Increased Serum Alanine Aminotransferase Research Articles

Hepatoprotective effect of jojoba oil against lead-induced toxicity in rats

Background Previous investigations showed that jojoba oil exhibited a protective effect against hepatotoxicity caused by different toxicants, however, to the best of our knowledge, no prior research has been done to determine the effectiveness of jojoba oil in protecting against lead toxicity. Objective This study assessed the hepatoprotective properties of jojoba oil against lead toxicity in rats. Materials and methods The study included four groups, each consisting of six Sprague Dawley male rats, and orally administered jojoba oil (JO group), lead acetate (LA group), and lead acetate plus jojoba oil (protective group) Results and conclusion The results showed that lead acetate-induced hepatotoxic effects were revealed by increased serum alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase activities with hepatic histomorphological changes. There was a significant increase in serum total cholesterol, triglycerides, and low-density lipoprotein-cholesterol, while levels of high-density lipoprotein-cholesterol significantly declined compared to normal rats. Additionally, lead acetate triggered oxidative damage of hepatocytes, evidenced by a significant increase of malondialdehyde levels and a decrease of reduced glutathione levels and activities of superoxide dismutase and glutathione S-transferase. Administration of lead was associated with a change in the distribution of cells over different cell cycle phases, characterized by a marked increase in the sub G1 cell population and a significant decrease in the G0/G1 cell population. Supplementation of jojoba oil with lead acetate relieved the toxic impacts of lead acetate with an enhancement of the liver enzyme activities, antioxidant status, lipid profile parameters, and histopathological alterations. In conclusion, jojoba oil might be an effective natural product that offers a promising preventive action towards lead-induced liver damage in rats.

Causal associations between liver enzymes and diabetic microvascular complications: A univariable and multivariable Mendelian randomization.

Observational studies show that liver enzymes are diabetes risk factors. However, previous observational investigations on the relationship between liver enzymes and diabetic microvascular complications produced contradictory results. The purpose of this research is to examine the independent causal effects of liver enzymes on diabetic microvascular complications. Univariable Mendelian randomization (UVMR) and multivariable Mendelian randomization (MVMR) were utilized to disentangle the causal effects. The genome-wide association study (GWAS) summary-level statistics were collected from the UK biobank and the FinnGen consortium. Single nucleotide polymorphisms (SNPs) were selected as genetic instruments with genome-wide significance (p < 5 ×10-8). Five UVMR approaches, including inverse variance weighted (IVW), Bayesian weighted Mendelian randomization, MR-Pleiotropy Residual Sum and Outlier (MR-PRESSO), weighted median, and MR-Egger, and three MVMR approaches, including the extended versions of IVW, MR-Egger, and the Q-minimization methods, were performed to evaluate the causal effects. The robustness of the MR results was further confirmed using several sensitivity analyses. UVMR revealed that a genetically predisposed per standard deviation increase in serum alanine aminotransferase (ALT) level increased the risk of diabetic retinopathy (DR) in type 2 diabetes mellitus (T2DM) (IVW OR = 1.489, 95% CI = 1.206-1.772, p = 0.006). Likewise, serum aspartate aminotransferase (AST) levels showed similar results (IVW OR = 1.376, 95% CI = 1.115-1.638, p = 0.017). Furthermore, these effects were consistent after controlling for glycemia and blood pressure using MVMR analysis. Additionally, sensitivity analyses further strengthened the causality. However, no significant associations were found between alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), and diabetic microvascular complications. Robust evidence was demonstrated for an independent causal effect of serum ALT or AST concentration on the risk of DR in T2DM. Further investigations are necessary to elucidate the potential biological mechanisms and confirm their clinical significance for early prevention and intervention.

ROLE OF EMBLICA OFFICINALIS IN COPPER INDUCED LIVER TOXICITY IN ADULT ALBINO RATS

Background: Copper (Cu) is an important heavy metal used widely in all industries. However, its toxicity on various organs is established. Emblica officinalis, commonly known as Amla, is a potential antioxidant and can prevent Cu induced hepatotoxicity. &#x0D; Objective: To evaluate the effects of Emblica officinalis extract on liver histology and Alanine Aminotransferase (ALT) levels after Cu induced toxicity on adult albino rats.&#x0D; Methods: This was an experimental study of 28 days duration. 36 adult male albino rats were divided into three groups of twelve animals each. Group A was control group in which rats were given 1.5 ml normal saline while group B rats were given CuSO4 200mg/kg b.w./day. Rats in Group C were given both CuSO4 (200mg/kg b.w/day) and Emblica officinalis fruit extract (300mg/kg bw/day). The agents were fed via orogastric tube for four weeks and rats were sacrificed 24 hours after administration of last dose.&#x0D; Results: Cu treated rats showed necrosis of hepatocytes and Increased serum ALT levels. Emblica officinalis co-treatment attenuated Cu-induced hepatic necrosis and variation in ALT levels. The difference among the groups was statistically significant with p-value &lt;0.05.&#x0D; Conclusion: Emblica officinalis fruit extract improves liver function in Cu induced hepatotoxicity by limiting oxidative damage.

Hepatoprotective Effect of Alcoholic Extract of Ficus carica Leaves ‎Against ‎‎Cypermethrin-Induced Liver Toxicity in Male Albino Rats

Cypermethrin (CYP), a synthetic pyrethroid, is recognized for its insecticidal properties but ‎poses potential risks of hepatotoxicity. In traditional medicine, Ficus (F.) carica (common ‎fig) leaves have historically been used for various therapeutic applications. This study ‎aimed to evaluate the hepatoprotective effect of the methanolic extract of F. carica‎‎ leaves ‎against CYP-induced liver damage in adult male albino rats (Rattus norvegicus). The ‎animals (n=30), 8-12 weeks old ‎and weighing 200-250 g‎, were randomly divided into five ‎experimental groups (n=6) and treated as follows: the negative control group received ‎distilled water; the CYP-Only group was exposed to 4.74 mg/kg BW for 45 days; the ‎CYP+post-treatment group received the same CYP dosage followed by F. carica‎‎ methanolic ‎leaf extract at 500 mg/kg BW orally for two weeks; the pre-treatment+CYP group received ‎ ‎F. carica‎‎ methanolic leaf extract at 500 mg/kg BW orally for two weeks followed by CYP ‎exposure for 45 days; and the F. carica‎‎ extract-Only group was administered the methanolic ‎leaf extract at 500 mg/kg BW orally for two weeks. At the end of the experiment, serum and ‎liver samples were analyzed for biochemical and histopathological changes. CYP-Only ‎exposed group showed significantly increased serum alanine aminotransferase (ALT) and ‎alkaline phosphatase (ALP) and caspase-3 levels (P&lt;0.05). Histopathological examination ‎in group exposed CYP only revealed liver damages as evidenced by central vein congestion, ‎scattered perivascular mononuclear cell infiltration, prominence of ‎Kupffer cells, nuclear ‎pyknosis, and severe hepatocytic necrosis. Treatment with F. carica‎‎ leaf extract, either ‎before or after CYP exposure, as well as solely with F. carica‎‎ leaf ‎‎extract, ameliorated both ‎the biochemical and histological indices of liver ‎damage. The findings suggest that the ‎methanolic extract of F. carica‎‎ leaves provides promising hepatoprotective effects against ‎CYP-induced liver damage in albino rats, likely via its antioxidative properties‎‎.

Prevalence and clinical relevance of liver dysfunction after thoracic surgery: a retrospective study

Postoperative elevation of serum aminotransferase or alkaline phosphatase levels after liver and heart surgeries has been widely reported. The prevalence and clinical significance of hypertransaminasemia/liver dysfunction after thoracic surgery remains largely unknown. Significant differences in surgical procedures between thoracic and extra-thoracic surgeries may suggest different risks of liver dysfunction. We retrospectively analyzed data from 224 consecutive patients who underwent thoracic surgery. Liver function tests were recorded the day before surgery, 12 h, 1 day, 5, and 10 days after the surgical procedure. Patients were studied to identify the frequency of hypertransaminasemia and/or hyperbilirubinemia and/or increase of INR levels. 37,5% of patients showed an increase in serum alanine aminotransferase (ALT) level after thoracic surgery, whereas an increase in gamma glutamyl transferase (GGT) serum levels of any grade was observed in 53,6% of patients. Approximately 83% of patients who experienced an increase in the serum GGT or ALT levels showed a grade 1 or 2 change. Operative time was associated with hypertransaminasemia in the univariate and multivariate analyses, whereas the use of metformin was associated with a lower risk of ALT increase.

FRI037 Time-restricted Feeding Prevents Progression Of Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis Through IPMK

Abstract Disclosure: I. Jung: None. F. Anokye-Danso: None. S. Jin: None. R.S. Ahima: None. S. Kim: None. Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide, with a broad spectrum ranging from simple steatosis to advanced stage of nonalcoholic steatohepatitis (NASH). Although many clinical trials for NAFLD treatment are undergoing, there are currently no approved therapies. Insulin resistance is central to the progression of NAFLD and implicated in disease progression from steatosis to NASH. Therefore, modulation of insulin resistance represents a potential strategy for NAFLD treatment. We have reported that inositol polyphosphate multikinase (IPMK), a key enzyme in inositol polyphosphate biosynthesis, plays a role in regulating hepatic insulin signaling and gluconeogenesis both in vitro and in vivo. However, the roles of IPMK in hepatic lipid metabolism were not investigated. To determine the role of IPMK in NAFLD/NASH, we fed high fat diet (HFD) or methionine-choline deficient diet (MCDD) in both wild type (WT) and liver-specific IPMK knockout (LKO) mice. We also examined the effect of time-restricted feeding (TRF), which is known to be beneficial for metabolic disease without influencing the food intake, in NAFDL/NASH. Here, we show that hepatic IPMK protein was decreased in WT mice fed a MCDD compared to a normal chow diet (ND) and loss of IPMK in the liver augments hepatic steatosis and steatohepatitis in mice fed a HFD as well as MCDD. Compared to the WT mice, triglycerides (TG) and pro-inflammatory gene expression in the liver increase significantly in the LKO mice fed HFD. Importantly, MCDD-fed LKO mice exhibit exacerbated NAFLD/NASH accompanied by an increase in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), hepatic TG accumulation and fibrosis, and pro-inflammatory gene expression. Finally, TRF by limiting a food access only during the dark cycle led to an increase in expression hepatic IPMK protein in MCDD mice. Importantly, TRF alleviates NAFLD/NASH reflected by reduced hepatic TG accumulation, lowered serum ALT and AST levels, downregulated pro-inflammatory gene expression compared with ad libitum mice. Our results demonstrate that loss of IPMK mediates the progression of NAFLD/NASH and may be potentially targeted for treatment of NAFLD/NASH. Presentation: Friday, June 16, 2023

Loss of carnitine palmitoyltransferase 1a reduces docosahexaenoic acid-containing phospholipids and drives sexually dimorphic liver disease in mice

Background and aimsGenome and epigenome wide association studies identified variants in carnitine palmitoyltransferase 1a (CPT1a) that associate with lipid traits. The goal of this study was to determine the role of liver-specific CPT1a on hepatic lipid metabolism. Approach and resultsMale and female liver-specific knockout (LKO) and littermate controls were placed on a low-fat or high-fat diet (60% kcal fat) for 15 weeks. Mice were necropsied after a 16 h fast, and tissues were collected for lipidomics, matrix-assisted laser desorption ionization mass spectrometry imaging, kinome analysis, RNA-sequencing, and protein expression by immunoblotting. Female LKO mice had increased serum alanine aminotransferase levels which were associated with greater deposition of hepatic lipids, while male mice were not affected by CPT1a deletion relative to male control mice. Mice with CPT1a deletion had reductions in DHA-containing phospholipids at the expense of monounsaturated fatty acids (MUFA)-containing phospholipids in whole liver and at the level of the lipid droplet (LD). Male and female LKO mice increased RNA levels of genes involved in LD lipolysis (Plin2, Cidec, G0S2) and in polyunsaturated fatty acid metabolism (Elovl5, Fads1, Elovl2), while only female LKO mice increased genes involved in inflammation (Ly6d, Mmp12, Cxcl2). Kinase profiling showed decreased protein kinase A activity, which coincided with increased PLIN2, PLIN5, and G0S2 protein levels and decreased triglyceride hydrolysis in LKO mice. ConclusionsLiver-specific deletion of CPT1a promotes sexually dimorphic steatotic liver disease (SLD) in mice, and here we have identified new mechanisms by which females are protected from HFD-induced liver injury.

In vivo evaluation of liver function by multimodal imaging in an alcohol-induced liver injury model.

Visually evaluating liver function is a hot topic in hepatology research. There are few reliable and practical visualization methods for evaluating the liver function in vivo in experimental studies. In this study, we established a multimodal imaging approach for in vivo liver function evaluation and compared healthy mice with chronic alcoholic liver injury (cALI) model mice to explore its potential applicability in experimental research. In vivo fluorescence imaging (IVFI) technology was utilized to visually represent the clearance of indocyanine green from the liver of both healthy mice and mice with cALI. The reserve liver function was evaluated via IVFI using the Cy5.5-galactosylated polylysine probe, which targets the asialoglycoprotein receptor of hepatocytes. Hepatic microcirculation was assessed through laser speckle perfusion imaging of hepatic blood perfusion. The liver microstructure was then investigated by in vivo confocal laser endomicroscopy imaging. Finally, hepatic asialoglycoprotein receptor expression, histology, and the levels of serum alanine aminotransferase and aspartate aminotransferase were measured. In vivo multimodal imaging results intuitively and dynamically showed that indocyanine green clearance [mean ± standard deviation (SD): 30.83±14.71, 95% confidence interval (CI): 20.3 to 41.35], the fluorescence signal intensity (mean ± SD: 1,217.92±117.63; 95% CI: 1,148.38 to 1,290.84) and fluorescence aggregation area (mean ± SD: 5,855.80±1,271.81; 95% CI: 5,051.57 to 6,653.88) of Cy5.5-galactosylated polylysine targeting the asialoglycoprotein receptor, and hepatic blood perfusion (mean ± SD: 1,494.86±299.33; 95% CI: 1,316.98 to 1,690.16) in model mice were significantly lower than those in healthy mice (all P<0.001). Compared to healthy mice, the model mice exhibited a significant decline in liver asialoglycoprotein receptor expression (mean ± SD: 219.03±16.34; 95% CI: 208.97 to 230.69; P<0.001), increased serum alanine aminotransferase (mean ± SD: 149.70±47.89 U/L; 95% CI: 81.75 to 128.89; P=0.01) and aspartate aminotransferase levels (mean ± SD: 106.30±36.13 U/L; 95% CI: 122.01 to 180.17; P=0.021), hepatocyte swelling and deformation, disappearance of the hepatic cord structure, partial necrosis, and disintegration of hepatocytes. The imaging features of fluorescence signals in liver regions, hepatic blood perfusion and microstructure were biologically related to hepatic asialoglycoprotein receptor expression, serum indices of liver function, and histopathology in model mice. Utilizing in vivo multimodal imaging technology to assess liver function is a viable approach for experimental research, providing dynamic and intuitive visual evaluations in a rapid manner.

KDM2A Deficiency in the Liver Promotes Abnormal Liver Function and Potential Liver Damage.

Dysregulation of metabolic functions in the liver impacts the development of diabetes and metabolic disorders. Normal liver function can be compromised by increased inflammation via the activation of signaling such as nuclear factor (NF)-κB signaling. Notably, we have previously identified lysine demethylase 2A (KDM2A)-as a critical negative regulator of NF-κB. However, there are no studies demonstrating the effect of KDM2A on liver function. Here, we established a novel liver-specific Kdm2a knockout mouse model to evaluate KDM2A's role in liver functions. An inducible hepatic deletion of Kdm2a, Alb-Cre-Kdm2afl/fl (Kdm2a KO), was generated by crossing the Kdm2a floxed mice (Kdm2afl/fl) we established with commercial albumin-Cre transgenic mice (B6.Cg-Tg(Alb-cre)21Mgn/J). We show that under a normal diet, Kdm2a KO mice exhibited increased serum alanine aminotransferase (ALT) activity, L-type triglycerides (TG) levels, and liver glycogen levels vs. WT (Kdm2afl/fl) animals. These changes were further enhanced in Kdm2a liver KO mice in high-fat diet (HFD) conditions. We also observed a significant increase in NF-κB target gene expression in Kdm2a liver KO mice under HFD conditions. Similarly, the KO mice exhibited increased immune cell infiltration. Collectively, these data suggest liver-specific KDM2A deficiency may enhance inflammation in the liver, potentially through NF-κB activation, and lead to liver dysfunction. Our study also suggests that the established Kdm2afl/fl mouse model may serve as a powerful tool for studying liver-related metabolic diseases.

Safety of immune checkpoint inhibitors after proton beam therapy in head and neck mucosal melanoma: a case series.

Proton beam therapy (PBT) has shown promising efficacy in treating locally advanced head and neck mucosal melanoma despite its poor prognosis. Although PBT may improve the efficacy of subsequent immune checkpoint inhibitors (ICIs), the safety of ICIs in patients who have previously received PBT has not been established. Hence, this study evaluated the safety of ICIs in patients who had recurrent mucosal melanoma after PBT. Between April 2013 and June 2022, we retrospectively reviewed the medical records of patients diagnosed with cutaneous or mucosal melanoma at the National Cancer Center Hospital East. Seven patients were treated with ICIs after their head and neck mucosal melanoma (HNMM) recurred after PBT. Four of the seven patients experienced grade immune-related adverse events (irAEs). Due to irAE in the irradiation field, two patients had grade 3 hypopituitarism. Other grade 3 or higher irAEs included an increase in serum alanine aminotransferase in two patients and gastritis in one, and two patients discontinued ICI due to the irAEs. All irAEs were resolved with appropriate management. Although administering ICIs after PBT may increase the risk of irAEs, especially in the irradiation field, they appear manageable. These findings could help in the development of a treatment strategy for locally advanced HNMM that includes PBT and subsequent ICIs.

Protective Effect of Andropraphis Paniculata Aqueous Extract (EAAp) Against Isoniazid and Rifampicin-Induced Rat Liver Damage

Isoniazid (INH) and rifampicin (RIF) are first-line antituberculosis drugs (OAT) in tuberculosis treatment that are used for at least 6 months. The use of OAT has been associated with toxic reactions in the liver and causes hepatitis. This study aimed to determine the effect of an aqueous extract of Andrographis paniculata (EAAp) on liver damage induced by INH and RIF. Method: Male Sprague-Dawley rats weighing 250–300g were divided into 5 groups, each consisting of 6 mice. Animals were given isoniazid and rifampicin at 100 mg/kg, respectively, to induce liver damage, silymarin (25 mg/kg) for the positive control group, and Ap extract at doses of 200mg and 300 mg/kg for the test group. All treatments were given orally once daily for 28 days. Measurement of serum aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), bilirubin, and liver histopathology levels was carried out to determine the effect of EAAp on liver damage by INH and RIF. Results: Rats treated with INH+RIF were hepatotoxic, as evidenced by increased serum ALT, AST, and ALP activity, total bilirubin levels, and histopathological changes in the liver. Administration of Ap extract doses of 200 mg/kg and 300 mg/kg significantly decreased liver biochemical and histological changes caused by OAT. Conclusions: EAAp has a protective effect against hepatotoxic-induced INH and RIF in animal models.

Comparative study of carbohydrate levels on growth, oxidative stress and glucolipid metabolism of hybrid fish between Megalobrama amblycephala (♀) × Culter alburnus (♂) and Culter alburnus

The present study used hybrid fish (Megalobrama amblycephala ♀ × Culter alburnus ♂, abbreviated as BT) and topmouth culter (Culter alburnus, abbreviated as TC) as research subjects to assess and compare the effects of carbohydrate on the growth, oxidative stress and glucolipid metabolism of the two fish. The TC (initial weight, 13.10 ± 0.10 g) and BT (initial weight, 12.85 ± 0.13 g) were fed isonitrogenous (43% crude protein) and isolipidic (6.5% crude lipid) diets with carbohydrate levels of 10% (LC diet) and 30% (HC diet) for 11 weeks, respectively. The results showed that the HC diet resulted in a significant decrease in specific growth rate (SGR) of both fish. However, the SGR in BT was significantly higher than in TC, regardless of diet. Furthermore, HC diet significantly increased serum alanine transaminase (GPT) and hepatic malondialdehyde (MDA) content, decreased hepatic catalase (CAT) activity and resulted in increased hepatocyte volume, nucleus deficiency and nucleus deviation from the center of cytoplasm in both fish. However, BT had significantly higher glutathione peroxidase (GPx) activity and lower serum GPT and aspartate transaminase (GOT) content compared to TC. The HC diet induced significant increases in hepatosomatic index (HSI), liver lipid droplet area, liver glycogen, serum glucose (GLU) and triglyceride (TG) content in both fish. However, HSI and lipid droplet area were significantly higher in BT than in TC, while serum GLU and TG content were significantly lower in BT than in TC. Both fish can adapt to the HC diet by up-regulating the expression of glycolysis-related gene (glucokinase (gk)) and lipogenesis-related genes (acetyl-CoA carboxylase a (acca), fatty acid synthase (fas)). However, the expression levels of glucose transporter 2 (glut2), glycolysis-related gene (phosphofructokinase liver b (pfklb)) and lipogenesis-related genes (sterol regulatory element-binding protein 1 (srebp1), ATP citrate lyase a (aclya)) were increased only in BT fed HC diet. In summary, the BT liver has stronger glucose transport, glycolysis, and lipid tolerance compared to TC, thus exhibiting better glucose homeostasis and growth performance. It indicates that hybridization may help to produce new strain of fish with high carbohydrate utilization capacity.

Predictive factors to estimate the severity of nonalcoholic fatty liver disease in candidates for Roux-en-Y gastric bypass

ObjectivesNon-alcoholic fatty liver disease (NAFLD) is related to obesity, insulin resistance, dyslipidemia, and metabolic syndrome. The increasing prevalence of NAFLD results in a significant number of patients manifesting chronic liver disease over time. The aim of this study was to analyze the predictive factors to estimate NAFLD severity in patients who are candidates for Roux-en-Y gastric bypass. MethodsThis descriptive observational study was conducted with 136 obese patients who were candidates for Roux-en-Y gastric bypass and had mild, moderate, or severe NAFLD. ResultsSevere NAFLD was more prevalent among the men (P = 0.007), and mild NAFLD was more prevalent among the women (P = 0.007). Hyperferritinemia was observed in the group with severe NAFLD (P = 0.01). Neck circumference and waist-to-height ratio were associated with an increased risk when comparing the groups with mild and severe NAFLD and those with moderate and severe NAFLD (P = 0.023 and P = 0.001, respectively); the alanine aminotransferase (ALT) and aspartate aminotransferase ratio values were >1 (P = 0.002) in the same comparisons. The regression analyses showed that an increase of 1 ng/mL in vitamin D reduced the chances of severe steatosis by 10% (P = 0.043), and an increase of 1 U/L ALT increased the chances of severe steatosis by 13% (P = 0.002). ConclusionHigh neck circumference and low waist-to-height ratio values, male sex, hyperferritinemia, increased serum ALT values, and decreased vitamin D levels were related to the risk for severe NAFLD.

Disulfide-HMGB1 signals through TLR4 and TLR9 to induce inflammatory macrophages capable of innate-adaptive crosstalk in human liver transplantation

Ischemia-reperfusion injury (IRI) during orthotopic liver transplantation (OLT) contributes to graft rejection and poor clinical outcomes. The disulfide form of high mobility group box 1 (diS-HMGB1), an intracellular protein released during OLT-IRI, induces pro-inflammatory macrophages. How diS-HMGB1 differentiates human monocytes into macrophages capable of activating adaptive immunity remains unknown. We investigated if diS-HMGB1 binds toll-like receptor (TLR) 4 and TLR9 to differentiate monocytes into pro-inflammatory macrophages that activate adaptive immunity and promote graft injury and dysfunction. Assessment of 106 clinical liver tissue and longitudinal blood samples revealed that OLT recipients were more likely to experience IRI and graft dysfunction with increased diS-HMGB1 released during reperfusion. Increased diS-HMGB1 concentration also correlated with TLR4/TLR9 activation, polarization of monocytes into pro-inflammatory macrophages, and production of anti-donor antibodies. In vitro, healthy volunteer monocytes stimulated with purified diS-HMGB1 had increased inflammatory cytokine secretion, antigen presentation machinery, and reactive oxygen species production. TLR4 inhibition primarily impeded cytokine/chemokine and costimulatory molecule programs, whereas TLR9 inhibition decreased HLA-DR and reactive oxygen species production. diS-HMGB1–polarized macrophages also showed increased capacity to present antigens and activate T memory cells. In murine OLT, diS-HMGB1 treatment potentiated ischemia-reperfusion–mediated hepatocellular injury, accompanied by increased serum alanine transaminase levels. This translational study identifies the diS-HMGB1/TLR4/TLR9 axis as potential therapeutic targets in OLT-IRI recipients.

A multicenter phase I/II trial of induction chemotherapy followed by camrelizumab, apatinib, plus chemotherapy as first-line treatment for extensive-stage small-cell lung cancer.

8590 Background: Extensive-stage small-cell lung cancer (ES-SCLC) is a highly aggressive tumor with poor prognosis and limited treatment options. It is necessary to explore new first-line therapeutic strategies to improve patients’ outcomes. This study aimed to assess the safety and efficacy of induction chemotherapy followed by camrelizumab, apatinib plus chemotherapy as first-line treatment in patients with ES-SCLC. Methods: Patients (pts) aged 18-75 years with histopathologically confirmed ES-SCLC and ECOG performance score of 0-1 who did not receive systemic treatment were prospectively enrolled to this study. After two 21-day cycles of induction chemotherapy (etoposide 100 mg/m2 on days 1-3 and carboplatin AUC 5 mg/mL/min on day 1 [EC]), pts received camrelizumab (200 mg, q3w) plus apatinib (250 mg, qd) and EC for 2-4 cycles, then followed by camrelizumab and apatinib as maintenance treatment until disease progression/unacceptable toxicity/up to two years. The primary endpoint was safety. Secondary endpoints were objective response rate (ORR), PFS and OS. Targeted sequencing and whole transcriptome sequencing (WTS) were performed for pts who had sufficient tissue samples. Results: From Jan 28, 2021 to Aug 20, 2022, 40 eligible pts were enrolled. At the data cut-off (Jan 21, 2023), the median follow-up time was 13.6 months. Grade 3/4 treatment-related adverse events (TRAEs) were reported in 72.5% (29/40) of pts. The most common grade 3/4 TRAEs were decreased neutrophil count (35.0%, 14/40), anemia (15.0%, 6/40), decreased platelet count (12.5%, 5/40), increased serum alanine aminotransferase (12.5%, 5/40), and hyponatremia (12.5%, 5/40). Hemoptysis was observed in 15.0% of (6/40) pts, all of whom were grade 1-2. No treatment-related deaths occurred. Efficacy was evaluated in 36 pts who received two cycles of induction therapy and had at least one post-treatment efficacy evaluation. The ORR after two cycles of induction chemotherapy was 66.7% (24/36). The overall ORR and disease control rate reached 88.9% (32/36) and 97.2% (35/36), respectively. The median PFS was 7.4 months (95% CI: 6.5-8.3). The 1-year OS rate was 63.4%. Thirty and 20 pts underwent targeted sequencing and WTS, respectively. Pts with high tumor mutational burden level (TMB ≥ 7.0, p &lt; 0.001), high homologous recombination deficiency score (HRD ≥ 34.0, p = 0.012), and altered RB1 (p &lt; 0.001) presented a longer PFS, respectively. WTS suggested that high expression of cancer-associated fibroblast signature was associated with a shorter PFS (p = 0.001). Conclusions: Induction chemotherapy followed by camrelizumab, apatinib plus EC and then maintenance therapy showed acceptable safety and encouraging efficacy, and might be a promising regimen as first-line treatment in ES-SCLC. TMB, HRD and RB1 might be predictive biomarkers of response to the regimen. Clinical trial information: NCT05001412 .

Pathogenesis of flares in liver inflammation in hepatitis B virus-infected women during and after pregnancy

Abstract Women with chronic hepatitis B (CHB) are at risk of increased liver inflammation during pregnancy. To investigate the pathogenesis of these hepatic flares we studied immune responses and gut microbiota in 19 women with CHB (12 without and 7 with antiviral (NUC) treatment) and 3 uninfected controls in each trimester and at two and six months postpartum. Increased serum alanine aminotransferase (ALT) activity as a liver inflammation marker was defined as a value greater than the upper limit of normal and twice the baseline value. While increased plasma levels of soluble CD163, inflammatory cytokines and chemokines generally occurred during episodes of liver inflammation, increases of IL-22 and IFN-γ levels during pregnancy preceded a postpartum ALT increase. In contrast, levels of IL-27, a cytokine produced by the trophoblast, increased also in women with normal ALT levels. The fecal microbiota of HBV-infected patients with and without NUC treatment had lower α-diversity (inverse Simpson index) than those of uninfected controls. 16srRNA amplicon analysis and PCA showed patient-specific clustering of microbiota. To identify factors predictive of a postpartum ALT increase, we compared 16srRNA DNA data from patients with a postpartum ALT increase to those with normal postpartum ALT levels (four patients per group). Combining all time points, the gut microbiota of those with postpartum ALT increase differed significantly from those with normal ALT activities (UMAP, PERMANOVA p&amp;lt;0.003). In conclusion, the composition of the fecal microbiota was patient-rather than time point-specific and differed between patients with and without postpartum ALT increase. Supported by NIH Bench-to-Bedside Award (B.R. and D.T.Y.L.)

Pregnenolone protects the liver against doxorubicin-induced cellular injury by anti-inflammatory, antioxidant, and antiapoptotic mechanisms: role of Keap1/Nrf2/HO-1 and P-glycoprotein.

Doxorubicin (DOX) is a widely used cytotoxic anthracycline antibiotic characterized by increased adverse effects that limit its clinical usefulness. Pregnenolone is a pregnane X receptor (PXR) agonist that increases the expression of xenobiotic transporters with anti-inflammatory and antioxidant potential. Thus, we hypothesized that pregnenolone would protect against DOX-induced hepatotoxicity. Male Wistar rats (180-200 g) were randomized into four groups (n = 7): Control, Control + Pregnenolone (35 mg/kg/day, orally), DOX (15 mg/kg, i.p.) single dose on day five, and Pregnenolone + DOX. All treatments continued for seven consecutive days. Twenty-four hours after the last treatment, serum and liver tissues were collected for biochemical and histopathological assessment. The possible interaction between pregnenolone and DOX on cell viability was tested in HepG2 cells in vitro by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. DOX treatment resulted in hepatic damage and fibrosis with increased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Liver samples of the DOX-treated group showed increased oxidative stress [malondialdehyde (MDA) and total nitrite/nitrate and decreased reduced glutathione (GSH) and superoxide dismutase (SOD)], increased hepatic tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), transforming growth factor-beta1 (TGF-β1), and mRNA of interleukin-1beta (IL-1β) and interleukin-6 (IL-6). Pretreating the rats with pregnenolone antagonized these DOX-induced effects. Moreover, pregnenolone upregulated the hepatic expression of Nrf2, heme oxygenase-1 (HO-1), and P-glycoprotein and decreased Keap1, opposing the effects of DOX. Moreover, pregnenolone prevented the DOX-induced activation and nuclear translocation of NFκB and increased cleaved caspase-3. Pregnenolone potentiated DOX-mediated cytotoxicity in HepG2 cells. These results illustrate the protective effects of pregnenolone against DOX-induced hepatotoxicity without limiting its anticancer activity.

Liver Injury and Metabolic Dysregulation in Largemouth Bass (Micropterus salmoides) after Ammonia Exposure.

Elevated environmental ammonia leads to respiratory disorders and metabolic dysfunction in most fish species, and the majority of research has concentrated on fish behavior and gill function. Prior studies have rarely shown the molecular mechanism of the largemouth bass hepatic response to ammonia loading. In this experiment, 120 largemouth bass were exposed to total ammonia nitrogen of 0 mg/L or 13 mg/L for 3 and 7 days, respectively. Histological study indicated that ammonia exposure severely damaged fish liver structure, accompanied by increased serum alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase activity. RT-qPCR results showed that ammonia exposure down-regulated the expression of genes involved in glycogen metabolism, tricarboxylic acid cycle, lipid metabolism, and urea cycle pathways, whereas it up-regulated the expression of genes involved in gluconeogenesis and glutamine synthesis pathways. Thus, ammonia was mainly converted to glutamine in the largemouth bass liver during ammonia stress, which was rarely further used for urea synthesis. Additionally, transcriptome results showed that ammonia exposure also led to the up-regulation of the oxidative phosphorylation pathway and down-regulation of the mitogen-activated protein kinase signaling pathway in the liver of largemouth bass. It is possible that the energy supply of oxidative phosphorylation in the largemouth bass liver was increased during ammonia exposure, which was mediated by the MAPK signaling pathway.

Hepatoprotective Mechanism of Apigenin via Suppression of Oxidative Inflammatory Signaling and Apoptosis against Hepatotoxicity Induced by CCl4 in Rats

Background: Carbon tetrachloride (CCl4) is a critical hepatotoxicant causing liver injury and fibrosis via hepatic production of reactive oxygen species (ROS). Apigenin (APG) is a natural bioactive compound and flavonoid antioxidant. We, therefore, evaluated whether APG could mitigate CCl4-mediated hepatotoxicity. Methods: Rats were randomly divided and administered APG and/or CCl4 in Control group, CCl4 group, APG + CCl4 groups (APG: 10 and 20 mg/kg bw) and APG groups (APG: 10 and 20 mg/kg bw) 2 times per week for 7 consecutive weeks. Result: Rats exposed to CCl4 demonstrated marked increases in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and monoamine oxidase (MAO) activities and decreased hepatic malondialdehyde (MDA) level compared to control. The hepatic activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) decreased appreciably. The CCl4 intoxication caused significant increases in inflammatory cytokines (IL-6 and TNF-α) and apoptosis markers, while the anti-inflammatory cytokines (IL-4 and IL-10) decreased with evident histopathological lesions compared to control. APG-dose-dependently-prevented these hepatic alterations.

A Prospective Study of Preemptive Tenofovir Disoproxil Fumarate Therapy in HBsAg-Positive Patients With Diffuse Large B-Cell Lymphoma Receiving Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone.

This prospective study aimed to investigate the efficacy and safety of preemptive antiviral therapy with tenofovir disoproxil fumarate (TDF) for HBsAg-positive patients with newly diagnosed diffuse large B-cell lymphoma receiving rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy. We enrolled 73 patients from 20 institutions. The primary end point was the absolute risk of hepatitis B virus (HBV)-related hepatitis during preemptive TDF therapy and for 24 weeks after withdrawal from TDF. Hepatitis was defined as a more than 3-fold increase in serum alanine aminotransferase from baseline or an alanine aminotransferase level of ≥100 U/L. HBV-related hepatitis was defined as hepatitis with an increase in serum HBV-DNA to >10 times that of the pre-exacerbation baseline or an absolute increase of ≥20,000 IU/mL compared with the baseline. No patient developed HBV reactivation or HBV-related hepatitis during preemptive antiviral therapy (until 48 weeks after completion of R-CHOP chemotherapy) with TDF. All adverse events were grade 1 or 2. HBV reactivation was reported in 17 (23.3%) patients. All HBV reactivation was developed at a median of 90 days after withdrawal from TDF (range, 37-214 days). Six (8.2%) patients developed HBV-related hepatitis at a median of 88 days after withdrawal from TDF (range, 37-183 days). Preemptive TDF therapy in HBsAg-positive patients with diffuse large B-cell lymphoma receiving R-CHOP chemotherapy was safe and effective for preventing HBV-related hepatitis. However, a long-term maintenance strategy of preemptive TDF therapy should be recommended because of the relatively high rate of HBV-related hepatitis after withdrawal from TDF ( ClinicalTrials.gov ID: NCT02354846).