei, spirulina and M. oleifera, the effectiveness and safety of which need further confirmation by well-designed randomized controlled trials. The mechanisms for the protective role of these nutritional interventions on TBLI warrant further study, particularly by establishing the animal model of TBLI using the tuberculosis drugs separately.

Hepatoprotective effects of natural drugs: Current trends, scope, relevance and future perspectives.

BACKGROUND: The liver is a well-known player in the metabolism and removal of drugs. Drug metabolizing enzymes in the liver detoxify drugs and xenobiotics, ultimately leading to the acquisition of homeostasis. However, liver toxicity and cell damage are not only related to the nature and dosage of a particular drug but are also influenced by other factors such as aging, immune status, environmental contaminants, microbial metabolites, gender, obesity, and expression of individual genes Furthermore, factors such as drugs, alcohol, and environmental contaminants could induce oxidative stress, thereby impairing the regenerative potential of the liver and causing several diseases. Persons suffering from other ailments and those with comorbidities are found to be more prone to drug-induced toxicities. Moreover, drug composition and drug-drug interactions could further aggravate the risk of drug-induced hepatotoxicity. A plethora of mechanisms are responsible for initiating liver cell damage and further aggravating liver cell injury, followed by impairment of homeostasis, ultimately leading to the generation of reactive oxygen species, immune-suppression, and oxidative stress. OBJECTIVE: To summarize the potential of phytochemicals and natural bioactive compounds to treat hepatotoxicity and other liver diseases. STUDY DESIGN: A deductive qualitative content analysis approach was employed to assess the overall outcomes of the research and review articles pertaining to hepatoprotection induced by natural drugs, along with analysis of the interventions. METHODS: An extensive literature search of bibliographic databases, including Web of Science, PUBMED, SCOPUS, GOOGLE SCHOLAR, etc., was carried out to understand the role of hepatoprotective effects of natural drugs. RESULTS: Bioactive natural products, including curcumin, resveratrol, etc., have been seen as neutralizing agents against the side effects induced by the drugs. Moreover, these natural products are dietary and are readily available; thus, could be supplemented along with drugs to reduce toxicity to cells. Probiotics, prebiotics, and synbiotics have shown promise of improving overall liver functioning, and these should be evaluated more extensively for their hepatoprotective potential. Therefore, selecting an appropriate natural product or a bioactive compound that is free of toxicity and offers a reliable solution for drug-induced liver toxicity is quintessential. CONCLUSIONS: The current review highlights the role of natural bioactive products in neutralizing drug-induced hepatotoxicity. Efforts have been made to delineate the possible underlying mechanism associated with the neutralization process.

Acute Fulminant Hepatic Failure in 23-Year-Old Female Taking Homeopathic Remedy.

Homeopathic remedies made primarily from eggshells, and therefore calcium, can be marketed for treatment of back pain and vaginal discharge. We present a case of a 23-year-old otherwise healthy woman who presented with acute liver failure (ALF) ultimately requiring liver transplantation as a result of taking increased doses of a homeopathic product with the primary ingredient of eggshells. Although relatively uncommon compared with medications such as acetaminophen, herbal supplements have been reported to cause drug-induced liver injury (DILI), thought to be primarily due to contaminants. This is the first known report of DILI resulting from a homeopathic product with the primary ingredient of eggshells, and it demonstrates the importance of early ALF recognition and treatment, as well as the importance of practicing caution when using homeopathic supplements.

Enhanced efficacy with reduced toxicity of tripterygium glycoside tablet by compatibility with total glucosides of paeony for rheumatoid arthritis therapy.

BACKGROUND AND AIMS: Drug-induced liver injury remains a critical issue to hinder clinical application of Tripterygium Glycosides Tablets (TGTs) for rheumatoid arthritis (RA) therapy. Combination of TGTs with Total Glucosides of Peony (TGP) may be the most common therapeutic strategy for enhancing TGTs' efficacy and reducing its toxicity. Herein, we aimed to investigate the efficacy-enhancing and toxicity-reducing properties and mechanisms of TGT-TGP combination. METHODS: Both TGT-induced acute and chronic liver injury animal models were established. ELISA, transmission electron microscopy, immunohistochemistry, western blot and quantitative PCR were performed to determine the efficacy, toxicity and regulatory mechanisms of TGT-TGP combination. RESULTS: The compatibility of TGP significantly reduced the abnormal serum ALT and AST levels, and improved liver histopathological changes in both acute and chronic DILI animal models induced by TGTs, with the most effective dosage of TGP-M (medium-dose TGP, 450 mg/kg). Additionally, TGP and TGT synergistically alleviated joint swelling and improved the elevation of serum inflammatory factors, in line with the positive changes in joint histopathological features of collagen induced arthritis mice, with the same effective dosage of TGP-M following 5 weeks' drug combination treatment. Mechanically, TGT significantly increased the number of autophagosomes and the expression of LC3II protein while reducing p62 protein expression in the liver tissues, which were significantly reversed by the compatibility with TGP, similar to the findings based on the inflamed joint tissues. CONCLUSIONS: These findings suggest an enhanced efficacy with reduced toxicity of TGT by the compatibility with TGP for RA therapy, possibly through regulating various autophagy-related proteins.

Curcumin as a hepatoprotective agent against chemotherapy-induced liver injury.

Despite significant advances in cancer therapeutics, chemotherapy remains the cornerstone of treatment for many tumors. Importantly, however, chemotherapy-induced toxicity, including hepatotoxicity, can lead to the interruption or discontinuation of potentially effective therapy. In recent years, special attention has been paid to the search for complementary therapies to mitigate chemotherapy-induced toxicity. Although there is currently a lack of specific interventions to mitigate or prevent hepatotoxicity in chemotherapy-treated patients, the polyphenol compound curcumin has emerged as a potential strategy to overcome this adverse effect. Here we review, firstly, the molecular and physiological mechanisms and major risk factors of chemotherapy-induced hepatotoxicity. We then present an overview of how curcumin has the potential to mitigate hepatotoxicity by targeting specific molecular mechanisms. Hepatotoxicity is a well-described side effect of cytotoxic drugs that can limit their clinical application. Inflammation and oxidative stress are the most common mechanisms involved in hepatotoxicity. Several studies have shown that curcumin could prevent and/or palliate chemotherapy-induced liver injury, mainly due to its anti-inflammatory, antioxidant, antifibrotic and hypolipidemic properties. Further clinical investigation using bioavailable curcumin formulations is warranted to demonstrate its efficacy as an hepatoprotective agent in cancer patients.