Hepatocellular Injury Research Articles

Biochemical enzymes effects of analgesics treatment on post operative patients

Albeit 60 years have passed since it opened up on the restorative market, analgesics measurements in patients with liver illness stays a questionable subject. Fulminant hepatic disappointment has been a proven and factual result of analgesics over portion since its presentation, while short and long haul use have both been related with height of liver transaminases, a proxy marker for intense liver injury. From these reports it has been expected that analgesics use ought to be confined or the measurement decreased in patients with persistent liver sickness. We survey the elements that have been suspected to build hazard of hepatocellular injury from analgesics and the pharmacokinetic changes in various pathologies of persistent liver illness which might influence this gamble. We propose that unintentional under-dosing might bring about focuses excessively low to empower viability. Explicit examination to further develop the proof base for endorsing analgesics in patients with various an etiologies of constant liver sickness is required.. Results communicated that the study just with discoveries communicated that the patients which are not related with contamination but rather they impacted disease (498 numbers and 33.2%) for lesser rate and numbers when contrasted and disease related sicknesses (802 Numbers and 53.5%). The various degrees of SGOT results demonstrated after the medications taken pain+ tachyarrthymia (2.5 ± 0.4↑) patients levels of SGOT were fundamentally expanded contrasted with before drugs taken torment embraced patients. The various levels SGPT results made sense of for ensuing to the medications taken torment + aggravation ( 1.65 ± 0.003↓ ) patients levels of SGPT were widely diminished when contrasted with sooner than drugs taken torment. A more sensible manual for help the shriveling youngster expected by clear notification high philological hindrances with social and extreme contrasts. Additionally course expected to help the youngster and other gathering patients gone through chemotherapy radiation for therapy post operatively.

Macrophage PTEN controls STING-induced inflammation and necroptosis through NICD/NRF2 signaling in APAP-induced liver injury

BackgroundPhosphatase and tensin homolog deleted on chromosome 10 (PTEN) signaling has been known to play a critical role in maintaining cellular and tissue homeostasis, which also has an essential role in the inflammatory response. However, it remains unidentified whether and how the macrophage PTEN may govern the innate immune signaling stimulator of interferon genes (STING) mediated inflammation and hepatocyte necroptosis in APAP-induced liver injury (AILI).MethodsMyeloid-specific PTEN knockout (PTENM−KO) and floxed PTEN (PTENFL/FL) mice were treated with APAP (400 mg/kg) or PBS. In a parallel in vitro study, bone marrow-derived macrophages (BMMs) were isolated from these conditional knockout mice and transfected with CRISPR/Cas9-mediated Notch1 knockout (KO) or CRISPR/Cas9-mediated STING activation vector followed by LPS (100 ng/ml) stimulation.ResultsHere, we report that myeloid-specific PTEN knockout (PTENM−KO) mice were resistant to oxidative stress-induced hepatocellular injury with reduced macrophage/neutrophil accumulation and proinflammatory mediators in AILI. PTENM−KO increased the interaction of nuclear Notch intracellular domain (NICD) and nuclear factor (erythroid-derived 2)-like 2 (NRF2) in the macrophage nucleus, reducing reactive oxygen species (ROS) generation. Mechanistically, it is worth noting that macrophage NICD and NRF2 co-localize within the nucleus under inflammatory conditions. Additionally, Notch1 promotes the interaction of immunoglobulin kappa J region (RBPjκ) with NRF2. Disruption of the Notch1 signal in PTEN deletion macrophages, reduced RBPjκ and NRF2 binding, and activated STING signaling. Moreover, PTENM−KO macrophages with STING activated led to ROS generation and TNF-α release, resulting in hepatocyte necroptosis upon co-culture with primary hepatocytes.ConclusionsOur findings demonstrate that the macrophage PTEN-NICD/NRF2-STING axis is critical to regulating oxidative stress-induced liver inflammation and necroptosis in AILI and implies the therapeutic potential for managing sterile liver inflammation.-_SzJnLNvYmjVKnhJWJTYKVideo Graphical

Lp-PLA2 silencing ameliorates inflammation and autophagy in nonalcoholic steatohepatitis through inhibiting the JAK2/STAT3 pathway.

Nonalcoholic steatohepatitis (NASH), a common cause of liver-related morbidity and mortality worldwide, is characterized by inflammation and hepatocellular injury. Our research focuses on lipoprotein-associated phospholipase A2 (Lp-PLA2), an inflammation-related biomarker that has recently garnered interest in the context of NASH due to its potential roles in disease pathogenesis and progression. We established a NASH mouse model using a high-fat diet (HFD) and treated it with sh-Lp-PLA2 and/or rapamycin (an mTOR inhibitor). Lp-PLA2 expression in NASH mice was detected by qRT-PCR. Serum levels of liver function parameters and inflammatory cytokines were detected using corresponding assay kits. We examined pathological changes in liver using hematoxylin-eosin, oil red O, and Masson staining, and observed autophagy through transmission electron microscopy. The protein levels of Lp-PLA2, mTOR, light chain 3 (LC3) II/I, phosphorylated Janus kinase 2 (p-JAK2)/JAK2, and phosphorylated signal transducer and activator of transcription 3 (p-STAT3)/STAT3 were determined by western blotting. Kupffer cells extracted from C57BL/6J mice were treated to replicate NASH conditions and treated with sh-Lp-PLA2, rapamycin, and/or a JAK2-inhibitor to further verify the roles and mechanisms of Lp-PLA2 in NASH. Our data indicate an upregulation of Lp-PLA2 expression in HFD-induced NASH mice. Silencing Lp-PLA2 in NASH mice reduced liver damage and inflammation markers (aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol (TC), triglycerides (TG), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6)), while increasing IL-10 levels, an anti-inflammatory cytokine. Additionally, Lp-PLA2 silencing decreased lipid and collagen accumulation and promoted autophagy. The beneficial effects of sh-Lp-PLA2 on NASH were enhanced by rapamycin. Furthermore, Lp-PLA2 silencing resulted in the downregulation of the expression of p-JAK2/JAK2 and p-STAT3/STAT3 in NASH mice. Similar results were observed in Kupffer cells treated under NASH conditions; Lp-PLA2 silencing promoted autophagy and repressed inflammation, effects which were potentiated by the addition of rapamycin or a JAK2-inhibitor. Our findings suggest that silencing Lp-PLA2 promotes autophagy via deactivating the JAK2/STAT3 signaling pathway, thereby restraining NASH progression. This highlights the potential therapeutic value of targeting Lp-PLA2, adding a new dimension to our understanding of NASH pathogenesis and treatment strategies.

The Protective Effect of Nutraceuticals on Hepatic Ischemia-Reperfusion Injury in Wistar Rats.

Nutraceuticals are bioactive compounds present in foods, utilized to ameliorate health, prevent diseases, and support the proper functioning of the human body. They have gained attention due to their ability to hit multiple targets and act as antioxidants, anti-inflammatory agents, and modulators of immune response and cell death. Therefore, nutraceuticals are being studied to prevent and treat liver ischemia-reperfusion injury (IRI). This study evaluated the effect of a nutraceutical solution formed by resveratrol, quercetin, omega-3 fatty acid, selenium, ginger, avocado, leucine, and niacin on liver IRI. IRI was performed with 60 min of ischemia and 4 h of reperfusion in male Wistar rats. Afterward, the animals were euthanized to study hepatocellular injury, cytokines, oxidative stress, gene expression of apoptosis-related genes, TNF-α and caspase-3 proteins, and histology. Our results show that the nutraceutical solution was able to decrease apoptosis and histologic injury. The suggested mechanisms of action are a reduction in gene expression and the caspase-3 protein and a reduction in the TNF-α protein in liver tissue. The nutraceutical solution was unable to decrease transaminases and cytokines. These findings suggest that the nutraceuticals used favored the protection of hepatocytes, and their combination represents a promising therapeutic proposal against liver IRI.

ACUTE AND CHRONİC DEGREE OF TOXICITY IN TRAMADOL CONSUMPTİON ON PLASMA PROTEIN, ASPARTATE AMİNOTRANSFERASE (AST), ALANİNE AMİNOTRANSFERASE (ALT) AND ALKALİNE PHOSPHATASE (ALP) İN ADULT WISTAR RATS

Although the mechanism of hepatotoxicity from tramadol overdoses is unknown, it is most likelycaused by direct hepatocellular injury, either as a result of ischemia or mitochondrial toxicity. Overdosingon tramadol has been reported to cause acute liver failure. Tramadol-related minor enzyme increases areoften asymptomatic, self-limited, and resolve even when medication is continued. This investigationexamines the short- and long-term effects of tramadol use on liver enzymes in an animal model. The studyinvolved sixty (60) mature Wistar rats of both sexes. Tramadol (300g) were administered to the animals inthe experimental and control groups in the following ways: Before being sacrificed, Group A (n = 5 Malesand 5 Females) received no treatment within the study's time frame. Group B (n = 5 Males and 5 Females)received tramadol 30 mg/kg body weight for 7 days and were sacrificed; Group C (n = 5 Males and 5Females) received tramadol 30 mg/kg body weight for 14 days and were sacrifice; Group D (n = 5 Malesand 5 Females) received tramadol 30 mg/kg body weight for 21 days and were sacrifice, Group E (n = 5Male and 5 Female) received tramadol 30 mg/kg body weight for 42 days and were sacrificed, while GroupF (n = 5 Male and 5 Female) withdrew for 3 weeks after receiving tramadol 30 mg/kg for three weeksbefore sacrificing. Liver was removed from the animals for biochemical examination. The findings of theSPSS analysis on the generated data were expressed as mean SEM. After three and six weeks of tramadoladministration, the results obtained demonstrated a progressive increase in weight and an increase in theactivities of ALT, ALP, and AST in the plasma while decreasing the level of total protein, albumin, directbilirubin as well as indirect bilirubin as compared to the control rats. Therefore, this study comes to theconclusion that tramadol has harmful effects, both acute and chronic, on the structure and operation ofhepatic tissue in wistar rats. As a result, tramadol use needs to be monitored.

Choledocholithiasis Can Present with Marked Transaminases Elevation: Systematic Review and Meta-Analysis.

Extreme transaminase elevation > 1000 international units per liter (IU/L) is typically caused by hepatocellular injury due to ischemia, drugs, or viral infection. Acute choledocholithiasis can also present with marked transaminase elevation mimicking severe hepatocellular injury, contrary to the presumed cholestatic pattern. We searched PubMed/Medline, EMBASE, Cochrane Library, and Google Scholar for studies reporting the proportion of marked elevation of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 1000IU/L in patients with common bile duct (CBD) stones. A proportion meta-analysis with a corresponding 95% confidence interval (CI) was used to pool the proportion of patients with extreme transaminase elevation. I2 was used to examine heterogeneity. We used CMA software utilizing a random effect model for statistical analysis. Three studies (n = 1328 patients) were included in our analysis. The reported frequency of ALT or AST > 1000IU/L in choledocholithiasis patients ranged between 6 and 9.6%, with pooled frequency of 7.8% (95% CI 5.5-10.8%, I2 61%). The frequency of patients with ALT or AST > 500IU/L was higher, ranging between 28 and 47%, with pooled frequency of 33.1% (95% CI 25.3-42%, I2 88%). This is the first meta-analysis to study prevalence of severe hepatocellular injury in patients with CBD stones. Results revealed that approximately one-third of patients with choledocholithiasis present with ALT or AST > 500IU/L. Furthermore, levels > 1000IU/L are not uncommon. An elaborate work-up for alternative etiologies of severe transaminase elevation is likely unwarranted in cases with clear evidence of choledocholithiasis.

Severity of Hepatocyte Damage and Prognosis in Cirrhotic Patients Correlate with Hepatocyte Magnesium Depletion.

We aimed to evaluate the magnesium content in human cirrhotic liver and its correlation with serum AST levels, expression of hepatocellular injury, and MELDNa prognostic score. In liver biopsies obtained at liver transplantation, we measured the magnesium content in liver tissue in 27 cirrhotic patients (CIRs) and 16 deceased donors with healthy liver (CTRLs) by atomic absorption spectrometry and within hepatocytes of 15 CIRs using synchrotron-based X-ray fluorescence microscopy. In 31 CIRs and 10 CTRLs, we evaluated the immunohistochemical expression in hepatocytes of the transient receptor potential melastatin 7 (TRPM7), a magnesium influx chanzyme also involved in inflammation. CIRs showed a lower hepatic magnesium content (117.2 (IQR 110.5-132.9) vs. 162.8 (IQR 155.9-169.8) μg/g; p < 0.001) and a higher percentage of TRPM7 positive hepatocytes (53.0 (IQR 36.8-62.0) vs. 20.7 (10.7-32.8)%; p < 0.001) than CTRLs. In CIRs, MELDNa and serum AST at transplant correlated: (a) inversely with the magnesium content both in liver tissue and hepatocytes; and (b) directly with the percentage of hepatocytes stained intensely for TRPM7. The latter also directly correlated with the worsening of MELDNa at transplant compared to waitlisting. Magnesium depletion and overexpression of its influx chanzyme TRPM7 in hepatocytes are associated with severity of hepatocyte injury and prognosis in cirrhosis. These data represent the pathophysiological basis for a possible beneficial effect of magnesium supplementation in cirrhotic patients.

Rapid Clinical Resolution in Patients with Indeterminate Pediatric Liver Failure and Immune Dysregulation Hepatitis Treated with Ruxolitinib

IntroductionIndeterminate pediatric acute liver failure (iPALF) is a rare, life-threatening diagnosis associated with high rates of liver transplant and reduced survival. Immune dysregulation hepatitis shares many of the same clinical features as iPALF but is defined by an INR ≤ 1.5. Both present with progressive new-onset hepatocellular injury with predominant cytotoxic T-cell mediated inflammation and diffuse cytokine release. Importantly, the optimal medical therapy for these conditions of severe hepatic injury is not known. Here, we present two pediatric cases of steroid-refractory liver dysfunction where use of ruxolitinib, a JAK-STAT pathway inhibitor, led to significant clinical improvement. Case DescriptionsA 12-year-old male (patient A) presented with iPALF, while a 7-year-old female (patient B) presented with immune dysregulation hepatitis. Both patients had coagulopathy, transaminitis and hyperbilirubinemia (Table 1). Ischemia, toxin exposure, autoimmune hepatitis, and infection screens were negative. Immune evaluation demonstrated significantly elevated soluble IL-2 receptor, CXCL9, and sCD163, with mild hyperferritinemia (Table 1). Patient B had IgM EBV antibodies on repeat testing, which may have contributed to her immune dysregulation. Each patient’s next generation sequencing for inborn errors of immunity were negative. Both liver biopsies revealed a cytotoxic T-cell infiltrate, activated Kupffer cells, absence of iron, and absent plasma cell activity. During initial management, patient A received methylprednisolone 2 mg/kg daily, while patient B received 10 mg/kg daily before weaning to 2 mg/kg daily. Steroid-refractory disease was highlighted by ongoing liver damage on serial labs with worsening jaundice and fatigue. Both patients were transitioned to JAK-STAT inhibition with ruxolitinib. Patient A was loaded with 10 mg BID for one week before transitioning to 5 mg BID for 3 months, while patient B started and remained on 5 mg BID for 4 months. Both patients experienced rapid clinical improvement within one week and normalization of immune dysregulation on serial lab work by one month without need for further invasive interventions. Therapy was well tolerated without infectious or thrombotic complications.Table 1Maximum lab values prior to ruxolitinib initiationSoluble IL-2R (175.3–858.2 pg/mL)CXCL9 (< = 647 pg/mL)sCD163(<991 ng/mL)Ferritin (7–271 ng/mL)INRAST (< =60 U/L)ALT (10–49 U/L)Total Bilirubin (0.2–1.0 mg/dL)Patient A8664199731 0965971.62226275815.6Patient B243615 41881994291.43010228411.4Table 1. (abstract: 96) Selected laboratory test results. Values below or above reference are indicated with blue and red respectively. Not shown: IL-2, IL-4, IL-5, IL-8, IL-12, IL-13, IL-17 were normal. Fecal blood testing at baseline was negative. T cell memory population percentages were normal. T cell proliferation studies were normal. Pre-SCIG = pre-subcutaneous IgG (SCIG) treatment. Post-SCIG = post-SCIG treatment sample obtained after ~4 months of SCIG. n/a = sample not available. ConclusionThese cases suggest in iPALF and severe acute hepatitis where immune dysregulation is present, JAK-STAT inhibition may have benefit and deserves consideration for preventing disease progression and reducing morbidity and mortality.

Serum keratin 18-M65 levels detect progressive forms of alcohol-associated liver disease in early noncirrhotic stages.

The progression of alcohol-associated liver disease (ALD) in its early precirrhotic stages can be a silent process. Serum keratin 18 levels (K18-M65) predict severe events and mortality in advanced stages of ALD, but data on this biomarker in early stages are scarce. We evaluated the diagnostic accuracy of K18-M65 levels in identifying early forms of ALD. We prospectively evaluated two cohorts of actively drinking patients with alcohol use disorder (AUD) following a rehabilitation program (training (n = 162) and validation (n = 78)) and matched healthy controls (n = 21). Clinical, laboratory, and imaging data were used to distinguish AUD patients with simple steatosis (minimal ALD) and steatohepatitis/fibrosis (early ALD). We measured serum K18-M65 levels and assessed their ability to predict early ALD. High levels of K18-M65 characterized AUD patients with early ALD, while levels in the minimal ALD group were similar to those in healthy controls. K18-M65 levels distinguished minimal liver disease from early ALD (AUROC = 0.8704; p < 0.0001) with an optimal cutoff at 265.9 U/L. K18-M65 levels strongly correlated with transaminases and predicted early ALD (OR 25.81; 95% CI 3.166-336.1; p < 0.0001), controlled attenuation parameter, and liver stiffness independently from transaminases and other potential confounders. K18-M65 levels did not discriminate between fibrosis and steatohepatitis but correlated with histological signs of hepatocellular injury and inflammation (all p < 0.05). The K18-M65 cutoff detected early ALD in the validation cohort with high accuracy (sensitivity 86.67%, specificity 96.67%) and a very high positive likelihood ratio (28.6; 95% CI 4.14-197.73). Serum K18-M65 levels can be used as a biomarker to detect early ALD stages with excellent predictive value.

Biomolecular map of albumin identifies signatures of severity and early mortality in acute liver failure

Acute liver failure (ALF) is associated with high mortality. Alterations in albumin structure and function have been shown to correlate with outcomes in cirrhosis. We undertook a biomolecular analysis of albumin to determine its correlation with hepatocellular injury and early mortality in ALF. Altogether, 225 participants (200 patients with ALF and 25 healthy controls [HC]) were enrolled. Albumin was purified from the baseline plasma of the training cohort (ALF, n= 40; survivors, n= 8; non-survivors, n= 32; and HC, n= 5); analysed for modifications, functionality, and bound multi-omics signatures; and validated in a test cohort (ALF, n= 160; survivors, n= 53; non-survivors, n= 107; and HC, n= 20). In patients with ALF, albumin is more oxidised and glycosylated with a distinct multi-omics profile than that in HC, more so in non-survivors (p <0.05). In non-survivors, albumin was more often bound (p <0.05, false discovery rate <0.01) to proteins associated with inflammation, advanced glycation end product, metabolites linked to arginine, proline metabolism, bile acid, and mitochondrial breakdown products. Increased bacterial taxa (Listeria, Clostridium, etc.) correlated with lipids (triglycerides [4:0/12:0/12:0] and phosphatidylserine [39:0]) and metabolites (porphobilinogen and nicotinic acid) in non-survivors (r2 >0.7). Multi-omics signature-based probability of detection for non-survival was >90% and showed direct correlation with albumin functionality and clinical parameters (r2 >0.85). Probability-of-detection metabolites built on the top five metabolites, namely, nicotinic acid, l-acetyl carnitine, l-carnitine, pregnenolone sulfate, and N-(3-hydroxybutanoyl)-l-homoserine lactone, showed diagnostic accuracy of 98% (AUC 0.98, 95% CI 0.95-1.0) and distinguish patients with ALF predisposed to early mortality (log-rank <0.05). On validation using high-resolution mass spectrometry and five machine learning algorithms in test cohort 1 (plasma and paired one-drop blood), the metabolome panel showed >92% accuracy/sensitivity and specificity for prediction of mortality. In ALF, albumin is hyperoxidised and substantially dysfunctional. Our study outlines distinct 'albuminome' signatures capable of distinguishing patients with ALF predisposed to early mortality or requiring emergency liver transplantation. Here, we report that the biomolecular map of albumin is distinct and linked to severity and outcome in patients with acute liver failure (ALF). Detailed structural, functional, and albumin-omics analysis in patients with ALF led to the identification and classification of albumin-bound biomolecules, which could segregate patients with ALF predisposed to early mortality. More importantly, we found albumin-bound metabolites indicative of mitochondrial damage and hyperinflammation as a putative indicator of <30-day mortality in patients with ALF. This preclinical study validates the utility of albuminome analysis for understanding the pathophysiology and development of poor outcome indicators in patients with ALF.

Chrysin and its nanoliposome ameliorated non-alcoholic steatohepatitis via inhibiting TLR4 signalling pathway.

Non-alcoholic steatohepatitis (NASH) is a chronic liver disease histologically characterized by liver steatosis, hepatocellular injury, inflammation and fibrosis, resulting in cirrhosis and hepatocellular carcinoma, but effective measures and obvious pathogenesis for NASH remain elusive. Chrysin (CH) has been reported to have anti-inflammatory effects but shows lower bioavailability. In this study, a chrysin nanoliposome (CH-NL) was first prepared and characterized. Then, we used the methionine-choline-deficient (MCD) diet to induce a mouse model of NASH. Finally, the effects of CH and CH-NL on NASH were evaluated in the liver of NASH mice. The results showed that CH or CH-NL significantly reduced the accumulation of lipids in hepatocytes, alleviated liver injury, decreased the generation of radical oxygen species, and attenuated the accumulation of collagen fibre in the liver of NASH mice. In addition, CH and its nano-liposomes markedly inhibited the production of inflammatory cytokines and inflammatory cell infiltration in the liver of NASH mice. Further studies found that CH-NL and CH-NL downregulated the MCD diet-induced activation of Toll-like receptor 4 (TLR4) signalling pathway in the liver of mice. CH and its nanoliposome alleviated MCD diet-induced NASH in mice, which might be through inhibiting TLR4 signalling pathway.

COVID-19 related biliary injury: A review of recent literature

Since its emergence in 2019, it has become apparent that coronavirus 2019 (COVID-19) infection can result in multi systemic involvement. In addition to pulmonary symptoms, hepatobiliary involvement has been widely reported. Extent of hepatic involvement ranges from minor elevation in liver function tests (LFTs) to significant hepatocellular or cholestatic injury. In majority of cases, resolution of hepatic injury or improvement in LFTs is noted as patients recover from COVID-19 infection. However, severe biliary tract injury progressing to liver failure has been reported in patients requiring prolonged intensive care unit stay or mechanical ventilation. Due to the timing of its presentation, this form of progressive cholestatic injury has been referred to as COVID-19 cholangiopathy or post-COVID-19 cholangiopathy, and can result in devastating consequences for patients. COVID-19 cholangiopathy is recognized by dramatic elevation in serum alkaline phosphatase and bilirubin and radiologic evidence of bile duct injury. Cholangiopathy in COVID-19 occurs weeks to months after the initial infection and during the recovery phase. Imaging findings and pathology often resemble bile duct injury associated with primary or secondary sclerosing cholangitis. Etiology of COVID-19 cholangiopathy is unclear. Several mechanisms have been proposed, including direct cholangiocyte injury, vascular compromise, and cytokine release syndromes. This review summarizes existing data on COVID-19 cholangiopathy, including reported cases in the literature, proposed pathophysiology, diagnostic testing, and long-term implications.

Absence of Increased Susceptibility to Acetaminophen-Induced Liver Injury in a Diet-Induced NAFLD Mouse Model.

Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease and its influence on drug-induced liver injury (DILI) is not fully understood. We investigated whether NAFLD can influence acetaminophen (APAP [N-acetyl-p-aminophenol])-induced hepatotoxicity in a diet-induced obese (DIO) mouse model of NAFLD. The male C57BL/6NTac DIO mice, fed a high-fat diet for more than 12 weeks, developed obesity, hyperinsulinemia, impaired glucose tolerance, and hepatomegaly with hepatic steatosis, similar to human NAFLD. In the acute toxicity study after a single dose of APAP (150 mg/kg), compared with control lean mice, the DIO mice had decreased serum transaminase levels and less severe hepatocellular injury. The DIO mice also had altered expression of genes related to APAP metabolism. Chronic APAP exposure for 26 weeks did not predispose the DIO mice with NAFLD to more severe hepatotoxicity compared with the lean mice. These results suggested that the C57BL/6NTac DIO mouse model appears to be more tolerant to APAP-induced hepatotoxicity than lean mice, potentially related to altered xenobiotic metabolizing capacity in the fatty liver. Further mechanistic studies with APAP and other drugs in NAFLD animal models are necessary to investigate the mechanism of altered susceptibility to intrinsic DILI in some human NAFLD patients.

Antioxidant and hepatoprotective activities of methanolic extract of Fimbristylis miliacea (L.) Vahl

BackgroundFimbristylis miliacea (Cyperaceae) is a grass like herb, widely used in traditional medicine. In our previous study, this plant demonstrated promising in vitro antioxidant activities. The present work evaluated antioxidant and hepatoprotective activities of methanolic extract of F. miliacea through in vivo studies. MethodsThe overall study was structured involving CCl4 toxicant mice model for antioxidant and hepatoprotective effects. Three different doses of 100, 200 and 400 mg/kg.bw were administered to mice. HPLC-DAD was performed for chemical characterization of methanolic extract of F. miliacea. ResultsMethanolic extract of F. miliacea increased superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and decreased malondialdehyde (MDA) level in liver, kidney and brain. Concentrations of liver marker enzymes including alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and bilirubin in serum were also reduced and restored to normal level after extract administration. Liver histopathology showed recovery of hepatocellular injury after administration of plant extract. In HPLC, ten polyphenolic compounds were detected including caffeic acid and kaempferol, both at high concentrations. ConclusionThe study indicated that F. miliacea has antioxidant and hepatoprotective potentials and contains potential bioactive compounds.

Effect of Nutmeg on Transaminase Activities in Liver and Serum of Adult Wistar rats

This study examines the activities of alanine aminotransaminase (ALT) and aspartate aminotransferase (AST) in the liver of 30 adult Wistar rats exposed to nutmeg for 30 days. 1 g of nutmeg was administered to group A (n=10), 2 g of nutmeg to group B (n=10) and group C (n=10) was used as the control. Enzyme activities were assayed in both serum and liver (tissue homogenate) spectrophotometrically. Results obtained showed a significant increase (p &lt; 0.05) in level of AST in serum of rats in group A and B (20.2±7.29 and 23.2 ± 3.27 U/L) when compared to the control group (14.8± 1.78 U/L) while serum ALT level was significantly reduced (5.2± 1.78 and 4.2 ± 0.04 U/L) compared to the control group (7.0 ± 2.6 U/L) but the differences based on dosage was statistically insignificant (p≥ 0.05). The enzyme activities in liver tissue homogenate showed a significant increase (p˂ 0.05) in AST levels (13.8 ± 1.14, 14.6 ± 1.78 and 12.8 ± 0.08 U/L) among test groups and between controls but ALT levels though lower in treated groups than control, was statistically insignificant (p≥ 0.05) among test and between control group (4.6 ± 1.34, 4.0 ± 0.08 and 5.8 ± 0.03 U/L). Differences in enzyme activities due to nutmeg administration may lead to hepatocellular injury as well as myocardial infarction. The results suggests that dosage and long-term consumption of nutmeg could have severe health implication as it affects liver function as well as other associated organ of the body.

Propofol/dexmedetomidine Versus Desflaurane Effects on Post Hepatectomy Hepatocellular Injury

ABSTRACT Objective The Pringle maneuver used during hepatectomy causes ischemic reperfusion injury to the liver remnant. In this study, we compared the effect of maintenance of general anesthesia with propofol dexmedetomidine intravenous infusion versus desflurane inhalational anesthesia on post-hepatectomy hepatocellular injury in patients undergoing partial hepatectomy during the first six postoperative days. Methods Group A (15 patients) received total intravenous anesthesia with a combination of propofol and dexmedetomidine for anesthesia maintenance, and group B (15 patients) received desflurane for anesthesia maintenance. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum albumin, serum bilirubin, prothrombin time (PT), and international normalized ratio (INR) were measured before surgery and at 1, 3, and 6 days after surgery. Results Transaminase levels, which were comparable in both groups, peaked between the first and the third postoperative days. The peak ALT was 224.27 ± 29.7 and 318.20 ± 52.5 U/L in group A and group B, respectively (P < 0.001). The peak AST was 265.60 ± 22.3 U/L in group A and 349.27 ± 56.1 U/L in group B (P < 0.001). Albumin levels at day 1 showed no significant differences between both groups, but at days 3 and 6, group A showed significantly higher albumin levels than group B. Other liver function tests including serum albumin, total and direct bilirubin, PT, and INR showed lower values in the propofol/dexmedetomidine group. Conclusion The main finding of this study is that propofol/dexmedetomidine as a technique for the maintenance of anesthesia resulted in less hepatocellular injury and better hepatic functions than desflurane in patients undergoing partial hepatectomy during the first six postoperative days.

Variations in Biodistribution and Acute Response of Differently Shaped Titania Nanoparticles in Healthy Rodents

Titanium dioxide nanoparticles (TiO2 NPs) are one of the main sources of the nanoparticulate matter exposure to humans. Although several studies have demonstrated their potential toxic effects, the real nature of the correlation between NP properties and their interaction with biological targets is still far from being fully elucidated. Here, engineered TiO2 NPs with various geometries (bipyramids, plates, and rods) have been prepared, characterized and intravenously administered in healthy mice. Parameters such as biodistribution, accumulation, and toxicity have been assessed in the lungs and liver. Our data show that the organ accumulation of TiO2 NPs, measured by ICP-MS, is quite low, and this is only partially and transiently affected by the NP geometries. The long-lasting permanence is exclusively restricted to the lungs. Here, bipyramids and plates show a higher accumulation, and interestingly, rod-shaped NPs are the most toxic, leading to histopathological pulmonary alterations. In addition, they are also able to induce a transient increase in serum markers related to hepatocellular injury. These results indicate that rods, more than bipyramidal and spherical geometries, lead to a stronger and more severe biological effect. Overall, small physico-chemical differences can dramatically modify both accumulation and safety.

Polyphenols and pectin enriched golden kiwifruit (Actinidia chinensis) alleviates high fructose-induced glucolipid disorders and hepatic oxidative damage in rats: in association with improvement of fatty acids metabolism

This study aimed to investigate the protective effects of fleshes from two Actinidia chinensis (ACF), pericarps from two A. chinensis (ACP), and fleshes with pericarps from two A. chinensis (ACFP) on high fructose (HF)-instigated dyslipidemia, hepatic steatosis, oxidative stress, insulin resistance, and fatty acid metabolism disorders in rats. In general, the above abnormalities were improved after 10 weeks intervention of ACF, ACP, and ACFP. Especially, ACFP considerably ameliorated HF-induced abnormal changes in body weight gain, serum TC, TG, LDL-C and HDL-C levels, as well as serum and hepatic SFAs, MUFAs and PUFAs contents. ACFP also alleviated HF-induced hyperglycemia and hyperinsulinemia, stabilized HF-caused increase in hepatic MDA and serum ALT, AST levels, and restored HF-declined hepatic T-SOD and GSH-Px activities. Besides, histopathology of the liver further endorsed the protective effects of ACFP on hepatocellular injury. Moreover, ACFP increased HF-dropped acetic, propionic and butyric acid levels. Overall, ACFP employs more efficacious protective effects against HF-induced metabolic disorders and liver damage than ACF and ACP. This study delivers a scientific foundation for developing kiwifruit (counting peel)-based dietary supplements for those with glucolipid-metabolic disorders and liver damage.

Doxofylline ameliorates liver fibrosis by regulating the ferroptosis signaling pathway.

Liver fibrosis, a compensatory repair response to chronic liver injury, is caused by various pathogenic factors, and hepatic stellate cell (HSC) activation and phenotypic transformation are regarded as key events in its progression. Ferroptosis, a novel form of programmed cell death, is also closely related to different pathological processes, including those associated with liver diseases. Here, we investigated the effect of doxofylline (DOX), a xanthine derivative with potent anti-inflammatory activity, on liver fibrosis as well as the associated mechanism. Our results indicated that in mice with CCl4-induced liver fibrosis, DOX attenuated hepatocellular injury and the levels of liver fibrosis indicators, inhibited the TGF-β/Smad signaling pathway, and significantly downregulated the expression of HSC activation markers, both in vitro and in vivo. Furthermore, inducing ferroptosis in activated HSCs was found to be critical for its anti-liver fibrosis effect. More importantly, ferroptosis inhibition using the specific inhibitor, deferoxamine (DFO) not only abolished DOX-induced ferroptosis, but also led to resistance to the anti-liver fibrosis effect of DOX in HSCs. In summary, our results showed an association between the protective effect of DOX against liver fibrosis and HSC ferroptosis. Thus, DOX may be a promising anti-hepatic fibrosis agent.

High-fat diet increases mortality and intensifies immunometabolic changes in septic mice

Immunometabolic changes in the liver and white adipose tissue caused by high-fat (HF) diet intake may worse metabolic adaptation and protection against pathogens in sepsis. We investigate the effect of chronic HF diet (15 weeks) on mortality and immunometabolic responses in female mice after sepsis induced by cecum ligation and perforation (CLP). At week 14, animals were divided into four groups: sham C diet, sepsis C diet (C-Sp), sham HF diet (HF-Sh) and sepsis HF diet (HF-Sp). The surviving animals were euthanized on the 7th day. The HF diet decreased survival rate (58.3% vs. 76.2% C-Sp group), increased serum cytokine storm (IL-6 [1.41 ×; vs. HF-Sh], IL-1β [1.37 ×; vs. C-Sp], TNF [1.34 ×; vs. C-Sp and 1.72 ×; vs. HF-Sh], IL-17 [1.44 ×; vs. HF-Sh], IL-10 [1.55 ×; vs. C-Sp and 1.41 ×; HF-Sh]), white adipose tissue inflammation (IL-6 [8.7 ×; vs. C-Sp and 2.4 ×; vs. HF-Sh], TNF [5 ×; vs. C-Sp and 1.7 ×; vs. HF-Sh], IL-17 [1.7 ×; vs. C-Sp], IL-10 [7.4 ×; vs. C-Sp and 1.3 ×; vs. HF-Sh]), and modulated lipid metabolism in septic mice. In the HF-Sp group liver's, we observed hepatomegaly, hydropic degeneration, necrosis, an increase in oxidative stress (reduction of CAT activity [−81.7%; vs. HF-Sh]; increase MDA levels [82.8%; vs. HF-Sh], and hepatic IL-6 [1.9 ×; vs. HF-Sh], and TNF [1.3 × %; vs. HF-Sh]) production. Furthermore, we found a decrease in the total number of inflammatory, mononuclear cells, and in the regenerative processes, and binucleated hepatocytes in a HF-Sp group livers. Our results suggested that the organism under metabolic stress of a HF diet during sepsis may worsen the inflammatory landscape and hepatocellular injury and may harm the liver regenerative process.