Acute and subchronic effects of petroleum on the freshwater fish Hoplias aff. malabaricus / Efeitos agudo e subcrônico do petróleo no peixe de água doce Hoplias aff. malabaricus

Abstract Petroleum water soluble fraction (WSF) impairs organisms, but damages may vary among cell and tissue levels. The aim of the present study was to evaluate the acute (24 h, 48 h, 72 h) and subchronic effects (36 days) of WSF (0%, 25% and 100%) in juveniles of the Neotropical top predator fish Hoplias aff. malabaricus. The effects of WSF were evaluated at a molecular level using the comet assay and micronucleus test for genome damage; and at a morphological level through histological identification of liver pathologic lesions. In both acute and subchronic exposure we found low levels of DNA damage (< 10% of comet tail) and non-significant frequency of micronucleus in WSF exposed fish. The most significant liver lesions in WSF exposed fish were fatty vacuolization, hypertrophy and focal necrosis. Since these tissue injuries were progressive and persistent, their irreversibility may negatively affect fish recruitment, even in a such resistant top predator.

Resumo A fração solúvel de petróleo (WSF) prejudica os organismos, porém os danos podem variar entre os níveis celular e tecidual. O objetivo do presente estudo foi avaliar o efeito agudo (24 h, 48 h e 72 h) e subcrônico (36 dias) da WSF (0%, 25% e 100%) em juvenis do peixe neotropical predador topo Hoplias aff. malabaricus. Os efeitos da WSF foram avaliados no nível molecular utilizando o ensaio do cometa e o teste do micronúcleo para o dano genômico e no nível morfológico através da identificação histológica de lesões patológicas no fígado. Em ambas exposições (aguda e subcrônica) encontramos baixos níveis de dano no DNA (< 10% de DNA na cauda do cometa) e frequência de micronúcleos não significativa em peixes expostos a WSF. As lesões mais significativas no fígado dos peixes expostos a WSF foram a vacuolização lipídica, hipertrofia e focos de necroses. Como estas lesões foram progressivas e persistentes, sua irreversibilidade pode afetar negativamente o recrutamento dos peixes, mesmo sendo um predador topo resistente.

Effects of Solanum lycopersicum L. (tomato) against isoniazid and rifampicin induced hepatotoxicity in wistar albino rats / Efeitos de Solanum lycopersicum L. (tomate) contra hepatotoxicidade induzida por isoniazida e rifampicina em ratos albinos wistar

Anti-tuberculosis drugs are reported to cause hepatotoxicity, which varies from asymptomatic rise of the hepatic enzymes. Hepatoprotective plants plays important role to protect liver. This study investigated the hepatoprotective potential of the Solanum lycopersicum in rats intoxicated with Isoniazid and Rifampicin (INH+RIF) to induce hepatotoxicity. Thirty wistar albino rats were divided into five groups of six animals each. Group 1 rats were kept control while groups II, III, IV and V were administered with INH+RIF (75+150 mg/kg) orally, for seven consecutive days. For treatment, rats in group III received silymarin while animals in group IV and V were provided with 40 mg/kg and 80 mg/kg of Solanum lycopersicum extract, respectively. On day 0 and 8th blood samples were collected for the analysis of hepatic biomarkers. The data were subjected to one-way ANOVA and Bonferroni's post hoc test for statistical analysis. Hepatotoxicity induced by INH+RIF resulted in significant elevation of serum hepatic enzymes including Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Alkaline phosphatase (ALP), and total bilirubin while decreased the albumin level. The Solanum lycopersicum at dose of 80 mg/kg significantly reduced the hepatic enzymes AST, ALT, ALP and bilirubin while the albumin level was significantly increased. The treatment had non-significant effect on body and liver weight. Drug induced hepatotoxicity can be effectively treated with Solanum lycopersicum at 80 mg/kg dose.

As drogas antituberculose são relatadas como causadoras de hepatotoxicidade, ocasionando o aumento assintomático das enzimas hepáticas. As plantas hepatoprotetoras desempenham um papel importante na proteção do fígado. Este estudo investigou o potencial hepatoprotetor de Solanum lycopersicum em ratos que foram intoxicados com isoniazida e rifampicina (INH + RIF) para induzir hepatotoxicidade. Trinta ratos wistar albinos foram divididos em cinco grupos de seis animais cada. Os ratos do grupo 1 representaram o grupo controle, enquanto os ratos dos grupos II, III, IV e V receberam INH + RIF (75 + 150 mg/kg) por via oral, por sete dias consecutivos. Para o tratamento, os ratos do grupo III receberam silimarina, enquanto os animais do grupo IV e V receberam 40 mg/kg e 80 mg/kg de extrato de S. lycopersicum, respectivamente. Nos dias 0 e 8, foram coletadas amostras de sangue para análise de biomarcadores hepáticos. Os dados foram submetidos a teste unilateral (ANOVA) e post hoc de Bonferroni para análise estatística. A hepatotoxicidade induzida por INH + RIF resultou em elevação significativa das enzimas hepáticas séricas, incluindo aspartato aminotransferase (AST), alanina aminotransferase (ALT), fosfatase alcalina (ALP) e bilirrubina total, enquanto houve a diminuição do nível de albumina. O S. lycopersicum, na dose de 80 mg / kg, reduziu significativamente as enzimas hepáticas AST, ALT, ALP e bilirrubina, enquanto o nível de albumina aumentou de forma significativa. O tratamento não teve efeito significativo no peso corporal e hepático. A hepatotoxicidade induzida por drogas pode ser tratada de forma eficaz com S. lycopersicum na dose de 80 mg/kg.

Alterations of serum biochemical parameters and tyrosine phosphorylation in kidney and liver of chronic stress-induced rats / Alterações dos parâmetros bioquímicos séricos e fosforilação da tirosina em rim e fígado de ratos induzidos por estresse crônico

Chronic stress (CS) can contribute to dysfunction in several organs including liver and kidney. This study was performed to investigate the changes in serum biochemistry, histological structure, as well as in localization of tyrosine phosphorylated proteins (TyrPho) and Heat shock protein 70 (Hsp-70) in liver and kidney tissues of CS rats induced by two stressors (restrained and force swimming) for 60 consecutive days. Samples of blood, liver, and kidney were collected from adult male Sprague-Dawley rats in each group. Our results showed that serum biochemical parameters including corticosterone, blood sugar, urea nitrogen, creatinine, cholesterol, triglyceride, HDL-C, LDL-C, ALT, AST, alkaline phosphatase in CS group were significantly different from that in normal group in both liver and kidney tissues. Although histological structure was not changed. TyrPho expression was significantly increased in liver lysate but significantly decreased in kidney. Hsp-70 expression in liver increased whereas in kidney decreased. In conclusion, CS can induce changes in liver and kidney functions.

O estresse crônico (SC) pode contribuir para a disfunção em vários órgãos, incluindo fígado e rim. Este estudo foi realizado para investigar as alterações na bioquímica sérica, estrutura histológica, bem como na localização de proteínas tirosina fosforiladas (TyrPho) e proteína de choque térmico 70 (Hsp-70) em tecidos hepáticos e renais de ratos CS induzidas por dois estressores (restrito e natação forçada) por 60 dias consecutivos. Amostras de sangue, fígado e rim foram coletadas de ratos Sprague-Dawley machos adultos em cada grupo. Nossos resultados mostraram que os parâmetros bioquímicos séricos, incluindo corticosterona, glicemia, nitrogênio ureico, creatinina, colesterol, triglicerídeos, HDL-C, LDL-C, ALT, AST, fosfatase alcalina no grupo CS foram significativamente diferentes do grupo normal em ambos os fígados e tecidos renais. Embora a estrutura histológica não tenha sido alterada, a expressão de TyrPho aumentou significativamente no lisado hepático, mas diminuiu significativamente no rim. A expressão de Hsp-70 no fígado aumentou, enquanto que no rim diminuiu. Em conclusão, a CS pode induzir alterações nas funções hepáticas e renais.

Beneficial effects of coconut oil (Cocos nucifera) on hematobiochemicl and histopathological markers in CCL4-intoxicated rabbits / Efeitos benéficos do óleo de coco (Cocos nucifera) em marcadores hematobioquímicos e histopatológicos em coelhos intoxicados com CCL4

The study was designed to investigate the effect of Coconut Oil on the levels of some liver and hematological parameters in carbon tetrachloride intoxicated rabbits. Also the antioxidant capacity of Coconut Oil for various concentrations was assessed on the basis of percent scavenging of (DPPH) free radical. Experimental animals were divided into five groups, eight rabbits in each group. These were: group A (Normal control), group B (Toxic control), group C (Standard control), group D (Treated with Coconut Oil 50 mL/kg body weight after CCl4 intoxication), group E (Treated with Coconut Oil 200 mL/kg body weight after CCl4 intoxication). The effects observed were compared with a standard hepatoprotective drug silymarine (50 mL/kg body weight). The Coconut Oil (200 mL/kg body weight) significantly (P<0.05) reduced the elevated serum levels of alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP) when compared to a toxic control rabbits. The results of extract treated rabbits were similar to silymarine administered rabbits group. Treatment with Coconut Oil root and silymarine caused no significant changes in RBC, Platelets, (Hb), (MCH) concentration and (HCT) values. However, significant (P<0.05) increase was observed in the total WBC count. The present study suggested that Coconut Oil can be used as an herbal alternative (need further exploration i.e to detect its bioactive compound and its efficacy) for hepatoprotective activit.

O estudo foi desenhado para investigar o efeito do óleo de coco nos níveis de alguns parâmetros hepáticos e hematológicos em coelhos intoxicados com tetracloreto de carbono. Também a capacidade antioxidante do óleo de coco para várias concentrações foi avaliada com base na porcentagem de eliminação de radicais livres (DPPH). Os animais experimentais foram divididos em cinco grupos, oito coelhos em cada grupo. Estes foram: grupo A (controle normal), grupo B (controle tóxico), grupo C (controle padrão), grupo D (tratado com óleo de coco 50 mL/kg de peso corporal após intoxicação por CCl4), grupo E (tratado com óleo de coco 200 mL/kg de peso corporal após intoxicação por CCl4). Os efeitos observados foram comparados com um fármaco hepatoprotetor padrão silimarina (50 mL/kg de peso corporal). O óleo de coco (200 mL/kg de peso corporal) reduziu significativamente (P<0,05) os níveis séricos elevados de alanina transaminase (ALT), aspartato transaminase (AST) e fosfatase alcalina (ALP), quando comparado a um coelho controle tóxico. Os resultados dos coelhos tratados com extrato foram semelhantes aos do grupo de coelhos administrados com silimarina. O tratamento com raiz de óleo de coco e silimarina não causou alterações significativas nos valores de RBC, Plaquetas, (Hb), (MCH) e (HCT). No entanto, observou-se aumento significativo (P<0,05) na contagem total de leucócitos. O presente estudo sugeriu que o óleo de coco pode ser usado como uma alternativa fitoterápica (precisa de mais exploração, ou seja, para detectar seu composto bioativo e sua eficácia) para atividade hepatoprotetora.

Therapeutic potential of stem cell and melatonin on the reduction of CCl4-induced liver fibrosis in experimental mice model / Potencial terapêutico de células-tronco e melatonina na redução da fibrose hepática induzida por CCl4 no modelo de ratos experimentais

Liver fibrosis is initial stage of any chronic liver disease and its end stage is develops into cirrhosis. Chronic liver diseases are a crucial global health issue and the cause of approximately 2 million deaths per year worldwide. Cirrhosis is currently the 11th most common cause of death globally. Mesenchymal stem cell (MSCs) treatment is the best way to treat acute and chronic liver disease. The aim of this study is to improve the therapeutic potential of MSCs combined with melatonin (MLT) to overcome CCl4-induced liver fibrosis and also investigate the individual impact of melatonin and MSCs against CCl4-induced liver impairment in animal model. Female BALB/c mice were used as CCL4-induced liver fibrotic animal model. Five groups of animal model were made; negative control, Positive control, CCl4+MSCs treated group, CCl4+MLT treated group and CCl4+MSCs+MLT treated group. Cultured MSCs from mice bone marrow were transplanted to CCl4-induced liver injured mice model, individually as well as together with melatonin. Two weeks after MSCs and MLT administration, all groups of mice were sacrificed for examination. Morphological and Histopathological results showed that combined therapy of MSCs+MLT showed substantial beneficial impact on CCl4-induced liver injured model, compared with MSCs and MLT individually. Biochemically, considerable reduction was observed in serum bilirubin and ALT levels of MLT+MSC treated mice, compared to other groups. PCR results shown down-regulation of Bax and up-regulation of Bcl-xl and Albumin, confirm a significant therapeutic effect of MSCs+MLT on CCI4-induced liver fibrosis. From the results, it is concluded that combined therapy of MSCs and MLT show strong therapeutic effect on CCL4-induced liver fibrosis, compared with MSCs and MLT individually.

A fibrose hepática é a fase inicial de qualquer doença hepática crônica, e em sua fase final desenvolve-se para cirrose. As doenças hepáticas crônicas são uma questão de saúde global crucial e a causa de aproximadamente 2 milhões de mortes por ano em todo o mundo. A cirrose, hoje em dia, é a 11ª causa mais comum de morte globalmente. O tratamento da célula-tronco mesenquimal (MSCs) é uma maneira eletiva de tratar a doença hepática aguda e crônica. O objetivo deste estudo é melhorar o potencial terapêutico dos MSCs combinados com a melatonina (MLT) para superar a fibrose hepática induzida por CCl4 e também investigar o impacto individual da melatonina e MSCs contra o comprometimento do fígado induzido por CCl4 no modelo animal. Os ratos BALB / C fêmeas foram usados ​​como modelo de animal fibrótico de fígado induzido por CCl4. Cinco grupos de modelo animal foram feitos: Controle Negativo, Controle Positivo, CCl4 + MSCs Tratados Grupo, Grupo Tratado CCl4 + MLT e Grupo Tratado CCl4 + MSCs + MLT. MSCs cultivados da medula óssea dos ratos foram transplantados para o modelo de camundongos de fígado induzido por CCl4, individualmente, bem como em conjunto com a melatonina. Duas semanas após a administração MSCs e MLT, todos os grupos de camundongos foram sacrificados para o exame. Os resultados morfológicos e histopatológicos mostraram que a terapia combinada do MSCs + MLT mostrou impacto benéfico substancial no modelo ferido no fígado induzido pelo CCl4, em comparação com o MSCs e o MLT individualmente. A redução bioquimicamente considerável foi observada em bilirrubina sérica e níveis ALT de ratinhos tratados com MLT + MSCs, em comparação com outros grupos. Os resultados de PCR mostraram regulação negativa do BAX e regulação positiva do BCL-XL e da albumina, confirmando um efeito terapêutico significativo do MSCs + MLT na fibrose hepática induzida por CCl4. Dos resultados, conclui-se que a terapia combinada de MSCs e MLT mostram um forte efeito terapêutico na fibrose hepática induzida por CCl4, em comparação com MSCs e MLT individualmente.

Role of Machine Perfusion in Liver Transplantation.

Given the current severe shortage of available livers for transplantation, there is an urgent need to maximize the utilization of donor organs. One of the strategies to increase the number of available livers for transplantation is to improve organ utilization through the use of elderly, overweight, or organs donated after circulatory death. However, the utilization of these "marginal" organs was associated with an increased risk of early allograft dysfunction, primary nonfunction, ischemic biliary complications, or even re-transplantation. Ischemia-reperfusion injury is a key mechanism in the pathogenesis of these complications.

Donation After Circulatory Death Liver Transplantation: Early Challenges, Clinical Improvement, and Future Directions.

Donation after circulatory death (DCD) liver allografts remain a widely underutilized source of donor organs for transplantation. Although initially linked with inferior outcomes, DCD liver transplant can achieve excellent patient and graft survival with suitable matching of donor and recipient characteristics, rapid donor recovery and precise donor assessment, and appropriate perioperative management. The advent of clinical liver perfusion modalities promises to redefine the viability parameters for DCD liver allografts and hopefully will encourage more widespread usage of this growing source of donor livers.

Targeting ferroptosis with natural products in liver injury: new insights from molecular mechanisms to targeted therapies.

BACKGROUND: Ferroptosis is a brand-new type of controlled cell death that is distinguished by its reliance on iron and the production of lipid peroxidation. The role of ferroptosis in damaging liver disorders has attracted a lot of attention in recent years. One effective strategy to reduce liver damage is to target ferroptosis. PURPOSE: The purpose of this review is to clarify the connection between ferroptosis and liver damage and to look into the potential contribution of natural products to the clinical management of liver damage and the discovery of novel medications. METHODS: To study the methods by which natural products operate on ferroptosis to cure liver damage and their main signaling pathways, we searched databases from the time of initial publication to August 2023 in PubMed, EMBASE, Web of Science, Ovid, ScienceDirect, and China National Knowledge Infrastructure. The liver illness that each natural product treats is categorized and summarized. It's interesting to note that several natural compounds, such Artemether, Fucoidan sulfate, Curcumin, etc., have the benefit of having many targets and multiple pathways of action. RESULTS: We saw that in human samples or animal models of liver injury, ferroptosis indicators were activated, lipid peroxidation levels were elevated, and iron inhibitors had the ability to reduce liver damage. Liver damage can be treated with natural products by regulating ferroptosis. This is mostly accomplished through the modulation of Nrf2-related pathways (e.g., Conclusions and Astaxanthin), biological enzymes like GPX4 and the SIRT family (e.g., Chrysophanol and Decursin), and transcription factors like P53 (e.g., Artemether and Zeaxanthin). CONCLUSIONS: This review proposes a promising path for the therapeutic therapy of liver damage by providing a theoretical foundation for the management of ferroptosis utilizing natural ingredients.

Drug-induced liver injury and anti-hepatotoxic effect of herbal compounds: a metabolic mechanism perspective.

BACKGROUND: Drug-induced liver injury (DILI) is the most challenging and thought-provoking liver problem for hepatologists owing to unregulated medication usage in medical practices, nutritional supplements, and botanicals. Due to underreporting, analysis, and identification issues, clinically evaluated medication hepatotoxicity is prevalent yet hard to quantify. PURPOSE: This review's primary objective is to thoroughly compare pharmaceutical drugs and herbal compounds that have undergone clinical trials, focusing on their metabolic mechanisms contributing to the onset of liver illnesses and their hepatoprotective effects. METHODS: The data was gathered from several online sources, such as PubMed, Scopus, Google Scholar, and Web of Science, using appropriate keywords. RESULTS: The prevalence of conventional and herbal medicine is rising. A comprehensive understanding of the metabolic mechanism is necessary to mitigate the hepatotoxicity induced by drugs and facilitate the incorporation or substitution of herbal medicine instead of pharmaceuticals. Moreover, pre-clinical pharmacological research has the potential to facilitate the development of natural products as therapeutic agents, displaying promising possibilities for their eventual clinical implementation. CONCLUSIONS: Acetaminophen, isoniazid, rifampicin, diclofenac, and pyrogallol have been identified as the most often reported synthetic drugs that produce hepatotoxicity by oxidative stress, inflammation, apoptosis, and fibrosis during the last several decades. Due to their ability to downregulate many factors (such as cytokines) and activate several enzyme/enzyme systems, herbal substances (such as Gingko biloba extract, curcumin, resveratrol, and silymarin) provide superior protection against harmful mechanisms which induce hepatotoxicity with fewer adverse effects than their synthetic counterparts.

Whole-liver flip-angle shimming at 7 T using parallel-transmit kT -point pulses and Fourier phase-encoded DREAM B 1 + mapping.

PURPOSE: To obtain homogeneous signal throughout the human liver at 7 T. Flip angle (FA) shimming in 7T whole-liver imaging was performed through parallel-transmit kT -point pulses based on subject-specific multichannel absolute B 1 + $$ {\mathrm{B}}_1^{+} $$ maps from Fourier phase-encoded dual refocusing echo acquisition mode (PE-DREAM). METHODS: The optimal number of Fourier phase-encoding steps for PE-DREAM B 1 + $$ {\mathrm{B}}_1^{+} $$ mapping was determined for a 7T eight-channel parallel-transmission system. FA shimming experiments were performed in the liver of 7 healthy subjects with varying body mass index. In these subjects, first B 0 $$ {\mathrm{B}}_0 $$ shimming and Fourier PE-DREAM B 1 + $$ {\mathrm{B}}_1^{+} $$ mapping were performed. Subsequently, three small-flip-angle 3D gradient-echo scans were acquired, comparing a circularly polarized (CP) mode, a phase shim, and a kT -point pulse. Resulting homogeneity was assessed and compared with estimated FA maps and distributions. RESULTS: Fourier PE-DREAM with 13 phase-encoding steps resulted in a good tradeoff between B 1 + $$ {\mathrm{B}}_1^{+} $$ accuracy and scan time. Lower coefficient of variation values (average [min-max] across subjects) of the estimated FA in the volume of interest were observed using kT -points (7.4 [6.6%-8.0%]), compared with phase shimming (18.8 [12.9%-23.4%], p < 0.001) and CP (43.2 [39.4%-47.1%], p < 0.001). kT -points delivered whole-liver images with the nominal FA and the highest degree of homogeneity. CP and phase shimming resulted in either inaccurate or imprecise FA distributions. Here, locations having suboptimal FA in the estimated FA maps corresponded to liver areas suffering from inconsistent signal intensity and T1 -weighting in the gradient-echo scans. CONCLUSION: Homogeneous whole-liver 3D gradient-echo acquisitions at 7 T can be obtained with eight-channel kT -point pulses calculated based on subject-specific multichannel absolute Fourier PE-DREAM B 1 + $$ {\mathrm{B}}_1^{+} $$ maps.

Black mulberry extract inhibits hepatic adipogenesis through AMPK/mTOR signaling pathway in T2DM mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Black mulberry (Morus nigra L.) is an ancient dual-use plant resource for medicine and food. It is widely used in Uyghur folklore for hypoglycemic treatment and is a folkloric plant medicine with regional characteristics. However, the mechanism of Morus nigra L. treatment in diabetes mellitus has not been fully understood, especially from the perspective of hepatic lipid accumulation is less reported. OBJECTIVE OF THIS STUDY: This study was to explore the potential of Morus nigra L. fruit ethyl acetate extract (MNF-EA) to reduce blood sugar levels by preventing the production of hepatic lipogenesis and to provide more evidence for the use of MNF-EA as an adjuvant therapy for type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: In this study, the chemical composition of MNF-EA was first analyzed and characterized using UPLC-Q-TOF-MS technique. A series of in vitro studies were performed with HepG2-IR cells and oleic acid (OA)-induced HepG2 cells, including MTT assay, glucose uptake assay, oil red O staining and Western blot analysis. The STZ-HFD co-induced T2DM mice were employed for in vivo research, including physical indices, biochemical analysis, histopathological examination, and Western blot analysis. RESULTS: The 19 compounds in MNF-EA were identified by UPLC-Q-TOF-MS technique. Insulin resistance (IR) and lipid droplet accumulation in HepG2 cells were greatly improved by MNF-EA treatment, which had no appreciable side effects at the dosage used. In T2DM mice, MNF-EA decreased fasting blood glucose (FBG), saved body weight, and significantly improved oral glucose tolerance (OGTT) and IR status. In addition, MNF-EA treatment also improved lipid metabolism disorders and liver function in T2DM mice. Histopathological sections showed that MNF-EA treatment reduced hepatic steatosis. Mechanistic studies suggest that MNF-EA acted through the AMPK/mTOR pathway. CONCLUSIONS: These results suggest that MNF-EA has great potential to reverse the metabolic abnormalities associated with T2DM by regulating the AMPK/mTOR signaling pathway. Therefore, we believe that MNF is a promising medicinal and food-homologous agent to improve T2DM.

Prunella vulgaris L. attenuates gut dysbiosis and endotoxin leakage against alcoholic liver disease.

ETHNOPHARMACOLOGICAL RELEVANCE: Prunella vulgaris L. (PVL) is a perennial herb belonging to the Labiate family, first recorded in the "Shen Nong's Classic of the Materia Medica". PVL can enter the liver and gallbladder channel to show its function in clearing the liver fire, dispersing nodules, dissolving swelling, and improving vision. The traditional use of PVL is to protect liver function and has clinical applications in liver diseases therapy. The modern pharmacological studies have been shown to possess potential hepatoprotection, but its underlying mechanisms against alcoholic liver disease (ALD) in mice remains to be elucidated. AIM OF THE STUDY: This study aimed to explore the protective effect and potential mechanism of PVL on alcohol induced liver injury. MATERIALS AND METHODS: We used Lieber-DeCarli ethanol liquid diet fed Male C57BL/6 mice for four weeks plus a single binge (NIAAA modified model) to establish an ALD model and explored the protective effects of PVL extract against ALD. Western blot, Flow cytometry and RT-qPCR methods were used to detect lipid metabolism disorders and the inflammatory response induced by macrophages in ALD mice, and the gut microbiota composition changes were detected by 16s rRNA to reveal the potential mechanism of PVL against ALD. RESULTS: In ALD mice, PVL can ameliorate excessive alcohol intake-induced liver injury and lipid metabolism disorders associated with improvement of gut microbiota dysbiosis and intestinal barrier damage. PVL reduced the translocation of endotoxin, which subsequently inhibits hepatic inflammation mediated by the TLR4/MyD88 signaling pathway. CONCLUSION: These findings demonstrated the protective potential of PVL against gut dysbiosis and endotoxin leakage in ALD mice, which provides a theoretical basis for PVL against liver diseases.

Berberine-silybin salt achieves improved anti-nonalcoholic fatty liver disease effect through regulating lipid metabolism.

ETHNOPHARMACOLOGICAL RELEVANCE: Berberine (BBR) and silybin (SIY) are natural compounds obtained from Berberidaceae members and Silybum marianum (L.) Gaertn., respectively. These compounds have been demonstrated to regulate lipid metabolism and indue hepatoprotective effects, establishing their importance for the treatment of liver injury. Combination therapy has shown promise in treating ailments with complex pathophysiology, such as liver diseases. However, the inconsistent dissolution and poor absorption of BBR and SIY limit their efficacy. AIM OF THE STUDY: This study compared the salt formulation (BSS) and physical mixture (BSP) of BBR and SIY for their efficacy in treating nonalcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS: The formation of the BSS was confirmed using various techniques, including nuclear magnetic resonance spectroscopy, Fourier-transform infrared spectroscopy, differential scanning calorimetry, scanning electron microscopy, and powder X-ray diffractometry. In addition, dissolution, trans-epithelial permeability, and bioavailability experiments were conducted to evaluate the absorption and distribution of drugs. Pharmacodynamics and mechanisms were investigated through in vivo experiments. RESULTS: BSS form demonstrated synchronized dissolution of both components, unlike BSP. Additionally, the transepithelial permeability results revealed that BSS exhibited superior penetration and absorption of both BBR and SIY in comparison to BSP. Furthermore, BSS significantly increased the bioavailability of SIY in both plasma and the liver (2.2- and 4.5-fold, respectively) when compared with BSP. Moreover, BSS demonstrated a more potent inhibitory effect on lipid production in HepG2 cells than BSP. In mouse models (BALB/c) of NAFLD, BSS improved disease outcomes, as evidenced by decreased adipose levels, normalized blood lipid levels, and reduced liver parenchyma injury. Preliminary transcriptomics analysis suggested that BSS achieved its anti-NAFLD effect by regulating the expression of fatty acid transporter CD36, recombinant fatty acid binding protein 4, and stearyl coenzyme A dehydrogenase 1, which are associated with the synthesis and uptake of fatty acid-related proteins. CONCLUSIONS: The study demonstrated that compared with physical mixing, salification improved the efficacy of BBR and SIY, as demonstrated in animal experiments. These findings provide valuable insights into the development of more effective treatments for NAFLD and provide new possibilities for combination therapies.

Calenduloside E ameliorates non-alcoholic fatty liver disease via modulating a pyroptosis-dependent pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver condition that can have multiple underlying causes. There are no satisfactory chemical or biological drugs for the treatment of NAFLD. Longyasongmu, the bark and root of Aralia elata (Miq.) Seem, is used extensively in traditional Chinese medicine (TCM) and has been used in treating diverse liver diseases including NAFLD. Based on Aralia elata (Miq.) Seem as the main ingredient, Longya Gantai Capsules have been approved for use in China for the treatment of acute hepatitis and chronic hepatitis. Calenduloside E (CE), a natural pentacyclic triterpenoid saponin, is a significant component of saponin isolated from the bark and root of Aralia elata (Miq.) Seem. However, the role and mechanism of anti-NAFLD effects of CE is still unclear. AIM OF THE STUDY: The objective of this study was to examine the potential mechanisms underlying the protective effect of CE on NAFLD. MATERIALS AND METHODS: In this study, an NAFLD model was established by Western diet in apoE-/- mice, followed by treatment with various doses of CE (5 mg/kg, 10 mg/kg). The anti-NAFLD effect of CE was assessed by the liver injury, lipid accumulation, inflammation, and pro-fibrotic phenotype. The mechanism of CE in ameliorating NAFLD was studied through transcriptome sequencing (RNA-seq). In vitro, the mouse hepatocytes (AML-12) were stimulated in lipid mixtures with CE and performed the exploration and validation of the relevant pathways using Western blot, immunofluorescence, etc. RESULTS: The findings revealed a significant improvement in liver injury, lipid accumulation, inflammation, and pro-fibrotic phenotype upon CE administration. Furthermore, RNAseq analysis indicated that the primary pathway through which CE alleviates NAFLD involves pyroptosis-related inflammatory cascade pathways. Furthermore, it was observed that CE effectively suppressed inflammasome-mediated pyroptosis both in vivo and in vitro. Remarkably, the functional enrichment analysis of RNA-seq data revealed that the PI3K-Akt signaling pathway is the primarily Signaling transduction pathway modulated by CE treatment. Subsequent experimental outcomes provided further validation of CE's ability to hinder inflammasome-mediated pyroptosis through the inhibition of PI3K/AKT/NF-κB signaling pathway. CONCLUSIONS: These findings present a novel pharmacological role of CE in exerting anti-NAFLD effects by inhibiting pyroptosis signaling pathways.

Annickia affinis (Exell) Versteegh & Sosef methanol stem bark extract, potent fractions and isolated Berberine alkaloid target both blood and liver stages of malaria parasites.

ETHNOPHARMACOLOGICAL RELEVANCE: Having identified Annickia affinis as the most potent antiplasmodial plant constituent in a hepta-herbal Agbo-iba (HHA) formula commonly used to manage malaria in Benin city, Nigeria, we have in this study attempted to identify the specialized metabolites responsible for antiplasmodial activity of A. affinis through anti-blood stage malaria parasite activity guided isolation of potent molecules from its stem bark methanol extract. After that, phenotypic effects, including stage-specific kill kinetics, were investigated. Further, the crude extract, its potent fractions, and specialized metabolites were also tested against the liver-stage malaria parasite. MATERIALS AND METHODS: A. affinis was subjected to molecular PCR-based analysis to confirm its identity. Thereafter, extraction of its stem bark with methanol was carried out. Alkaloid enriched fractions from this stem bark extract were obtained using the acid-base-solvent extraction method. These alkaloid-enriched fractions were subjected to various chromatographic techniques that led to the isolation of two protoberberine alkaloids identified as berberine and palmatine based on NMR and mass spectrometry analysis. The efficacy of crude extract, fractions and purified alkaloids was tested against the malaria parasite's blood and liver stages, respectively. RESULTS AND DISCUSSION: Annickia affinis methanol extract, fractions, and the isolated protoberberine alkaloids showed excellent antiplasmodial activity with good selectivity against blood-stage malaria parasite. Thus, their IC50 against various strains of the parasite ranged from 0.95 to 18.65 µg/ml, while CC50 against Human embryonic kidney (HEK) and the human hepatoma (HUH-7) cell lines ranged between 10 and > 100 µg/ml. Interestingly, the crude extract and the alkaloid enriched fractions showed promising activity against the liver-stage malaria parasite. Between berberine and palmatine isolated from the potent fractions, only the former showed ∼100% and 90% inhibitions of liver stage parasite at 5 µg/ml and 1 µg/ml, respectively, while the latter showed no inhibition even at 20 µg/ml. CONCLUSION: This study reports that the ethnomedicinal use of HHA to manage malaria can be attributed to the presence of promising antiplasmodial protoberberine alkaloids together with synergistic effects via either enhancement of bioavailability or improved pharmacokinetics by other phytoconstituent(s) coming from other HHA constituent plants. The protoberberine alkaloids isolated have been identified as fast-acting antiplasmodial agents, with activity against all erythrocytic stages of the malaria parasite. Further, A. affinis methanol stembark extract and the protoberberine alkaloid berberine isolated from it also displayed excellent activity (>90% inhibition at 1 µg/ml) against the liver-stage malaria parasite. A. affinis and HHA can thus be useful as both liver-stage prophylactic and blood-stage curative agents.

Mn3O4 nanozymes prevent acetaminophen-induced acute liver injury by attenuating oxidative stress and countering inflammation.

Acetaminophen (APAP) overdose is steadily becoming the chief reason for drug-induced acute liver failure, yet limited treatment is currently clinically available. Considering that the mechanism of APAP-induced hepatotoxicity is inseparable from oxidative stress and inflammation, a biocompatible Mn3O4 nanozyme mimicking superoxide dismutase (SOD) and catalase (CAT) activities and possessing reactive oxygen species (ROS)-scavenging capacity and antiapoptotic properties, is reported herein as a promising nanodrug to treat APAP-induced liver injury (AILI). Possessing bioactive enzyme-like functions, Mn3O4 nanoparticles (NPs) can not only reduce the oxidative stress on the liver by decreasing ROS accumulation but also downregulate the infiltration of inflammatory macrophages that secrete proinflammatory cytokines (tumor necrosis factor-α, interleukin-1ß, and interleukin-6). Notably, the bifunctional Mn3O4 NPs mediate nuclear factor-erythroid 2 p45-related factor 2 signaling pathway activation and nuclear factor kappa B signaling pathway inhibition to effectively prevent the already fragile APAP-overdosed murine hepatocytes from being attacked again, thus mitigating hepatocyte apoptosis and alleviating APAP-induced liver damage. Thus, the Mn3O4 nanozyme (Mn3O4 NPs) evaluated in this study has potential preventive and therapeutic effects on AILI.

Induced swimming modified the antioxidant status of gilthead seabream (Sparus aurata).

Swimming has relevant physiological changes in farmed fish, although the potential link between swimming and oxidative stress remains poorly studied. We investigated the effects of different medium-term moderate swimming conditions for 6 h on the antioxidant status of gilthead seabream (Sparus aurata), analyzing the activity of enzymes related to oxidative stress in the liver and skeletal red and white muscle. Forty fish were induced to swim individually with the following conditions: steady low (SL, 0.8 body length (BL)·s-1), steady high (SH, 2.3 BL·s-1), oscillating low (OL, 0.2-0.8 BL·s-1) and oscillating high (OH, 0.8-2.3 BL·s-1) velocities, and a non-exercised group with minimal water flow (MF, < 0.1 BL·s-1). All swimming conditions resulted in lower activities of superoxide dismutase (SOD), glutathione reductase (GR), and glutathione-S-transferase (GST) in the liver compared to the MF group, while steady swimming (SL and SH) led to higher reduced glutathione/oxidized glutathione ratio (GSH/GSSG) compared to the MF condition. Swimming also differently modulated the antioxidant enzyme activities in red and white muscles. The OH condition increased lipid peroxidation (LPO), catalase (CAT) and glutathione peroxidase (GPx) activities in the red muscle, decreasing the GSH/GSSG ratio, whereas the SL condition led to increased GSH. Oscillating swimming conditions (OL and OH) led to lower CAT activity in the white muscle, although GPx activity was increased. The GSH/GSSG ratio in white muscle was increased in all swimming conditions. Liver and skeletal muscle antioxidant status was modulated by exercise, highlighting the importance of adequate swimming conditions to minimize oxidative stress in gilthead seabream.

Serum infrared spectral profile is predictive of the degree of hepatic fibrosis in chronic hepatitis C patients.

Assessment of liver fibrosis is crucial to guide the therapeutic strategy in patients with chronic liver disease. We investigated the potential of serum Fourier transform infrared (FTIR) spectroscopy for assessing the degree of hepatic fibrosis in patients with chronic hepatitis C (CHC). The study was conducted on dried serum samples from 94 CHC patients at different histological stages of hepatic fibrosis: METAVIR F0 (n = 20), F1 (n = 17), F2 (n = 20), F3 (n = 20) and F4 (n = 17). Transmission FTIR spectra were acquired in the 4000-400 cm-1 range. Wavenumbers were selected by genetic algorithm (GA) according to their diagnostic performance as assessed by a partial least squares discriminant analysis (PLS-DA) model using a training and a validation set to differentiate severe stages of fibrosis from mild or moderate ones. The GA procedure was applied 50 times on randomly selected sets. Furthermore, the best set of wavenumbers was re-tested in 1000 randomly selected validation sets. Wavenumbers selected by GA corresponded to functional groups present in lipids, proteins, and carbohydrates. This model allowed to identify patients with cirrhosis (METAVIR F4), patients with advanced fibrosis (METAVIR F3 and F4), and patients with significant fibrosis (METAVIR F2, F3 and F4), with AUROC (Area Under the Receiver Operating Characteristic) of 0.88, 0.85 and 0.85, respectively. Thus, serum FTIR spectroscopy appears to have a strong potential as a new diagnostic tool for assessing the degree of fibrosis in patients with chronic liver disease.

Custom Hyperspectral Imaging System Reveals Unique Spectral Signatures of Heart, Kidney, and Liver Tissues.

The rapid advancement of diagnostic and therapeutic optical techniques for oncology demands a good understanding of the optical properties of biological tissues. This study explores the capabilities of hyperspectral (HS) cameras as a non-invasive and non-contact optical imaging system to distinguish and highlight spectral differences inbiological soft tissuesof three structures (kidney, heart, and liver) for use inendoscopic interventionoropen surgery. The study presents an optical system consisting of two individual setups, the transmission setup, and the reflection setup, both incorporating anHS camerawith apolychromatic light sourcewithin the range of 380 to 1050 nm to measure tissue's light transmission (Tr) and diffuse light reflectance (Rd), respectively. The optical system was calibrated with a customizedliquid optical phantom, then 30 samples from various organs were investigated fortissue characterizationby measuring both Tr and Rd at the visible and near infrared (VIS-NIR) band. We exploited the ANOVA test, subsequently by a Tukey's test on the created three independent clusters (kidney vs. heart: group I / kidney vs. liver: group II / heart vs. liver: group III) to identify the optimum wavelength for each tissue regarding their spectroscopic optical properties in the VIS-NIR spectrum. The optimum spectral span for the determined light Tr of the three groups was 640 âˆ¼ 680 nm, and the ideal range was 720 âˆ¼ 760 nm for the measured light Rd for mutual group I and group II. However, the group III range was different at a range of 520 âˆ¼ 560 nm. Therefore, the investigation provides vital information concerning theoptimum spectral scalefor the computed light Tr and Rd of the investigatedbiological tissues(kidney, liver, and heart) to be employed in diagnostic andtherapeutic medical applications.

A physiologically based pharmacokinetic model of diethyl phthalates in humans.

Phthalates are a family of industrial and consumer product chemicals, among which diethyl phthalate (DEP) has been widely used. DEP is metabolized into the active metabolite monoethyl phthalate (MEP) and exposure to DEP may induce male reproductive toxicity, developmental toxicity and hepatotoxicity. To better assess the toxicity of DEP and MEP, it is important to understand and predict their internal concentrations, especially in reproductive organs. Here we present a human physiologically based pharmacokinetic (PBPK) model of DEP. Implemented in R, the PBPK model consists of seven tissue compartments, including blood, gut, liver, fat, skin, gonad, and rest of body (RB). In the blood both DEP and MEP partition into free and bound forms, and tissue distribution is considered as blood flow-limited. DEP is metabolized in the gut and liver into MEP which is further glucuronidated and cleared through the urine. The chemical-specific parameters of the model were predicted in silico or estimated based on published human urinary MEP data after exposure to DEP in the air at 250 or 300 µg/m3 for 3 or 6 h through inhalation and dermal absorption. Sensitivity analysis identified important parameters including partition coefficients of DEP for fat, RB, and skin compartments, and the rate constants for glucuronidation of MEP and urinary excretion, with regard to Cmax, area under the curve (AUC), and clearance half-lives of DEP and MEP. A subset of the sensitive parameters was then included in hierarchical population Bayesian Markov chain Monte Carlo (MCMC) simulations to characterize the uncertainty and variability of these parameters. The model is consistent with the notion that dermal absorption represents a significant route of exposure to DEP in ambient air and clothing can be an effective barrier. The developed human PBPK model can be utilized upon further refinement as a quantitative tool for DEP risk assessment.