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Background Persons with HIV and tuberculosis (TB) co-infection require transaminase monitoring while on hepatotoxic medications. A novel paper-based, point-of-care transaminase test is in development at an anticipated cost of $1 per test. Methods To project long-term clinical outcomes and estimate the cost-effectiveness of using a paper-based fingerstick test to monitor for drug-induced liver injury (DILI), as compared with automated testing and with no laboratory monitoring. The design was a decision analytic model, including deterministic and probabilistic sensitivity analyses. Data sources were observational cohorts and a validation study of the paper-based test. The target population was HIV/TB co-infected persons in South Africa on antiretroviral therapy who were initiating TB therapy. Interventions: (1) clinical (no laboratory) monitoring; (2) monitoring using the paper-based test with a ≥120 IU/mL threshold for positivity; (3) monitoring using the paper-based test with a ≥200 IU/mL threshold for positivity; (4) monitoring using the paper-based test using 1 of 3 categories: <120 IU/mL, 120 to 200 IU/mL, and >200 IU/mL (“bin placement”); (5) monitoring using automated ALT testing using the same 3 categories (“automated testing”). The outcome measures were discounted quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs). Results The ICER of automated testing was $5180/QALY. Use of the paper-based test with the bin placement strategy was cost-effective compared with clinical monitoring alone. Conclusion At its current performance, monthly DILI monitoring by bin placement using the paper-based test was cost-effective, compared with clinical monitoring, in HIV/TB co-infected persons in South Africa. [ABSTRACT FROM AUTHOR]

Branched-chain amino acid aminotransferases, widely present in natural organisms, catalyze bidirectional amino transfer between branched-chain amino acids and branched-chain a-ketoacids in cells. Branched-chain amino acid aminotransferases play an important role in the metabolism of branchedchain amino acids. In this paper, the interspecific evolution and biological characteristics of branched-chain amino acid aminotransferases are introduced, the related research of branched-chain amino acid aminotransferases in animals, plants, microorganisms and humans is summarized and the molecular mechanism of branched-chain amino acid aminotransferase is analyzed. It has been found that branched-chain amino acid metabolism disorders are closely related to various diseases in humans and animals and plants, such as diabetes, cardiovascular diseases, brain diseases, neurological diseases and cancer. In particular, branched-chain amino acid aminotransferases play an important role in the development of various tumors. Branched-chain amino acid aminotransferases have been used as potential targets for various cancers. This article reviews the research on branched-chain amino acid aminotransferases, aiming to provide a reference for clinical research on targeted therapy for various diseases and different cancers. [ABSTRACT FROM AUTHOR]

Presents articles to be published in the "European Journal of Biochemistry." "Characterization of a cDNA Clone Encoding Mollusc Insulin-Related Peptide II of Lymnaea Stagnalis," by A. B. Smith, W. P. M. Geraerts, I. Meester, H. van Heerikhuizen and J. Joosse; "Effects of Dexamethasone and cAMP on Tyrosine Aminotransferase Expression in Cultured Fetal Rat Hepatocytes," by L. L. Shelly and G. C. T. Yeoh; "Transient Kinetics of Flavin-Photosensitized Oxidation of Reduced Redox Proteins--Comparison of c-type Cytochromosomes and Plastocyanins," by J. A. Navarro, M. A. De la Rosa and G. Tollin; "Membrane-Bound Cytochromes in Chloroflexus Aurantiacus Studied by EPR," by P. van Vliet, D. Zannoni, W. Nitschke and A. W. Rutherford; Others.

Simple Summary: This paper presents a paradigm-shifted approach for adverse event (AE) analysis from classic descriptive summary into modern informative statistics to fulfill precision medicine. It defines early AE and derives a series of innovative AE biomarkers to assess grade, treatment relatedness, occurrence, frequency, and duration. Comprehensive data analysis generates opportunities for global discovery of predictive early AE-derived biomarkers. A proof of concept in two lung cancer studies demonstrates the potential clinical utility of early AE-derived biomarkers in patients with advanced non-small cell lung cancer treated with immunotherapy. The methodology also provides a useful tool to help discover predictive AE biomarkers for treatment response and survival outcomes. Rationale: Adverse events (AEs) have been shown to have clinical associations, in addition to patient safety assessments of drugs of interest. However, due to their complex content and associated data structure, AE evaluation has been restricted to descriptive statistics and small AE subset for efficacy analysis, limiting the opportunity for global discovery. This study takes a unique approach to utilize AE-associated parameters to derive a set of innovative AE metrics. Comprehensive analysis of the AE-derived biomarkers enhances the chance of discovering new predictive AE biomarkers of clinical outcomes. Methods. We utilized a set of AE-associated parameters (grade, treatment relatedness, occurrence, frequency, and duration) to derive 24 AE biomarkers. We further innovatively defined early AE biomarkers by landmark analysis at an early time point to assess the predictive value. Statistical methods included the Cox proportional hazards model for progression-free survival (PFS) and overall survival (OS), two-sample t-test for mean difference of AE frequency and duration between disease control (DC: complete response (CR) + partial response (PR) + stable disease (SD)) versus progressive disease (PD), and Pearson correlation analysis for relationship of AE frequency and duration versus treatment duration. Two study cohorts (Cohort A: vorinostat + pembrolizumab, and B: Taminadenant) from two immunotherapy trials in late-stage non-small cell lung cancer were used to test the potential predictiveness of AE-derived biomarkers. Data from over 800 AEs were collected per standard operating procedure in a clinical trial using the Common Terminology Criteria for Adverse Events v5 (CTCAE). Clinical outcomes for statistical analysis included PFS, OS, and DC. Results: An early AE was defined as event occurrence at or prior to day 30 from initial treatment date. The early AEs were then used to calculate the 24 early AE biomarkers to assess overall AE, each toxicity category, and each individual AE. These early AE-derived biomarkers were evaluated for global discovery of clinical association. Both cohorts showed that early AE biomarkers were associated with clinical outcomes. Patients previously experienced with low-grade AEs (including treatment related AEs (TrAE)) had improved PFS, OS, and were associated with DC. The significant early AEs included low-grade TrAE in overall AE, endocrine disorders, hypothyroidism (pembrolizumab's immune-related adverse event (irAE)), and platelet count decreased (vorinostat related TrAE) for Cohort A and low-grade AE in overall AE, gastrointestinal disorders, and nausea for Cohort B. In contrast, patients with early development of high-grade AEs tended to have poorer PFS, OS, and correlated with PD. The associated early AEs included high-grade TrAE in overall AE, gastrointestinal disorders with two members, diarrhea and vomiting, for Cohort A and high-grade AE in overall AE, three toxicity categories, and five related individual AEs for Cohort B. One low-grade TrAE, alanine aminotransferase increased (vorinostat + pembrolizumab related), was an irAE and correlated with worse OS in Cohort A. Conclusions: The study demonstrated the potential clinical utility of early AE-derived biomarkers in predicting positive and negative clinical outcomes. It could be TrAEs or combination of TrAEs and nonTrAEs from overall AEs, toxicity category AEs, to individual AEs with low-grade event leaning to encouraging effect and high-grade event to undesirable impact. Moreover, the methodology of the AE-derived biomarkers could change current AE analysis practice from a descriptive summary into modern informative statistics. It modernizes AE data analysis by helping clinicians discover novel AE biomarkers to predict clinical outcomes and facilitate the generation of vast clinically meaningful research hypotheses in a new AE content to fulfill the demands of precision medicine. [ABSTRACT FROM AUTHOR]

Protein engineering is a powerful and widely applied tool for tailoring enzyme properties to meet application-specific requirements. An attractive group of biocatalysts are PLP-dependent amine transaminases which are capable of converting prochiral ketones to the corresponding chiral amines by asymmetric catalysis. The enzymes often display high enantioselectivity and accept various amine donors. Practical applications of these amine transaminases can be hampered by enzyme instability and by their limited substrate scope. Various strategies to improve robustness of amine transaminases and to redirect their substrate specificity have been explored, including directed evolution, rational design and computation-supported engineering. The approaches used and results obtained are reviewed in this paper, showing that different strategies can be used in a complementary manner and can expand the applicability of amine transaminases in biocatalysis. [ABSTRACT FROM AUTHOR]

Food safety is a global public health issue, which often arises from asymmetric information between consumers and suppliers. With the development of information technology in human life, building a food traceability information sharing platform is viewed as one of the best ways to overcome the trust crisis and resolve the problem of information asymmetry in China. However, among the myriad information available from the food supply chain, there is a lack of knowledge on consumer preference. Based on the best-worst scaling approach, this paper investigated consumer preferences for vegetable, pork, and dairy product traceability information. Specifically, this paper measured the relative importance that consumers place on the traceable information. The results indicate that consumers have varying priorities for information in different cases. “Pesticide/veterinary use,” “picking/slaughtering date,” and “fertilizer/feed use” are the most preferred traceable information for Chinese consumers in the case of vegetables, while “picking/slaughtering date” and “history of illness and taking protective measures” are the most preferred information in the case of pork. In the case of dairy products, consumers prefer “processing information,” “environmental information of the origin,” and “traceable tag certification information” most. The results of this study call for the direct involvement of the Chinese government in the food safety information sharing system as following. First, given consumers’ diverse preferences, different types of traceable information should be recorded into the information sharing platform depending on food types. Second, the government could promote the step-by-step construction of such a platform based on the priority of consumers’ preferences. Third, new technology should be applied to guarantee the reliability of traceable information. Finally, local preferences in terms of the way consumers receive and understand information should be taken into consideration. [ABSTRACT FROM AUTHOR]

Artificial intelligence technologies such as machine learning have been applied to protein engineering, with unique advantages in protein structure, function prediction, catalytic activity, and other issues in recent years. Screening better mutants is still a bottleneck in protein engineering. In this paper, a new sequence-activity relationship method was analyzed for its application in improving the thermal stability of Aspergillus terreus (R)-ω-selective amine transaminase. The experimental data from 6 single-point mutated enzymes were used as a learning dataset to build models and predict the thermostability of 26 mutants. Based on digital signal processing (DSP), this method digitized the amino acid sequence of proteins by fast Fourier transform (FFT) and then established the best model applying partial least squares regression (PLSR) to screen out all possible mutants, especially those with high performance. In protein engineering, the innovative sequence activity relationship (ISAR) method can make a reasonable prediction using limited experimental data and significantly reduce the experimental cost. The half-life ( T 1 / 2 ) of (R)-ω-transaminase was fitted with the amino acid sequence by the ISAR algorithm, resulting in an R 2 of 0.8929 and a cvRMSE of 4.89. At the same time, the mutants with higher T 1 / 2 than the existing ones were predicted, laying the groundwork for better (R)-ω-transaminase in the later stage. The ISAR algorithm is expected to provide a new technique for protein evolution and screening. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The COVID-19 pandemic is progressing rapidly, sending the world into a great panic. Healthcare professionals have responded by embarking on a concerted search for therapies to cure and prevent COVID-19. Recently, interferon (IFN) has emerged as a potential therapy as it is associated with reducing lung inflammation and suppressing viral replication. This research paper assessed the efficacy of high-dose nebulized IFN α 2b in severe COVID-19 pneumonia. METHODS: This is a retrospective study. It commenced on April 9 and ended on June 17, 2020. Researchers selected participants from hospitalized patients aged 18 years and above who were diagnosed with severe COVID-19 pneumonia. Other inclusion criteria were bilateral pneumonia on lung or chest X-ray scan and severe respiratory distress. SMART-COP, which is a risk stratification scoring tool, and radiologic severity index (RSI) were used to assess pneumonia severity. Patients in the treatment cohort received nebulized IFN α 2b at a dose of 10 million IU every 12 hours for 5 days, in addition to standard treatment. Patients in the control cohort received standard treatment only. RESULTS: Seventy-three patients met the inclusion criteria; 37 were included in the treatment cohort and 36 in the control cohort. Mechanical ventilation was needed in 14 of 36 (38.9%) patients in the control cohort, compared with 6 of 37 (27.4%) patients in the treatment cohort (HR 5.62 [95% CI 1.81-17.48]; P = .003). For pneumonia severity, there was a hazard ratio (HR) of 3.72 [95% CI 1.74-7.98]; P = ·.01. After 5 days of treatment, chest X-rays indicated significant beneficial changes in the treatment group (HR 2.24 [CI 1.05-4.79]; P = .036). Multivariate analysis revealed that pneumonia severity and RSI remained higher in the control group. The HR was 3.44 [95% CI 1.49-7.94]; P = .004 and 2.26 [95% CI 0.99-5.16]; P = .05, respectively. There was an increase in liver aminotransferases in 5 (14%) participants in the control cohort and 3 (8%) participants in the treatment cohort. CONCLUSION: High-dose nebulized IFN α 2b has potential efficacy in mitigating severe COVID-19 pneumonia. This study established that administering high-dose nebulized IFN α 2b significantly reduces pneumonia severity in COVID-19 patients. We also found a strong relationship between using nebulized IFN α 2b and reduced need for mechanical ventilation among patients with severe COVID-19 pneumonia. However, a well-designed control trial is needed to confirm the drug's efficacy in reducing the COVID-19 pneumonia severity. [ABSTRACT FROM AUTHOR]

Simple Summary: The degree of liver damage after liver resection is generally assessed by serum ALT levels. Postoperative ALT levels may have a multifactorial cause correlated with the extent of resection, duration of surgery and of vascular clamping. Extensive and prolonged manipulation of the liver during open hepatectomy could also be correlated with hepatocyte injury. The aim of our study was to assess if a minimally invasive approach for liver resection, with less manipulation of the liver, may be associated with less transient hepatic damage and with consequent lower postoperative ALT levels than those detected after open hepatectomy. The results showed that liver resections performed using a minimally invasive approach were associated with significantly lower postoperative ALT values when compared with those performed by open approach. Moreover, the duration of hepatic pedicle clamping and multiple liver resections were independent predictors for high postoperative peak ALT levels on POD 1 and the minimally invasive approach showed a protective effect. Background: Postoperative serum ALT levels are one of the most frequently used marker to detect liver tissue damage following liver resection. The aim of this study was to evaluate if minimally invasive liver surgery (MILS) may result in less hepatic injury than open hepatectomy by assessing the differences of postoperative ALT levels. Methods: Patients who underwent MILS between 2009 and 2019 at our unit were included and compared with open liver resections. Median ALT levels was measured on postoperative day (POD) 1, 3 and 5. Postoperative peak transaminase (PPT) of ALT was determined on POD 1. The stabilized inverse probability treatment weighing (SIPTW) process was used to balance the two groups. A multivariable logistic regression analysis was used to analyze factors associated with high PPT. Results: After SIPTW, 292 MILS were compared with 159 open resections. Median ALT levels on POD 1, 3 and 5 were significantly higher in the open group than in the MILS group (301 vs. 187, p = 0.002; 180 vs. 121, p < 0.0001; 104 vs. 60, p < 0.0001; respectively). At the multivariable logistic regression analysis, MILS showed a protective effect for high PPT. Conclusions: MILS was associated with significantly lower postoperative ALT levels compared with open liver resections. MILS showed a protective effect for high PPT. [ABSTRACT FROM AUTHOR]

Background: There are contradictory effects regarding the effect of NAD + precursor on glucose metabolism and liver enzymes. In order to obtain a better viewpoint from them, this study aimed to comprehensively investigate the effects of NAD + precursor supplementation on glucose metabolism, C-reactive protein (CRP), and liver enzymes. Methods: PubMed/MEDLINE, Web of Science, SCOPUS, and Embase databases were searched using standard keywords to identify all controlled trials investigating the glucose metabolism, CRP, and liver enzymes effects of NAD + precursor. Pooled weighted mean difference (WMD) and 95% confidence intervals (95% CI) were achieved by random-effects model analysis for the best estimation of outcomes. Results: Forty-five articles with 9256 participants' were included in this article. The pooled findings showed that NAD + precursor supplementation had a significant increase in glucose (WMD: 2.17 mg/dL, 95% CI: 0.68, 3.66, P = 0.004) and HbA1c (WMD: 0.11, 95% CI: 0.06, 0.16, P < 0.001) as well as a significant decrease in CRP (WMD: -0.93 mg/l, 95% CI -1.47 to -0.40, P < 0.001) compared with control group, and was not statistically significant with respect to insulin and homeostasis model assessment of insulin resistance (HOMA-IR). However, we found no systemic changes in aspartate transaminase (AST), alanine transaminase (ALT), or alkaline phosphatase (ALP) levels after NAD + precursor supplementation. The results of the subgroup analysis showed that the intake of NAD + precursor during the intervention of more than 12 weeks caused a greater increase in the glucose level. Furthermore, Nicotinic acid supplementation (NA) causes a greater increase in glucose and HbA1c levels than nicotinamide (NE) supplementation. Conclusions: Overall, these findings suggest that NAD + precursor supplementation might have an increase effect on glucose metabolism as well as a decrease in CRP. [ABSTRACT FROM AUTHOR]

Aminotransferases (ATs) are an ancient enzyme family that play central roles in core nitrogen metabolism, essential to all organisms. However, many of the AT enzyme functions remain poorly defined, limiting our fundamental understanding of the nitrogen metabolic networks that exist in different organisms. Here, we traced the deep evolutionary history of the AT family by analyzing AT enzymes from 90 species spanning the tree of life (ToL). We found that each organism has maintained a relatively small and constant number of ATs. Mapping the distribution of ATs across the ToL uncovered that many essential AT reactions are carried out by taxon-specific AT enzymes due to wide-spread nonorthologous gene displacements. This complex evolutionary history explains the difficulty of homology-based AT functional prediction. Biochemical characterization of diverse aromatic ATs further revealed their broad substrate specificity, unlike other core metabolic enzymes that evolved to catalyze specific reactions today. Interestingly, however, we found that these AT enzymes that diverged over billion years share common signatures of multisubstrate specificity by employing different nonconserved active site residues. These findings illustrate that AT family enzymes had leveraged their inherent substrate promiscuity to maintain a small yet distinct set of multifunctional AT enzymes in different taxa. This evolutionary history of versatile ATs likely contributed to the establishment of robust and diverse nitrogen metabolic networks that exist throughout the ToL. The study provides a critical foundation to systematically determine diverse AT functions and underlying nitrogen metabolic networks across the ToL. [ABSTRACT FROM AUTHOR]

Background: Platelets were shown to be relevant for liver regeneration. In particular, platelet-stored serotonin (5-HT) proved to be a pro-regenerative factor in this process. The present study aimed to investigate the perioperative course of 5-HT and evaluate associations with patient and graft outcomes after othotopic liver transplantation (OLT). Methods: 5-HT was quantified in plasma and serum of 44 OLT recipients perioperatively, and in their respective donors. Olthoff's criteria for early allograft dysfunction (EAD) were used to evaluate postoperative outcomes. Results: Patients with higher donor intra-platelet 5-HT per platelet (IP 5-HT PP) values had significantly lower postoperative transaminases (ASAT POD1: p = 0.006, ASAT POD5: p = 0.006, ASAT POD10: p = 0.02, ALAT POD1: p = 0.034, ALAT POD5: p = 0.017, ALAT POD10: p = 0.04). No significant differences were seen between postoperative 5-HT values and the occurrence of EAD. A tendency was measured that donor IP 5-HT PP is lower in donor-recipient pairs that developed EAD (p = 0.07). Conclusions: Donor IP 5-HT PP might be linked to the postoperative development of EAD after OLT, as higher donor levels are correlated with a more favorable postoperative course of transaminases. Further studies with larger cohorts are needed to validate these findings. [ABSTRACT FROM AUTHOR]

Gallbladder small cell carcinoma (SCC) comprises only 0.5 % of all gallbladder cancer and consists of aggressive tumors with poor survival outcomes against current treatments. These tumors are most common in elderly females, particularly those with cholecystolithiasis. We report the case of a 79-year-old woman with gallbladder small cell carcinoma. The patient had intermittent right upper quadrant abdominal pain and was admitted to our hospital due to suspected acute cholecystitis. She regularly received medical treatment for diabetes, hypertension, and dyslipidemia. On initial laboratory evaluation, the levels of aspartate aminotransferase (AST), total bilirubin, and C-reactive protein (CRP) were markedly elevated. She underwent computed tomography (CT) for screening. CT images showed a thick-walled gallbladder containing multiple stones and multiple 3-cm-sized round nodular lesions, which were suggestive of metastatic lymph nodes. After percutaneous transhepatic gallbladder drainage was performed, endoscopic ultrasound-guided fine needle aspiration of enlarged lymph nodes resulted in a diagnosis of small cell carcinoma or adenocarcinoma. However, we could not identify the primary lesion before the surgery because of no decisive factors. We performed cholecystectomy because there was a possibility of cholecystitis recurrence risk and also partial liver resection because we suspected tumor invasion. The final pathological diagnosis was neuroendocrine carcinoma of the gallbladder, small cell type. The tumor stage was IVb, T3aN1M1. The patient died 13 weeks after the surgery. In the present paper, we review the current available English-language literature of gallbladder SCC. [ABSTRACT FROM AUTHOR]

Effect of cobalt manganese ferrite nanoparticles (M-NPs) (Co0.5Mn0.5Fe2O4) on vanadium hazards was assessment in the present study. Four groups of adult male albino rats [control group and three variably treated groups with ammonium metavanadate accompanied with or without cobalt M-NPs] were studied. The oral administration of ammonium metavanadate (Am.V) (20 mg/kg b.wt.) demonstrated the facility of vanadium to distribute and accumulate in the distinctive body organs and ordered as kidney > liver > lung > brain > spleen. Also, Am.V administration induce a significant disturbance in many physiological parameters (RBS, cholesterol, triglyceride, aspartate transaminase, alanine transaminase, Alb., bilirubin, Alk.Ph., urea, creat., Hb%, red blood cell count and packed cell volume) which might be expected to the liberation of free radicals according to the vanadium intoxication or its ability to disturb many body metabolisms. On the other hand, the intraperitoneal administration of 5% M-NPs in parallel with Am.V orally administration showed the ability of M-NPs to reduce Am.V dangerous impacts, which might be resulted from the essentiality of M-NPs metals to the body metabolism and to its free radicals scavenging properties. So, M-NPs could reduce Am.V hazardous effects. [ABSTRACT FROM AUTHOR]

Introduction and aim: Methamphetamine-use disorder is a pressing global public health issue. In Sudan, the escalating methamphetamine (METH) consumption has become a significant social and health problem. This study aims to evaluate liver and kidney biomarkers in methamphetamine addicts in Khartoum state Material and methods: The study was an analytical prospective cross-sectional hospital-based study. One hundred participants were enrolled in this study, fifty were cases (methamphetamine addicts), and others were healthy non-METH users as a comparative group. Results: METH users had a mean age of (27±7) years and had been using METH for an average of (14±9) months. Urea and creatinine levels were also significantly elevated in METH users compared to non-users, with p<0.001 and p=0.044, respectively. Their aspartate transaminase (AST) and alanine transaminase (ALT) levels were significantly higher compared to non-users, with p<0.001. Concusion: There was significant increases in creatinine, urea, and aminotransferases levels in the case group. ALT showed a moderate positive correlation with abuse duration, while AST showed no significant correlation. Urea and creatinine levels had strong and moderate positive correlations with abuse duration, respectively. [ABSTRACT FROM AUTHOR]

In all reported cases of foreign body migration or impaction in the biliary tree, there is no mention of the presence of hypereosinophilia among the laboratory findings. This could possibly be attributed to the local tissue reaction caused by the impacted foreign body. Here, we present our experience with the removal of a screw from a surgical retractor that became lodged in the common bile duct (CBD) and migrated in a patient who had previously undergone a left lateral hepatectomy for hepatic hydatidosis. The imaging was not sufficient to make a diagnosis, and the interpretation of hypereosinophilia in such a case could pose a challenge. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the addition of liquid cellulose, produced by Humicola grisea, in 21-day-old broiler chickens' diets. The treatments comprised control rations of corn and soybean meal and rations to which 500 mL/t and 1000 mL/t of cellulase were added. A total of 180 male broiler chickens were used, distributed in a completely randomized design, with three treatments and six replicates. Broiler chicken performance was monitored during the period from 1 to 21 days old. Significant effects were detected for digestibility only between four and seven days old, when a reduced dry matter nitrogen intake was recorded, and for nitrogen digestibility in the broilers fed cellulase-supplemented rations at a dose of 1000 m/L. Among the analyzed digestive organs, only the biometrics of the large intestine were affected significantly at seven days old. The absolute weights of the liver and pancreas and the activities of amylase, alkaline phosphatase, and transaminases were not affected significantly, indicating that cellulase did not affect the metabolism of these organs. No significant effect was detected in the serum for electrolytes, total protein, or alkaline phosphatase. So, the addition of liquid cellulase produced by Humicola grisea did not affect performance and metabolism in 21-day-old broiler chickens. [ABSTRACT FROM AUTHOR]

Our genetic background has not changed over the past century, but chronic diseases are on the rise globally. In addition to the genetic component, among the critical factors for many diseases are inhabitants of our intestines (gut microbiota) as a crucial environmental factor. Dysbiosis has been described in liver diseases with different etiologies like non-alcoholic fatty liver disease (NAFLD), alcohol-related liver disease (ALD), viral hepatitis, autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), cirrhosis, hepatocellular carcinoma (HCC). On the other hand, new technologies have increased our understanding of liver disease genetics and treatment options. Genome-wide association studies (GWAS) identify unknown genetic risk factors, positional cloning of unknown genes associated with different diseases, gene tests for single nucleotide variations (SNVs), and next-generation sequencing (NGS) of selected genes or the complete genome. NGS also allowed studying the microbiome and its role in various liver diseases has begun. These genes have proven their effect on microbiome composition in host genome–microbiome association studies. We focus on altering the intestinal microbiota, and supplementing some bacterial metabolites could be considered a potential therapeutic strategy. The literature data promote probiotics/synbiotics role in reducing proinflammatory cytokines such as TNF-α and the interleukins (IL-1, IL-6, IL-8), therefore improving transaminase levels, hepatic steatosis, and NAFLD activity score. However, even though microbial therapy appears to be risk-free, evaluating side effects related to probiotics or synbiotics is imperative. In addition, safety profiles for long-term usage should be researched. Thus, this review focuses on the human microbiome and liver diseases, recent GWASs on liver disease, the gut-liver axis, and the associations with the microbiome and microbiome during/after liver disease therapy. [ABSTRACT FROM AUTHOR]

Ursodeoxycholic acid (UDCA) is a hydrophilic bile acid deriving from 7β epimerization of primary bile compound chenodeoxycholic acid. It may have antioxidant, immunomodulatory, antifibrotic and cytoprotective effects, therefore it has been extensively used in the treatment of cholestatic chronic liver diseases (primary biliary cirrhosis, primary sclerosing cholangitis, cholestasis of pregnancy, etc.). Due to the effectiveness of UDCA in decreasing serum liver enzyme levels also in non-cholestatic patients with chronic liver damage of various etiologies, this bile acid is now extensively used in clinical practice in combination with standard therapies, or as alternative treatment. In this paper, after a review of the biochemistry and physiology of UDCA, we have analyzed available data from the international literature on the efficacy and safety of UDCA in patients with hypertransaminasemia due to non-cholestatic chronic liver diseases, such as chronic viral hepatitis B and C and liver steatosis, the three main causes of aminotransferase elevation in western countries. [ABSTRACT FROM AUTHOR]

Objective:Herbal medicine and medical plants such as Ziziphus Jujuba are widely used in the treatment of diseases such as diabetes mellitus. We investigated the effects of ethanol extracts of Ziziphus Jujuba fruit on serum glucose, triglycerides, LDL-cholesterol, HDL-cholesterol, cholesterol and activities of aminotransferase enzymes in streptozocin-induced diabetic adult male rats. Materials and Methods: Adult Wistar rats were rendered hyperglycemic. Animals were divided into four equal groups (7 per group). Animals in all groups were treated for 14 days. Blood samples were collected from the heart of the animals. Results: Continuous supplementation of ethanol extract in drinkable water of diabetic rats resulted to a significant decrease of fasting blood glucose, cholesterol and increase in high density lipoprotein levels after 14 days (P<0.05), but the levels of triglycerides, LDL-cholestrol, activities of alanine aminotransferase and aspartate aminotransferase did not changed significantly in treatment group compared to control group(P>0.05). Conclusion: This paper discussed the antidiabetic effect of an alcoholic extract of Ziziphus Jujuba on streptozocin-induced diabetes in rats. Researchers showed that Streptozocin injection led to diabetes mellitus, which may be due to destruction of β cells of the islets of Langerhans. [ABSTRACT FROM AUTHOR]

Please cite this paper as: Papic et al. (2011) Liver involvement during influenza infection: perspective on the 2009 influenza pandemic. Influenza and Other Respiratory Viruses 6(3), e2-e5. Elevation of liver transaminase levels is a frequent observation during systemic infections. The aim of our study was to investigate liver damage during pandemic 2009 influenza A/H1N1 infection in comparison with seasonal influenza. Serum levels of aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transpeptidase (GGT) were significantly higher in patients with pandemic influenza compared to seasonal influenza, which was strongly correlated with hypoxia. Moreover, a positive correlation between C-reactive protein and serum GGT, alkaline phosphatase, and lactate dehydrogenase was noticed. Our findings support the hypothesis that the pandemic 2009 influenza A/H1N1 is an illness with a significant immune response to infection leading to hepatocellular injury. [ABSTRACT FROM AUTHOR]

Auxin is an essential hormone, but its biosynthetic routes in plants have not been fully defined. In this paper, we show that the TRYPTOPHAN AMINOTRANSFERASE OF ARABIDOPSIS (TAA) family of amino transferases converts tryptophan to indole-3-pyruvate (IPA) and that the YUCCA (YUC) family of flavin monooxygenases participates in converting IPA to indole-3-acetic acid, the main auxin in plants. Both the YUCs and the TAAs have been shown to play essential roles in auxin biosynthesis, but it has been suggested that they participate in two independent pathways. Here, we show that all of the taa mutant phenotypes, including defects in shade avoidance, root resistance to ethylene and N-1-naphthylphthalamic acid (NPA), are phenocopied by inactivating YUC genes. On the other hand, we show that the taa mutants in several known auxin mutant backgrounds, including pid and npy1, mimic all of the well-characterized developmental defects caused by combining yuc mutants with the auxin mutants. Furthermore, we show that overexpression of YUC1 partially suppresses the shade avoidance defects of taa1 and the sterile phenotypes of the weak but not the strong taa mutants. In addition, we discovered that the auxin overproduction phenotypes of YUC overexpression lines are dependent on active TAA genes. Our genetic data show that YUC and TAA work in the same pathway and that YUC is downstream of TAA. The yuc mutants accumulate IPA, and the taa mutants are partially IPA-deficient, indicating that TAAs are responsible for converting tryptophan to IPA, whereas YUCs play an important role in converting IPA to indole-3-acetic acid. [ABSTRACT FROM AUTHOR]

Coagulopathy is an important complication associated with hepatitis E virus (HEV) infection in pregnant women. Postpartum haemorrhage (PPH) remains a serious risk while managing the labour of these women. The aim of this paper is to study the factors influencing the occurrence of PPH in pregnant women with hepatitis E infection with coagulopathy. The labours of 38 pregnant women with hepatitis E and deranged coagulation profile were followed. Factors that may predict postpartum bleeding complications in women with HEV infection and deranged coagulation profile were statistically analysed. Of 38 pregnant women with acute viral hepatitis due to HEV, 13 (34%) suffered a PPH while 25 (66%) did not. On univariate analysis low alanine aminotransferase (P = 0.016), high international normalized ratio (P = 0.003), high levels of D-dimer (P = 0.008), presence of hepatic encephalopathy (P = 0.028), intrauterine fetal death (P = 0.001) and gastrointestinal bleeding (P = 0.004) were found to predict PPH. However, on multivariate analysis the only independent variable that predicted PPH was the presence gastrointestinal (GI) bleeding (odds ratio [OR] 11.363; 95% CI: 1.003, 125; P = 0.050). Women with GI bleeding have 11 times higher risk of PPH than those without a GI bleed; however, the confidence interval is very wide. Administration of fresh frozen plasma in the peripartum period reduces the risk of PPH. In conclusion, early recognition of factors which predict the risk of PPH and timely intervention with judicious use of blood and blood components in the peripartum period can improve the outcome of pregnant women with HEV infection with deranged coagulation. [ABSTRACT FROM AUTHOR]

One of the major goals of pharmacogenetics is to elucidate mechanisms and identify patients at increased risk of adverse events (AEs). To date, however, there have been only a few successful examples of this type of approach. In this paper, we describe a retrospective case–control pharmacogenetic study of an AE of unknown mechanism, characterized by elevated levels of serum alanine aminotransferase (ALAT) during long-term treatment with the oral direct thrombin inhibitor ximelagatran. The study was based on 74 cases and 130 treated controls and included both a genome-wide tag single nucleotide polymorphism and large-scale candidate gene analysis. A strong genetic association between elevated ALAT and the MHC alleles DRB1*07 and DQA1*02 was discovered and replicated, suggesting a possible immune pathogenesis. Consistent with this hypothesis, immunological studies suggest that ximelagatran may have the ability to act as a contact sensitizer, and hence be able to stimulate an adaptive immune response.The Pharmacogenomics Journal (2008) 8, 186–195; doi:10.1038/sj.tpj.6500458; published online 15 May 2007 [ABSTRACT FROM AUTHOR]

Background: Metabolic syndrome (MetS) is a group of metabolic abnormalities characterised by hypertension, central obesity, dyslipidaemia and dysregulation of blood glucose, associated with the risk of diabetes, cardiovascular disease and overall mortality. The presence of elevated liver enzymes may precede the development of MetS, with alterations of the liver being observed that are directly related to metabolic problems. The study aims to provide the best evidence on the association between liver enzymes (ALT, AST, GGT) and MetS by determining the effect size of these biomarkers. Methods: A systematic review and meta-analysis of studies indexed in PubMed and Scopus databases were performed. Study quality was assessed using the STROBE tool. The Grade Pro tool was used to evaluate the evidence, and the quantitative synthesis was performed using RevMan (Cochrane Collaboration). Results: Seventeen articles comparing liver enzyme concentrations between 76,686 with MetS (MetS+) and 201,855 without MetS (MetS-) subjects were included. The concentration of ALT, AST and GGT in the MetS + subjects was significantly higher than in the control group 7.13 IU/L (CI95% 5.73–8.54; p < 0.00001; I2 = 96%), 2.68 IU/L (CI95% 1.82–3.54; p < 0.00001; I2 = 96%) and 11.20 IU/L (CI95% 7.11–15.29; p < 0.00001; I2 = 96%), respectively. Conclusions: The evaluation of the relationship of liver enzymes in the pathophysiological process of MetS could lead to new insights into early diagnosis. [ABSTRACT FROM AUTHOR]

Diterpenoid alkaloids (DAs) have been often utilized in clinical practice due to their analgesic and anti‐inflammatory properties. Natural DAs are prevalent in the family Ranunculaceae, notably in the Aconitum genus. Nevertheless, the evolutionary origin of the biosynthesis pathway responsible for DA production remains unknown. In this study, we successfully assembled a high‐quality, pseudochromosome‐level genome of the DA‐rich species Aconitum vilmorinianum (A. vilmorinianum) (5.76 Gb). An A. vilmorinianum‐specific whole‐genome duplication event was discovered using comparative genomic analysis, which may aid in the evolution of the DA biosynthesis pathway. We identified several genes involved in DA biosynthesis via integrated genomic, transcriptomic, and metabolomic analyses. These genes included enzymes encoding target ent‐kaurene oxidases and aminotransferases, which facilitated the activation of diterpenes and insertion of nitrogen atoms into diterpene skeletons, thereby mediating the transformation of diterpenes into DAs. The divergence periods of these genes in A. vilmorinianum were further assessed, and it was shown that two major types of genes were involved in the establishment of the DA biosynthesis pathway. Our integrated analysis offers fresh insights into the evolutionary origin of DAs in A. vilmorinianum as well as suggestions for engineering the biosynthetic pathways to obtain desired DAs. [ABSTRACT FROM AUTHOR]

The assessment of the nutritional and inflammatory status of paediatric patients with coeliac disease is an interesting approach to early diagnosis and functional follow-up. Most authors agree that the normalisation of symptoms takes about one year. The aim of the study was to evaluate the clinical manifestation and normalisation of routine analytics in Spanish children diagnosed with celiac disease. Methods: We performed a retrospective case–control study in Spanish paediatric patients, including 21 celiac patients and 20 healthy controls. The 21 patients selected in the case–control study were followed for 5 years after starting a gluten-free diet (GFD). All patients had type 3 villous atrophy according to the Marsh–Oberhuber classification. A total of 39 blood samples were taken before the start of the GFD, and 109 were taken after. Twenty control sera from healthy donors were used for comparison. Results: We found that patients had a subclinical but statistically significant increase in blood calcium, transaminases, and white blood cells, and a decrease in serum iron, at the time of diagnosis. Our study also shows that analytical values normalise within five years on a gluten-free diet. Conclusions: The use of a combination of subclinical changes, including low iron, high calcium, elevated leukocytes, lymphocytes, and ALT levels in blood samples, together with a low growth percentile, is pertinent in detecting coeliac disease. This set of parameters could help in the diagnosis of patients without clinical symptoms. We can also show that the levels of Fe, Ca, transaminases, and leucocytes remain subclinically altered after 3 years, despite the gluten-free diet. [ABSTRACT FROM AUTHOR]

This paper presents the first purification of the mitochondrial branched‐chain amino acid aminotransferase (BCATm) from sheep placenta. It is a homodimer with an apparent subunit molecular mass of 41 kDa. The enzyme differs from those of the rat and human as it appears to form at least one intermolecular disulfide bond. The sheep BCATm cDNA (1.4 kb) encodes a mature polypeptide of 366 amino acids with a calculated molecular mass of 41 329 Da and a partial mitochondrial targeting sequence of seven amino acids. The sheep BCATm sequence shares higher identity with other mammalian BCATm isoenzymes (82–85%) than with the cytosolic isoenzymes (60%). By Northern blot analysis, a message of 1.7 kb was detected in sheep placenta and skeletal muscle. Measurements of BCAT activity, mRNA and BCATm protein in sheep placenta and skeletal muscle revealed that BCATm is the sole BCAT isoenzyme expressed in placenta, whereas it contributes 57 and 71% of the BCAT activity in tensor fascia latae and masseter muscles from weaned lambs respectively. Skeletal muscle, the main site of branched‐chain amino acid transamination, exhibits significantly lower BCAT activity in sheep than in rat. Our results suggest that the low BCATm mRNA level probably accounts for the low BCAT activity in sheep skeletal muscle, and that the metabolic scheme for branched‐chain amino acid catabolism is specific to each species. [ABSTRACT FROM AUTHOR]

The subcellular distribution of hepatic alanine:glyoxylate aminotransferase 1 (AGT) has changed, under the influence of dietary selection pressure, on several o occasions during the evolution of mammals. In some species (e.g. human and rabbit) AGT is entirely peroxisomal; in other species (e.g. marmoset and rat) this enzyme is found in similar amounts in peroxisomes and mitochondria; in yet other species (e.g. cat) it is mainly mitochondrial. The molecular basis of the species-specific dual intracellular targeting of AGT has been partially elucidated in the human and rabbit (as examples of the first group), and in the rat and marmoset (as examples of the second group). As part of a wider study on the molecular evolution of AGT intracellular targeting, we report in the present paper the results of an investigation into the molecular basis of the subcellular distribution of AGT in the cat (as an example of the third group). Cat liver AGT cDNA has been cloned and sequenced, and shown to have a high degree of similarity to AGT from human, rabbit, marmoset and rat. Southern-blotting analysis showed that AGT in the cat is probably encoded by a single gene, as it is in other species. Transcript analysis by RNase protection indicated that almost all of the AGT mRNA would possess an open reading frame encoding a polypeptide of 414 amino acids and a molecular mass of 45,508 Da. The N-terminal 22 amino acids comprised the putative mitochondrial-targeting sequence (by analogy with the equivalent sequence in marmoset and rat pre-mitochondrial AGT). The very low level of peroxisomal AGT in cat liver is compatible with the absence of any RNase-protected transcripts initiating downstream of the first putative translation initiation codon (i.e. absence of any transcripts in which the mitochondrial-targeting sequence is excluded from the open reading frame). [ABSTRACT FROM AUTHOR]

Fatty acid β-oxidation in peroxisomes requires the continued uptake of fatty acids or their derivatives into peroxisomes and export of β-oxidation products plus oxidation of NADH to NAD. in an earlier study we provided evidence for the existence of an NAD(H) redox shuttle in which peroxisomal malate dehydrogenase plays a pivotal role. In analogy to the NAD(H)-redox-shuttle systems in mitochondria we have investigated whether a malate/aspartate shuttle is operative in peroxisomes. The results described in this paper show that peroxisomes of oleate-grown Saccharomyces cerevisiae contain aspartate aminotransferase (AAT) activity. Whereas virtually all cellular AAT activity was peroxisomal in oleate-grown cells, we found that in glucose-grown cells most of the AAT activity resided in the cytosol. We demonstrate that the gene AAT2 codes for the cytosolic and peroxisomal AAT activities. Disruption of the AAT2 gene did not affect growth on oleate. Furthermore β-oxidation of palmitate was normal. These results indicate that AAT2 is not essential for the peroxisomal NAD(H) redox shuttle. [ABSTRACT FROM AUTHOR]

1. Tryptic hydrolysates of denaturated glutamic-aspartic transaminase fractionated on a Sephadex G-25 column, gave an elution diagram containing six main fractions. When peptide maps were developed from the transaminase digest 37 spots were detected on the paper sheet. 2. It was demonstrated that the transaminase fractions (groups of peptides) as well as some of the individual peptides eluted from the map spots, possessed immunological activity. This was proved by their capacity to interact with rabbit pig heart antienzyme and rabbit antiserum against the pig-heart whole tryptic transaminase hydrolysate as well as to inhibit the homologous transaminase-antitransaminase reaction. Higher immunological reactivity was found among peptides moving faster in electrophoresis and chromatography. 3. The catalytic activity of rabbit transaminase (heart, liver, skeletal muscles), was inhibited to a substantial degree by the rabbit anti-pig heart transaminase. The above enzymes however, as was otherwise expected, gave negative precipitin reactions with antitransaminase. A comparative study of the reactivity between transaminases from pig, ox and rabbit and rabbit anti-transaminase against pig and ox heart enzymes as well as against pig-heart whole tryptic transaminase hydrolysate is presented here. [ABSTRACT FROM AUTHOR]

Linked Content This article is linked to Liberal et al paper. To view this article visit https://doi.org/10.1111/apt.13907. [ABSTRACT FROM AUTHOR]

Glutamate is excitotoxic to neurons. The entry of glutamine or glutamate from the blood into the brain is limited. To overcome this, branched-chain amino acids (BCAAs) catabolism replenishes the glutamate in brain cells. Branched-chain amino acid transaminase 1 (BCAT1) activity is silenced by epigenetic methylation in IDH mutant gliomas. However, glioblastomas (GBMs) express wild type IDH. Here, we investigated how oxidative stress promotes BCAAs' metabolism to maintain intracellular redox balance and, consequently, the rapid progression of GBMs. We found that reactive oxygen species (ROS) accumulation promoted the nuclear translocation of lactate dehydrogenase A (LDHA), which triggered DOT1L (disruptor of telomeric silencing 1-like)-mediated histone H3K79 hypermethylation and enhanced BCAA catabolism in GBM cells. Glutamate derived from BCAAs catabolism participates in antioxidant thioredoxin (TxN) production. The inhibition of BCAT1 decreased the tumorigenicity of GBM cells in orthotopically transplanted nude mice, and prolonged their survival time. In GBM samples, BCAT1 expression was negatively correlated with the overall survival time (OS) of patients. These findings highlight the role of the non-canonical enzyme activity of LDHA on BCAT1 expression, which links the two major metabolic pathways in GBMs. Glutamate produced by the catabolism of BCAAs was involved in complementary antioxidant TxN synthesis to balance the redox state in tumor cells and promote the progression of GBMs. [ABSTRACT FROM AUTHOR]

Serine:glyoxylate aminotransferase (SGAT) converts glyoxylate and serine to glycine and hydroxypyruvate during photorespiration. Besides this, SGAT operates with several other substrates including asparagine. The impact of this enzymatic promiscuity on plant metabolism, particularly photorespiration and serine biosynthesis, is poorly understood. We found that elevated SGAT activity causes surprisingly clear changes in metabolism and interferes with photosynthetic CO2 uptake and biomass accumulation of Arabidopsis. The faster serine turnover during photorespiration progressively lowers day-time leaf serine contents and in turn induces the phosphoserine pathway. Transcriptional upregulation of this additional route of serine biosynthesis occurs already during the day but particularly at night, efficiently counteracting night-time serine depletion. Additionally, higher SGAT activity results in an increased use of asparagine as the external donor of amino groups to the photorespiratory pathway but does not alter leaf asparagine content at night. These results suggest leaf SGAT activity needs to be dynamically adjusted to ensure (i) variable flux through the photorespiratory pathway at a minimal consumption of asparagine and (ii) adequate serine levels for other cellular metabolism. [ABSTRACT FROM AUTHOR]

Simple Summary: This review reports the risk and management of the hepatotoxicity of all the approved protein kinase inhibitors (PKIs) for cancer. Hepatotoxicity is one of the major safety concerns of these drugs, as reflected by the discontinuation of the development of some of them due to liver injury, or by the significant number of warnings for hepatotoxicity reported in drug labeling. Although these side effects are usually reversible by dose adjustment or therapy suspension, or by switching to an alternative PKI, and fatality is uncommon, all patients undergoing these drugs should be carefully pre-evaluated and monitored during treatment. Small molecule protein kinase inhibitors (PKIs) have become an effective strategy for cancer patients. However, hepatotoxicity is a major safety concern of these drugs, since the majority are reported to increase transaminases, and few of them (Idelalisib, Lapatinib, Pazopanib, Pexidartinib, Ponatinib, Regorafenib, Sunitinib) have a boxed label warning. The exact rate of PKI-induced hepatoxicity is not well defined due to the fact that the majority of data arise from pre-registration or registration trials on fairly selected patients, and the post-marketing data are often based only on the most severe described cases, whereas most real practice studies do not include drug-related hepatotoxicity as an end point. Although these side effects are usually reversible by dose adjustment or therapy suspension, or by switching to an alternative PKI, and fatality is uncommon, all patients undergoing PKIs should be carefully pre-evaluated and monitored. The management of this complication requires an individually tailored reappraisal of the risk/benefit ratio, especially in patients who are responding to therapy. This review reports the currently available data on the risk and management of hepatotoxicity of all the approved PKIs. [ABSTRACT FROM AUTHOR]

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One of the main factors hampering the implementation in industry of transaminase-based processes for the synthesis of enantiopure amines is their often low storage and operational stability. Our still limited understanding of the inactivation processes undermining the stability of wild-type transaminases represents an obstacle to improving their stability through enzyme engineering. In this paper we present a model describing the inactivation process of the well-characterized (S)-selective amine transaminase from Chromobacterium violaceum. The cornerstone of the model, supported by structural, computational, mutagenesis and biophysical data, is the central role of the catalytic lysine as a conformational switch. Upon breakage of the lysine-PLP Schiff base, the strain associated with the catalytically active lysine conformation is dissipated in a slow relaxation process capable of triggering the known structural rearrangements occurring in the holo-to-apo transition and ultimately promoting dimer dissociation. Due to the occurrence in the literature of similar PLP-dependent inactivation models valid for other non-transaminase enzymes belonging to the same fold-class, the role of the catalytic lysine as conformational switch might extend beyond the transaminase enzyme group and offer new insight to drive future non-trivial engineering strategies. [ABSTRACT FROM AUTHOR]

Aim of the study: Significant fibrosis is an indication for treatment in hepatitis B patients with normal transaminase levels. The present study was aimed at analyzing the factors associated with significant fibrosis in incidentally detected asymptomatic hepatitis B subjects (IDAHS) and developing a model for fibrosis prediction for use in low-resource settings. Material and methods: This is a single-center retrospective analysis of data on IDAHS who had undergone FibroScan. The variables associated with significant fibrosis in the derivation cohort were subjected to multivariate analysis by logistic regression. The model was applied to the validation cohort for fibrosis prediction. Results: A total of 299 patients (mean age: 42.6 years, males: 63.2%) were included in the model derivation. Significant fibrosis was found in 27.4% (82/299) of the patients and 16.8% (30/178) of those with normal transaminase. On multivariate analysis, age, lower platelet count, and presence of diabetes were associated with fibrosis. Serum glutamic pyruvic transaminase (SGPT) was included in the model as it was nearing towards in multivariate analysis. The DAPS (diabetes, age, platelet count, SGPT) score was proposed with equal weightage to each variable. Based on the cumulative score, patients were categorized as having low risk (DAPS score 0-2) or high risk (DAPS score 3-4). The specificity of the model in derivation and validation cohorts was 98.2% and 97.6%, respectively, while the accuracy was 83.6% and 80%, respectively. Conclusions: Approximately 17% of IDAHS with normal transaminase have significant fibrosis. The DAPS score can be used easily as a bedside tool for assessment of significant fibrosis in IDAHS with excellent specificity. [ABSTRACT FROM AUTHOR]

Background: Rhabdomyolysis is caused by the release of enzymes from skeletal muscles into the blood, which leads to systemic complications with diverse etiologies. This study evaluated the serum aminotransferases in patients with rhabdomyolysis following acute intoxication with either psychotropic drugs or other chemical agents. Methods: This study randomly recruited 140 patients suffering from rhabdomyolysis. They were divided into two groups affected by either psychotropic drugs or chemical agents. Rhabdomyolysis was defined as having serum creatine kinase (CK) levels greater than 250 U/L, based on the poisoning severity score. Results: On day 1, the CK/AST correlation was significantly stronger in the psychotropic than the chemical group (P=0.0009). On day 5, patients in the psychotropic group had significantly higher AST (P=0.0138) and ALT (P=0.0129) than those poisoned with other chemicals. The difference in the strength of the CK/ALT correlation between the two groups was insignificant. Between the two groups, the differences between the CK levels and the following serum parameters were insignificant: Alkaline phosphatase; gamma-glutamyl transferase; prothrombin time; total bilirubin; and albumin. Conclusion: The elevated aminotransferases in patients with rhabdomyolysis due to acute psychotropic toxicity might have resulted from the skeletal muscle injury rather than hepatotoxicity. In rhabdomyolysis patients poisoned with other chemicals, the elevated serum aminotransferases are likely due to liver toxicity arising from the consumed substances. These patients are likely to manifest clinically severe long-term multi-organ failure. Intoxications with typical agents, such as herbicides, petroleum distillates, and corrosives were responsible for the rhabdomyolysis in the second group. [ABSTRACT FROM AUTHOR]

Background. Gastric cancer (GC) is one of the gastrointestinal tumors with the highest mortality rate. The number of GC patients is still high. As a way of iron-dependent programmed cell death, ferroptosis activates lipid peroxidation and accumulates large reactive oxygen species. The role of ferroptosis in GC prognosis was underrepresented. The objective was to investigate the role of ferroptosis-related genes (FRGs) in the prognosis and development of GC. Methods. Datasets of GC patients were obtained from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) database that include clinical information and RNA seq data. Through nonnegative matrix factorization (NMF) clustering, we identified and unsupervised cluster analysis of the expression matrix of FRGs. And we constructed the co-expression network between genes and clinical characteristics by consensus weighted gene co-expression network analysis (WGCNA). The prognostic model was constructed by univariate and multivariate regression analysis. The potential mechanisms of development and prognosis in GC were explored by Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, gene ontology (GO), tumor immune microenvironment (TIME), and tumor mutation burden (TMB). Results. Two molecular subclusters with different expression patterns of FRGs were identified, which have significantly different survival states. Ferroptosis subcluster-related modular genes were identified by WGCNA. Based on 8 ferroptosis subcluster-related modular genes (collagen triple helix repeat containing 1 (CTHRC1), podoplanin (PDPN), procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (PLOD2), glutamine-fructose-6-phosphate transaminase 2 (GFPT2), ATP-binding cassette subfamily A member 1 (ABCA1), G protein-coupled receptor 176 (GPR176), serpin family E member 1 (SERPINE1), dual specificity phosphatase 1 (DUSP1)) and clinicopathological features, a nomogram was constructed and validated for their predictive efficiency on GC prognosis. Through receiver operating characteristic (ROC) analysis, the results showed that the area under the curve (AUC) of 1-, 3-, and 5-year survival were 0.721, 0.747, and 0.803, respectively, indicating that the risk-scoring model we constructed had good prognosis efficacy in GC. The degree of immune infiltration in high-risk group was largely higher than low-risk group. It indicated that the immune cells have a good response in high-risk group of GC. The TMB of high-risk group was higher, which could generate more mutations and was more conducive to the body's resistance to the development of cancer. Conclusion. The risk-scoring model based on 8 ferroptosis subcluster-related modular genes has shown outstanding advantages in predicting patient prognosis. The interaction of ferroptosis in GC development may provide new insights into exploring molecular mechanisms and targeted therapies for GC patients. [ABSTRACT FROM AUTHOR]

Background: Type 2 Diabetes Mellitus (T2DM) is one of the health issues causing untoward low-grade systemic inflammation. Aerobic Training (AT) and Vitamin D (Vit D) supplementation are among the approaches that improve lipid profile and liver enzymes in T2DM. However, the mechanisms responsible for these improvements are not fully elucidated. Objectives: This study aimed to evaluate the effects of AT and Vit D supplementation on lipid profile, liver enzymes, Interleukin-6 (IL-6), Interleukin-10 (IL-10), Cluster of differentiation 27 (CD27), Chemokine (C-X-C motif) Ligand 13 (CXCL13), Interferon-Gamma (IFN-γ) and Transforming Growth Factor-Beta 1 (TGF-β1) gene expressions in patients with T2DM. Methods: In this study, 40 male T2DM patients aged 35–50 years were randomly selected and assigned into four groups (n = 10 for each); AT+vitamin D supplementation (AT+Vit D), AT+placebo (AT), Vit D supplementation (Vit D), and control+placebo (C). The intervention consisted of 8 weeks of 20–40 minutes AT protocol at 60–75% HRmax 3 sessions/week and taking 50,000 IU of Vit D supplement once a week. Serum levels of lipid profile and liver enzymes and gene expression of IL-6, IL-10, CD27, CXCL13, IFN-γ, and TGF-β1 in Peripheral Blood Mononuclear Cells (PBMCs) were measured. One-way analysis of variance (ANOVA), Tukey's post hoc, and paired sample t-test at P-values less than 0.05 were used to analyze the data using SPSS software. Results: AT+Vit D, AT, and Vit D significantly decreased TC, TG, LDL, AST, ALT, and GGT while increased HDL after 8 weeks in favor of AT+Vit D. Also, gene expressions of IL-6, IL-10, CD27, CXCL13, IFN-γ, and TGF-β1 were downregulated significantly in AT+Vit D, AT, and Vit D, while upregulated in C. Furthermore, compared to individual AT or Vit D, AT+Vit D significantly downregulated IL-6 (P = 0.013; P = 0.025), IL-10 (P = 0.012; P = 0.026), CD27 (P = 0.023; P = 0.041), CXCL13 (P = 0.014; P = 0.025), IFN-γ (P = 0.017; P = 0.026), and TGF-β1 (P = 0.001; P = 0.028). Conclusion: In comparison to individual AT or Vit D, AT+Vit D may enhance lipid profile, and liver enzymes and drive the balance to favor inhibition of inflammation by downregulating gene expression of inflammation-related factors. As a result, AT+Vit D may be considered appropriate therapy for managing T2DM. [ABSTRACT FROM AUTHOR]

Objective. To observe the improvement effect of aerobic exercise on liver tissue of rats with NAFLD, explore whether it can reduce NAFLD symptoms without drug dependence, and provide certain data support for the relief of NAFLD by aerobic exercise. Methods. 40 healthful male SD rats have been divided into ordinary diet and high-fat diet. To observe whether the molding is forming after 6 weeks, then divide the rats into control (C), model (M), and exercise (E) group. E group received 8-week aerobic exercise intervention. Serum and liver samples were taken and analyzed after the last intervention. Results. The morphological of hepatocytes between C and M group becomes different, and the accumulation of fat and inflammatory cells was significant, suggesting that NAFLD symptoms appeared, that is, the model was successfully established. Compared with M group, the morphology of rats in E group was improved in varying degrees. The quantity of ALT, AST, and MDA of rats in M group is increased, and the SOD activity is significantly reduced (P < 0.01). However, aerobic exercise intervention changed those result (P < 0.01). Conclusions. Aerobic exercise can relieve oxidative stress damage, lipid peroxidation levels, and chronic inflammatory status in rats with NAFLD, which can reduce NAFLD symptoms without drug dependence, and is expected to become a means of NAFLD treatment. [ABSTRACT FROM AUTHOR]

Transaminases play key roles in central metabolism, transferring the amino group from a donor substrate to an acceptor. These enzymes can often act, with low efficiency, on compounds different from the preferred substrates. To understand what might have shaped the substrate specificity of this class of enzymes, we examined the reactivity of six human cytosolic transaminases towards amino acids whose main degradative pathways do not include any transamination. We also tested whether sugars and sugar phosphates could serve as alternative amino group acceptors for these cytosolic enzymes. Each of the six aminotransferases reacted appreciably with at least three of the alternative amino acid substrates in vitro, albeit at usually feeble rates. Reactions with L-Thr, L-Arg, L-Lys and L-Asn were consistently very slow—a bias explained in part by the structural differences between these amino acids and the preferred substrates of the transaminases. On the other hand, L-His and L-Trp reacted more efficiently, particularly with GTK (glutamine transaminase K; also known as KYAT1). This points towards a role of GTK in the salvage of L-Trp (in cooperation with ω-amidase and possibly with the cytosolic malate dehydrogenase, MDH1, which efficiently reduced the product of L-Trp transamination). Finally, the transaminases were extremely ineffective at utilizing sugars and sugar derivatives, with the exception of the glycolytic intermediate dihydroxyacetone phosphate, which was slowly but appreciably transaminated by some of the enzymes to yield serinol phosphate. Evidence for the formation of this compound in a human cell line was also obtained. We discuss the biological and evolutionary implications of our results. [ABSTRACT FROM AUTHOR]

Objective. The side effects of chemotherapy as a treatment of liver cancer cannot be ignored. Grain-sized moxibustion, a characteristic external therapy, has been shown to reduce the toxic and side effects of chemotherapy and regulate the immune function. The purpose of this study was to explore the synergistic antitumor activity of grain-sized moxibustion combined with cyclophosphamide (CTX). Methods. A hepatoma 1–6 (Hepa1-6)-bearing mouse model was established by injecting mice with Hepa1-6 cancer cells. CTX and grain-sized moxibustion on Dazhui (DU14), Zusanli (ST36), and Sanyinjiao (SP6) were used for treatment, and mouse survival status, body weight, and tumor growth, weight, and volume were measured. White blood cells (WBCs) and bone marrow nucleated cells (BMNCs) were quantified. The spleens and livers of Hepa1-6-bearing mice were pathologically examined and scored. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were measured with enzyme-linked immunosorbent assay (ELISA) kits, and protein and mRNA expression levels of Ki67 and proliferating cell nuclear antigen (PCNA) in tumor tissues were measured with immunohistochemistry and real-time quantitative polymerase chain reaction (RT-qPCR) techniques. Results. Both grain-sized moxibustion and CTX could restrain the growth of Hepa1-6 tumors, reducing both tumor volume and weight; the combined treatment had a greater effect. Grain-sized moxibustion down-regulated the expression of proliferation genes Ki67 and PCNA, weakened the proliferation ability of Hepa1-6 tumor cells, inhibited tumor growth, and enhanced the antitumor effect of CTX. In addition, grain-sized moxibustion significantly improved the signs of CTX-induced toxicity (including weight loss, leukopenia, bone marrow suppression, and hepatotoxicity), down-regulated serum AST and ALT levels, reduced spleen and liver inflammation, and improved liver and spleen indices. Conclusion. Grain-sized moxibustion can synergize with CTX to enhance the antitumor effect of CTX and alleviate its toxic and side effects. It may be a promising adjuvant therapy to chemotherapy. [ABSTRACT FROM AUTHOR]

Endotoxemia is mainly caused by a massive burst of inflammatory cytokines as a result of lipopolysaccharide (LPS) invasion. Chitooligosaccharides (COS) is expected to be a potential drug for relieving endotoxemia due to its anti-inflammatory properties. However, the structural parameters of COS are often ambiguous, and the effect of degree of acetylation (DA) of COS on its anti-inflammatory remains unknown. In this study, four COSs with different DAs (0%, 12%, 50% and 85%) and the same oligomers distribution were successfully obtained. Their structures were confirmed by 1H NMR and MS analysis. Then, the effect of DA on the anti-inflammatory activity and relieving endotoxemia potential of COS was researched. The results revealed that COS with a DA of 12% had better anti-inflammatory activity than COSs with other DAs, mainly in inhibiting LPS-induced inflammatory cytokines burst, down-regulating its mRNA expression and reducing phosphorylation of IκBα. Furthermore, this COS showed an obviously protective effect on endotoxemia mice, such as inhibiting the increase in inflammatory cytokines and transaminases, alleviating the injury of liver and intestinal tissue. This study explored the effect of DA on the anti-inflammatory activity of COS for the first time and lays the foundation for the development of COS as an anti-inflammatory drug against endotoxemia. [ABSTRACT FROM AUTHOR]

In this study we consider the theoretical coupling of an otherwise thermodynamically limited ω-transaminase reaction to an Oppenauer oxidation, in order to shift the equilibria of both reactions, with the aim of achieving a significant (and important) increase in the yield of the desired chiral amine product. Using 2-propylamine as the amine donor of the ω-transaminase reaction, gives acetone as a by-product, which in turn allows the coupling of the ω-transaminase reaction with the Oppenauer oxidation. The Oppenauer reaction converts secondary alcohols into ketones, and these can subsequently be fed to the ω-transaminase reaction. In this way, one of the products of the ω-transaminase reaction becomes the reactant of the Oppenauer reaction, and vice versa , creating a cycle which shifts the equilibria of both reactions. Such coupled reactions are frequently found in nature. The purpose of this paper is to report the development of a mathematical model as a tool for the simulation and potential design of such a process for the production of a range of chiral amines. The mathematical model developed considers that each reaction is performed in a single ideally mixed isothermal reactor operating sequentially in fed batch–batch mode. Both reactors are interconnected through a semi-permeable membrane, where multicomponent intra-membrane transport takes place by diffusion and viscous flow. The kinetic modeling of both reactions has been carried out and model simulations show that in this way a significant increase in the yield of the chiral amine product may be obtained. Finally, the role of the different parameters involved in the process model has been analyzed. [ABSTRACT FROM AUTHOR]

Paracetamol is a commonly used analgesic/antipyretic whose long-term intake or overdose is associated with renal and hepatic injuries. The aim of this study was to determine the hepatonephroprotective mechanisms of the aqueous extract of Amblygonocarpus andongensis stem bark (AEAASB) on renal and hepatic failure resulting from paracetamol overdose. Forty-five rats were divided into nine groups (n = 5); these were treated once daily for 8 days with 5 ml/kg distilled water (normal, negative, and satellite controls); 0.9% normal saline and 140 mg/kg N-acetyl-cysteine (positive controls); 125, 250, and 500 mg/kg AEAASB (test groups); and 500 mg/kg AEAASB (satellite test). On day 8 after different treatments, hepatonephrotoxicity was induced in all the groups except the normal group by oral administration of a single dose of paracetamol (1000 mg/kg). Urinary, hematological, serum, and oxidative stress parameters and in vitro antioxidant activity of AEAASB were evaluated. Histological sections of the liver and kidney were performed. AEAASB significantly decreased urea, creatinine, transaminases, alkaline phosphatase, and bilirubin (p < 0.001) at 500 mg/kg compared to the negative control. Significant decreases in hepatic (p < 0.01) and renal (p < 0.001) malondialdehyde levels were associated with increases in superoxide dismutase, catalase, and reduced glutathione levels in 500 mg/kg AEAASB compared with the negative control. Histological analysis showed that AEAASB prevented paracetamol-induced renal and liver tissue damage. Furthermore, AEAASB revealed a very strong antioxidant activity (inhibitory concentration 50 = 180 μ g / ml , antioxidant activity index = 5.55) with an ability to scavenge 63.03% 2,2-diphenyl-2-picrylhy-drazyl radical and reduced ferric iron by 52.68 mgEqVitC/100 g DM. The hepatonephroprotective effect of AEAASB might result from its ability to improve the antioxidant status through the stimulation of antioxidant factors and the scavenging of free radicals. This property could be ascribed to the presence of some classes of bioactive compounds such as phenolic compounds in great amounts. [ABSTRACT FROM AUTHOR]

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