Increased Aspartate Aminotransferase Research Articles

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.

Pulmonary artery banding in sheep: a novel large animal model for congestive hepatopathy.

Congestive hepatopathy is becoming increasingly recognized among Fontan-palliated patients. Elevated central venous pressure is thought to drive the pathologic progression, characterized by sinusoidal dilatation, congestion, and fibrosis. A clinically relevant large animal model for congestive hepatopathy would provide a valuable platform for researching novel biomarkers, treatment, and prevention. Here, we report on a titratable, sheep pulmonary artery banding model for this disease application. Pulmonary artery banding was achieved by progressively inflating the implanted pulmonary artery cuff. Right ventricular catheter was implanted to draw venous blood samples and measure pressure. The pulmonary artery cuff pressure served as a surrogate for the intensity of pulmonary artery banding and was measured weekly. After about 9 wk, animals were euthanized, and the liver was harvested for histopathological assessment. Nine animal subjects received pulmonary artery banding for 64 ± 8 days. Four of the nine subjects exhibited moderate to severe liver injury, and three of those four exhibited bridging fibrosis. Increasing pulmonary artery cuff pressure significantly correlated with declining mixed venous oxygen saturation (P = 3.29 × 10-5), and higher congestive hepatic fibrosis score (P = 0.0238), suggesting that pulmonary artery banding strategy can be titrated to achieve right-sided congestion and liver fibrosis. Blood analyses demonstrated an increase in plasma bile acids, aspartate aminotransferase, and γ-glutamyltransferase among subjects with moderate to severe injury, further corroborating liver tissue findings. Our large animal pulmonary artery banding model recapitulates congestive hepatopathy and provides a basis to bridge the current gaps in scientific and clinical understanding about the disease.NEW & NOTEWORTHY We present here a large animal platform for congestive hepatopathy, a disease growing in clinical prevalence due to the increasing number of Fontan-palliated patients. Further data are needed to develop a better clinical management strategy for this poorly characterized patient population. Previous reports of animal models to study this disease have mostly been in small animals with limited fidelity. We show that congestive hepatopathy can be replicated in a chronic, progressive pulmonary artery banding model in sheep. We also show that the banding strategy can be controlled to titrate the level of liver injury. To date, we do not know of any other large animal model that can achieve this level of control over disease phenotype and clinical relevance.

Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRASG12C mutation: a randomised, open-label, phase 3 trial

Sotorasib is a specific, irreversible inhibitor of the GTPase protein, KRASG12C. We compared the efficacy and safety of sotorasib with a standard-of-care treatment in patients with non-small-cell lung cancer (NSCLC) with the KRASG12C mutation who had been previously treated with other anticancer drugs. We conducted a randomised, open-label phase 3 trial at 148 centres in 22 countries. We recruited patients aged at least 18 years with KRASG12C-mutated advanced NSCLC, who progressed after previous platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor. Key exclusion criteria included new or progressing untreated brain lesions or symptomatic brain lesions, previously identified oncogenic driver mutation other than KRASG12C for which an approved therapy is available (eg EGFR or ALK), previous treatment with docetaxel (neoadjuvant or adjuvant docetaxel was allowed if the tumour did not progress within 6 months after the therapy was terminated), previous treatment with a direct KRASG12C inhibitor, systemic anticancer therapy within 28 days of study day 1, and therapeutic or palliative radiation therapy within 2 weeks of treatment initiation. We randomly assigned (1:1) patients to oral sotorasib (960 mg once daily) or intravenous docetaxel (75 mg/m2 once every 3 weeks) in an open-label manner using interactive response technology. Randomisation was stratified by number of previous lines of therapy in advanced disease (1 vs 2 vs >2), ethnicity (Asian vs non-Asian), and history of CNS metastases (present or absent). Treatment continued until an independent central confirmation of disease progression, intolerance, initiation of another anticancer therapy, withdrawal of consent, or death, whichever occurred first. The primary endpoint was progression-free survival, which was assessed by a blinded, independent central review in the intention-to-treat population. Safety was assessed in all treated patients. This trial is registered at ClinicalTrials.gov, NCT04303780, and is active but no longer recruiting. Between June 4, 2020, and April 26, 2021, 345 patients were randomly assigned to receive sotorasib (n=171 [50%]) or docetaxel (n=174 [50%]). 169 (99%) patients in the sotorasib group and 151 (87%) in the docetaxel group received at least one dose. After a median follow-up of 17·7 months (IQR 16·4-20·1), the study met its primary endpoint of a statistically significant increase in the progression-free survival for sotorasib, compared with docetaxel (median progression-free survival 5·6 months [95% CI 4·3-7·8] vs 4·5 months [3·0-5·7]; hazard ratio 0·66 [0·51-0·86]; p=0·0017). Sotorasib was well tolerated, with fewer grade 3 or worse (n=56 [33%] vs n=61 [40%]) and serious treatment-related adverse events compared with docetaxel (n=18 [11%] vs n=34 [23%]). For sotorasib, the most common treatment-related adverse events of grade 3 or worse were diarrhoea (n= 20 [12%]), alanine aminotransferase increase (n=13 [8%]), and aspartate aminotransferase increase (n=9 [5%]). For docetaxel, the most common treatment-related adverse events of grade 3 or worse were neutropenia (n=13 [9%]), fatigue (n=9 [6%]), and febrile neutropenia (n=8 [5%]). Sotorasib significantly increased progression-free survival and had a more favourable safety profile, compared with docetaxel, in patients with advanced NSCLC with the KRASG12C mutation and who had been previously treated with other anticancer drugs. Amgen.

Curcuma aromatica Salisb. Protects from Acetaminophen-Induced Hepatotoxicity by Regulating the Sirt1/HO-1 Signaling Pathway.

Acetaminophen (APAP) overdose-induced hepatotoxicity reduces the activity of sirtuin-1 (Sirt1) along with heme oxygenase 1 (HO-1) and promotes inflammatory responses and oxidative stress. Although the extract of Curcuma aromatica Salisb. (CAS) possesses hepatoprotective properties, scientific evidence on whether CAS prevents hepatotoxicity and the underlying molecular mechanisms are lacking. Here, we hypothesized that CAS ameliorates hepatotoxicity by inhibiting inflammation and oxidative stress via Sirt1/HO-1 signaling. CAS pretreatment at doses of 200 and 400 μg/mL significantly increased cell viability in APAP-treated primary hepatocytes. The expression of inducible nitric oxide synthase (iNOS) substantially increased after APAP treatment; however, this expression significantly decreased in cells pretreated with 100, 200, and 400 µg/mL CAS. CAS increased Sirt1 and HO-1 levels in APAP-treated hepatocytes in a dose-dependent manner. When CAS was orally administered to mice at doses of 20 or 100 mg/kg for 7 days, the APAP-induced increase in serum aspartate aminotransferase and alanine aminotransferase levels was inhibited. Moreover, CAS decreased IL-6, TNF-α, and IL-1β, increased IL-10, suppressed ROS generation, increased glutathione levels, inhibited iNOS and cyclooxygenase-2, and enhanced Sirt1 and HO-1 in the mouse model of APAP-induced hepatotoxicity. These findings suggest that CAS could be used as a natural hepatoprotective drug to treat APAP-induced injury.

A phase II single-arm study of the FGFR inhibitor pemigatinib in patients with metastatic colorectal cancer (mCRC) harboring FGF/FGFR alterations.

139 Background: The fibroblast growth factor receptor (FGFR) pathway plays a key role in cellular proliferation, migration, survival and angiogenesis. Aberrant signaling through FGFR in colorectal cancer and other malignancies results from gene amplification or mutation, chromosomal translocation or ligand-dependent activation of the receptors. Pemigatinib is an oral inhibitor of FGFR1-3 with proven efficacy in FGFR-altered cholangiocarcinoma and myeloid/lymphoid neoplasms, among others. We hypothesized that pemigatinib would improve response rates compared to historical controls in patients with refractory FGF/FGFR-altered mCRC. Methods: ACCRU-GI-1701 was a multicenter, single-arm, Simon’s two-stage phase II clinical trial (NCT04096417) of the FGFR inhibitor pemigatinib in patients (pts) with FGF/FGFR-altered mCRC. Eligible pts had received prior fluoropyrimidine, oxaliplatin, irinotecan, and anti-VEGF/anti-EGFR/anti-PD-1 if eligible. Pts received pemigatinib 13.5 mg once daily on d1-21 of each cycle, with option to escalate to 18 mg in c2 if well tolerated. The primary endpoint was (unconfirmed) objective response (OR). A sample size of 21 evaluable pts would provide 82% power to detect a true OR rate of 20% or greater compared to a historical control of 5 % with a one-sided type I error rate of 0.1. A prespecified interim analysis for futility was planned after 12 evaluable patients. Results: A total of 14 patients were enrolled in the first stage of the study, and all were evaluable for the primary endpoint. No OR were observed (out of 12) crossing the futility boundary and resulting in permanent closure of the study. Among all enrolled patients, median age was 60.5 years, 71.4% were male, 92.9% Caucasian, 42.9% with no prior exposure to TAS-102 or regorafenib, and 64.3% with left-sided primary tumors. Treated patients all had tumors with FGFR1-4 mutations and/or FGF/FGFR amplifications by tissue- and/or blood-based molecular testing; no FGFR translocations were present. OR rate for this study was 0% (95% CI, 0-23.2%), with one patient achieving stable disease as best response. Median progression-free survival was 9.1 weeks (95% CI, 7.9-not evaluable [NE]), and median overall survival was 7.9 months (95% CI, 3.4-NE). Grade 3+ adverse events (AE) were seen in 42.9% of treated patients (including 1 grade 5 AE). Most commonly occurring AEs of any grade were anemia, hyperphosphatemia, alkaline phosphatase increased, aspartate aminotransferase increase, and fatigue. Conclusions: Pemigatinib demonstrated evidence of safety but not clinical activity in this population of patients with FGF/FGFR-altered mCRC. It is unknown whether pemigatinib would be active in mCRC patients with FGFR translocations/fusions as these were not represented in our trial. Translational studies are planned to investigate mechanisms of resistance to this therapy. Clinical trial information: NCT04096417 .

Investigating the effect of myricetin against arsenic-induced cardiac toxicity in rats.

Arsenic intoxication is a serious health hazard worldwide. Its toxicity is associated with several disorders and health problems in humans. Recent studies revealed that myricetin has various biological effects, including anti-oxidation. The aim of this study is to investigate the protective effect of myricetin against arsenic-induced cardiotoxicity in rats. Rats were randomized to one of the following groups: control, myricetin (2mg/kg), arsenic (5mg/kg), myricetin (1mg/kg)+arsenic, and myricetin (2mg/kg)+arsenic. Myricetin was given intraperitoneally 30min before arsenic administration (5mg/kg for 10days). After treatments, the activity of lactate dehydrogenase (LDH) and the levels of aspartate aminotransferase (AST), creatine kinase myocardial band (CK-MB), lipid peroxidation (LPO), total antioxidant capacity (TAC), and total thiol molecules (TTM) were determined in serum samples and cardiac tissues. Also, histological changes in cardiac tissue were evaluated. Myricetin pretreatment inhibited arsenic-induced increase in LDH, AST, CK-MB, and LPO levels. Pretreatment with myricetin also enhanced the decreased TAC and TTM levels. In addition, myricetin improved histopathological alterations in arsenic-treated rats. In conclusion, the results of the present study demonstrated that treatment with myricetin prevented arsenic-induced cardiac toxicity at least in part by decreasing oxidative stress and restoring the antioxidant system.

The transmission risk factors of hepatitis B and C infection in dental treating and tattooing among hemodialysis patients

For four decades, hepatitis often strikes hemodialysis (HD) patients. The seroprevalence of hepatitis infection in HD ranges from country to country. The study design of two parts, the first partisan estimate of the prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) in Baghdad teaching hospital/departmentof HD, and the second part is an association between HBV, and HCV transmission and other suspected risk factors dental office and tattooing. A one hundred patients who underwent serum anti-HBC and anti-HCV examination at Baghdad teaching hospital/department of dialysis were enrolled in the study. The chemiluminescence assay has been used to test HBV and HCV antibodies, and an automated kinetic method was used for liver function tests. HCVAb was detected in thirty-five (35%) dialysis patients, and the total HBcAb and infection HBsAg were detected in five (5%) and zero (0%) respectively. No Co-infection was observed. Seroprevalence results related to transfusion requirement was 4 (7.4%) for total HBcAb, zero (0%) for HBsAg, and 32 (59.3%) for HCVAb. There was no significant difference between blood transfusion and non-transfusion in risk prevalence of total HBcAb and HBsAg, but the risk of HCV infection was significantly higher in the blood transfusion (p < 0.001). In the logit model analysis, the main risk factor for HCV infection in the entire sample was blood transfusion (OR = 20.8, 95% CI: 5.7-75.7, p < 0.001). The association between HCV transmission and risk behavior among patients that contribute its spread in society such as dental healthcare (DHC) (OR = 0.98, 95% CI: 0.925-1.615, p < 0.05) and tattoos (OR = 0.75, 95% CI: 0.503-1.119). A non-significant increase in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin, while, non-significant decrease in albumin in HCV-positive hemodialysis patients compared with HCV-negative dialysis patients. Our findings indicate a high incidence of HCV virus infection in patients who received blood. However, no transmitting risk appeared from such patients when using dental tools or tattoos tools.

Evaluation of the Possible Protective Role of Nobiletin against Arsenic-Induced Liver Damage in Male Albino Rats.

Arsenic (As) is a toxic contaminant present in organic and inorganic forms in the environment. Nobiletin (NOB) is a polymethoxy flavone that has recently gained substantial consideration due to its curative impacts. The present experiment was conducted to assess the hepatoprotective efficiency of NOB on As-generated hepatotoxicity. Twenty-four adult rats were equally distributed into four groups and designated as control, As (50 mg/kg)-treated, As + NOB (50 mg/kg and 25 mg/kg, respectively), and NOB (25 mg/kg)-treated groups. After 30 days, experimental animals were decapitated, then blood and tissue samples were collected for further analysis. The group treated with As showed a significant decrease in the activity of antioxidant enzymes, including catalase (CAT), superoxide dismutase (SOD), peroxidase (POD), glutathione (GSH), glutathione reductase (GSR), and total antioxidant status (TAS), and a substantial increase in the accumulation of As in liver tissues, levels of total oxidant status (TOS), hydrogen peroxide (H2O2), and lipid peroxidation (TBARS). Significant increases in alanine aminotransferase (ALT), alkaline phosphatase (ALP), and aspartate aminotransferase (AST) levels were observed in As-treated rats. Moreover, nuclear factor (NF)-κB, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, interleukin (IL)-6, and cyclo-oxygenase (COX)-2 activity, as well as the levels of pro-apoptotic markers (Bax, Caspase-3, and Caspase-9) were increased on exposure to As. In contrast, the anti-apoptotic marker (Bcl-2) level was significantly decreased. As administration showed a significant disturbance in hepatic tissue histology. However, cotreatment of NOB with As considerably increased the antioxidant enzyme activity, with a noteworthy reduction in the deposition of As in hepatic tissues, TBARS, and H2O2 levels. NOB-administrated rats showed considerable recovery in terms of inflammation, apoptosis, and histological damage. Hence, NOB can be considered a useful curative compound due to its medicinal properties against As-prompted hepatotoxicity.

Associations of polycyclic aromatic hydrocarbons, water-soluble ions and metals in PM2.5 with liver function: Evidence from schizophrenia cohort

BackgroundFine particulate matter (PM2.5) was reported to impact liver function, but the roles of specific PM2.5 chemical components remained to be explored. Besides, severe liver dysfunction in schizophrenia patients deserves attention. ObjectiveTo investigate the associations of short-term PM2.5 components with liver function in schizophrenia patients. MethodsA repeated-measures study based on schizophrenia cohort including 1023 visits (n = 446) was conducted during 2017–2020. Liver function was reflected by 10 indicators including liver enzymes, proteins and bilirubin et al. Monitoring data of PM2.5 and its components, including 16 polycyclic aromatic hydrocarbons (PAHs), 4 water-soluble ions and 10 metals were collected. Linear mixed effect and Bayesian kernel machine regression (BKMR) models were used to evaluate the single and combined effects of PM2.5 components (0–3 day) on liver function in schizophrenia patients. ResultsSeveral PAHs were significantly associated with liver enzymes, while water-soluble ions and metal components had almost no association. Specifically, with per interquartile range (IQR) increased in Fluoranthene, levels of alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate transaminase (AST) and gamma-glutamyl transpeptidase (GGT) increased by 2.06 %, 5.07 %, 4.94 % and 5.56 %, respectively. An IQR increases in Benzo[a]pyrene was significantly associated with 6.62 %, 3.67 % and 7.83 % increase in ALT, AST and GGT. Almost all PAHs, sulfate, nitrate, ammonium, Sb, Al, As, Pb, Mn and Tl were positively associated with albumin (ALB). Phenanthrene was associated with increased levels of direct bilirubin (DBIL) and total bilirubin (TBIL). The combined effects of significant PM2.5 components on ALP, GGT, ALB, globulin (GLOB), ratio of albumin to globulin (A/G), TBIL and total bile acid (TBA) were found by BKMR, respectively. ConclusionsFindings highlight the short-term combined effects of PM2.5 components, especially PAHs, on liver function in schizophrenia patients, which contribute to the management of PM2.5 sources including combustion activities and traffic emissions as well as improving schizophrenia comorbidities.

Futibatinib for FGFR2-Rearranged Intrahepatic Cholangiocarcinoma

BackgroundAlterations in fibroblast growth factor receptor 2 (FGFR2) have emerged as promising drug targets for intrahepatic cholangiocarcinoma, a rare cancer with a poor prognosis. Futibatinib, a next-generation, covalently binding FGFR1–4 inhibitor, has been shown to have both antitumor activity in patients with FGFR-altered tumors and strong preclinical activity against acquired resistance mutations associated with ATP-competitive FGFR inhibitors.MethodsIn this multinational, open-label, single-group, phase 2 study, we enrolled patients with unresectable or metastatic FGFR2 fusion–positive or FGFR2 rearrangement–positive intrahepatic cholangiocarcinoma and disease progression after one or more previous lines of systemic therapy (excluding FGFR inhibitors). The patients received oral futibatinib at a dose of 20 mg once daily in a continuous regimen. The primary end point was objective response (partial or complete response), as assessed by independent central review. Secondary end points included the response duration, progression-free and overall survival, safety, and patient-reported outcomes.ResultsBetween April 16, 2018, and November 29, 2019, a total of 103 patients were enrolled and received futibatinib. A total of 43 of 103 patients (42%; 95% confidence interval, 32 to 52) had a response, and the median duration of response was 9.7 months. Responses were consistent across patient subgroups, including patients with heavily pretreated disease, older adults, and patients who had co-occurring TP53 mutations. At a median follow-up of 17.1 months, the median progression-free survival was 9.0 months and overall survival was 21.7 months. Common treatment-related grade 3 adverse events were hyperphosphatemia (in 30% of the patients), an increased aspartate aminotransferase level (in 7%), stomatitis (in 6%), and fatigue (in 6%). Treatment-related adverse events led to permanent discontinuation of futibatinib in 2% of the patients. No treatment-related deaths occurred. Quality of life was maintained throughout treatment.ConclusionsIn previously treated patients with FGFR2 fusion or rearrangement–positive intrahepatic cholangiocarcinoma, the use of futibatinib, a covalent FGFR inhibitor, led to measurable clinical benefit. (Funded by Taiho Oncology and Taiho Pharmaceutical; FOENIX-CCA2 ClinicalTrials.gov number, NCT02052778.)

Pterostilbene-Loaded Soluplus/Poloxamer 188 Mixed Micelles for Protection against Acetaminophen-Induced Acute Liver Injury.

Excessive acetaminophen (APAP) induces excess reactive oxygen species (ROS), leading to liver damage. Pterostilbene (PTE) has excellent antioxidant and anti-inflammatory activities, but poor solubility limits its biological activity. In this study, we prepared PTE-loaded Soluplus/poloxamer 188 mixed micelles (PTE-MMs), and the protective mechanism against APAP-induced liver injury was investigated. In vitro results showed that PTE-MMs protected H2O2-induced HepG2 cell proliferation inhibition, ROS accumulation, and mitochondrial membrane potential destruction. Immunofluorescence results indicated that PTE-MMs significantly inhibited H2O2-induced DNA damage and cGAS-STING pathway activation. For in vivo protection studies, PTE-MMs (25 and 50 mg/kg) were administered orally for 5 days, followed by APAP (300 mg/kg). The results showed that APAP significantly induced injury in liver histopathology as well as an increase in serum aspartate aminotransferase and alanine aminotransferase levels. Moreover, the above characteristics of APAP-induced acute liver injury were inhibited by PTE-MMs. In addition, APAP-induced changes in the activities of antioxidant enzymes such as SOD and GSH in liver tissue were also inhibited by PTE-MMs. Immunohistochemical results showed that PTE-MMs inhibited APAP-induced DNA damage and cGAS-STING pathway activation in liver tissues. For in vivo therapeutic effect study, mice were first given APAP (300 mg/kg), followed by oral administration of PTE-MMs (50 mg/kg) for 3 days. The results showed that PTE-MMs exhibited promising therapeutic effects on APAP-induced acute liver injury. In conclusion, our study shows that the Soluplus/poloxamer 188 MM system has the potential to enhance the biological activity of PTE in the protection and therapeutic of liver injury.

Hepatoprotective Effect of Curcumin Nano-Lipid Carrier against Cypermethrin Toxicity by Countering the Oxidative, Inflammatory, and Apoptotic Changes in Wistar Rats.

This study investigated the potential hepatoprotective activity of curcumin-incorporated nano-lipid carrier (Cur-NLC) against cypermethrin (Cyp) toxicity in adult Wistar male rats. All animals in groups III, IV, V, and VI were subjected to Cyp (50 mg/kg) toxicity for 15 days. Three different doses of Cur-NLC (1, 2.5, and 5 mg/kg/day) were administered orally for 10 days. The toxic effects were evaluated considering the increases in serum hepatic biomarkers alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total protein and albumin, and lipid peroxidation (LPO), as well as a decrease in antioxidative activity (reduced glutathione (GSH), superoxide dismutase (SOD), and catalase) and the upregulation of inflammatory cytokines (IL-1β, IL-6, and TNF-α). Immunohistochemistry studies of proteins (NF-κB, Apaf-1, 4-HNE, and Bax) showed enhanced expression, and histopathological examination revealed architectural changes in liver cells, indicating liver toxicity in animals. Toxicity was determined by quantitative and qualitative determinations of DNA fragmentation, which show massive apoptosis with Cyp treatment. The administration of Cur-NLC significantly ameliorates all changes caused by Cyp, such as a decrease in the levels of serum liver markers, an increase in antioxidative parameters, a decrease in expression of inflammatory cytokines (IL-1β, IL-6, TNF-α, and NF-κB), and apoptosis (caspases-3, 9, Apaf-1, 4-HNE, and Bax), according to calorimetric and immunohistochemistry studies. The smear-like pattern of DNA is ameliorated similarly to the control at a high dose of Cur-NLC. Furthermore, all histopathological changes were reduced to a level close to the control. In conclusion, Cur-NLC could be a potent nutraceutical that exhibits a hepatoprotective effect against Cyp-induced hepatotoxicity in rats.

The metabolic effects of hormonal treatment in transgender males: Safety of the testosterone gender-affirming therapy.

Gender dysphoria is characterised by a sense of distress because of discordance between the self-perception of gender identity and the assigned sex. Hormonal treatment of transgender males uses testosterone to induce and preserve masculinisation. The study investigated the safety of testosterone therapy in transgender males. The present study used a retrospective file review of transgender male subjects who were treated with testosterone (initially transdermal testosterone gel and subsequently parenteral testosterone undecanoate) for at least 18 months and had subsequently achieved a serum testosterone level within the normal range of cisgender male counterparts. Changes in somatometric data and blood biomarkers were investigated. The mean testosterone serum levels after approximately 18 months of treatment were about 545 ng/dL (SD ± 94 ng/dL). There was a statistically significant rise in body mass index (𝜒d = +1.23 kg/m2) with a reduction in blood glucose (𝜒d = -5.33 mg/dL) as well as statistically significant increases in aspartate transaminase (𝜒d = +4.3 U/L), haemoglobin (𝜒d = +1.72 g/dL), and haematocrit (𝜒d = +4.76%). In contrast, there were no significant changes in the lipidaemic profile of the subjects. Treatment with testosterone is routinely used for the promotion of virilising physical changes in transgender males. However, the likelihood of adverse effects of continuous treatment is still unclear. This study contributed to the notion that achieving testosterone levels within the target range is a prerequisite for the safety of the gender-affirming treatment.

Hepatocurative Effect of Some Ethnomedicinal Plants on Liver Function Indices in Alloxan- Induced Diabetic Rats

Aims: This research investigated the curative effects of Moringa oleifera (MO), Treculia africana (T.A.), and Albizzia chevalieri (A.C.) plant extracts on the liver function indices in Alloxan-induced diabetic rats.
 Study Design: Albino rats were grouped into five (5) main groups MO, TA, A.C., Normal Control (N.C.), and Diabetic Control (D.C.) groups.
 Place and Duration of Study: Department of Science Laboratory Technology, Federal Polytechnic Kaura Namoda, between May 2021 and July 2021.
 Methodology: Diabetes mellitus was caused by a single dose intraperitoneal injection of Alloxan 150 mg/kg body weight. Liver function indices were determined using standard methods.
 Results: Intraperitoneal injection of 150 mg/kg of Alloxan in the albino rats resulted in a significant (p<0.05) increase of Aspartate aminotransferase (AST), Alanine aminotransferase (ALT) and Alkaline phosphatase (ALP) activities, Direct and Total bilirubin while total protein concentration was significantly (p<0.05) decreased in the diabetic albino rats when compared with that of the non-diabetic rats (N.C.) group. Oral administration of MO, TA, and A.C. extracts to the diabetic albino rats for 21 days significantly (p<0.05) decreased AST, ALT, and ALP activities, direct and total bilirubin concentration. While total protein concentration was significantly (p<0.05) increased in the diabetes-treated groups. Histopathological studies confirmed the toxic effect of Alloxan in the liver of induced diabetic albino rats and the hepatocurative effect of the studied medicinal plants. MO (800mg/kg) demonstrated the most significant (p<0.05) curative effect compared to T.A. and A.C. Possible mechanism for hepatocurative of the studied medicinal plants may be due to free radical scavenging potential in the plant extracts.
 Conclusion: In conclusion, the results of the present study demonstrate that Moringa oleifera, in a dose-dependent manner, has the most potent hepatocurative effect, followed by Albizzia chevalieri, then Trecullia Africana against Alloxan-induced liver damage.

First-in-human phase I dose-escalation and dose-expansion trial of the selective MEK inhibitor HL-085 in patients with advanced melanoma harboring NRAS mutations

BackgroundHL-085 is a selective, orally administered MEK1/2 inhibitor. We aimed to evaluate the safety and efficacy of HL-085 in patients with advanced melanoma harboring NRAS mutations.MethodsThis was a multicenter phase 1 study. HL-085 was administered twice daily in a standard 3 + 3 dose-escalation design (10 dose cohorts; 0.5–18 mg twice daily), followed by dose expansion at the recommended phase II dose (RP2D). The primary endpoints included tolerability, dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and RP2D.ResultsBetween September 13, 2017, and January 18, 2021, 42 patients were enrolled (dose escalation phase: n = 30; dose expansion phase: n = 12). No DLT was reported during dose escalation and MTD was not reached with HL-085 doses up to 18 mg twice daily. The RP2D was 12 mg twice daily. The most common all-grade drug-related adverse events (AEs) across all dose levels were rash (61.9%), increased creatine phosphokinase (CK, 59.5%), face edema (50.0%), increased aspartate aminotransferase (47.6%), peripheral edema (40.5%), diarrhea (33.3%), alanine aminotransferase (33.3%), and paronychia (19.0%), most of which were grade 1 and 2. Most frequency of grade ≥ 3 AEs were CK (14.2%), asthenia (7.1%), peripheral edema (4.8%), and acneiform dermatitis (4.8%). In the cohort of 12 mg twice daily dose (15 patients), confirmed objective response rate was 26.7%; disease control rate was 86.7%; median duration of response was 2.9 months; median progression-free survival was 3.6 months.ConclusionsThe HL-085 showed acceptable tolerability and substantial clinical activity in patients with advanced melanoma harboring NRAS mutations.Trial registrationTrial registration ClinicalTrials.gov number: NCT03973151.

COVID-19 risk factors for mortality in hospitalized patients: results of a retrospective study

Objective. To identify risk factors for fatal outcome and COVID-19-associated liver damage in hospitalized adult patients with coronavirus infection. Materials and Methods. In a retrospective cohort study, 389 cases of patients with coronavirus infection complicated by bilateral viral pneumonia were studied. Demographic characteristics, clinical features of the course of the disease, anamnestic data, results of laboratory and instrumental methods of examination were analyzed and correlated with mortality. At the time of admission, the following were taken into account: fever, severity of the patient’s condition according to COVID-19 classification of severity, body mass index (BMI), oxygen saturation (SpO2), percentage of lung tissue damage according to computed tomography (CT). Laboratory indices of biochemical blood analysis were assessed in dynamics: alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, total protein, albumin, C-reactive protein (CRP). Data analysis was performed using the R programming language (ver. 4.1.1.). Results. The following risk factors, assessed at the time of hospitalization, increased the likelihood of death: severe and extremely severe condition of the patient (RR = 4.77; 95% CI: 3.33–6.83); SpO2 less than 93% (RR = 3.76; 95% CI: 2.57–5.49); diabetes mellitus (RR = 2.94; 95% CI: 2.01–4.30); lung tissue damage CT-3 and CT-4 (RR = 2.66; 95% CI: 1.79–3.75); concomitant chronic pyelonephritis and chronic kidney disease (CKD) (RR = 2.59; 95% CI: 1.79–3.74); age 65 years and older (RR = 2.50; 95% CI: 1.70–3.67); ischemic heart disease (IHD) (RR = 2.39; 95% CI: 1.42–4.01); an increase in the level of CRP more than 15 mg/l (RR = 2.22; 95% CI: 1.16–4.24); BMI 35 kg/m2 or more (RR = 1.89; 95% CI: 1.28–2.77); AST level more than 2 upper limit of normal (ULN) (RR = 1.75; 95% CI: 1.20–2.55). Risk factors for an increase in AST more than 2 ULN were: SpO2 less than 93% (RR = 1.53; 95% CI: 1.15– 2.03), severe and extremely severe course of coronavirus infection (RR = 1.83; 95% CI: 1.38–2.43), concomitant chronic liver disease (RR = 1.45, 95% CI: 1.08–1.95). Conclusions. Risk factors for fatal COVID-19 in hospitalized patients are: severe and extremely severe initial condition of the patient, oxygen saturation less than 93%, lung tissue damage more than 50%, age older than 65 years, presence of concomitant diabetes mellitus, chronic pyelonephritis and CHD, CHD, obesity, increased CRP level more than 15 mg/l, and AST more than 70 units/l. Elevation of AST over 2 IU/L can be considered as one of the prognostic laboratory markers of adverse prognosis COVID-19.

Serum Mineral Levels and Haematobiochemical Parameters in Buffalo Calves with Allotriophagy (Pica Syndrome)

Pica is defined as a depraved or abnormal appetite characterized by licking and eating non-nutritive substances. The aim of this study was to report changes in the serum mineral levels and haematobiochemical parameters of buffalo calves with pica. The study included 30 buffalo calves exhibiting pica behaviour, such as licking stall walls or eating wool and non-food items (pica group), and 6 buffalo calves without the signs of pica behaviour (control group). The age of both groups ranged between 1 and 6 months. In the pica group, the haematological analysis revealed a decrease in red blood cells (P < 0.001) and red cell distribution width (P < 0.05) as well as an increase in the mean corpuscular volume and mean corpuscular haemoglobin (P < 0.001), whereas the biochemical parameters were characterized by an increase in aspartate aminotransferase (P < 0.01), alanine aminotransferase (P < 0.001) and lactate dehydrogenase (P < 0.05) levels and a decrease in creatinine and glucose (P < 0.01) levels. Furthermore, the pica group showed a significant decrease in serum manganese, iron, zinc, selenium (P < 0.001) and copper (P < 0.01) concentrations. In conclusion, it was determined that deficiencies in the levels of serum iron, copper, zinc, manganese and selenium play an important role in the aetiology of pica in buffalo calves.

The Prospects for Using Bioluminescent Enzymatic Analysis to Reveal the Exercise Capacity of Sports Horses

Bioluminescent testing of saliva of sports horses, selected before and after physical exercise, was carried out using a coupled enzyme reaction catalyzed by NADH:FMN-oxidoreductase and bacterial luciferase. The inhibitory effect of saliva on the intensity of the light emission was shown, which depended on an increase in the pH of saliva after muscle work. A decrease in the integral bioluminescent index after low-intensity muscular work correlated with the content of total protein and glucose in the blood an serum increase in the bioluminescent index at high intensity was due to a decrease in creatinine or an increase in aspartate aminotransferase and is corelated with an increase in heart rate. It has been shown for the first time that the inhibition of bioluminescence can be an indicator of the functional state of a horse in training, which can be used in sports horse breeding to prevent overloads.

Phytochemical evaluation and acute oral toxicity of crude methanol extract of Pleurotus tuber-regium (Fr.) Singer in laboratory mice (Mus musculus)

This research aimed to evaluate the phytochemical components of the crude methanol extract (CME) of Pleurotus tuber-regium and its acute toxicity in mice, Mus musculus. Before being filtered and evaporated, the crushed mushroom was macerated in 70% methanol for 72 hours. The phytochemical screening and acute oral toxicity were carried out using standard procedures. The CME consists of alkaloids, cardiac glycosides, saponins, phenolic compounds, tannins, steroids, carbohydrates, flavonoids, and terpenoids. When given orally, the LD50 was shown to be greater than 5000 mg/kg with no outward symptoms of toxicity. Haematology showed a significant (p < 0.05) decrease in packed cell volume, hemoglobin concentration, total red blood cell, and neutrophil counts in the treatment group as compared to the control group, while total white blood cell and lymphocyte counts significantly (p < 0.05) increased. On serum biochemistry, a significant (p < 0.05) increase in aspartate aminotransferase, alanine transferase, alanine phosphatase, blood urea nitrogen, and creatinine was observed in the treated group. There was however no significant (p > 0.05) difference in serum albumin and total protein. In conclusion, 5000 mg/kg of extract had a significant influence on the hematological and biochemical profiles of mice but didn’t cause irreparable liver and kidney damage.

Comparison of Biochemical, Haematological and Plasmatic Butyrylcholinesterase Parameters in Farmers and Non-Farmers, Morocco.

The long-term use of pesticides can cause harmful consequences to both human health and the environment. In the present research, we aimed to compare biochemical, hematological, and plasmatic measurements of butyrylcholinesterase (BChE) between farmers and non-farmers. The study is cross-sectional and included 270 participants, with 135 farmers using pesticides and a control population of 135 non-farmers. The recruitment of the participants was conducted from August 2017 to the end of December 2019. Blood samples from participants were collected for the evaluation of biochemical markers of the function of the liver and determination of BChE activity. A whole blood sample with ethylenediamine tetraacetic anticoagulant (EDTA) was also taken for a complete blood count. The results showed a statistically significant (P = 0.03) decrease in mean corpuscular hemoglobin (MCH) in the cases (28.45 ± 2.94 pg) as compared with controls (29.17 ± 2.54 pg). The statistical analysis of the renal parameters between the two groups determined that the uremia value was significantly higher in cases (34 ± 12 mg/dL) when compared to the control group (29 ± 8 mg/dL) P < 0.001. The cases recorded a significant increase in aspartate aminotransferase (AST) (26.22 ± 11.59 U/L) and alanine aminotransferase (ALT) (25.63 ± 13.47 U/L) enzyme activities among cases versus controls. The results obtained showed a significantly decreased BChE activity in the group of cases exposed to pesticides (7554.52 ± 2107 U/l) compared to the unexposed control group (10135.58 ± 1909 U/l) (t-test, P < 0.001). The education of the farmers on correct practices concerning phytosanitary use has the potential of reducing their exposure to these products.