Rapid liver self-recovery: A challenge for rat models of tissue damage.

Animal models, mainly murine, stay as a fundamental resource in diverse research pursuits, notably contributing to significant strides in discovering novel treatments for therapeutic applications. Preclinical assays must consider the existence of self-recovery mechanisms in the murine species to achieve a well-designed control group. This study focuses on unveiling the innate rapid regenerative capacity of rat liver by utilizing the thioacetamide-induced sub-chronic liver injury model. Employing histopathological, biochemical, and molecular liver function tests, we assessed the recovery of liver tissue functionality. Moreover, animals were housed with voluntary running wheels and locomotory activity was recorded and employed as an indirect index of overall animal recuperation. Remarkably, basal locomotory activity reestablished to normal levels only two weeks post-thioacetamide exposure. Our results raise vital considerations about the importance of temporal synchronicity in comparative assays to validate the real action of treatments, emphasizing the role of the rapid rat liver endogenous self-recovery.

Epidemiology of Hepatitis C Virus in HIV Patients from West Mexico: Implications for Controlling and Preventing Viral Hepatitis.

The complex epidemiology of hepatitis C virus (HCV) infection among human immunodeficiency virus (HIV) patients in West Mexico remains poorly understood. Thus, this study aimed to investigate the HCV prevalence, HCV-associated risk factors, and HCV genotypes/subtypes and assess their impacts on liver fibrosis in 294 HIV patients (median age: 38 years; 88.1% male). HCV RNA was extracted and amplified by PCR. Hepatic fibrosis was assessed using three noninvasive methods: transient elastography (TE), the aspartate aminotransferase (AST)-to-platelets ratio index score (APRI), and the fibrosis-4 score (FIB4). Patients with liver stiffness of ≥9.3 Kpa were considered to have advanced liver fibrosis. HCV genotypes/subtypes were determined by line probe assay (LiPA) or Sanger sequencing. The prevalence of HIV/HCV infection was 36.4% and was associated with injection drug use (odds ratio (OR) = 13.2; 95% confidence interval (CI) = 5.9-33.6; p < 0.001), imprisonment (OR = 3.0; 95% CI = 1.7-5.4; p < 0.001), the onset of sexual life (OR = 2.6; 95% CI = 1.5-4.5; p < 0.001), blood transfusion (OR = 2.5; 95% CI = 1.5-4.2; p = 0.001), tattooing (OR = 2.4; 95% CI = 1.4-3.9; p = 0.001), being a sex worker (OR = 2.3; 95% CI = 1.0-5.4; p = 0.046), and surgery (OR = 1.7; 95% CI = 1.0-2.7; p = 0.042). The HCV subtype distribution was 68.2% for 1a, 15.2% for 3a, 10.6% for 1b, 3.0% for 2b, 1.5% for 2a, and 1.5% for 4a. The advanced liver fibrosis prevalence was highest in patients with HIV/HCV co-infection (47.7%), especially in those with HCV subtype 1a. CD4+ counts, albumin, direct bilirubin, and indirect bilirubin were associated with liver fibrosis. In conclusion, HCV infection had a significant impact on the liver health of Mexican HIV patients, highlighting the need for targeted preventive strategies in this population.

Sucralose: From Sweet Success to Metabolic Controversies-Unraveling the Global Health Implications of a Pervasive Non-Caloric Artificial Sweetener.

Sucralose is a food additive initially used to mitigate glycemic peaks and calorie intake in patients with diabetes and obesity. Although sucralose has been considered safe for human consumption, the World Health Organization (WHO) issued a global alert in 2023 concerning the potential health implications of this artificial sweetener. This review aims to comprehensively explore the effects of sucralose intake on human health by understanding sucralose absorption, metabolism, and excretion. We also outline the role of the sweet taste 1 receptor 3 (T1R3) in mediating sucralose-dependent signaling pathways that regulate satiety, incretin release, and insulin response. Finally, we discuss the impact of sucralose on microbiome dysbiosis, inflammatory response origin, liver damage, and toxicity. Gaining a deeper understanding of the manifold effects of sucralose on human physiology will help promote further studies to ensure its consumption is deemed safe for a broader population, including children, adolescents, and pregnant women.

Mineral profile and histopathological findings in the liver of white-lipped frog (Leptodactylidae) from the morphoclimatic domain of the Caatingas, Brazil.

This study aimed to investigate the mineral profile and histopathological findings in the liver of Leptodactylus macrosternum (white-lipped frog) and to assess the association between melanomacrophage areas and hepatic fungal granuloma with several factors such as weight, snout-cloacal length, sex, hepatosomatic index, season (dry and rainy), and condition factor K. A total of 135 frogs of different ages were collected from three areas in the city of Petrolina, Pernambuco, with varying land use (conventional agriculture, organic agriculture, and Caatinga stricto sensu). The liver of all specimens exhibited changes such as granulomatous lesions, inflammatory cell infiltrate, blood vessel congestion, and sinusoid dilation. The melanomacrophage areas were influenced by weight, snout-cloacal length, and hepatosomatic index. Our findings revealed a positive correlation between body size (weight and snout-cloacal length) and melanomacrophage/hepatic granuloma, while the hepatosomatic index showed a negative relationship. For the condition factor K, only age presents relationship. Eleven elements were quantified for the mineral profile, with aluminum (Al), iron (Fe), and zinc (Zn) being the most abundant in both liver and muscle. Although the histopathological findings and mineral profile of the liver and muscle in this study indicate an effect on the health of L. macrosternum in different collection areas, confirming the relationship between environmental characteristics and these findings requires future studies. Furthermore, long-term studies would be necessary to allow the monitoring of all stages of development of these populations, from tadpoles to adults, for a better evaluation of these effects in L. macrosternum.

Liver and kidney damage in quail embryos hatched from eggs sprayed once with chlorpyrifos during artificial incubation.

Birds have enough conditions to be used as bioindicators for the presence of environmental contaminants. Notably, chlorpyrifos (CPF) remains extensively employed in Argentina, particularly in fruit plantations and livestock settings This study aimed to assess the potential impacts of CPF on common quail (Coturnix coturnix) embryos through external eggshell application during key embryonic stages (days 1, 4, and 14). Concentrations equivalent to those used in fruit applications, 5× and 10 × (38.4, 192, and 384 µg/egg), were employed. A 48% commercial formulation of CPF (Pirfos - Icona®) was utilized. An increase in embryonic deaths, as well as a statistical association between the degree of liver or kidney lesions and CPF concentrations was observed. The results suggest that CPF can induce embryotoxic effects with a single exposure to quail embryos and compromise the viability of the organisms. The study suggests a potential exposure risk for embryos through contact with the insecticide on the eggshell's exterior.

Didymin protects against polystyrene nanoplastic-induced hepatic damage in male albino rats by modulation of Nrf-2/Keap-1 pathway

Polystyrene nanoplastics (PS-NPs) are ubiquitous environmental pollutants that can cause oxidative stress in various organs, including the liver. Didymin is a dietary flavanone that displays multiple pharmacological activities. Therefore, the present study evaluated the palliative role of didymin against PS-NPs-induced hepatic damage in rats. Albino rats (n=48) were randomly distributed into 4 groups: control, PS-NPs treated group, PS-NPs + didymin co-administered group, and didymin supplemented group. After 30 days, PS-NPs intoxication lowered the expression of Nrf-2 and anti-oxidant genes [catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GSR), glutathione-S-transferase (GST), and heme oxygenase-1 (HO-1)], whereas the expression of KEAP1 kelch like ECH associated protein 1 (Keap-1) was increased. PS-NPs exposure also reduced the activities of anti-oxidants enzymes (CAT, SOD, GPx, GSR, GST, GSH, and OH-1), while malondialdehyde (MDA) and reactive oxygen species (ROS) levels were increased. The levels of alanine transaminase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) were increased in PS-NPs-exposed rats. Moreover, inflammatory indices [interleukin-1β (IL-1β), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), nuclear factor-kappa B (NF-κB), and cyclooxygenase-2 (COX-2)] were increased in PS-NPs-exposed rats. Furthermore, PS-NPs intoxication increased the expressions of apoptotic markers including Bax and Caspase-3, as well as reducing Bcl-2 expression. The histopathological analysis showed significant damage in PS-NPs-treated rats. However, didymin supplementation ameliorated all the PS-NPs-induced damage in the liver of rats. Therefore, it was concluded that didymin can act as a remedy against PS-NPs-induced liver toxicity due to its anti-apoptotic, anti-oxidant, and anti-inflammatory activities.

Hepatoprotective Mechanisms Induced by Spinach Methanolic Extract in Rats with Hyperglycemia-An Immunohistochemical Analysis.

Spinach methanolic extract (SME) has a hepatoprotective effect due to its polyphenolic antioxidants; however, its action in parenchymal (PQ) and non-parenchymal (nPQ) cells remains unknown. This study investigates the hepatoprotective effect of SME on streptozotocin-induced hyperglycemic rats (STZ), focusing on immunohistochemical analyses. Methods: The extract was prepared, and the total polyphenols and antioxidant activity were quantified. Adult male Wistar rats were divided into four groups (n = 8): normoglycemic rats (NG), STZ-induced hyperglycemic (STZ), STZ treated with 400 mg/kg SME (STZ-SME), and NG treated with SME (SME) for 12 weeks. Serum liver transaminases and lipid peroxidation levels in tissue were determined. The distribution pattern and relative levels of markers related to oxidative stress [reactive oxygen species (ROS), superoxide dismutase-1, catalase, and glutathione peroxidase-1], of cytoprotective molecules [nuclear NRF2 and heme oxygenase-1 (HO-1)], of inflammatory mediators [nuclear NF-κB, TNF-α], proliferation (PCNA), and of fibrogenesis markers [TGF-ß, Smad2/3, MMP-9, and TIMP1] were evaluated. Results: SME had antioxidant capacity, and it lowered serum transaminase levels in STZ-SME compared to STZ. It reduced NOX4 staining, and lipid peroxidation levels were related to low formation of ROS. In STZ-SME, the immunostaining for antioxidant enzymes increased in nPQ cells compared to STZ. However, enzymes were also localized in extra and intracellular vesicles in STZ. Nuclear NRF2 staining and HO-1 expression in PQ and nPQ were higher in STZ-SME than in STZ. Inflammatory factors were decreased in STZ-SME and were related to the percentage decrease in NF-κB nuclear staining in nPQ cells. Similarly, TGF-ß (in the sinusoids) and MMP-9 (in nPQ) were increased in the STZ-SME group compared to the other groups; however, staining for CTGF, TIMP1, and Smad2/3 was lower. Conclusions: SME treatment in hyperglycemic rats induced by STZ may have hepatoprotective properties due to its scavenger capacity and the regulation of differential expression of antioxidant enzymes between the PQ and nPQ cells, reducing inflammatory and fibrogenic biomarkers in liver tissue.

[Hyper-IgM syndrome with early liver involvement]. / Síndrome de hiper-IgM con afectación hepática temprana.

INTRODUCTION: Hyper-IgM syndrome is an innate error of immunity in which there is a defect in change of isotype of immunoglobulins, with decreased values of IgG, IgA, and IgE, but normal or increased level of IgM. This predisposes to infectious processes at the respiratory and gastrointestinal levels, as well as autoimmune diseases and neoplasm. CASE REPORT: A 5 year 7-month-old boy with a history of 2 pneumonias, one of them severe, and chronic diarrhea since he was 2 years old. Persistent moderate neutropenia decreased IgG and elevated IgM. Cytometry flow confirmed absence of CD40L. Clinical evolution with early hepatic involvement. DISCUSSION: Hyper-IgM syndrome predisposes to liver damage, so a complete evaluation is required as well as early diagnosis. Active anti-infective treatment and control of the inflammatory response are key to the treatment of liver damage.

INTRODUCCIÓN: El síndrome de hiper-IgM es un error innato de la inmunidad, caracterizado por un defecto en el cambio de isotipo de inmunoglobulina, con valores disminuidos de IgG, IgA e IgE, y concentraciones normales o elevadas de IgM. Predispone a procesos infecciosos en el sistema respiratorio y aparato gastrointestinal, además de enfermedades autoinmunes y neoplasias. REPORTE DE CASO: Paciente pediátrico de género masculino, de 5 años y 7 meses de edad, con antecedente de dos cuadros de neumonía (uno de estos grave) y diarrea crónica desde los 2 años. Neutropenia moderada persistente, disminución de la concentración de IgG y elevación de IgM. La citometría de flujo confirmó la ausencia de CD40L. Durante la evolución clínica tuvo afectación hepática temprana. CONCLUSIÓn: El síndrome de hiper-IgM predispone a daño hepático, por lo que se requiere la evaluación completa y el diagnóstico oportuno. El tratamiento antiinfeccioso activo y el control de la respuesta inflamatoria son factores decisivos para establecer el tratamiento del daño hepático.

Effect of Gestational Fish Oil Supplementation on Liver Metabolism and Mitochondria of Male and Female Rat Offspring Programmed by Maternal High-Fat Diet.

SCOPE: Perinatal maternal moderately high-fat diet (mHFD) is associated with obesity and fatty liver disease in offspring, and maternal fish oil (FO: n-3 PUFA source) supplementation may attenuate these disorders. This study evaluates the effects of FO given to pregnant rats fed a mHFD on the offspring's liver at weaning. METHODS AND RESULTS: Female Wistar rats receive an isoenergetic, control (CT: 10.9% from fat) or high-fat (HF: 28.7% from fat) diet before mating, and throughout pregnancy and lactation. FO supplementation (HFFO: 2.9% of FO in the HF diet) is given to one subgroup of HF dams during pregnancy. At weaning, male and female mHFD offspring display higher body mass, adiposity, and hepatic cellular damage, steatosis, and inflammation, accompanied by increased damaged mitochondria. FO does not protect pups from systemic metabolic alterations and partially mitigates hepatic histological damage induced by mHFD only in females. However, FO reduces mRNA expression of lipogenic genes, and mitochondrial damage, and modified mitochondrial morphology suggestive of early adaptations via mitochondrial dynamics. CONCLUSIONS: Gestational FO supplementation has limited beneficial effects on the damage caused by perinatal mHFD consumption in offspring's liver at weaning. However, FO imprinting effect on lipid metabolism and mitochondria may have beneficial long-term outcomes.

In Vivo and In Silico Studies of the Hepatoprotective Activity of Tert-Butylhydroquinone.

Tert-butylhydroquinone (TBHQ) is a synthetic food antioxidant with biological activities, but little is known about its pharmacological benefits in liver disease. Therefore, this work aimed to evaluate TBHQ during acute liver damage induced by CCl4 (24 h) or BDL (48 h) in Wistar rats. It was found that pretreatment with TBHQ prevents 50% of mortality induced by a lethal dose of CCl4 (4 g/kg, i.p.), and 80% of BDL+TBHQ rats survived, while only 50% of the BDL group survived. Serum markers of liver damage and macroscopic and microscopic (H&E staining) observations suggest that TBHQ protects from both hepatocellular necrosis caused by the sublethal dose of CCl4 (1.6 g/kg, i.p.), as well as necrosis/ductal proliferation caused by BDL. Additionally, online databases identified 49 potential protein targets for TBHQ. Finally, a biological target candidate (Keap1) was evaluated in a proof-of-concept in silico molecular docking assay, resulting in an interaction energy of -5.5491 kcal/mol, which was higher than RA839 and lower than monoethyl fumarate (compounds known to bind to Keap1). These findings suggest that TBHQ increases the survival of animals subjected to CCl4 intoxication or BDL, presumably by reducing hepatocellular damage, probably due to the interaction of TBHQ with Keap1.

Effects of Hydroxytyrosol Supplementation on Performance, Fat and Blood Parameters of Broiler Chickens.

The study aimed to evaluate the effects of dietary supplementation of hydroxytyrosol (HT) on performance, fat, and blood parameters of broilers. In total, 960 male chicks were distributed into four treatments groups with 12 replicates with 20 birds per pen, with varying HT levels (0, 5, 10, and 50 mg/kg of feed) added to the basal diet from 1 to 42 days old. Feed intake, body weight gain, and feed conversion ratio were evaluated. Enzymes related to liver injury were evaluated in blood. Fatty acid profile and malondialdehyde (MDA) concentration were determined in the breast meat. Dietary supplementation of HT did not improve broilers' performance (p > 0.05). Birds fed 50 mg HT/kg had lower AST, ALT, and GGT concentrations (p ≤ 0.05), whereas broilers fed 5, 10, and 50 mg HT/kg, had lower TBIL concentrations (p ≤ 0.05). Breast meat of broilers fed 50 mg HT/kg had lower lipid content, saturated fatty acid, unsaturated fatty acids, MDA concentrations (p ≤ 0.05), and polyunsaturated fatty acids (p < 0.0001). In summary, supplementation of 5, 10, and 50 mg HT/kg does not improve the performance of broilers, but the dose of 50 mg HT/kg helps the liver against inflammation and improves fat parameters.

A Critical Appraisal of the Most Recent Investigations on the Hepatoprotective Action of Brazilian Plants.

Conventional treatments for liver diseases are often burdened by side effects caused by chemicals. For minimizing this problem, the search for medicines based on natural products has increased. The objective of this review was to collect data on the potential hepatoprotective activity of plants of the Brazilian native flora. Special attention was given to the modes of extraction, activity indicators, and identification of the active compounds. The databases were Science direct, Pubmed, and Google Academic. Inclusion criteria were: (a) plants native to Brazil; (b) studies carried out during the last 15 years; (c) high-quality research. A fair number of communications met these criteria. Various parts of plants can be used, e.g., fruit peels, seeds, stem barks, and leaves. An outstanding characteristic of the active extracts is that they were mostly obtained from plant parts with low commercial potential, i.e., by-products or bio-residues. The hepatoprotective activities are exerted by constituents such as flavonoids, phenolic acids, vitamin C, phytosterols, and fructose poly- and oligosaccharides. Several Brazilian plants present excellent perspectives for the obtainment of hepatoprotective formulations. Very important is the economical perspective for the rural producers which may eventually increase their revenue by selling increasingly valued raw materials which otherwise would be wasted.

Caracterización clínica y epidemiológica de los pacientes con hepatitis alcohólica en el Hospital Regional de Talca: estudio retrospectivo de 5 años (2017-2022) / Clinical and epidemiological characterisation of patients with alcoholic hepatitis in the Regional Hospital of Talca - 5-year retrospective study (2017-2022)

Alcoholic Hepatitis (HA) represent to one of the pathological entities in the context of liver damage associated with excessive and prolonged alcohol consumption. Despite its high mortality, making the early diagnosis is still a challenge for physicians. The local information of this pathology is limited, so this work consists of conducting a retrospective study on the clinical and epidemiological characteristics of patients diagnosed with HA at the Regional Hospital of Talca (HRT); in order to make available to the treating doctors, the greatest amount of data contributing to decision-making for the benefit of patients. Methods: The clinical records of all patients discharged from the HRT with a diagnosis of HA during the period between January 2017 and August 2022 were reviewed. Background information such as: chief complaint, main symptoms, comorbidities, laboratory tests, treatment, evolution and survival, etc., was collected for analysis and to obtain the conclusions presented. Results: A total of 16 patients were studied; 93.75 % were male and 6.24 % female; with a mean age of 52. Of the patients, 87.5 % had a history of DHC. All had alcohol abuse for more than 5 years and 93.75% had active alcoholism. The most frequent laboratory findings included hyperbilirubinaemia (93.75 %), GOT/GPT ratio >2 (50 %) and leukocytosis (56.25 %). Of the total patients studied, 68.75% had a survival of more than 1 year after the event, while 12.5% died during hospitalisation.

Drug-Induced Liver Injury Used in the Treatment of Inflammatory Bowel Disease.

Therapeutic options for the management of inflammatory bowel disease [IBD] have been expanding in recent decades. New biological and small molecule therapies have been incorporated into the pharmacological arsenal, allowing a more personalized management, and seeking increasingly strict remission goals. However, the fear of developing adverse events represents one of the most important limitations in deciding its use by patients and by a multidisciplinary team. Despite the risk of hepatotoxicity of thiopurines and methotrexate, these drugs are still used either as monotherapy or as combined therapy with anti-tumour necrosis factor [anti-TNF] biological agents. Although drug-induced liver injury [DILI] appears to be less frequent with anti-TNF agents, newer biologics and small molecules, liver tests should be considered in the follow-up of these patients, especially regarding future combined therapy of biologics or of these drugs with small molecules. The objective of this review is to show data on the risk of developing DILI in patients with IBD who are undergoing treatment with traditional therapy or new drugs, whether biological or small molecules.

Evaluación hepática en pacientes con leucemia promielocítica tratados con el protocolo LPM-TOA / Hepatic evaluation in patients with promyelocytic leukemia treated with the LPM-TOA protocol

Introducción: Con el protocolo LPM-TOA para el tratamiento de la leucemia promielocítica se obtienen excelentes resultados, se prolonga la sobrevida global y es posible la curación de los enfermos. En la de inducción a la remisión se utilizan dos drogas, una antraciclina y trióxido de arsénico, y en la consolidación los enfermos reciben de nuevo una dosis elevada de arsénico. Objetivo: Evaluar la toxicidad hepática tardía en pacientes con leucemia promielocítica tratados según el protocolo LPM-TOA. Métodos: Se realizó estudio longitudinal prospectivo que incluyó20 pacientes tratados con dicho protocolo, todos con más de dos años de haberlo suspendido. Se revisaron las historias clínicas para evaluar mediante los valores iniciales y evolutivos de las enzimas hepáticas, la función hepática inicial y evolutiva. Se determinó el índice de Ritis para predecir evolución a la cronicidad de existir daño hepático. Resultados: Hombres y mujeres se presentaron con la misma frecuencia y la media para la edad del sexo masculino fue 36,39 y para el femenino 39, con desviación estándar de ±14,02 y ±9,43, respectivamente. La variedad morfológica más frecuente fue la hipergranular, el promedio del índice de Ritis fue de solo 1,006 con desviación estándar de 0,745. Conclusiones: No hubo evidencias clínica ni enzimática de toxicidad hepática tardía en los pacientes estudiados(AU)

Introduction: With the LPM-TOA protocol for the treatment of acute promyelocytic leukemia, excellent results are obtained, overall survival is prolonged and the patients are cured, in the induction to remission two drugs are used, an anthracycline and arsenic trioxide, and in consolidation the patients again receive a high dose of arsenic. Objective: To assess late liver toxicity in patients with promyelocytic leukemia treated according to the PML-TOA protocol. Methods: A prospective longitudinal study was carried out that included 20 patients treated with this protocol, all with more than two years of having suspended treatment. The clinical histories were reviewed and by means of the initial and evolutionary values of liver enzymes, the initial and evolutionary liver function was evaluated and the Ritis index was determined to predict evolution to chronicity if there is liver damage. Results: Men and women presented with the same frequency and the mean age for males was 36.39 and for females it was 39, with a standard deviation of ± 14.02 and ± 9.43 respectively. The most frequent morphological variety was hypergranular, the average Ritis index was only 1.006 with a standard deviation of 0.745. Conclusions: There was no clinical or enzymatic evidence of late liver toxicity in the patients studied(AU)

Proteomic Analysis of Niemann-Pick Type C Hepatocytes Reveals Potential Therapeutic Targets for Liver Damage.

Niemann-Pick type C disease (NPCD) is a lysosomal storage disorder caused by mutations in the NPC1 gene. The most affected tissues are the central nervous system and liver, and while significant efforts have been made to understand its neurological component, the pathophysiology of the liver damage remains unclear. In this study, hepatocytes derived from wild type and Npc1-/- mice were analyzed by mass spectrometry (MS)-based proteomics in conjunction with bioinformatic analysis. We identified 3832 proteins: 416 proteins had a p-value smaller than 0.05, of which 37% (n = 155) were considered differentially expressed proteins (DEPs), 149 of them were considered upregulated, and 6 were considered downregulated. We focused the analysis on pathways related to NPC pathogenic mechanisms, finding that the most significant changes in expression levels occur in proteins that function in the pathways of liver damage, lipid metabolism, and inflammation. Moreover, in the group of DEPs, 30% (n = 47) were identified as lysosomal proteins and 7% (n = 10) were identified as mitochondrial proteins. Importantly, we found that lysosomal DEPs, including CTSB/D/Z, LIPA, DPP7 and GLMP, and mitocondrial DEPs, AKR1B10, and VAT1 had been connected with liver fibrosis, damage, and steatosis in previous studies, validiting our dataset. Our study found potential therapeutic targets for the treatment of liver damage in NPCD.

Crosstalk Between Plasma Cytokines, Inflammation, and Liver Damage as a New Strategy to Monitoring NAFLD Progression.

Cytokines are involved in the immunopathogenesis of nonalcoholic fatty liver disease (NAFLD), but the relationship between them and clinical parameters of NAFLD progression is still unknown. Using flow cytometry, we evaluated the plasma levels of IL-1ß, IL-6, IL-12, TNF and IL-10 and their association with clinical and biochemical parameters of liver function during simple steatosis (NAFL) and nonalcoholic steatohepatitis (NASH) in biopsy-proven patients. The NASH patients showed higher levels of IL-6 associated with a lower IL-10/IL-6 ratio. Besides heatmaps were similar in the NAFL and NASH groups, the same did not occur in signature curves, the NASH patients were high producers to IL-12 and IL-6 while the NAFL patients were not high producers of any cytokines evaluated. Integrative biomarker network analysis revealed that cytokines are differently correlated with clinical parameters, while IL-12, IL-10 presented moderate and negative correlations with glycemic and lipid profile in the NAFL group. The NASH group IL-12 and TNF revealed stronger and positive correlations with transient elastography parameters and NAFLD liver fibrosis score. These data suggest that IL-6 and IL-10 might act in chronic inflammation and insulin resistance whereas IL-12 and TNF may be involved in promoting liver damage and NAFLD progression. Plasma concentration analysis of these molecules and their association with clinical parameters can be used as new biomarkers to monitoring NAFLD progression and to reflect NASH development.

Resveratrol and Quercetin as Regulators of Inflammatory and Purinergic Receptors to Attenuate Liver Damage Associated to Metabolic Syndrome.

Nonalcoholic fatty liver disease (NAFLD) is considered a manifestation of metabolic syndrome (MS) and is characterized by the accumulation of triglycerides and a varying degree of hepatic injury, inflammation, and repair. Moreover, peroxisome-proliferator-activated receptors (PPARs) play a critical role in the pathophysiological processes in the liver. There is extensive evidence of the beneficial effect of polyphenols such as resveratrol (RSV) and quercetin (QRC) on the treatment of liver pathology; however, the mechanisms underlying their beneficial effects have not been fully elucidated. In this work, we show that the mechanisms underlying the beneficial effects of RSV and QRC against inflammation in liver damage in our MS model are due to the activation of novel pathways which have not been previously described such as the downregulation of the expression of toll-like receptor 4 (TLR4), neutrophil elastase (NE) and purinergic receptor P2Y2. This downregulation leads to a decrease in apoptosis and hepatic fibrosis with no changes in hepatocyte proliferation. In addition, PPAR alpha and gamma expression were altered in MS but their expression was not affected by the treatment with the natural compounds. The improvement of liver damage by the administration of polyphenols was reflected in the normalization of serum transaminase activities.

In vivo protective effect of cinnamon aqueous extract in carbon tetrachloride-treated male albino rats

The liver as an organ is important for the metabolism of drugs and toxins. However, it is not immune from environmental insults. Exposure of liver cells to carbon tetrachloride (CCl4) results in the generation of tricholoromethyl radicals, which induce liver toxicity. This study aims at investigating the ameliorative effect of the cinnamon aqueous extract (CAE) against CCl4-induced hepatotoxicity in male albino rats. Hepatotoxicity was induced in rats through the intraperitoneal administration of 0.5 mL kg-1body weight of CCl4. The analyses of the results obtained showed significant reduction in the levels of serum biochemical markers for 400 and 600 mg kg-1bw of CAE protected rats as compared with CCl4group. In addition, CAE administration reversed liver tissue damaged via increased antioxidants markers. Histopathological examination of CAE treatment on rats showed improved changes to the liver damage caused by CCl4 with no evidence of steatosis and inflammation. This result hence suggests that CAE has marked hepatoprotective and healing activities against CCl4-induced liver damage and could serve as a suitable candidate in drug discovery for the treatment of liver toxicity.

Molecular Mechanisms That Link Oxidative Stress, Inflammation, and Fibrosis in the Liver.

Activated hepatic stellate cells (HSCs) and myofibroblasts are the main producers of extracellular matrix (ECM) proteins that form the fibrotic tissue that leads to hepatic fibrosis. Reactive oxygen species (ROS) can directly activate HSCs or induce inflammation or programmed cell death, especially pyroptosis, in hepatocytes, which in turn activates HSCs and fibroblasts to produce ECM proteins. Therefore, antioxidants and the nuclear factor E2-related factor-2 signaling pathway play critical roles in modulating the profibrogenic response. The master proinflammatory factors nuclear factor-κB (NF-κB) and the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome may coordinate to produce and activate profibrogenic molecules such as interleukins 1ß and 18, which effectively activate HSCs, to produce large amounts of fibrotic proteins. Furthermore, the NLRP3 inflammasome activates pro-caspase 1, which is upregulated by NF-κB, to produce caspase 1, which induces pyroptosis via gasdermin and the activation of HSCs. ROS play central roles in the activation of the NF-κB and NLRP3 signaling pathways via IκB (an inhibitor of NF-κB) and thioredoxin-interacting protein, respectively, thereby linking the molecular mechanisms of oxidative stress, inflammation and fibrosis. Elucidating these molecular pathways may pave the way for the development of therapeutic tools to interfere with specific targets.