Glycyrrhizin and the Related Preparations: An Inspiring Resource for the Treatment of Liver Diseases.

Liver diseases and their related complications endanger the health of millions of people worldwide. The prevention and treatment of liver diseases are still serious challenges both in China and globally. With the improvement of living standards, the prevalence of metabolic liver diseases, including non-alcoholic fatty liver disease and alcoholic liver disease, has increased at an alarming rate, resulting in more cases of end-stage liver disease. Therefore, the discovery of novel therapeutic drugs for the treatment of liver diseases is urgently needed. Glycyrrhizin (GL), a triterpene glycoside from the roots of licorice plants, possesses a wide range of pharmacological and biological activities. Currently, GL preparations (GLPs) have certain advantages in the treatment of liver diseases, with good clinical effects and fewer adverse reactions, and have shown broad application prospects through multitargeting therapeutic mechanisms, including antisteatotic, anti-oxidative stress, anti-inflammatory, immunoregulatory, antifibrotic, anticancer, and drug interaction activities. This review summarizes the currently known biological activities of GLPs and their medical applications in the treatment of liver diseases, and highlights the potential of these preparations as promising therapeutic options and their alluring prospects for the treatment of liver diseases.

First-in-class MKK4 inhibitors enhance liver regeneration and prevent liver failure.

Diminished hepatocyte regeneration is a key feature of acute and chronic liver diseases and after extended liver resections, resulting in the inability to maintain or restore a sufficient functional liver mass. Therapies to restore hepatocyte regeneration are lacking, making liver transplantation the only curative option for end-stage liver disease. Here, we report on the structure-based development and characterization (nuclear magnetic resonance [NMR] spectroscopy) of first-in-class small molecule inhibitors of the dual-specificity kinase MKK4 (MKK4i). MKK4i increased liver regeneration upon hepatectomy in murine and porcine models, allowed for survival of pigs in a lethal 85% hepatectomy model, and showed antisteatotic and antifibrotic effects in liver disease mouse models. A first-in-human phase I trial (European Union Drug Regulating Authorities Clinical Trials [EudraCT] 2021-000193-28) with the clinical candidate HRX215 was conducted and revealed excellent safety and pharmacokinetics. Clinical trials to probe HRX215 for prevention/treatment of liver failure after extensive oncological liver resections or after transplantation of small grafts are warranted.

Autoimmune liver disease triggered by SARS-CoV-2: a case report and review of the literature.

BACKGROUND: An increasing number of coronavirus disease 2019 (COVID-19) related autoimmune hepatitis (AIH) and autoimmune liver disease (AILD) has been already described so far in the last three years. This rise has set up some diagnostic and therapeutic concerns, although steroid therapy has mostly been efficient, avoiding main significant side effects. CASE REPORT: We report the case of a 52-year-old subject displaying liver function impairment at the laboratory tests while positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) swab. Needle liver biopsy showed severe portal inflammation, interface hepatitis, lobular inflammation, abundant plasma cells, bridging necrosis, endothelialitis, bile duct vanishing disease, and ductular reaction. The diagnosis of autoimmune liver disease (AILD) was performed. After a month of steroid and ursodeoxycholic acid medications, liver function fully recovered. Azathioprine was introduced, and steroids were gradually reduced. CONCLUSIONS: Probably triggered by the SARS-CoV-2-induced cytokine storm, the association between COVID-19 and autoimmune-related inflammatory injury may display a particular paradigm of AILD pathogenesis.

Pharmacokinetics of long-acting lenacapavir in participants with hepatic or renal impairment.

Lenacapavir is a novel, first-in-class, multistage inhibitor of HIV-1 capsid function approved for the treatment of multidrug-resistant HIV-1 infection in combination with other antiretrovirals for heavily treatment-experienced people with HIV. Two Phase 1, open-label, parallel-group, single-dose studies assessed the pharmacokinetics (PK) of lenacapavir in participants with moderate hepatic impairment [Child-Pugh-Turcotte (CPT) Class B: score 7-9] or severe renal impairment [15 ≤ creatinine clearance (CLcr) ≤29 mL/min] to inform lenacapavir dosing in HIV-1-infected individuals with organ impairment. In both studies, a single oral dose of 300 mg lenacapavir was administered to participants with normal (n = 10) or impaired (n = 10) hepatic/renal function who were matched for age (±10 years), sex, and body mass index (±20%). Lenacapavir exposures [area under the plasma concentration-time curve from time 0 to infinity (AUCinf) and maximum concentration (Cmax)] were approximately 1.47- and 2.61-fold higher, respectively, in participants with moderate hepatic impairment compared to those with normal hepatic function, whereas lenacapavir AUCinf and Cmax were approximately 1.84- and 2.62-fold higher, respectively, in participants with severe renal impairment compared to those with normal renal function. Increased lenacapavir exposures with moderate hepatic or severe renal impairment were not considered clinically meaningful. Lenacapavir was considered generally safe and well tolerated in both studies. These results support the use of approved lenacapavir dosing regimen in patients with mild (CPT Class A: score 5-6) or moderate hepatic impairment as well as in patients with mild (60 ≤ CLcr ≤ 89 mL/min), moderate (30 ≤ CLcr ≤ 59 mL/min), and severe renal impairment.

Recent trends in the delivery of RNA drugs: Beyond the liver, more than vaccine.

RNAs are known for versatile functions and therapeutic utility. They have gained significant interest since the approval of several RNA drugs, including COVID-19 mRNA vaccines and therapeutic agents targeting liver diseases. There are increasing expectations for a new class of RNA drugs for broader applications. Successful development of RNA drugs for new applications hinges on understanding their diverse functions and structures. In this review, we explore the last five years of literature to understand current approaches to formulate a spectrum of RNA drugs, focusing on new efforts to expand their applications beyond vaccines and liver diseases.

Improvement of liver histology in hepatic sarcoidosis due to treatment with corticosteroids and ursodeoxycholic acid: a case report.

We report the case of a 48-year-old male with a history of pulmonary and ocular sarcoidosis. Non-caseating granulomas, identified histologically, are the most characteristic manifestation of sarcoidosis. Hepatic sarcoidosis is difficult to diagnose using radiological imaging. In the patient reported in this study, ultrasound and contrast-enhanced computed tomography scans identified multiple intra-abdominal lymphadenopathies, with evidence of liver and splenic infiltrations. The first liver biopsy revealed non-caseating granulomatous hepatitis consistent with hepatic sarcoidosis. The patient was treated with ursodeoxycholic acid (UDCA), but his laboratory parameters did not improve. Prednisone was initiated at a dose of 30 mg daily and slowly tapered. At a dose of 12.5 mg daily, marked improvements in the fibrotic and sarcoid-like lesions were noted at the second biopsy. A third biopsy was performed, with the patient on a prednisone taper of 5 mg/day showed mild fibrous expansion in the portal tracts and mild parenchymal necro-inflammatory lesions. However, overall, fibrosis marker levels remained stable over the course of treatment. A fourth biopsy was performed after a 5-year course of 5 mg/day prednisone. This revealed minimal lobular inflammation without fibrosis. Thus, treatment of this patient with corticosteroids and UDCA resulted in marked improvements in his biochemical and histological parameters.

Pathophysiological-Based Nutritional Interventions in Cirrhotic Patients with Sarcopenic Obesity: A State-of-the-Art Narrative Review.

In recent decades, following the spread of obesity, metabolic dysfunction has come to represent the leading cause of liver disease. The classical clinical presentation of the cirrhotic patient has, therefore, greatly changed, with a dramatic increase in subjects who appear overweight or obese. Due to an obesogenic lifestyle (lack of physical activity and overall malnutrition, with an excess of caloric intake together with a deficit of proteins and micronutrients), these patients frequently develop a complex clinical condition defined as sarcopenic obesity (SO). The interplay between cirrhosis and SO lies in the sharing of multiple pathogenetic mechanisms, including malnutrition/malabsorption, chronic inflammation, hyperammonemia and insulin resistance. The presence of SO worsens the outcome of cirrhotic patients, affecting overall morbidity and mortality. International nutrition and liver diseases societies strongly agree on recommending the use of food as an integral part of the healing process in the comprehensive management of these patients, including a reduction in caloric intake, protein and micronutrient supplementation and sodium restriction. Based on the pathophysiological paths shared by cirrhosis and SO, this narrative review aims to highlight the nutritional interventions currently advocated by international guidelines, as well as to provide hints on the possible role of micronutrients and nutraceuticals in the treatment of this multifaceted clinical condition.

The Impact of Red Yeast Rice Extract Use on the Occurrence of Muscle Symptoms and Liver Dysfunction: An Update from the Adverse Event Reporting Systems and Available Meta-Analyses.

Red yeast rice (RYR) has a cholesterol-lowering effect due to the presence of bioactive components (monacolins, mainly monacolin K) that act by inhibiting the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. The European Food Safety Authority (EFSA) assessed the use of RYR and, while pointing out several uncertainties regarding the available data, raised a warning related to the safety of RYR when used as a food supplement at a dose of monacolin as low as 3 mg/day. In their decision in June 2023, EFSA approved the use of monacolins from RYR at doses less than 3 mg/day. We therefore decided to interrogate the different adverse event reporting systems (FAERS and CAERS) and analyse the characteristics of the cases reported to be associated with RYR supplements, and we reviewed the most recent meta-analyses with a focus on the occurrence of muscle symptoms and liver dysfunction. In terms of all musculoskeletal disorders from September 2013 (when the first case related to RYR consumption was recorded) to 30 September 2023, 363,879 cases were reported in the FAERS, with the number of cases related to RYR consumption being very small and accounting for 0.008% of cases. In the same time frame, 27,032 cases of hepatobiliary disorders were reported, and the cases attributable to RYR ingestion accounted for 0.01% of all cases. A low rate of muscle symptoms and liver dysfunction attributed to RYR ingestion was also observed in the CAERS database, where only 34 cases of adverse muscle events and 10 cases of adverse liver events reported RYR as the suspect product, while 19 cases of both muscle events and 10 cases of adverse liver events reported it as a concomitant product. This profile mirrors that of meta-analyses of randomised clinical trials of RYR, in which RYR use was not associated with either liver dysfunction or muscular adverse symptoms.

Mortality and associated factors among people living with HIV admitted at a tertiary-care hospital in Uganda: a cross-sectional study.

BACKGROUND: Hospital admission outcomes for people living with HIV (PLHIV) in resource-limited settings are understudied. We describe in-hospital mortality and associated clinical-demographic factors among PLHIV admitted at a tertiary-level public hospital in Uganda. METHODS: We performed a cross-sectional analysis of routinely collected data for PLHIV admitted at Kiruddu National Referral Hospital between March 2020 and March 2023. We estimated the proportion of PLHIV who had died during hospitalization and performed logistic regression modelling to identify predictors of mortality. RESULTS: Of the 5,827 hospitalized PLHIV, the median age was 39 years (interquartile range [IQR] 31-49) and 3,293 (56.51%) were female. The median CD4 + cell count was 109 cells/µL (IQR 25-343). At admission, 3,710 (63.67%) were active on antiretroviral therapy (ART); 1,144 (19.63%) had interrupted ART > 3 months and 973 (16.70%) were ART naïve. In-hospital mortality was 26% (1,524) with a median time-to-death of 3 days (IQR 1-7). Factors associated with mortality (with adjusted odds ratios) included ART interruption, 1.33, 95% confidence intervals (CI) 1.13-1.57, p 0.001; CD4 + counts ≤ 200 cells/µL 1.59, 95%CI 1.33-1.91, p < 0.001; undocumented CD4 + cell count status 2.08, 95%CI 1.73-2.50, p < 0.001; impaired function status 7.35, 95%CI 6.42-8.41, p < 0.001; COVID-19 1.70, 95%CI 1.22-2.37, p 0.002; liver disease 1.77, 95%CI 1.36-2.30, p < 0.001; co-infections 1.53, 95%CI 1.32-1.78, p < 0.001; home address > 20 km from hospital 1.23, 95%CI 1.04-1.46, p 0.014; hospital readmission 0.7, 95%CI 0.56-0.88, p 0.002; chronic lung disease 0.62, 95%CI 0.41-0.92, p 0.019; and neurologic disease 0.46, 95%CI 0.32-0.68, p < 0.001. CONCLUSION: One in four admitted PLHIV die during hospitalization. Identification of risk factors (such as ART interruption, function impairment, low/undocumented CD4 + cell count), early diagnosis and treatment of co-infections and liver disease could improve outcomes.

UDCA for Drug-Induced Liver Disease: Clinical and Pathophysiological Basis.

Drug-induced liver injury (DILI) is an adverse reaction to medications and other xenobiotics that leads to liver dysfunction. Based on differential clinical patterns of injury, DILI is classified into hepatocellular, cholestatic, and mixed types; although hepatocellular DILI is associated with inflammation, necrosis, and apoptosis, cholestatic DILI is associated with bile plugs and bile duct paucity. Ursodeoxycholic acid (UDCA) has been empirically used as a supportive drug mainly in cholestatic DILI, but both curative and prophylactic beneficial effects have been observed for hepatocellular DILI as well, according to preliminary clinical studies. This could reflect the fact that UDCA has a plethora of beneficial effects potentially useful to treat the wide range of injuries with different etiologies and pathomechanisms occurring in both types of DILI, including anticholestatic, antioxidant, anti-inflammatory, antiapoptotic, antinecrotic, mitoprotective, endoplasmic reticulum stress alleviating, and immunomodulatory properties. In this review, a revision of the literature has been performed to evaluate the efficacy of UDCA across the whole DILI spectrum, and these findings were associated with the multiple mechanisms of UDCA hepatoprotection. This should help better rationalize and systematize the use of this versatile and safe hepatoprotector in each type of DILI scenarios.

Polysaccharides from Chinese herbal medicine: a review on the hepatoprotective and molecular mechanism.

Polysaccharides, predominantly extracted from traditional Chinese medicinal herbs such as Lycium barbarum, Angelica sinensis, Astragalus membranaceus, Dendrobium officinale, Ganoderma lucidum, and Poria cocos, represent principal bioactive constituents extensively utilized in Chinese medicine. These compounds have demonstrated significant anti-inflammatory capabilities, especially anti-liver injury activities, while exhibiting minimal adverse effects. This review summarized recent studies to elucidate the hepatoprotective efficacy and underlying molecular mechanisms of these herbal polysaccharides. It underscored the role of these polysaccharides in regulating hepatic function, enhancing immunological responses, and improving antioxidant capacities, thus contributing to the attenuation of hepatocyte apoptosis and liver protection. Analyses of molecular pathways in these studies revealed the intricate and indispensable functions of traditional Chinese herbal polysaccharides in liver injury management. Therefore, this review provides a thorough examination of the hepatoprotective attributes and molecular mechanisms of these medicinal polysaccharides, thereby offering valuable insights for the advancement of polysaccharide-based therapeutic research and their potential clinical applications in liver disease treatment.

Review article: Pharmacologic management of obesity - updates on approved medications, indications and risks.

BACKGROUND: Obesity has reached epidemic proportions, with >40% of the US population affected. Although traditionally managed by lifestyle modification, and less frequently by bariatric therapies, there are significant pharmacological advancements. AIMS: To conduct a narrative review of the neurohormonal and physiological understanding of weight gain and obesity, and the development, clinical testing, indications, expected clinical outcomes, and associated risks of current FDA-approved and upcoming anti-obesity medications (AOMs). METHODS: We conducted a comprehensive review in PubMed for articles on pathophysiology and complications of obesity, including terms 'neurohormonal', 'obesity', 'incretin', and 'weight loss'. Next, we searched for clinical trial data of all FDA-approved AOMs, including both the generic and trade names of orlistat, phentermine/topiramate, bupropion/naltrexone, liraglutide, and semaglutide. Additional searches were conducted for tirzepatide and retatrutide - medications expecting regulatory approval. Searches included combinations of terms related to mechanism of action, indications, side effects, risks, and future directions. RESULTS: We reviewed the pathophysiology of obesity, including specific role of incretins and glucagon. Clinical data supporting the use of various FDA-approved medications for weight loss are presented, including placebo-controlled or, when available, head-to-head trials. Beneficial metabolic effects, including impact on liver disease, adverse effects and risks of medications are discussed, including altered gastrointestinal motility and risk for periprocedural aspiration. CONCLUSION: AOMs have established efficacy and effectiveness for weight loss even beyond 52 weeks. Further pharmacological options, such as dual and triple incretins, are probable forthcoming additions to clinical practice for combating obesity and its metabolic consequences such as metabolic dysfunction-associated steatotic liver disease.

Ginsenoside Rg1 attenuates lipopolysaccharide-induced chronic liver damage by activating Nrf2 signaling and inhibiting inflammasomes in hepatic cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Ginseng (Panax ginseng C. A. Meyer) is a precious traditional Chinese medicine with multiple pharmacological effects. Ginsenoside Rg1 is a main active ingredient extracted from ginseng, which is known for its age-delaying and antioxidant effects. Increasing evidence indicates that Rg1 exhibits anti-inflammatory properties in numerous diseases and may ameliorate oxidative damage and inflammation in many chronic liver diseases. AIM OF THE STUDY: Chronic inflammatory injury in liver cells is an important pathological basis of many liver diseases. However, its mechanism remains unclear and therapeutic strategies to prevent its development need to be further explored. Thus, our study is to delve the protective effect and mechanism of Rg1 against chronic hepatic inflammatory injuries induced by lipopolysaccharide (LPS). MATERIALS AND METHODS: The chronic liver damage model in mice was build up by injecting intraperitoneally with LPS (200 µg/kg) for 21 days. Serum liver function indicators and levels of IL-1ß, IL-6 and TNF-α were examined by using corresponding Kits. Hematoxylin and Eosin (H&E), Periodic acid-Schiff (PAS), and Masson stains were utilized to visualize hepatic histopathological damage, glycogen deposition, and liver fibrosis. The nuclear import of p-Nrf2 and the generation of Col4 in the liver were detected by IF, while IHC was employed to detect the expressions of NLRP3 and AIM2 in the hepatic. The Western blot and q-PCR were used to survey the expressions of proteins and mRNAs of fibrosis and apoptosis, and the expressions of Keap1, p-Nrf2 and NLRP3, NLRP1, AIM2 inflammasome-related proteins in mouse liver. The cell viability of human hepatocellular carcinoma cells (HepG2) was detected by Cell Counting Kit-8 to select the action concentration of LPS, and intracellular ROS generation was detected using a kit. The expressions of Nuclear Nrf2, HO-1, NQO1 and NLRP3, NLRP1, and AIM2 inflammasome-related proteins in HepG2 cells were detected by Western blot. Finally, the feasibility of the molecular interlinking between Rg1 and Nrf2 was demonstrated by molecular docking. RESULTS: Rg1 treatment for 21 days decreased the levels of ALT, AST, and inflammatory factors of serum IL-1ß, IL-6 and TNF-α in mice induced by LPS. Pathological results indicated that Rg1 treatment obviously alleviated hepatocellular injury and apoptosis, inflammatory cell infiltration and liver fibrosis in LPS stimulated mice. Rg1 promoted Keap1 degradation and enhanced the expressions of p-Nrf2, HO-1 and decreased the levels of NLRP1, NLRP3, AIM2, cleaved caspase-1, IL-1ß and IL-6 in livers caused by LPS. Furthermore, Rg1 effectively suppressed the rise of ROS in HepG2 cells induced by LPS, whereas inhibition of Nrf2 reversed the role of Rg1 in reducing the production of ROS and NLRP3, NLRP1, and AIM2 expressions in LPS-stimulated HepG2 cells. Finally, the molecular docking illustrated that Rg1 exhibits a strong affinity towards Nrf2. CONCLUSION: The findings indicate that Rg1 significantly ameliorates chronic liver damage and fibrosis induced by LPS. The mechanism may be mediated through promoting the dissociation of Nrf2 from Keap1 and then activating Nrf2 signaling and further inhibiting NLRP3, NLRP1, and AIM2 inflammasomes in liver cells.

Antioxidant therapy for hepatic diseases: a double-edged sword.

Liver diseases are complex conditions, significantly influenced by oxidative stress. This comprehensive review assesses the therapeutic role of antioxidants like l-ascorbic acid and α tocopherol, beta-carotene, various minerals, and plant-based ingredients in mitigating oxidative stress-induced liver diseases. The manuscript delves into the critical influence of genetic and epigenetic factors on disease susceptibility, progression, and response to antioxidant therapy. While animal studies suggest antioxidant efficacy in liver disease treatment, human trials remain inconclusive, and caution is advised due to its possible potential pro-oxidant effects. Moreover, the interactions of antioxidants with other drugs necessitate careful consideration in the management of polypharmacy in liver disease patients. The review underscores the need for further research to establish the clinical benefits of antioxidants with understanding of possible antioxidant toxicities to elucidate the intricate interplay of genetic, epigenetic, and environmental factors in liver diseases. The aim is to foster a better understanding of the knowledge on hepatic disease management with judicial antioxidant therapies.

Recent progress on the application of compound formulas of traditional Chinese medicine in clinical trials and basic research in vivo for chronic liver disease.

ETHNOPHARMACOLOGICAL RELEVANCE: Chronic liver diseases mainly include chronic viral liver disease, metabolic liver disease, cholestatic liver disease (CLD), autoimmune liver disease, and liver fibrosis or cirrhosis. Notably, the compound formulas of traditional Chinese medicine (TCM) is effective for chronic liver diseases in clinical trials and basic research in vivo, which provide evidence of chronic liver disease treatment with integrated TCM and traditional Western medicine. AIM OF THE REVIEW: This paper aims to provide a comprehensive review of the compound formulas of TCM for treating different chronic liver diseases to elucidate the composition, main curative effects, and mechanisms of these formulas and research methods. MATERIALS AND METHODS: Different keywords related to chronic liver diseases and keywords related to the compound formulas of TCM were used to search the literature. PubMed, Scopus, Web of Science, and CNKI were searched to screen out original articles about the compound formulas of TCM related to the treatment of chronic liver diseases, mainly including clinical trials and basic in vivo research related to Chinese patent drugs, classic prescriptions, proven prescriptions, and hospital preparations. We excluded review articles, meta-analysis articles, in vitro experiments, articles about TCM monomers, articles about single-medicine extracts, and articles with incomplete or uncertain description of prescription composition. Plant names were checked with MPNS (http://mpns.kew.org). RESULTS: In this review, the clinical efficacy and mechanism of compound formulas of TCM were summarized for the treatment of chronic viral hepatitis, nonalcoholic fatty liver disease, CLD, and liver fibrosis or cirrhosis developed from these diseases and other chronic liver diseases. For each clinical trial and basic research in vivo, this review provides a detailed record of the specific composition of the compound formulas of TCM, type of clinical research, modeling method of animal experiments, grouping methods, medication administration, main efficacy, and mechanisms. CONCLUSION: The general development process of chronic liver disease can be summarized as chronic hepatitis, liver fibrosis or cirrhosis, and hepatocellular carcinoma. The compound formulas of TCM have some applications in these stages of chronic liver diseases. Owing to the continuous progress of medical technology, the benefits of the compound formulas of TCM in the treatment of chronic liver diseases are constantly changing and developing.

The effects of pomegranate consumption on liver function enzymes in adults: A systematic review and meta-analysis.

BACKGROUND: We performed a systematic review and meta-analysis of all published clinical trial studies to provide a more accurate estimation of pomegranate effects on liver enzymes in different clinical conditions. METHODS: A systematic literature search was carried out using electronic databases, including PubMed, Web of Science, and Scopus, up to March 2023 to identify eligible randomized clinical trials (RCTs) evaluating the effect of pomegranate consumption on liver function enzymes. Heterogeneity tests of the selected trials were performed using the I2 statistic. Random effects models were assessed based on the heterogeneity tests, and pooled data were determined as the weighted mean difference with a 95% confidence interval. RESULTS: Out of 3811 records, 9 eligible RCTs were included in the current study. However, there are limitations in the included studies, which can be mentioned in the dose, duration, and type of interventions that are different among the studies, as well as the small number of included studies. All this causes heterogeneity among studies and this heterogeneity limits the consistency of the results. Our meta-analysis showed that pomegranate intake had a significant effect on lowering aspartate aminotransferase (AST) levels in long-term intervention (> 8 weeks), obese (BMI≥30) individuals, or patients with metabolic disorders. Furthermore, results showed a significant decrease in alanine aminotransferase (ALT) levels in the long-term intervention (> 8 weeks) or in patients with metabolic disorders following the pomegranate intake. Combined results from the random-effects model indicated a significant reduction in gamma-glutamyl transferase (GGT) levels (WMD: -5.43 IU/L 95% CI: -7.78 to -3.08; p < 0.001;) following the pomegranate intake. The results of Egger's test mentioned a significant publication bias for the trials examining the effect of pomegranate intake on AST (p = 0.007) and ALT (p = 0.036). CONCLUSION: Our results suggest that long-term pomegranate intake may be effective in ameliorating liver enzymes in adults with obesity and metabolic disorders who are more likely to have elevated baseline liver enzymes due to some degree of liver injury or tissue damage. However, some studies failed to conduct independent biochemical characterization of the product used, including the presence and quantity of polyphenols, antioxidants, and proanthocyanidins.

Paracetamol (acetaminophen) poisoning: The early years.

Paracetamol (acetaminophen) was marketed in the 1950s as a nonprescription analgesic/antipyretic without any preclinical toxicity studies. It became used increasingly for self-poisoning, particularly in the UK and was belatedly found to cause acute liver damage, which could be fatal. Management of poisoned patients was difficult as maximum abnormalities of liver function were delayed for 3 days or more after an overdose. There was no treatment and the mechanism of hepatotoxicity was not known. The paracetamol half-life was prolonged with liver damage occurring when it exceeded 4 h and the Rumack-Matthew nomogram was an important advance that allowed stratification of patients into separate zones of risk. It is used to guide prognosis and treatment and its predictive value could be increased by combining it with the paracetamol half-life. The problems of a sheep farmer in Australia in the early 1970s led to the discovery of the mechanism of paracetamol hepatotoxicity, and the first effective treatment of overdosage with intravenous (IV) cysteamine. This had unpleasant side effects and administration was difficult. N-acetylcysteine soon became the treatment of choice for paracetamol overdose and given early it was very effective when administered either IV or orally. N-acetylcysteine could cause anaphylactoid reactions, particularly early during IV administration when the concentrations were highest. Simpler and shorter regimes with slower initial rates of infusion have now been introduced with a reduced incidence of these adverse effects. In addition, there has been a move to use larger doses of N-acetylcysteine given over longer periods for patients who are more severely poisoned and those with risk factors. There has been much interest recently in the search for novel biomarkers such as microRNAs, procalcitonin and cyclophilin that promise to have greater specificity and sensitivity than transaminases. Paracetamol-protein adducts predict hepatotoxicity and are specific biomarkers of toxic paracetamol metabolite exposure. Another approach would be measurement of the plasma levels of cysteine and inorganic sulfate. It is 50 years since the first effective treatment for paracetamol poisoning and, apart from liver transplantation, there is still no effective treatment for patients who present late.

Melatonin and metformin co-loaded nanoliposomes efficiently attenuate liver damage induced by bile duct ligation in rats.

In the current study, the therapeutic effectiveness of the metformin (Met) and melatonin (Mel) co-loaded liposomes was investigated on cholestasis induced by bile duct ligation (BDL) in male rats. Histopathological analysis, biochemical analysis, and oxidative stress markers were assayed to determine the therapeutic effect of Met and Mel co-loaded liposomes on cholestasis. Histopathological analysis revealed that the simultaneous administration of Met and Mel, whether in the free (C-Mel-Met) or liposomal (C-Lipo-Mel-Met) forms, reduced inflammation as well as proliferation of bile ducts; however, results were more prominent in the liposomal form of Mel and Met. Additionaly, serum levels of aspartate aminotransferase (AST) were significantly (p < 0.001) higher in (C-Mel-Met) treated rats compared with (BDL) rats; however, (C-Lipo-Mel-Met) treated rats exhibited significant (p < 0.05) lower AST rates in comparison to (BDL) rats. Moreover, a significant (p < 0.0001) drop in bilirubin levels was detected in (C-Lipo-Mel-Met) treated rats in comparison to (BDL) rats; it is noteworthy mentioning that bilirubin levels in (C-Lipo-Mel-Met) treated rats were insignificant in comparison to sham-control (SC) rats. Furthermore, rats concomitantly administered Met and Mel, exhibited significant downregulation in the expression levels of inflammatory cytokine genes such as TNF-α and IL-1 gene expression, where the downregulation was more prominent in the liposomal from. Our findings demonestrate that the concomitant administration of metformin and melatonin in the liposomal form had more therapeutic effect on liver injury than their free forms through improving histological changes, reducing biochemical markers and favoring oxidant- antioxidant balance.