Aspirin for Metabolic Dysfunction-Associated Steatotic Liver Disease Without Cirrhosis: A Randomized Clinical Trial.

Importance: Aspirin may reduce severity of metabolic dysfunction-associated steatotic liver disease (MASLD) and lower the incidence of end-stage liver disease and hepatocellular carcinoma, in patients with MASLD. However, the effect of aspirin on MASLD is unknown. Objective: To test whether low-dose aspirin reduces liver fat content, compared with placebo, in adults with MASLD. Design, Setting, and Participants: This 6-month, phase 2, randomized, double-blind, placebo-controlled clinical trial was conducted at a single hospital in Boston, Massachusetts. Participants were aged 18 to 70 years with established MASLD without cirrhosis. Enrollment occurred between August 20, 2019, and July 19, 2022, with final follow-up on February 23, 2023. Interventions: Participants were randomized (1:1) to receive either once-daily aspirin, 81 mg (n = 40) or identical placebo pills (n = 40) for 6 months. Main Outcomes and Measures: The primary end point was mean absolute change in hepatic fat content, measured by proton magnetic resonance spectroscopy (MRS) at 6-month follow-up. The 4 key secondary outcomes included mean percentage change in hepatic fat content by MRS, the proportion achieving at least 30% reduction in hepatic fat, and the mean absolute and relative reductions in hepatic fat content, measured by magnetic resonance imaging proton density fat fraction (MRI-PDFF). Analyses adjusted for the baseline value of the corresponding outcome. Minimal clinically important differences for study outcomes were not prespecified. Results: Among 80 randomized participants (mean age, 48 years; 44 [55%] women; mean hepatic fat content, 35% [indicating moderate steatosis]), 71 (89%) completed 6-month follow-up. The mean absolute change in hepatic fat content by MRS was -6.6% with aspirin vs 3.6% with placebo (difference, -10.2% [95% CI, -27.7% to -2.6%]; P = .009). Compared with placebo, aspirin treatment significantly reduced relative hepatic fat content (-8.8 vs 30.0 percentage points; mean difference, -38.8 percentage points [95% CI, -66.7 to -10.8]; P = .007), increased the proportion of patients with 30% or greater relative reduction in hepatic fat (42.5% vs 12.5%; mean difference, 30.0% [95% CI, 11.6% to 48.4%]; P = .006), reduced absolute hepatic fat content by MRI-PDFF (-2.7% vs 0.9%; mean difference, -3.7% [95% CI, -6.1% to -1.2%]; P = .004]), and reduced relative hepatic fat content by MRI-PDFF (-11.7 vs 15.7 percentage points; mean difference, -27.3 percentage points [95% CI, -45.2 to -9.4]; P = .003). Thirteen participants (32.5%) in each group experienced an adverse event, most commonly upper respiratory tract infections (10.0% in each group) or arthralgias (5.0% for aspirin vs 7.5% for placebo). One participant randomized to aspirin (2.5%) experienced drug-related heartburn. Conclusions and Relevance: In this preliminary randomized clinical trial of patients with MASLD, 6 months of daily low-dose aspirin significantly reduced hepatic fat quantity compared with placebo. Further study in a larger sample size is necessary to confirm these findings. Trial Registration: ClinicalTrials.gov Identifier: NCT04031729.

A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a progressive liver disease with no approved treatment. Resmetirom is an oral, liver-directed, thyroid hormone receptor beta-selective agonist in development for the treatment of NASH with liver fibrosis. METHODS: We are conducting an ongoing phase 3 trial involving adults with biopsy-confirmed NASH and a fibrosis stage of F1B, F2, or F3 (stages range from F0 [no fibrosis] to F4 [cirrhosis]). Patients were randomly assigned in a 1:1:1 ratio to receive once-daily resmetirom at a dose of 80 mg or 100 mg or placebo. The two primary end points at week 52 were NASH resolution (including a reduction in the nonalcoholic fatty liver disease [NAFLD] activity score by ≥2 points; scores range from 0 to 8, with higher scores indicating more severe disease) with no worsening of fibrosis, and an improvement (reduction) in fibrosis by at least one stage with no worsening of the NAFLD activity score. RESULTS: Overall, 966 patients formed the primary analysis population (322 in the 80-mg resmetirom group, 323 in the 100-mg resmetirom group, and 321 in the placebo group). NASH resolution with no worsening of fibrosis was achieved in 25.9% of the patients in the 80-mg resmetirom group and 29.9% of those in the 100-mg resmetirom group, as compared with 9.7% of those in the placebo group (P<0.001 for both comparisons with placebo). Fibrosis improvement by at least one stage with no worsening of the NAFLD activity score was achieved in 24.2% of the patients in the 80-mg resmetirom group and 25.9% of those in the 100-mg resmetirom group, as compared with 14.2% of those in the placebo group (P<0.001 for both comparisons with placebo). The change in low-density lipoprotein cholesterol levels from baseline to week 24 was -13.6% in the 80-mg resmetirom group and -16.3% in the 100-mg resmetirom group, as compared with 0.1% in the placebo group (P<0.001 for both comparisons with placebo). Diarrhea and nausea were more frequent with resmetirom than with placebo. The incidence of serious adverse events was similar across trial groups: 10.9% in the 80-mg resmetirom group, 12.7% in the 100-mg resmetirom group, and 11.5% in the placebo group. CONCLUSIONS: Both the 80-mg dose and the 100-mg dose of resmetirom were superior to placebo with respect to NASH resolution and improvement in liver fibrosis by at least one stage. (Funded by Madrigal Pharmaceuticals; MAESTRO-NASH ClinicalTrials.gov number, NCT03900429.).

Low-dose deoxynivalenol exposure inhibits hepatic mitophagy and hesperidin reverses this phenomenon by activating SIRT1.

Deoxynivalenol (DON) is by far the most common mycotoxin contaminating cereal foods and feeds. Furthermore, cleaning up DON from contaminated cereal items is challenging. Low-dose DON consumption poses a danger to humans and agricultural animals. The benefits of hesperidin (HDN) include liver protection, anti-oxidative stress, nontoxicity, and a broad range of sources. The study used immunoblotting, immunofluorescence, and transmission electron microscopy to identify factors associated with mitophagy in vitro and in vivo. We demonstrated that low-dose DON exposure inhibited mitophagy in the liver tissue of mice. SIRT1 was a crucial regulator of mitophagy. Moreover, DON stimulated the dephosphorylation of SIRT1 and the acetylation-regulated FOXO3 protein, which resulted in the transcriptional inhibition of FOXO3-driven BNIP3 and compromised the stability of the PINK1 protein mediated by BNIP3. Moreover, HDN's effect was comparable to that of a SIRT1 agonist, which led to a significant decrease in the level of mitophagy inhibition caused by low-dose DON exposure. When combined, these findings suggested that HDN might be a useful treatment approach for liver damage brought on by low-dose DON exposure. Above all, this research will offer fresh perspectives on a viable approach that will encourage further research into risk reduction initiatives for low-dose DON exposure.

Environmental arsenic pollution induced liver oxidative stress injury by regulating miR-155 through inhibition of AUF1.

Arsenic (As), a common environmental pollutant, has become a hot topic in recent years due to its potentially harmful effects. Liver damage being a central clinical feature of chronic arsenic poisoning. However, the underlying mechanisms remain unclear. We demonstrated that arsenic can lead to oxidative stress in the liver and result in structural and functional liver damage, significantly correlated with the expression of AUF1, Dicer1, and miR-155 in the liver. Interestingly, knockdown AUF1 promoted the up-regulatory effects of arsenic on Dicer1 and miR-155 and the inhibitory effects on SOD1, which exacerbated oxidative damage in rat liver. However, overexpression of AUF1 reversed the up-regulatory effects of arsenic on Dicer1 and miR-155, restored arsenic-induced SOD1 depletion, and attenuated liver oxidative stress injury. Further, we verified the mechanism and targets of miR-155 in regulating SOD1 by knockdown/overexpression of miR-155 and nonsense mutant SOD1 3'UTR experiments. In conclusion, these results powerfully demonstrate that arsenic inhibits AUF1 protein expression, which in turn reduces the inhibitory effect on Dicer1 expression, which promotes miR-155 to act on the SOD1 3'UTR region after high expression, thus inhibiting SOD1 protein expression and enzyme activity, and inducing liver injury. This finding provides a new perspective for the mechanism research and targeted prevention of arsenic poisoning, as well as scientific evidence for formulating strategies to prevent and control environmental arsenic pollution.

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.

Catapol attenuates the aseptic inflammatory response to hepatic I/R injury in vivo and in vitro by inhibiting the HMGB1/TLR-4/NF-κB signaling pathway via the microRNA-410-3p.

BACKGROUND: Hepatic ischemia-reperfusion (I/R) injury involves inflammatory necrosis of liver cells as a significant pathological mechanism. Catapol possesses anti-inflammatory activity that is extracted from the traditional Chinese medicine, Rehmannia glutinosa. METHODS: The liver function and histopathology, Oxidative stress, and aseptic inflammatory responses were assessed in vivo, and the strongest dose group was selected. For mechanism, the expression of miR-410-3p, HMGB1, and TLR-4/NF-κB signaling pathways was detected. The dual luciferase assay can verify the targeting relationship between miR-410-3p and HMGB1. Knockdown of miR-410-3p in L02 cells is applied in interference experiments. RESULTS: CAT pre-treatment significantly decreased the liver function markers alanine and aspartate aminotransferases and reduced the areas of hemorrhage and necrosis induced by hepatic I/R injury. Additionally, it reduced the aseptic inflammatory response and oxidative stress, with the strongest protective effect observed in the high-dose CAT group. Mechanistically, CAT downregulates HMGB1, inhibits TLR-4/NF-κB signaling pathway activation, and reduces inflammatory cytokines TNF-α, and IL-1ß. In addition, the I/R-induced downregulation of microRNA-410-3p was inhibited by CAT pre-treatment in vivo and in vitro. HMGB1 was identified as a potential target of microRNA-410-3p using a dual-luciferase reporter assay. Knockdown of microRNA-410-3p abolished the inhibitory effect of CAT on HMGB1, p-NF-κB, and p-IκB-α protein expression. CONCLUSIONS: Our study showed that CAT pre-treatment has a protective effect against hepatic I/R injury in rats. Specifically, CAT attenuates the aseptic inflammatory response to hepatic I/R injury in vivo and in vitro by inhibiting the HMGB1/TLR-4/NF-κB signaling pathway via the microRNA-410-3p.

Bavachin induces liver injury and cell apoptosis by targeting Wnt/ß-catenin/DRP1 signaling pathway mediated mitochondrial dysfunction.

Psraleae Fructus (PF) is a well-known traditional Chinese medicine in China. While numerous liver injury reports caused by PF limits its clinical application. Bavachin, a flavonoid compound isolated from the fruits of Psoralea corylifolia L., has been validated to induce direct apoptosis in hepatocytes and liver tissues in our previous studies. However, the subcellular mechanisms of bavachin induced liver injury is still elusive. Here, utilizing 6-week-old C57BL/6 J mice and human embryonic hepatocytes (L02 cells), we report that bavachin activates dynamic-related protein 1 (DRP1) mediated excess mitochondrial fission and endoplasmic reticulum (ER) stress related apoptosis via Wnt/ß-catenin signaling pathway. Notably, DRP1 knockdown or XAV-939 induced Wnt/ß-catenin inhibition decreased bavachin-induced ER stress and cell apoptosis in L02 cells. In addition, bavachin impaired mitochondrial structural and function in the mice liver tissues. Mdivi-1, a mitochondrial fission inhibitor targeting DRP1, prevented bavachin-induced mitochondrial and ER structural damage, ER stress, and liver injury. Our results demonstrated that bavachin induced mitochondrial fission plays a crucial role in bavachin induced ER stress related liver injury, via the mechanism that involved activation of Wnt/ß-catenin signaling pathway.

Enhancing Healthcare Outcomes and Modulating Apoptosis- and Antioxidant-Related Genes through the Nano-Phytosomal Delivery of Phenolics Extracted from Allium ampeloprasum.

The application of nano drug delivery systems, particularly those utilizing natural bioactive compounds with anticancer properties, has gained significant attention. In this study, a novel nano-phytosome-loaded phenolic rich fraction (PRF) derived from Allium ampeloprasum L. was developed. The antitumor activity of the formulation was evaluated in BALB/c mice with TUBO colon carcinoma. The PRF-loaded nano-phytosome (PRF-NPs) exhibited a sphere-shaped structure (226 nm) and contained a diverse range of phenolic compounds. Animal trials conducted on TUBO tumor-bearing mice demonstrated that treatment with PRF-NPs at a dosage of 50 mg TPC/Kg/BW resulted in significant improvements in body weight and food intake, while reducing liver enzymes and lipid peroxidation. The expression of apoptosis-related genes, such as Bax and caspase-3, was upregulated, whereas Bcl2 was significantly downregulated (p < 0.05). Furthermore, the expression of GPx and SOD genes in the liver was notably increased compared to the control group. The findings suggest that the phytosomal encapsulation of the phenolic rich fraction derived from Allium ampeloprasum L. can enhance the bioavailability of natural phytochemicals and improve their antitumor properties. The development of PRF-NPs as a nano drug delivery system holds promise for effective breast cancer treatment.

Long-Term Impact of Direct-Acting Antivirals on Liver Fibrosis and Survival in HCV-Infected Liver Transplant Recipients.

(1) Background: Little is known about the long-term impact of sustained virological response (SVR) on fibrosis progression and patient survival in liver transplantation (LT) recipients treated with direct-acting antivirals (DAAs). We investigated liver fibrosis evolution and patient survival in hepatitis C virus (HCV)-infected patients receiving DAAs after LT. (2) Methods: All consecutive HCV-infected patients treated with DAAs after LT between May 2014 and January 2019 were considered. The clinical and virological features were registered at the baseline and during the follow-up. The liver fibrosis was assessed by liver biopsy and/or transient elastography (TE) at the baseline and at least 1 year after the end of treatment (EoT). (3) Results: A total of 136 patients were included. The SVR12 was 78% after the first treatment and 96% after retreatment. After the SVR12, biochemical tests improved at the EoT and remained stable throughout the 3-year follow-up. Liver fibrosis improved after the SVR12 (p < 0.001); nearly half of the patients with advanced liver fibrosis experienced an improvement of an F ≤ 2. The factors associated with lower survival in SVR12 patients were the baseline platelet count (p = 0.04) and creatinine level (p = 0.04). (4) Conclusions: The long-term follow-up data demonstrated that SVR12 was associated with an improvement in hepatic function, liver fibrosis, and post-LT survival, regardless of the baseline liver fibrosis. The presence of portal hypertension before the DAAs has an impact on patient survival, even after SVR12.

Assessment of the water quality and toxicity effects on zebrafish (Danio rerio) of a stream near a phosphorus chemical plant in Guizhou Province, southwestern China.

To reveal the influence of the phosphorus chemical industry (PCI) on regional water environmental quality and safety, the water quality and ecotoxicological effects of a stream near a phosphorus chemical plant (PCP) in Guizhou Province, southwestern China, were investigated based on water samples collected from the stream. The results showed that the average concentrations of NH3-N, TN, P, F-, Hg, Mn, and Ni were 3.14 mg/L, 30.09 mg/L, 3.34 mg/L, 1.18 mg/L, 1.06 µg/L, 45.82 µg/L, and 11.30 µg/L, respectively. The overall water quality of the stream was in the heavily polluted category, and NH3-N, TN, P, F-, and Hg were the main pollution factors. The degree of pollution was in the order of rainy period > transitional period > dry period, and the most polluted sample site was 1100 m from the PCP. After 28 days of exposure to stream water, there was no significant change in the growth parameters of zebrafish. The gills of zebrafish showed a small amount of epithelial cell detachment and a small amount of inflammatory cell infiltration, and the liver tissue displayed a large amount of hepatocyte degeneration with loose and lightly stained cytoplasm. Compared with the control group, the %DNA in tail, tail length, tail moment, and olive tail moment were significantly increased (p < 0.05), indicating that the water sample caused DNA damage in the peripheral blood erythrocytes of zebrafish. The stream water in the PCI area was found to be polluted and exhibited significant toxicity to zebrafish, which could pose a threat to regional ecological security.

Role of ERK1/2 Signaling in Cinnabarinic Acid-Driven Stanniocalcin 2-Mediated Protection against Alcohol-Induced Apoptosis.

We have previously shown that a bona fide aryl hydrocarbon receptor (AhR) agonist, cinnabarinic acid (CA), protects against alcohol-induced hepatocyte apoptosis via activation of a novel AhR target gene, stanniocalcin 2 (Stc2). Stc2 translates to a secreted disulfide-linked hormone, STC2, known to function in cell development, calcium and phosphate regulation, angiogenesis, and antiapoptosis-albeit the comprehensive mechanism by which the CA-AhR-STC2 axis confers antiapoptosis is yet to be characterized. In this study, using RNA interference library screening, downstream antiapoptotic molecular signaling components involved in CA-induced STC2-mediated protection against ethanol-induced apoptosis were investigated. RNA interference library screening of kinases and phosphatases in Hepa1 cells and subsequent pathway analysis identified mitogen-activated protein kinase (MAPK) signaling as a critical molecular pathway involved in CA-mediated protection. Specifically, phosphorylation of ERK1/2 was induced in response to CA treatment without alterations in p38 and JNK signaling pathways. Silencing Stc2 in Hepa1 cells and in vivo experiments performed in Stc2-/- (Stc2 knockout) mice, which failed to confer CA-mediated protection against ethanol-induced apoptosis, showed abrogation of ERK1/2 activation, underlining the significance of ERK1/2 signaling in CA-STC2-mediated protection. In conclusion, activation of ERK1/2 signaling in CA-driven AhR-dependent Stc2-mediated protection represents a novel mechanism of protection against acute alcohol-induced apoptosis. SIGNIFICANCE STATEMENT: Previous studies have shown the role of stanniocalcin 2 (Stc2) in cinnabarinic acid (CA)-mediated protection against alcohol-induced apoptosis. Here, using RNA interference library screening and subsequent in vivo studies, the functional significance of ERK1/2 activation in CA-induced Stc2-mediated protection against acute ethanol-induced apoptosis was identified. This study is thus significant as it illustrates a comprehensive downstream mechanism by which CA-induced Stc2 protects against alcoholic liver disease.

Protective Effect of Water-Soluble Acacetin Prodrug on APAP-Induced Acute Liver Injury Is Associated with Upregulation of PPARγ and Alleviation of ER Stress.

A water-soluble acacetin prodrug has been synthesized and reported by our group previously. Acetaminophen (APAP) overdose is a leading cause of acute liver injury. We found that subcutaneous injection of acacetin prodrug (5, 10, 20 mg/kg) decreased serum ALT, AST, and ALP, corrected the abnormal MDA and GSH in liver, and improved intrahepatic hemorrhage and destruction of liver structures in APAP (300 mg/kg)-treated mice. Molecular mechanism analysis revealed that the expressions of endoplasmic reticulum (ER) stress markers ATF6, CHOP, and p-PERK, apoptosis-related protein BAX, and cleaved caspase 3 were decreased by acacetin in a dose-dependent manner in vivo and in vitro. Moreover, via the acacetin-upregulated peroxisome-proliferator-activated receptor gamma (PPARγ) of HepG2 cells and liver, the suppressive effect of acacetin on ER stress and apoptosis was abolished by PPARγ inhibitor (GW9662) or PPARγ-siRNA. Molecular docking revealed that acacetin can bind to three active pockets of PPARγ, mainly by hydrogen bond. Our results provide novel evidence that acacetin prodrug exhibits significant protective effect against APAP-induced liver injury by targeting PPARγ, thereby suppressing ER stress and hepatocyte apoptosis. Acacetin prodrug is likely a promising new drug candidate for treating patients with acute liver injury induced by APAP.

Four-week repeated exposure to tire-derived 6-PPD quinone causes multiple organ injury in male BALB/c mice.

N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6-PPDQ) is the ozonation product of tire antioxidant 6-PPD. 6-PPDQ can be detected in different environments, such as roadway runoff and dust. Although 6-PPDQ toxicity has been frequently assessed in aquatic organisms, the possible toxic effects of 6-PPDQ on mammals remain largely unclear. We here aimed to perform systematic assessment to evaluate 6-PPDQ toxicity on multiple organs in mice. Male BALB/c mice were intraperitoneally injected with 6-PPDQ for two exposure modes, single intraperitoneal injection and repeated intraperitoneal injection every four days for 28 days. Serum, liver, kidney, lung, spleen, testis, brain, and heart were collected for injury evaluation by organ index, histopathology analysis and biochemical parameters. In 0.4 and 4 mg/kg 6-PPDQ single injected mice, no significant changes in organ indexes and biochemical parameters were detected, and only moderate pathological changes were observed in organs of liver, kidney, lung, and brain. Very different from this, in 0.4 and 4 mg/kg 6-PPDQ repeated injected mice, we observed the obvious increase in organ indexes of liver, kidney, lung, testis, and brain, and the decrease in spleen index. Meanwhile, the significant pathological changes were formed in liver, kidney, lung, spleen, testis, and brain in 0.4 and 4 mg/kg 6-PPDQ repeated injected mice. Biochemical parameters of liver (alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP)) and kidney (urea and creatinine) were all significantly upregulated by repeated injection with 0.4 and 4 mg/kg 6-PPDQ. After repeated exposure, most of 6-PPDQ was accumulated in liver and lung of mice. Therefore, our results suggested the risk of repeated exposure to 6-PPDQ in inducing toxicity on multiple organs in mice.

Prospective Protective Effects of Arthrospira platensis Against Acetaminophen Induced Hepato-Renal Toxicity in Rats / Efectos Protectores Prospectivos de Arthrospira platnesis Contra la Toxicidad Hepatorrenal Inducida por Paracetamol en Ratas

SUMMARY: The toxic effects of acetaminophen appear primarily in the liver and kidney. The protective effect of blue green alga Arthrospira platensis on hepato-renal toxicity caused by acetaminophen was evaluated in male rats. The obtained results showed that subcutaneous injection of acetaminophen at a dose 120 &240 սl acetaminophen/kg by weight resulted in an observed elevation in the enzyme activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and Alkaline phosphatase (ALP), serum total lipids, total cholesterol, creatinine, total bilirubin, urea, nitric oxide (NO), L- malondialdehyde (MDA) and interleukins (IL-2 &IL-6). However, there is a decrease in the serum total protein, albumin and loss in antioxidant enzyme activities in liver including; superoxide dismutase (SOD), catalase (CAT) and glutathione reductase (GSH). This effect was found to be dose and time dependent. In spite of, pre- oral administration of Arthrospira platensis 1000 mg/kg .b. wt. prior acetaminophen injection succeeded to modulate the effect of the observed abnormalities caused by acetaminophen. Moreover, there were no remarkable changes in serum biomarkers of rats received Arthrospira platensis only at a dose of 1000 mg/kg by weight (group 2). The histopathological findings confirm the biochemical results that indicates the safety use of Arthrospira platensis at the selected dose in this study. Therefore, the present results clarified the protective effect of blue green alga Arthrospira platensis on oxidative stress, hepatic and nephrotoxicity induced by acetaminophen in male Wister rats.

Los efectos tóxicos del paracetamol aparecen principalmente en el hígado y el riñón. Se evaluó en ratas macho Wistar el efecto protector del alga verde azulada Arthrospira platensis sobre la toxicidad hepatorrenal causada por paracetamol. Los resultados obtenidos mostraron que la inyección subcutánea de paracetamol a dosis de 120 y 240 µl de paracetamol/kg, resultó en una elevación en las actividades enzimáticas de la aspartato aminotransferasa (AST), alanina aminotransferasa (ALT) y fosfatasa alcalina (ALP), lípidos séricos totales, colesterol total, creatinina, bilirrubina total, urea, óxido nítrico (NO), L- malondialdehído (MDA) e interleucinas (IL-2 e IL-6). Sin embargo, hay una disminución en la proteína sérica total, albúmina y pérdida en las actividades de las enzimas antioxidantes en el hígado, incluyendo; superóxido dismutasa (SOD), catalasa (CAT) y glutatión reductasa (GSH). Se encontró que este efecto era dependiente de la dosis y el tiempo. A pesar de la administración preoral de Arthrospira platensis 1000 mg/kg, la inyección previa de acetaminofeno logró modular el efecto de las anormalidades observadas causadas por el acetaminofeno. Además, no hubo cambios notables en los biomarcadores séricos de ratas que recibieron Arthrospira platensis solo a una dosis de 1000 mg/kg (Grupo 2). Los hallazgos histopatológicos confirman los resultados bioquímicos que indican la seguridad del uso de Arthrospira platensis a la dosis seleccionada en este estudio. Por lo tanto, los presentes resultados aclararon el efecto protector del alga verde azulada Arthrospira platensis sobre el estrés oxidativo, la toxicidad hepática y la nefrotoxicidad inducida por paracetamol en ratas Wistar macho.

A web-based integrative transcriptome analysis, RNAseqChef, uncovers the cell/tissue type-dependent action of sulforaphane.

RNA sequencing (RNA-seq) is a powerful technique for understanding cellular state and dynamics. However, comprehensive transcriptomic characterization of multiple RNA-seq datasets is laborious without bioinformatics training and skills. To remove the barriers to sequence data analysis in the research community, we have developed "RNAseqChef" (RNA-seq data controller highlighting expression features), a web-based platform of systematic transcriptome analysis that can automatically detect, integrate, and visualize differentially expressed genes and their biological functions. To validate its versatile performance, we examined the pharmacological action of sulforaphane (SFN), a natural isothiocyanate, on various types of cells and mouse tissues using multiple datasets in vitro and in vivo. Notably, SFN treatment upregulated the ATF6-mediated unfolded protein response in the liver and the NRF2-mediated antioxidant response in the skeletal muscle of diet-induced obese mice. In contrast, the commonly downregulated pathways included collagen synthesis and circadian rhythms in the tissues tested. On the server of RNAseqChef, we simply evaluated and visualized all analyzing data and discovered the NRF2-independent action of SFN. Collectively, RNAseqChef provides an easy-to-use open resource that identifies context-dependent transcriptomic features and standardizes data assessment.

Peripheral modulation of antidepressant targets MAO-B and GABAAR by harmol induces mitohormesis and delays aging in preclinical models.

Reversible and sub-lethal stresses to the mitochondria elicit a program of compensatory responses that ultimately improve mitochondrial function, a conserved anti-aging mechanism termed mitohormesis. Here, we show that harmol, a member of the beta-carbolines family with anti-depressant properties, improves mitochondrial function and metabolic parameters, and extends healthspan. Treatment with harmol induces a transient mitochondrial depolarization, a strong mitophagy response, and the AMPK compensatory pathway both in cultured C2C12 myotubes and in male mouse liver, brown adipose tissue and muscle, even though harmol crosses poorly the blood-brain barrier. Mechanistically, simultaneous modulation of the targets of harmol monoamine-oxidase B and GABA-A receptor reproduces harmol-induced mitochondrial improvements. Diet-induced pre-diabetic male mice improve their glucose tolerance, liver steatosis and insulin sensitivity after treatment with harmol. Harmol or a combination of monoamine oxidase B and GABA-A receptor modulators extend the lifespan of hermaphrodite Caenorhabditis elegans or female Drosophila melanogaster. Finally, two-year-old male and female mice treated with harmol exhibit delayed frailty onset with improved glycemia, exercise performance and strength. Our results reveal that peripheral targeting of monoamine oxidase B and GABA-A receptor, common antidepressant targets, extends healthspan through mitohormesis.

[Advances in clinical diagnosis and treatment of drug-induced liver injury in children].

Drug-induced liver injury (DILI) is one of the most common adverse drug reactions that may seriously threaten the health of children and is receiving increasing clinical attention day by day. There is still no independent diagnosis and treatment guideline for DILI in children, but its clinical features are not completely similar to those in adults. This article reviews the epidemiology, clinical features, diagnosis, and treatment progress in order to provide a reference for the management of DILI in children.

Captopril inhibits thioacetamide-induced chronic liver injury associated with the suppression of inflammation / hypoxia- inducible factor 1-alpha / profibrogenic axis-mediated hepatotoxicity in rats / Captopril inhibe la lesión hepática crónica inducida por tioacetamida asociada con la supresión de la inflamación/factor 1-alfa inducible por hipoxia/hepatotoxicidad mediada por el eje profibrogénico en rata

SUMMARY: Liver transplantation is the only available method to treat liver failure induced by chronic liver injury. We sought to determine whether the angiotensin-converting enzyme inhibitor, captopril, can inhibit the development of chronic liver injury induced by the hepatotoxic agent thioacetamide (TAA) in association with the suppression of inflammation (hsCRP, TNF-α, and IL-6) / hypoxia- inducible factor 1-alpha (HIF-1α) / profibrosis (TIMP-1, MMP-9, and α-SMA) axis that mediates liver injury. Therefore, the model group of rats was injected for eight weeks with 200 mg/kg TAA starting at week two. The protective group was pretreated with 150 mg/ kg captopril daily for two weeks prior to TAA injections and continued receiving both capropril and TAA agents until being humanely scrificed at week 10. We observed a substantial damage to liver tissue in the model group as demonstrated by a significant (p<0.0001) increase in blood and hepatic tissue levels of high sensitivity C-reactive protein (hsCRP), tumor necrosis factor-a (TNF-α), interleukin- 6 (L-6), HIF-1α, tissue inhibitor of metalloproteinases-1 (TIMP-1), matrix metalloproteinase-9 (MMP-9), alpha-smooth muscle actin (α-SMA), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). All these parameters were significantly (p<0.0244) protected by captopril. Also, a significant (p<0.0001) positive correlation was observed between a-SMA (profibrosis) and the serum and tissue levels of hsCRP, TNF-α, HIF-1α, TIMP-1, MMP-9, and ALT. Thus, these findings suggest that the induction of chronic liver injury by the hepatotoxic compound, TAA is associated with the upregulation of inflammation/HIF-1α/profibrosis, with captopril exhibiting beneficial hepatic pleotropic effects.

El trasplante de hígado es el único método disponible para tratar la insuficiencia hepática inducida por una lesión hepática crónica. Buscamos determinar si el inhibidor de la enzima convertidora de angiotensina, captopril, puede inhibir el desarrollo de lesión hepática crónica inducida por el agente hepatotóxico tioacetamida (TAA) en asociación con la supresión de la inflamación (hsCRP, TNF-α e IL-6) / factor inducible por hipoxia 1-alfa (HIF-1α) / profibrosis (TIMP-1, MMP-9 y α- SMA) eje que media la lesión hepática. Por lo tanto, al grupo modelo de ratas se le inyectó durante ocho semanas 200 mg/kg de TAA a partir de la semana dos. El grupo protector fue pretratado con 150 mg/kg de captopril al día durante dos semanas antes de las inyecciones de TAA y continuó recibiendo capropril y agentes TAA hasta que fue sacrificado en la semana 10. Observamos un daño sustancial en el tejido hepático en el grupo modelo, como lo demuestra un aumento significativo (p<0,0001) de los niveles en sangre y tejido hepático de proteína C reactiva de alta sensibilidad (hsCRP), factor de necrosis tumoral-α (TNF-a), interleucina-6 (L-6), HIF-1α, inhibidor tisular de metaloproteinasas-1 (TIMP-1), metaloproteinasa de matriz-9 (MMP-9), actina de músculo liso alfa (α-SMA), alanina aminotransferasa (ALT) y aspartato aminotransferasa (AST). Todos estos parámetros estaban significativamente (p<0,0244) protegidos por captopril. Además, se observó una correlación positiva significativa (p<0,0001) entre α-SMA (profibrosis) y los niveles séricos y tisulares de hsCRP, TNF-α, HIF-1α, TIMP- 1, MMP-9 y ALT. Por lo tanto, estos hallazgos sugieren que la inducción de daño hepático crónico por el compuesto hepatotóxico, TAA, está asociada con la regulación al alza de la inflamación/HIF-1α/profibrosis, con captopril exhibiendo efectos pleotrópicos hepáticos beneficiosos.

Investigation of the protective effect of boric acid against hepatotoxic and nephrotoxic injury induced by acrylamide in rats / Investigación del efecto protector del ácido bórico contra lesiones hepatotóxicas y nefrotóxicas inducidas por acrilamida en ratas

SUMMARY: To investigate if the administration of boric acid (BA) would exert any protective effect against possible nephrotoxicity and hepatotoxicity induced by the exposure to acrylamide (ACR) in rats. In our study, we used a total of 28 rats that were divided into four equal groups. Group 1: the control group which was not treated with any procedure. Group 2: the ACR group that was administered ACR 50 mg/kg/day via intraperitoneal (i.p) route for 14 days. Group 3: the BA group that was administered BA 200 mg/kg/ day via gavage via peroral (p.o) route for 14 days. Group 4: the ACR+BA group that was administered BA simultaneously with ACR. Total antioxidant and oxidant (TAS/TOS) capacities were measured in all groups at the end of the experiment. In addition, the specimens obtained were evaluated with histopathological examination. Studies showed that the ACR and ACr+BA groups were not significantly different in terms of hepatic TAS level while the TOS level was higher in the ACR group than the ACR+BA group. The groups did not show any significant difference regarding renal TAS and TOS levels. In the histopathological examination of the hepatic tissue, the histopathological injury score of the ACR group was significantly higher than those of the other groups whereas it was significantly lower in the ACR+BA group than the ACR group. Our study concluded that Boric acid had a protective effect against acrylamide- induced hepatotoxicity, but not against nephrotoxicity.

El objetivo de este estudio fue investigar si la administración de ácido bórico (BA) ejercería algún efecto protector frente a la posible nefrotoxicidad y hepatotoxicidad inducida por la exposición a acrilamida (ACR) en ratas. En nuestro estudio, utilizamos un total de 28 ratas que se dividieron en cuatro grupos iguales. Grupo 1: grupo control que no fue tratado. Grupo 2: grupo ACR al que se le administró ACR 50 mg/kg/día por vía intraperitoneal (i.p) durante 14 días. Grupo 3: grupo BA al que se le administró BA 200 mg/kg/día por sonda por vía peroral (p.o) durante 14 días. Grupo 4: grupo ACR+BA al que se administró BA simultáneamente con ACR. Las capacidades antioxidantes y oxidantes totales (TAS/TOS) se midieron en todos los grupos al final del experimento. Además, los especímenes obtenidos fueron evaluados con examen histopatológico. Los estudios demostraron que los grupos ACR y ACr+BA no fueron significativamente diferentes en términos del nivel hepático de TAS, mientras que el nivel de TOS fue mayor en el grupo ACR que en el grupo ACR+BA. Los grupos no mostraron ninguna diferencia significativa con respecto a los niveles renales de TAS y TOS. En el examen histopatológico del tejido hepático, la puntuación de lesión histopatológica del grupo ACR fue significativamente mayor que la de los otros grupos, mientras que fue significativamente menor en el grupo ACR+BA que en el grupo ACR. Nuestro estudio concluyó que el ácido bórico tiene un efecto protector contra la hepatotoxicidad inducida por acrilamida, pero no contra la nefrotoxicidad.

A Case Report of Acute Hepatitis Involving the Medicinal Herb Tinospora cordifolia Along with Other Variables.

This is a 54-year-old woman from Germany of central European origin who developed an acute hepatitis while orally taking Ayurvedic herbal remedies, among those was the medicinal herb Tinospora cordifolia. She took the plant powders from July 1, 2021, to October 1, 2021, with the intention of relieving the symptoms of her subjectively irritated gastrointestinal tract. The patient's main symptoms of acute hepatitis were progressively increasing general fatigue, nausea, and exhaustion. During an inpatient hospital admission from November 4, 2021, to November 9, 2021, she was under clinical observation, but no specific therapeutic measures were deemed necessary; however, blood chemistry showed an acute toxic hepatitis. There was no clinical or laboratory evidence of acute liver failure. Aminotransferase values decreased to normal values on December 14, 2021, by themselves. This case report contributes to the ongoing discussion about the potential risks of triggering an acute hepatitis due to the intake of herbal remedies from the Tinospora genus in rare cases, differentiating other involved risk factors. The case also shows that causality assignments are not trivial in the context of multivariate clinical scenarios. In the case of known hepatic metabolism-associated risk factors, T. cordifolia should be used with more caution based on available case reports. At the same time, no hasty and exaggerated prejudgments should be made about this medicinal herb, which has been very successfully used in traditional South Asian systems of medicine for many centuries.