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Background: Diabetes mellitus (DM) is highly consequential to global health among chronic diseases. Due to a limited researches that have examined relationships between liver enzymes and DM, this study aimed to investigate the link between elevated liver enzymes and diabetes among Prospective Epidemiological Research Studies in Iran (PERSIAN) Guilan cohort study (PGCS) population. Methods: This cross-sectional study was conducted on 10519 individuals. The demographic and clinical information of the participants was recorded. The changes in alanine aminotransferases (ALT) and aspartate aminotransferases (AST), alkaline phosphatase (ALP), and γ-glutamyltransferase (GGT) were evaluated. IBM SPSS Version 21 was used to analyze the data, with a significance level < 0.05. Results: The frequency of diabetes was 24.1% and was more prevalent in women than men (27.4% vs. 20.2%, p< 0.001). After removing all confederates, patients with elevated ALT, AST, GGT, and ALP levels were 1.27, 1.27, 1.52, and 1.46 times more likely to have diabetes, respectively. The likelihood of developing diabetes rose in correlation with the number of elevated liver enzymes, up to almost 1.77-fold among subjects with three or four increased liver enzymes. Conclusion: Patients diagnosed with diabetes exhibited significantly increased levels of liver enzymes compared to those without diabetes. Also, impairment of three or four liver enzymes demonstrated a positive correlation with an elevated likelihood of DM. This indicates the importance of considering the liver status in the management of the DM population. [ABSTRACT FROM AUTHOR]

The first monomeric pyridoxal-5′-phosphate (PLP)-dependent transaminase from a marine, aromatic-compound-degrading, sulfate-reducing bacterium Desulfobacula toluolica Tol2, has been studied using structural, kinetic, and spectral methods. The monomeric organization of the transaminase was confirmed by both gel filtration and crystallography. The PLP-dependent transaminase is of the fold type IV and deaminates D-alanine and (R)-phenylethylamine in half-reactions. The enzyme shows high stereoselectivity; no deamination of L-amino acids and (S)-phenylethylamine is detected. Structural analysis and subsequent mutagenesis led to the conclusion that the monomeric architecture of the enzyme is the only one possible and sufficient for stereoselectivity and PLP binding, but not for the overall double-substrate transamination reaction and the stability of the holo form with the reduced cofactor—pyridoxamine-5′-phosphate. These results extend the structural university of the PLP fold type IV enzymes and demonstrate the need for deeper analysis of the sequence–structure–function relationships in the transaminases. [ABSTRACT FROM AUTHOR]

Branched-chain amino acids (BCAAs) are essential for muscle protein synthesis and are widely acknowledged for mitigating sarcopenia. Oligonol® (Olg), a low-molecular-weight polyphenol from Litchi chinensis, has also been found to attenuate sarcopenia by improving mitochondrial quality and positive protein turnover. This study aims to investigate the effect of Olg on BCAA-stimulated protein synthesis in sarcopenia. In sarcopenic C57BL/6 mice and senescence-accelerated mouse-prone 8 (SAMP8) mice, BCAAs were significantly decreased in skeletal muscle but increased in blood serum. Furthermore, the expressions of membrane L-type amino acid transporter 1 (LAT1) and branched-chain amino acid transaminase 2 (BCAT2) in skeletal muscle were lower in aged mice than in young mice. The administration of Olg for 8 weeks significantly increased the expressions of membrane LAT1 and BCAT2 in the skeletal muscle when compared with non-treated SAMP8 mice. We further found that BCAA deprivation via LAT1-siRNA in C2C12 myotubes inhibited the signaling of protein synthesis and facilitated ubiquitination degradation of BCAT2. In C2C12 cells mimicking sarcopenia, Olg combined with BCAA supplementation enhanced mTOR/p70S6K activity more than BCAA alone. However, blocked LAT1 by JPH203 reversed the synergistic effect of the combination of Olg and BCAAs. Taken together, changes in LAT1 and BCAT2 during aging profoundly alter BCAA availability and nutrient signaling in aged mice. Olg increases BCAA-stimulated protein synthesis via modulating BCAA transportation and BCAA catabolism. Combining Olg and BCAAs may be a useful nutritional strategy for alleviating sarcopenia. [ABSTRACT FROM AUTHOR]

Sustained or chronic inflammation in the placenta can result in placental insufficiency, leading to adverse reproductive outcomes such as pregnancy loss. Branched-chain amino acid transaminase 1 (BCAT1) expresses in the placenta and is involved in the pathological inflammatory response, but its role in recurrent miscarriage (RM) has not been fully investigated. In the present study, we delved into the effects of BCAT1 on trophoblast inflammation induced by lipopolysaccharide (LPS) and a mouse model of pregnancy loss induced by LPS. In vitro, after the HTR-8/SVneo cells were treated with LPS and BCATc inhibitor 2 (a selective BCAT inhibitor), the cell apoptosis was verified by TUNEL assay, and the activity of caspase-3 and caspase-9 was detected. Real-time PCR, enzyme-linked immunosorbent assay (ELISA), and immunofluorescence (IF) were used to determine the expression of inflammatory cytokines (TNF-α, IL-6, and IL-1β) and inflammasomes (NLRP3 and ASC) in LPS-treated trophoblast cells. Western blot analysis was performed to verify the expression of phospho-IκBα (p-IκBα) in cells and NF-κB p65 in the nuclei. IF staining was used to detect the nuclear translocation of NF-κB p65. The DNA binding activity of NF-κB was detected by an electrophoretic mobility shift assay (EMSA). The results demonstrated that inhibition of BCAT1 reduced trophoblast apoptosis, suppressed the release of proinflammatory cytokines, and prevented NLRP3 inflammasome activation in response to LPS. Additionally, BCAT1 inhibition blocked the activation of the NF-κB pathway in trophoblasts. This study highlights the potential therapeutic role of targeting BCAT1 in preventing adverse reproductive outcomes associated with chronic placental inflammation. [ABSTRACT FROM AUTHOR]

Background Biliary tract cancer (BTC) is a highly malignant tumor, with limited therapy regimens and short response duration. In this study, we aim to assess the efficacy and safety of the combination of camrelizumab, apatinib, and capecitabine as the first- or second-line treatment in patients with advanced BTC. Methods In this phase 2, nonrandomized, prospective study, eligible patients received camrelizumab (200 mg, d1, Q3W), apatinib (250 mg, qd, d1-d21, Q3W), and capecitabine (1000 mg/m², bid, d1-d14, Q3W) until trial discontinued. The primary endpoint was the objective response rate (ORR). The secondary endpoints were disease control rate, progression-free survival (PFS), overall survival (OS), and safety. Results From July 2019 to April 2023, we enrolled a total of 28 patients, of whom 14 patients were in the first-line treatment setting and 14 patients were in the second-line setting. At the data cutoff (April 30, 2023), the median follow-up duration was 18.03 months. Eight of 28 patients reached objective response (ORR: 28.57%), with an ORR of 50% and 7.1% for first-line and second-line treatment patients (P  = .033). The median PFS was 6.30 months and the median OS was 12.80 months. Grade 3 or 4 adverse events (AEs) occurred in 9 (32.14%) patients, including elevated transaminase, thrombocytopenia, etc. No serious treatment-related AEs or treatment-related deaths occurred. Conclusions In this trial, the combination of camrelizumab, apatinib, and capecitabine showed promising antitumor activity and manageable toxicity in patients with advanced BTC, especially in the first-line setting. Clinical Trial Registration NCT04720131. [ABSTRACT FROM AUTHOR]

Background/Objectives: A diet enriched with copper nanoparticles (CuNPs) exhibits a wide range of effects on liver metabolism, both positive and negative. Dietary fibers are the key components that may affect the absorption of minerals, including copper, and change their impact on organisms. Methods: Therefore, this study investigated whether and how supplementation with different sources of dietary fiber (cellulose, pectin, inulin, and psyllium) affects the function of CuNPs in the liver of male Wistar rats. Results: The results showed that CuNPs at different doses had varying effects on lipid metabolism and inflammation in the liver. Specifically, higher doses of CuNPs were associated with increased lipid accumulation and the activation of pro-inflammatory mechanisms. However, combining CuNPs with dietary fibers, such as psyllium and inulin, was beneficial in mitigating the effects of the examined nanoparticles, leading to reduced fat, cholesterol, and triglycerides in the liver. Combining psyllium with CuNPs showed the most substantial effect on liver metabolism and inflammation parameters. Furthermore, hepatic histology analyses showed that adding psyllium to the diet with CuNPs reduces changes associated with fat accumulation and mononuclear cell infiltration. The observed beneficial changes in the liver may have been related to a reduction in the gene expression level of sterol regulatory element-binding protein 1 and peroxisome proliferator-activated receptor gamma and cyclooxygenase-2. Conclusions: In conclusion, enriching the diet with dietary fibers such as psyllium can regulate the action of CuNPs, thereby improving lipid metabolism and reducing inflammation in the liver. [ABSTRACT FROM AUTHOR]

Neonicotinoids, widely used insecticides, pose severe environmental risks due to their persistence in soil and water, adversely affecting non-target organisms and ecosystem integrity. The present study examined the 56 days effects of imidacloprid (66.6 mg/l), clothianidin (30 mg/l), and their combination (33.3 mg/l and 15 mg/l) on Labeo rohita, using one-third of the LC50 sub-lethal concentrations. Survival, weight gain, and the hepatosomatic index decreased insignificantly in the IMI group and significantly in the CLO and Mix groups. Haematological indicators, including erythrocyte counts, haemoglobin, and haematocrit values, were also significantly reduced. Blood glucose and serum creatinine levels increased, while serum albumin, globulin, and plasma total proteins decreased. White blood cell counts elevated, while immunoglobulin (IgM), respiratory burst, and lysozyme activities were significantly inhibited. Liver, brain and muscle lactate and malate dehydrogenases were elevated, whereas succinate and glutamate dehydrogenases were decreased. Liver aspartate aminotransferase activity was substantially higher than that of brain and muscle, which had considerably higher levels of alanine aminotransferase in muscle than in the brain and liver. Additionally, muscle alkaline phosphatase activity was significantly higher than in the liver and brain, whereas liver acid phosphatase showed a greater elevation than in the muscle and brain. The physiological, haematological, and biochemical indices peaked on day 28 and slight recovery was observed on day 56 (IMI > CLO > Mix). The study highlights that the mixture of insecticides poses greater hazards compared to a single active compound, and the indiscriminate use of these insecticides jeopardizes non-target organisms, ecosystems, and public health. [ABSTRACT FROM AUTHOR]

Aim: To ditermine values of ASAT and ALAT and their ratio in different stages of liver cirrhosis. Material and methods: A retrospective study was conducted, including patients with newly diagnosed liver cirrhosis from 01.01. 2017 to 31.12. 2021. Of all, 258 (71%) were men and 103 (29%) were women. The mean age of the study population was 57±11.4 years, with alcohol as the leading etiology in 262 (72.6%) of all cases. AT were measured at an upper reference limit of 40UI/ml. All were staged by Child-Pough and MELD Na score. IBM SPSS 26 and Excel statistics for data processing were used at a significant level of p< 0.05. Results: Of all 361 individuals, normal AT were measured at 89 (24.7%), at 96 (25.76%) only with normal ASAT and at 233 (66.77%) only with normal ALAT. The mean value of ASAT increases significantly depending on the Child stage (p=.004) and is close to the significance of MELD Na (p=.036). Mean ALAT values were minimal to moderately elevated, with no significant association with them (p=.647, p=.020). 90% of individuals had an ASAT/ALAT ratio above 1, which showed substantial dependence on Child and MELD Na (p=.000, p=.000). A ratio above 2 was found at 194 (53.7%) mainly in Child C, which was associated with alcohol etiology. Conclusion: The absolute values of ASAT and ALAT have no relationship with the severity of liver cirrhosis, unlike their ratio, which significantly increases.

Translation of mRNA to protein is tightly regulated by transfer RNAs (tRNAs), which are subject to various chemical modifications that maintain structure, stability, and function. Deficiency of tRNA N7 -methylguanosine (m7 G) modification in patients causes a type of primordial dwarfism, but the underlying mechanism remains unknown. Here we report that the loss of m7 G rewires cellular metabolism, leading to the pathogenesis of primordial dwarfism. Conditional deletion of the catalytic enzyme Mettl1 or missense mutation of the scaffold protein Wdr4 severely impaired endochondral bone formation and bone mass accrual. Mechanistically, Mettl1 knockout decreased abundance of m7 G-modified tRNAs and inhibited translation of mRNAs relating to cytoskeleton and Rho GTPase signaling. Meanwhile, Mettl1 knockout enhanced cellular energy metabolism despite incompetent proliferation and osteogenic commitment. Further exploration revealed that impairment of Rho GTPase signaling upregulated the level of branched-chain amino acid transaminase 1 (BCAT1) that rewired cell metabolism and restricted intracellular α-ketoglutarate (αKG). Supplementation of αKG ameliorated the skeletal defect of Mettl1-deficient mice. In addition to the selective translation of metabolism-related mRNAs, we further revealed that Mettl1 knockout globally regulated translation via integrated stress response (ISR) and mammalian target of rapamycin complex 1 (mTORC1) signaling. Restoring translation by targeting either ISR or mTORC1 aggravated bone defects of Mettl1-deficient mice. Overall, our study unveils a critical role of m7 G tRNA modification in bone development by regulation of cellular metabolism and indicates suspension of translation initiation as a quality control mechanism in response to tRNA dysregulation. [ABSTRACT FROM AUTHOR]

Recycling cascades combining aldolases and transaminases from biodiversity were designed for the stereoselective synthesis of various isomers of γ‐hydroxy‐α‐amino acids. Aldolases with opposite enantioselectivities were combined with a d‐α‐transaminase to prepare in a single step, d‐syn or d‐anti‐4‐hydroxyglutamic acid with high yield and stereoselectivity. Bioactive (2S,3R,4S)‐4‐hydroxy‐isoleucine was also efficiently prepared via an aldolase‐transaminase recycling cascade. In that case, the unexpected high stereoselectivity was shown to result from the thermodynamically‐driven formation of a stable derivative of the product. This novel approach was applied to the synthesis of l‐syn and d‐syn‐4‐hydroxynorvaline as well as for 3 new β‐branched‐γ‐hydroxy‐α‐amino acids, analogues of 4‐hydroxyisoleucine. [ABSTRACT FROM AUTHOR]

Branched-chain amino acid transaminase 2 (BCAT2) encodes a crucial protein involved in the initial catalysis of branched-chain amino acid (BCAA) catabolism, with emerging evidence suggesting its association with tumor progression. This study explores BCAT2 in a pan-cancer multi-omics context and evaluates its prognostic significance. We utilized a multi-database approach, analyzing cBioPortal for genetic alterations, RNA-Seq data from TCGA and GTEx for expression patterns, and RSEM for transcript analysis. Protein expression and interaction networks were assessed using the Human Protein Atlas, UniProt, and STRING. Prognostic value was determined through Cox regression analysis of TCGA clinical survival data, while immune cell infiltration across various cancers was examined using TCGA data and the TIMER2 platform. Our results revealed that BCAT2 alterations are primarily amplifications and is upregulated in various tumors, correlating with poor survival rates in several tumor types, including GBMLGG, LGG, and UVM. Elevated BCAT2 protein levels were common in pan-cancer, interacting with a range of metabolic enzymes. Additionally, BCAT2 expression significantly influenced CD4+ T cells, CD8+ T cells, and Treg cells infiltration, with varied correlations across cancer types. These findings indicate BCAT2 as a potential biomarker for cancer diagnosis and therapy, potentially regulating key metabolic and immune factors to mediate tumor progression and the microenvironment. [ABSTRACT FROM AUTHOR]

Background: Insulin resistance (IR), hyperuricemia (HUA), and recurrent pregnancy loss (RPL) elevate the risk of cardiovascular disease and metabolic disorders, while also impacting reproductive health. The relationship between IR, HUA, and RPL has not been thoroughly investigated. This study investigates the relationship between four IR surrogates and the risk of HUA in RPL patients. Methods: Data from a real‐world study on RPL in China were analyzed using multivariable regression to determine the relationship between HUA and triglyceride and glucose (TyG) index, triglyceride glucose‐body mass index (TyG‐BMI), triglyceride to high‐density lipoprotein cholesterol (TG/HDL‐c) ratio, and metabolic score for insulin resistance (METS‐IR). The predictive ability of these surrogates for detecting HUA in RPL patients was evaluated using the area under the curve and receiver operating characteristic analysis. Sensitivity analysis was performed using bootstrapping resampling. Results: The study included 769 patients with a mean age of 30 ± 4 years old, 8.32% of whom had HUA. Four IR surrogates were closely related to HUA in patients of RPL after adjusting for age, menstrual cycle, creatinine, alanine transaminase, aspartate transaminase, total cholesterol, homocysteine, and low‐density lipoprotein, with area under the curve values of TyG index (OR = 0.693, 95% confidence interval [CI]: 0.626, 0.759), TyG‐BMI (OR = 0.731 95% CI: 0.657, 0.805), TG/HDL‐C (OR = 0.703, 95% CI: 0.641, 0.764), and METS‐IR (OR = 0.728, 95% CI: 0.655, 0.799). Bootstrap resampling yielded similar results. Conclusions: The TyG index, TyG‐BMI, TG/HDL‐c, and METS‐IR significantly correlated with HUA in patients with RPL. The TyG‐BMI had the highest predictive value of the four IR surrogates. [ABSTRACT FROM AUTHOR]

The article focuses on the use of continuous intravenous deferoxamine (DFO) for managing chronic iron overload in patients undergoing hemodialysis. Topics discussed include iron overload in transfusion-dependent patients, the administration of DFO through home parenteral therapy, and the adjustment of DFO dosage based on renal function and treatment response.

Introduction: Individuals who receive regular blood products, such as those with thalassemia, are at an elevated risk of contracting the hepatitis B virus (HBV). The objective of this study was to ascertain the correlation between HBV immunity and serum aminotransferases and iron indexes in transfusiondependent thalassemia patients who have received the HBV vaccine. Materials and Methods: This cross-sectional analytical study was conducted on 84 thalassemia patients in Jahrom-2024. Demographic information, serum levels of antibodies against HBV, and aminotransferases were extracted from the patient files. Serum ferritin and iron levels were determined by ELISA and spectrophotometry, respectively. The data was analyzed using SPSS-23, employing descriptive statistics (frequency and frequency percentage, mean and standard deviation) and analytical statistics (Chi-square and independent t tests). Results: Of the 84 patients included in the study, 52.4% were male, and 89.3% of them were immune to the HBV. No significant differences were observed in terms of age, sex, or history of splenectomy in relation to HBV immunity status (P>0.05). A statistically significant difference was observed in the mean values of ferritin, iron and TIBC between immune and non-immune patients (p<0.05). However, no significant difference was found in the mean values of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and between the two groups (p>0.05). Conclusion: In the studied patients, there was a significant inverse relationship between immunity to the HBV and the serum level of ferritin and iron. However, no statistically significant relationship was observed between immunity and the serum level of AST and ALT. Further studies are recommended to investigate the role of these factors and liver diseases on immunity to HBV. [ABSTRACT FROM AUTHOR]

In yeasts, the Leu3 transcriptional factor regulates the expression of genes encoding enzymes of the leucine biosynthetic pathway, in which the first committed step is catalyzed by α-isopropylmalate synthase (α-IPMS). This enzyme is feedback inhibited by leucine, and its product, α-isopropylmalate (α-IPM), constitutes a Leu3 co-activator. In S. cerevisiae, the ScBAT1 and ScBAT2 genes encode branched-chain aminotransferase isozymes. ScBAT1 transcriptional activation is dependent on the α-IPM concentration and independent of chromatin organization, while that of ScBAT2 is α-IPM-independent but dependent on chromatin organization. This study aimed at understanding whether chromatin remodeling determines the transcriptional regulation of orthologous KlBAT1 and LkBAT1 genes in Kluyveromyces lactis and Lachancea kluyveri under conditions in which the branched-chain amino acids are synthesized or degraded. The results indicate that, in K. lactis, KlBAT1 expression is reduced under catabolic conditions, while in L. kluyveri, LkBAT1 displays a constitutive expression profile. The chromatin organization of KlBAT1 and LkBAT1 promoters did not change, maintaining the Leu3-binding sites free of nucleosomes. Comparison of the α-IPMS sensitivities to feedback inhibition suggested that the main determinant of transcriptional activation of the KlBAT1 and LkBAT1 genes might be the availability of the α-IPM co-activator, as reported previously for the ScBAT1 gene of S. cerevisiae. [ABSTRACT FROM AUTHOR]

Background Given that obesity and insulin resistance play key roles in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and the connection between leptin and these metabolic diseases, the association between NAFLD and a leptin receptor gene (LEPR) polymorphism was examined. Methods In this genetic case-control association study, 144 biopsy-proven NAFLD patients and 144 controls were genotyped for the LEPR gene Gln223Arg (rs1137101) polymorphism using the polymerase chain reaction–restriction fragment length polymorphism method. Results The distributions of genotypes and alleles of Gln223Arg variant were in accordance with the Hardy-Weinberg equilibrium in the study groups (P >.05). Multivariate logistic regression analysis showed that the LEPR Gln223Arg Arg/Arg genotype was an independent risk factor for NAFLD; the Arg/Arg genotype, compared with the Gln/Gln genotype, was associated with a 2.09-fold increased risk for NAFLD (P =.036, odds ratio = 2.09 [95% CI = 1.31-5.95]). Conclusions We found that the LEPR Gln223Arg Arg/Arg genotype was independently associated with a more than 2-fold rise in biopsy-proven NAFLD risk. Our findings, however, need to be corroborated by further studies. [ABSTRACT FROM AUTHOR]

Summary: Aims: We conducted a clinical trial to determine the efficacy of the combination of vitamin E and/or docosahexaenoic acid (DHA) versus placebo in reducing liver fat content after 6 months of intervention in adults with MASLD. Methods: Adults with MASLD were randomised to one of four treatment arms (vitamin E 1000 mg/daily + DHA 1.89 g/daily or combination arm, vitamin E 1000 mg alone, DHA 1.89 g alone or placebo) following a 2:1:1:2 randomisation. The primary objective was to determine the efficacy of DHA + vitamin E versus placebo in reducing hepatic fat fraction (%) relative to baseline after 6 months of intervention. Secondary objectives were to determine the effect of vitamin E or DHA alone versus placebo on reducing liver fat at 6 months. Results: Our cohort consisted of 203 subjects with a mean age of 51 years, 53% female, 91% White, 59% Hispanic ethnicity. The combination of vitamin E + DHA had no effect on the primary endpoint of reducing hepatic steatosis as determined by MRI‐PDFF (p = 0.98). Neither vitamin E alone (p = 0.91) nor DHA alone (p = 0.14) significantly reduced hepatic steatosis compared to placebo. However, the trial was not powered adequately for this analysis. Compared with placebo, no statistically significant differences were detected in the 3‐month or 6‐month levels for ALT (U/L) or AST (U/L) in all three intervention groups. Conclusions: The combination of DHA + vitamin E or either agent alone did not demonstrate efficacy on reducing liver fat or aminotransferases in the studied population. [ABSTRACT FROM AUTHOR]

N‐acetylcysteine (NAC) is regarded as an effective treatment of paracetamol overdoses. However, in cases of "massive" paracetamol overdoses, recent studies indicate that patients may not be sufficiently treated with the standard dose of NAC (300 mg/kg over 20–21 h). The subject is further complicated because "massive overdoses" and "high‐risk" are defined differently; some studies use the ingested amount (e.g., >40 g), and some studies use blood concentrations of paracetamol and transaminases. This narrative review investigates whether high‐dose NAC significantly decreases the risk of hepatotoxicity in patients with massive paracetamol overdoses. Three observational studies were analysed; one study with 373 patients found no significant difference (odds ratio [OR]: 1.27, 95% confidence interval [CI]: 0.49–3.29). One study with 79 patients found a significant difference (OR: 0.27, 95% CI: 0.08–0.94). The third study with 89 patients found a significant difference in hepatoxicity between the groups (p = 0.043). There are no solid evidence to support that treatment with high‐dose NAC significantly reduces the rate of hepatotoxicity in patients presenting with massive paracetamol overdoses. Differences in inclusion criteria in the included studies make the studies incomparable. This paper shows that standardized inclusion is needed to determine whether a high‐dose NAC regimen should be included in clinical practice. [ABSTRACT FROM AUTHOR]

Baricitinib is an oral Janus kinase (JAK) inhibitor and a member of the targeted synthetic disease-modifying anti-rheumatic drugs. Baricitinib competitively binds to adenosine triphosphate and inhibits the synthesis of cytokines that play prominent roles in arthritis rheumatoid arthritis pathogenesis by selectively inhibiting JAK1 and JAK2 at an effective dose. Its bioavailability is approximately 80%, and 64% is excreted via the kidney. To evaluate the efficacy and safety of baricitinib, 19 clinical pharmacological studies and 3 phase II, 4 phase III, and one extension study were conducted in patients with rheumatoid RA. The effectiveness of baricitinib has been shown in these studies. Clinical research and real-world data suggest that barictinib is a safe drug; however, it has been reported to have some well-known side effects such as neutropenia, anemia, elevation of transaminase levels, hyperlipidemia, and increased risk of infections. In these studies, major cardiovascular events were found to be similar in frequency to placebo, and the incidence of malignancy was found to be similar to that of age-related cancer in the general population. However, as is the case with other JAK inhibitors, it is recommended to be used with caution in patients with risk factors for deep vein thrombosis, such as advanced age, obesity, and inactivity. [ABSTRACT FROM AUTHOR]

APOBEC proteins are cytidine deaminases that restrict the replication of viruses and transposable elements. Several members of the APOBEC3 family, APOBEC3A, APOBEC3B, and APOBEC3H-I, can access the nucleus and cause what is thought to be indiscriminate deamination of the genome, resulting in mutagenesis and genome instability. Although APOBEC3C is also present in the nucleus, the full scope of its deamination target preferences is unknown. By expressing human APOBEC3C in a yeast model system, I have defined the APOBEC3C mutation signature, as well as the preferred genome features of APOBEC3C targets. The APOBEC3C mutation signature is distinct from those of the known cancer genome mutators APOBEC3A and APOBEC3B. APOBEC3C produces DNA strand-coordinated mutation clusters, and APOBEC3C mutations are enriched near the transcription start sites of active genes. Surprisingly, APOBEC3C lacks the bias for the lagging strand of DNA replication that is seen for APOBEC3A and APOBEC3B. The unique preferences of APOBEC3C constitute a mutation profile that will be useful in defining sites of APOBEC3C mutagenesis in human genomes. [ABSTRACT FROM AUTHOR]

Objective: Pyrotinib, a new irreversible dual pan-human epidermal growth factor receptor 2 (HER2) receptor tyrosine kinase inhibitor blocking EGFR and HER2, has achieved a promising efficacy for advanced HER2-positive (HER2+) breast cancer. This study intended to further investigate the efficacy and safety of neoadjuvant pyrotinib and trastuzumab plus chemotherapy for HER2+ breast cancer treatment. Methods: Thirty-eight HER2+ breast cancer patients who received neoadjuvant pyrotinib and trastuzumab plus chemotherapy (docetaxel and carboplatin) were retrospectively reviewed. Clinical response by Response Evaluation Criteria in Solid Tumors (RECIST), pathological complete response (pCR), and adverse events data was retrieved. Results: According to the RECIST, the complete response rate was 0.0%, 10.5%, and 15.8% after second-cycle, fourth-cycle, and sixth-cycle therapy, respectively; whereas the objective response rate was 76.3%, 92.1%, and 100.0%, accordingly. The total pCR (tpCR) rate was 52.6%, the pCR rate of the breast was also 52.6%, and the pCR rate of lymph nodes was 86.8%. The tpCR rate was lower in patients with HER2 immunohistochemistry (IHC)++ and amplification by fluorescent in situ hybridization (FISH) than in those with HER2 IHC+++ (14.3% vs. 61.3%, p = 0.024), which was also lower in patients with Ki-67 expression ≥30% than in those with Ki-67 expression <30% (40.0% vs. 76.9%, p = 0.031). The common adverse events included diarrhea (84.2%), anemia (73.7%), nausea and vomiting (63.2%), fatigue (50.0%), hypomagnesemia (44.7%), leukopenia (42.1%), thrombocytopenia (39.5%), elevated transaminase (36.8%), and pruritus (31.6%). Conclusions: Pyrotinib and trastuzumab plus chemotherapy serve as an acceptable neoadjuvant regimen exhibiting good efficacy and tolerance in HER2+ breast cancer patients, while further large-scale validation is warranted. [ABSTRACT FROM AUTHOR]

The aim of this meta‐analysis is to investigate the sources of heterogeneity in randomized clinical trials examining the effects of curcumin supplementation on liver aminotransferases in subjects with nonalcoholic fatty liver disease (NAFLD). We conducted a systematic search of the PubMed, SCOPUS, and Web of Science databases for randomized clinical trials and identified 15 studies (n = 835 subjects). We used random‐effects models with DerSimonian‐Laird methods to analyze the serum levels of alanine aminotransferase and aspartate aminotransferase enzymes. Our results indicate that curcumin did not affect serum alanine aminotransferase, but it did reduce aspartate aminotransferase levels. Notably, both outcomes showed high heterogeneity (p < 0.01). Subgroup analysis revealed that adding piperine to curcumin did not benefit aminotransferase levels in NAFLD patients. Additionally, we found a negative correlation between the duration of the intervention and the relative (mg/kg/day) curcumin dose with the reduction in liver aminotransferases. In summary, the sources of heterogeneity identified in our study are likely attributed to the duration of the intervention and the relative dose of curcumin. Consequently, longer trials utilizing high doses of curcumin could diminish the positive impact of curcumin in reducing serum levels of aminotransferases in patients with NAFLD. [ABSTRACT FROM AUTHOR]

In yeasts, the Leu3 transcriptional factor regulates the expression of genes encoding enzymes of the leucine biosynthetic pathway, in which the first committed step is catalyzed by α-isopropylmalate synthase (α-IPMS). This enzyme is feedback inhibited by leucine, and its product, α-isopropylmalate (α-IPM), constitutes a Leu3 co-activator. In S. cerevisiae, the ScBAT1 and ScBAT2 genes encode branched-chain aminotransferase isozymes. ScBAT1 transcriptional activation is dependent on the α-IPM concentration and independent of chromatin organization, while that of ScBAT2 is α-IPM-independent but dependent on chromatin organization. This study aimed at understanding whether chromatin remodeling determines the transcriptional regulation of orthologous KlBAT1 and LkBAT1 genes in Kluyveromyces lactis and Lachancea kluyveri under conditions in which the branched-chain amino acids are synthesized or degraded. The results indicate that, in K. lactis, KlBAT1 expression is reduced under catabolic conditions, while in L. kluyveri, LkBAT1 displays a constitutive expression profile. The chromatin organization of KlBAT1 and LkBAT1 promoters did not change, maintaining the Leu3-binding sites free of nucleosomes. Comparison of the α-IPMS sensitivities to feedback inhibition suggested that the main determinant of transcriptional activation of the KlBAT1 and LkBAT1 genes might be the availability of the α-IPM co-activator, as reported previously for the ScBAT1 gene of S. cerevisiae.

Aminotransferases (ATs) catalyze pyridoxal 5'-phosphate-dependent transamination reactions between amino donor and keto acceptor substrates and play central roles in nitrogen metabolism of all organisms. ATs are involved in the biosynthesis and degradation of both proteinogenic and nonproteinogenic amino acids and also carry out a wide variety of functions in photorespiration, detoxification, and secondary metabolism. Despite the importance of ATs, their functionality is poorly understood as only a small fraction of putative ATs, predicted from DNA sequences, are associated with experimental data. Even for characterized ATs, the full spectrum of substrate specificity, among many potential substrates, has not been explored in most cases. This is largely due to the lack of suitable high-throughput assays that can screen for AT activity and specificity at scale. Here we present a new high-throughput platform for screening AT activity using bioconjugate chemistry and mass spectrometry imaging-based analysis. Detection of AT reaction products is achieved by forming an oxime linkage between the ketone groups of transaminated amino donors and a probe molecule that facilitates mass spectrometry-based analysis using nanostructure-initiator mass spectrometry or MALDI-mass spectrometry. As a proof-of-principle, we applied the newly established method and found that a previously uncharacterized Arabidopsis thaliana tryptophan AT-related protein 1 is a highly promiscuous enzyme that can utilize 13 amino acid donors and three keto acid acceptors. These results demonstrate that this oxime-mass spectrometry imaging AT assay enables high-throughput discovery and comprehensive characterization of AT enzymes, leading to an accurate understanding of the nitrogen metabolic network.

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 Various body tissues of β-thalassemia patients are exposed to the destructive effects of iron overload due to chronic blood transfusions. Therefore, the decision to start regular blood transfusion therapy for these patients often leads to the administration of iron chelators. Deferasirox as an orally effective iron-chelating drug could cause some therapy-related adverse events, such as increased liver enzymes, serum creatinine, and gastrointestinal bleeding. Objective This study evaluates the effect of deferasirox on serum levels of ferritin and liver aminotransferases in transfusion-dependent β-thalassemia patients. Methods In this study, changes in the serum levels of ferritin and liver aminotransferases in β-thalassemia patients receiving deferasirox, who were referred to the thalassemia department of the 17 Shahrivar Hospital and Beesat Clinic in Rasht City, Iran, have been evaluated, retrospectively. In this regard, 104 β-thalassemia major patients over two years of age receiving regular blood transfusions and deferasirox for at least two consecutive years were enrolled. Information of patients, including age, sex, blood transfusion frequency, deferasirox administration duration and dosage, and serum levels of ferritin and liver enzymes between baseline and at least two years after iron chelation therapy with deferasirox was recorded. Results The decreased serum levels of ferritin (P=0.017), aspartate aminotransferase (P=0.0001), and alanine aminotransferase (P=0.015) in the last blood testing after deferasirox therapy were statistically significant. However, there was no statistical significance between the decreased serum levels of liver aminotransferases and factors, including age, sex, blood transfusion frequency, duration, and dosage of deferasirox administration. Conclusion After a few months of taking defrazirox, rather than causing mild and rare liver complications, it can have a protective role for the liver against iron overload in the body and significantly reduce liver aminotransferase. [ABSTRACT FROM AUTHOR]

In recent years, there has been a significant trend to improve poultry zootechnical performances by biological methods to avoid the unwanted chemical growth factor's introduction into breeding process. Medicinal plants and their derivatives are good candidates to achieve this goal. Thus, this work aimed at evaluating the effect of poultry feed supplementation with the spices Curcuma longa and Zingiber officinale on the zootechnical performance, serological, and microbiological parameters of Ross 308 chicken. To achieve this purpose, 180 chicks divided into five groups and reared for 12 days. The experimental groups consisted of a control group receiving a conventional feed without antibiotics and four groups receiving a conventional feed with 0.5 and 1% turmeric and ginger doses, respectively. Results of the experiment revealed that supplementing the feed with 0.5% turmeric powder increased live weight, and average daily gain and decreased feed conversion compared to the other groups. Turmeric powder supplement (0.5 and 1%) affected blood serum parameters by decreasing triglyceride and aspartate aminotransferase (AST) concentrations. In comparison, the incorporation of 0.5% ginger in the diet decreased triglyceride concentrations, cholesterol, aspartate aminotransferases (ASAT), and alanine aminotransferases (ALAT). Cecum bacteriological analysis showed a total absence of coliforms, Salmonella sp., Clostridium sp., and lactic acid bacteria in the chick groups supplemented with different doses of turmeric and ginger (0.5 and 1%, respectively). Within this study's limits, using these two studied spices as additives in poultry feed allowed us to conclude that supplementing with 0.5% turmeric powder positively impacted the evaluated parameters. [ABSTRACT FROM AUTHOR]

The article presents a case study of an 81-year-old woman successfully treated with reduced oral steroid dosage for statin-induced anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) immune-mediated necrotizing myopathy. Topics discussed include the management strategies, clinical outcomes, and therapeutic adjustments in elderly patients experiencing rare immune-mediated muscle disorders associated with statin use.

Background: MASLD can manifest as hepatocellular damage, which can result in mild elevation of aminotransferases. However, in some patients, MASLD presents with cholestatic pattern. Objective: To assess the impact of the biochemical pattern on the natural course of MASLD, including liver damage in histology, the accuracy of non-invasive tests(NITs), and prognosis. Methods: Multicenter study enrolling 2156 patients with biopsy-proven MASLD, who were classified based on their[ALT/ULN)]/[(ALP/ULN)] levels at the time of biopsy: (a) hepatocellular pattern(H), > 5; (b) mixed pattern(M),2–5; (c) cholestatic pattern(C), < 2. Outcomes: (a) histological evaluation of the single components of NAS, MASH, and fibrosis; (b) NITs and transient elastography assessing advanced fibrosis; (c) prognosis determined by the appearance of decompensated cirrhosis and death. Results: Out of the 2156 patients, 22.9% exhibited the H-pattern, whilst 31.7% exhibited the C-pattern. Severe steatosis, ballooning, lobular inflammation, and MASH (56.4% H vs. 41.9% M vs. 31.9% C) were more common in H-pattern (p = 0.0001),whilst C-pattern was linked to cirrhosis (5.8% H vs. 5.6% M vs. 10.9% C; p = 0.0001). FIB-4(0.74(95% CI 0.69–0.79) vs. 0.83 (95% CI 0.80–0.85); p = 0.005) and Hepamet Fibrosis Score(0.77 (95% CI 0.69–0.85) vs. 0.84 (95% CI 0.80–0.87); p = 0.044)exhibited lower AUROCs in the H-pattern. The C-pattern[HR 2.37 (95% CI 1.12–5.02); p = 0.024], along with age, diabetes, and cirrhosis were independently associated with mortality. Most patients maintained their initial biochemical pattern during the second evaluation. Conclusions: The H-pattern exhibited greater necro-inflammation in the histology than the C-pattern, whereas the latter showed more cirrhosis. The accuracy of NITs in detecting fibrosis was decreased in H-pattern. The occurrence of decompensated events and mortality was predominant in C-pattern. Therefore, identifying MASLD phenotypes based on the biochemical presentation could be relevant for clinical practice. [ABSTRACT FROM AUTHOR]

In 2020, the US Food and Drug Administration approved liraglutide (glucagonlike- peptide-1-receptor-agonist) as an adjunctive therapy for weight management in adolescents aged 12 to 18 years in combination with a reduced-calorie diet and increased physical activity. The 2023 American Academy of Pediatrics guidelines recommend pharmacotherapy with glucagon-like-peptide-1-receptoragonist as a second-line therapy in obesity management. Although reports in adults have suggested a link between liraglutide and adverse effects including hepatic injury and acute kidney injury (AKI), these effects have not previously been reported among adolescents treated with liraglutide for weight loss. We present a 17-year-old male who developed AKI and evidence of hepatic injury (significant elevation of hepatic transaminases) after 3 months administration of the lowest dosage of liraglutide (0.6 mg/day) for management of class III obesity. The patient experienced significant loss of appetite, weight loss, and melancholy during the treatment period. One month after discontinuing liraglutide, his mood had improved, his liver enzymes had returned to normal, and AKI had resolved. The Adverse Drug Reaction Probability Scale suggested a high likelihood of a causative association between liraglutide and his symptoms. Our report highlights the importance of vigilance in monitoring for these potential adverse effects among adolescents treated for obesity with any dose of liraglutide. [ABSTRACT FROM AUTHOR]

Increasing public interest has resulted in the widespread use of non-pharmaceutical cannabidiol (CBD) products. The sales of CBD products continue to rise, accompanied by concerns regarding unsubstantiated benefits, lack of product quality control, and potential health risks. Both animal and human studies have revealed a spectrum of toxicological effects linked to the use of CBD. Adverse effects related to exposure of humans to CBD include changes in appetite, gastrointestinal discomfort, fatigue, and elevated liver aminotransferase enzymes. Animal studies reported changes in organ weight, reproduction, liver function, and the immune system. This review centers on human-derived data, including clinical studies and in vitro investigations. Animal studies are also included when human data is not available. The objective is to offer an overview of CBD-related hepatotoxicity, metabolism, and potential CBD-drug interactions, thereby providing insights into the current understanding of CBD's impact on human health. It's important to note that this review does not serve as a risk assessment but seeks to summarize available information to contribute to the broader understanding of potential toxicological effects of CBD on the liver. [ABSTRACT FROM AUTHOR]

Objectives: To present a rare case of neonatal lupus erythematosus (NLE) associated with suspected hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS). Case presentation: A female infant weighing 2,995 g was born to a mother without medical history of any disease. At birth, the patient had erythematous papules on her face and trunk. She was admitted at 1 day of age with elevated C-reactive protein levels. The patient was diagnosed with NLE based on the presence of anti-Ro/SSA and anti-La/SSB antibodies. Thereafter, it became clear that the antibody levels in her mother were also elevated. At 20 days of age, the infant showed elevated transaminases, ferritin, triglyceride, and soluble interleukin-2 receptor levels. Although HLH or MAS was suspected, she did not fulfill the diagnostic criteria. Thereafter, these abnormal values spontaneously improved, and the skin rash improved with the use of topical steroids. The patient was discharged at 39 days of age. At 1 year of age, the patient's growth and development were normal. Conclusion: NLE should be considered in infants with an unexplained skin rash at birth. When a diagnosis is made, close observation of the infant's clinical features is needed to determine whether they will develop HLH or MAS. [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]

Transaminase‐catalysed asymmetric amination is a valuable transformation for the synthesis of chiral amines. However, its use in synthetic chemistry has been curtailed by a narrow substrate scope and limited information on commercially available catalysts. In this work we have explored the substrate scope of selected commercially available transaminases, focusing on prochiral ketones bearing two bulky substituents and their application in both enzyme‐catalysed and enzyme‐triggered reactions. (R)‐ and/or (S)‐selective enzymes converted methyl‐, isopropyl‐, n‐butyl‐, and cyclohexyl‐phenone substrates to the corresponding amines in the range of 6–>99 % ee. In some cases, a stereochemical switch was detected, in which (R)‐enantioselectivity was observed with enzymes typically assigned as (S)‐selective. Upscaling of selected biotransformations provided chiral amines, in >99 % ee and up to 40 % isolated yield. Furthermore, transaminase‐triggered reactions, which were previously limited to methyl‐ and ethyl‐derivatives, were expanded to phenyl‐derivatives for the formation of a cis‐2,6‐disubstituted piperidine and 2,4‐diphenyl pyrroline, and isolated in up to 67 % yield. [ABSTRACT FROM AUTHOR]

We investigated the associations of low handgrip strength (HGS, i.e., a marker of muscular fitness) with liver fat content (LFC) and serum liver enzymes in a population‐based setting. We used data from 2700 participants (51.7% women), aged 21–90 years, from two independent cohorts of the population‐based Study of Health in Pomerania (SHIP‐START‐2 and SHIP‐TREND‐0). Cross‐sectional, multivariable adjusted regression models were performed to examine the associations of HGS with LFC, measured by magnetic resonance imaging and serum liver enzymes. We found significant inverse associations of HGS with both LFC and serum liver enzymes. Specifically, a 10‐kg lower HGS was associated with a 0.59% (95% confidence interval [CI]: 0.24–0.94; p = 0.001) higher LFC, a 0.051 µkatal/L (95% CI: 0.005–0.097; p = 0.031) higher gamma‐glutamyltransferase (GGT) concentration and a 0.010 µkatal/L (95% CI: 0.001–0.020; p = 0.023) higher aspartate aminotransferase (AST) concentration. The adjusted odds‐ratio for prevalent hepatic steatosis (defined by a MRI‐PDFF ≥5.1%) per 10‐kg lower HGS was 1.21 (95% CI: 1.04–1.40; p = 0.014). When considering only obese individuals, those with low HGS had a 1.58% (95% CI: 0.18–2.98; p = 0.027) higher mean LFC and higher chance of prevalent hepatic steatosis (adjusted OR 1.74, 95% CI: 1.15–2.62; p = 0.009) compared to individuals with high HGS. We found similar associations in individuals with overweight, but not in those with normal weight. Lower HGS was strongly associated with both higher LFC and higher serum GGT and AST concentrations. Future studies might clarify whether these findings reflect adverse effects of a sedentary lifestyle or aging on the liver. Highlights: We used magnetic resonance imaging, the most accurate and sensitive noninvasive diagnostic tool for determination of hepatic steatosisLower handgrip strength was strongly associated with both higher liver fat content and higher serum GGT and AST concentrationsEspecially overweight and obese individuals with low handgrip strength had a significant higher risk of prevalent hepatic steatosis [ABSTRACT FROM AUTHOR]

Background: The gastrointestinal (GI) tract represents one of the main targets of typical hemolytic uremic syndrome (HUS) in children. In this observational study, we tried to establish (1) the main features of GI complications during STEC-HUS and (2) the relationship between Escherichia coli serotypes and Shiga toxin (Stx) variants with hepatopancreatic involvement. Methods: A total of 79 STEC-HUS patients were admitted to our pediatric nephrology department between January 2012 and June 2021. Evidence of intestinal, hepatobiliary, and pancreatic involvements was reported for each patient, alongside demographic, clinical, and laboratory features. Frequency of gastrointestinal complications across groups of patients infected by specific E. coli serotypes and Stx gene variants was evaluated. Results: Six patients developed a bowel complication: two developed rectal prolapse, and four developed bowel perforation which resulted in death for three of them and in bowel stenosis in one patient. Acute pancreatitis was diagnosed in 13 patients. An isolated increase in pancreatic enzymes and/or liver transaminases was observed in 41 and 15 patients, respectively. Biliary sludge was detected in three, cholelithiasis in one. Forty-seven patients developed direct hyperbilirubinemia. Neither E. coli serotypes nor Shiga toxin variants correlated with hepatic or pancreatic involvement. Conclusions: During STEC-HUS, GI complications are common, ranging from self-limited elevation of laboratory markers to bowel perforation, a severe complication with a relevant impact on morbidity and mortality. Hepatopancreatic involvement is frequent, but usually short-lasting and self-limiting. [ABSTRACT FROM AUTHOR]

Monoclonal antibodies (mAbs) are biotherapeutics that have achieved outstanding success in treating many life-threatening and chronic diseases. The recognition of an antigen is mediated by the fragment antigen binding (Fab) regions composed by four different disulfide bridge-linked immunoglobulin domains. NMR is a powerful method to assess the integrity, the structure and interaction of Fabs, but site specific analysis has been so far hampered by the size of the Fabs and the lack of approaches to produce isotopically labeled samples. We proposed here an efficient in vitro method to produce [15N, 13C, 2H]-labeled Fabs enabling high resolution NMR investigations of these powerful therapeutics. As an open system, the cell-free expression mode enables fine-tuned control of the redox potential in presence of disulfide bond isomerase to enhance the formation of native disulfide bonds. Moreover, inhibition of transaminases in the S30 cell-free extract offers the opportunity to produce perdeuterated Fab samples directly in 1H2O medium, without the need for a time-consuming and inefficient refolding process. This specific protocol was applied to produce an optimally labeled sample of a therapeutic Fab, enabling the sequential assignment of 1HN, 15N, 13C′, 13Cα, 13Cβ resonances of a full-length Fab. 90% of the backbone resonances of a Fab domain directed against the human LAMP1 glycoprotein were assigned successfully, opening new opportunities to study, at atomic resolution, Fabs' higher order structures, dynamics and interactions, using solution-state NMR. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to analyse the clinical course of 45 children with severe alpha-1-antitrypsin deficiency (AATD) registered in our clinic to detect possible predictors of poor outcomes. Methods: The clinical and biological data of 45 patients with homozygous or compound heterozygous AATD were analysed. The data were collected retrospectively going back to 2005 and prospectively from May 2020 until October 2021. It was based on questionnaires, laboratory values, sonography, and biopsy findings. Liver disease was classified into four grades depending on the grade of liver disease: mild or no liver disease, moderate disease, severe disease, and liver transplantation. Results: Thirty-nine patients (86.7%) had a Pi*ZZ and five (11.1%) a Pi*SZ genotype. One patient showed a new, not-yet-described compound heterozygous genotype (Pi*Z + Asp95Asn). A total of 66.7% of the cohort showed mild or no liver disease, 20% moderate, and 13.3% severe. AATD was diagnosed in most cases because of liver abnormalities, such as the elevation of transaminases (42.2%). A total of 29.4% of the patients with neonatal icterus prolongatus developed severe liver disease, and 25.7% were born small for their gestational age (SGA). Diseases of the atopic type were reported in 47.4% of the cases. Conclusions: The presence of neonatal icterus prolongatus in the first weeks of life was significantly more likely in severe courses of liver disease (r = 0.371, p = 0.012). A tendency toward atopic comorbidity in AAT-deficient children needs to be further evaluated. [ABSTRACT FROM AUTHOR]

Background. Weight loss and lifestyle interventions are the mainstay of treatment in pediatric NAFLD. There are gaps in the literature on the objective improvement in BMI to meaningfully impact NAFLD in children. Aim. To determine the decrease in BMI associated with a significant decline in ALT and other metabolic parameters. Methods. Retrospective chart review of pediatric patients with the diagnosis of NAFLD. Data were collected at the baseline and 6 and 12 months. A linear regression model was used to assess the percent change in BMI predictive of change in ALT and other metabolic parameters. Results. 281 charts were included. 71% of patients who had up to a 2.5% loss in BMI at 6 months had a decrease in ALT of up to 10 U/L compared to 43% patients who did not have a decrease in BMI up to 2.5% loss at the same time period (P = 0.01). The linear regression model showed that 6-month and 12-month percent changes in BMI are predictive of 6-month and 12-month ALT changes (P = 0.01 and 0.02), respectively. ALT normalization was achieved on 12% of patients with a ≥2.5% decrease in BMI at 6 months compared to 1% of patients that had no decrease of ≥2.5% decrease in BMI at 6 months (P = 0.01). The mean BMI Z-score decline was 0.18 (P = 0.001) in the group with a ≥2.5% decrease in BMI at 6 months. Conclusions. BMI loss of up to 2.5% and the mean BMI Z-score 0.18 are associated with a significant decrease in ALT of up to 10 U/L. BMI percent change at 6 months and 12 months is predictive of changes in ALT. These results should help guide providers in clinical practice set objective goals for the management of children with NAFLD resulting from obesity. [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]

PF‐06817024 is a high affinity, humanized antibody that binds interleukin‐33, a proinflammatory type 2 cytokine, and thereby has the potential to inhibit downstream type 2 inflammation. This Phase 1, randomized, placebo‐controlled study was conducted in 3 parts to evaluate the safety, tolerability, pharmacokinetics (PK), immunogenicity, and pharmacodynamics of escalating single and limited repeat PF‐06817024 doses in healthy participants (Part 1), a single dose of PF‐06817024 in participants with chronic rhinosinusitis with nasal polyps (Part 2), and repeat doses of PF‐06817024 in participants with moderate to severe atopic dermatitis (atoptic dermatitis; Part 3). PF‐06817024 was generally well tolerated in all participant populations. Most participants experienced a treatment‐emergent adverse event (healthy participants, 78.4% and 100%; participants with chronic rhinosinusitis with nasal polyps, 90.9% and 88.9%; and participants with atoptic dermatitis, 60.0% and 62.5% in the PF‐06817024 and placebo groups, respectively). No substantial deviations from dose proportionality were observed for single intravenous doses of 10‐1000 mg, indicating linear PK in healthy participants. Mean terminal half‐life ranged from 83 to 94 days after single intravenous administration in healthy participants and was similar to that observed after administration in the studied patient populations. Incidences of antidrug antibodies in the studied populations were 10.8%, 9.1%, and 5.0% for healthy participants, participants with chronic rhinosinusitis with nasal polyps, and participants with atoptic dermatitis, respectively. In addition, dose‐dependent increases were observed in total serum interleukin‐33 levels of treated participants, indicating target engagement. Overall, the PK and safety profile of PF‐06817024 supports further investigation of the drug as a potential treatment for allergic diseases. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is a prominent etiological factor for liver cirrhosis worldwide. It is frequently associated with obesity, diabetes, dyslipidemia, and hypertension. The objective of this study is to assess the efficacy and safety of ginger (Zingiber officinale Roscoe) supplementation in patients with type 2 diabetes mellitus (T2DM) who have NAFLD. In a two-arm, double-blind, placebo-controlled clinical trial, seventy-six patients diagnosed with both T2DM and NAFLD were randomly assigned to receive either ginger powder capsules (1000 mg, twice daily) or placebo capsules (administered in the same manner) for a period of three months. Anthropometric measurements, blood pressure readings, biochemical profiles, and imaging parameters were assessed before and after the intervention. Safety measures were also evaluated. In both the ginger and placebo groups, there was a significant reduction in mean body mass index (BMI), waist and hip circumferences, as well as liver transaminase levels. Moreover, significant improvements in mean systolic and diastolic blood pressures were observed in the ginger group (p = 0.02 and < 0.0001, respectively). Within the ginger group, there was a decrease in serum insulin levels and insulin resistance (HOMA-IR) (p = 0.002 and 0.004, respectively). Furthermore, the ginger group exhibited an improvement in serum HDL-cholesterol level (p = 0.01). However, there were no significant changes in the assessed inflammatory markers or the indices obtained from fibroscan imaging, including steatosis percent and controlled attenuation parameter. This study demonstrates that ginger supplementation can significantly improve mean systolic and diastolic blood pressures. However, it does not have a significant impact on inflammatory markers or fibroscan imaging indices. Nonetheless, the three-month use of ginger improves serum insulin level, insulin resistance (HOMA-IR), and HDL-cholesterol level compared to baseline values. Further investigations with longer durations and larger sample sizes are recommended. [ABSTRACT FROM AUTHOR]

Background: Paclitaxel (PAX) is a widely used chemotherapy drug for various cancer types but often induces significant toxicity in multiple organ systems. Silymarin (SIL), a natural flavonoid, has shown therapeutic potential due to its multiple benefits. Aims: To evaluate the therapeutic efficacy of SIL in mitigating liver and kidney damage induced by PAX in rats, focusing on oxidative stress, inflammation, and apoptosis pathways. Study Design: Experimental animal model. Methods: The study included 28 male Wistar rats aged 12-14 weeks weighing 270-300 g. The rats were divided into four groups: control, SIL, PAX, and PAX + SIL, with seven in each group. The rats received intraperitoneal (i.p.) injections at a dose of 2 mg per kilogram of body weight of PAX for 5 successive days, followed by oral gavage with 200 mg/ kg body mass of SIL for 10 uninterrupted days. We examined the effect of SIL on specific serum biochemical parameters using an autoanalyzer and rat-specific kits. The spectrophotometric methods was used to investigate oxidative stress indicators in kidney and liver tissues. Aquaporin-2 (AQP-2), B-cell lymphoma-2 (Bcl-2), cysteine aspartate-specific protease-3 (caspase-3), interleukin-6 (IL-6), nuclear factor kappa B (NF-κB), and streptavidin-biotin staining were used to assess immunoreactivity in PAX-induced liver and kidney injury models. Results: SIL treatment significantly reduced serum levels of alanine aminotransferase, aspartate aminotransferase, creatinine, urea, and C-reactive protein, indicating its effectiveness in treating PAX-induced liver and kidney injury. SIL treatment significantly reduced oxidative stress by increasing essential antioxidant parameters, such as superoxide dismutase, catalase, glutathione peroxidase, and glutathione. It also reduced malondialdehyde levels in liver and kidney tissues of SIL-PAX groups (p < 0.05). SIL administration reduced NF-κB, caspase-3, and IL-6 expression while increasing Bcl-2 and AQP2 levels in liver and kidney tissues of rats treated with SIL and PAX (p < 0.05). Conclusion: Our findings indicate the potential of SIL to alleviate PAX-induced liver and kidney damage in rats by reducing oxidative stress, inflammation, and apoptotic processes. [ABSTRACT FROM AUTHOR]

For some patients with psoriasis, orally administered small molecule inhibitors of interleukin (IL)‐17A may represent a convenient alternative to IL‐17A‐targeting monoclonal antibodies. This first‐in‐human study assessed the safety, tolerability, pharmacokinetics (PKs), and peripherally circulating IL‐17A target engagement profile of single or multiple oral doses of the small molecule IL‐17A inhibitor LY3509754 (NCT04586920). Healthy participants were randomly assigned to receive LY3509754 or placebo in sequential escalating single ascending dose (SAD; dose range 10–2,000 mg) or multiple ascending dose (MAD; dose range 100–1,000 mg daily for 14 days) cohorts. The study enrolled 91 participants (SAD, N = 51 and MAD, N = 40) aged 21–65 years (71% men). LY3509754 had a time to maximum concentration (Tmax) of 1.5–3.5 hours, terminal half‐life of 11.4–19.1 hours, and exhibited dose‐dependent increases in exposure. LY3509754 had strong target engagement, indicated by elevated plasma IL‐17A levels within 12 hours of dosing. Four participants from the 400‐mg (n = 1) and 1,000‐mg (n = 3) MAD cohorts experienced increased liver transaminases or acute hepatitis (onset ≥ 12 days post‐last LY3509754 dose), consistent with drug‐induced liver injury (DILI). One case of acute hepatitis was severe, resulted in temporary hospitalization, and was classified as a serious adverse event. No adverse effects on other major organ systems were observed. Liver biopsies from three of the four participants revealed lymphocyte‐rich, moderate‐to‐severe lobular inflammation. We theorize that the DILI relates to an off‐target effect rather than IL‐17A inhibition. In conclusion, despite strong target engagement and a PK profile that supported once‐daily administration, this study showed that oral dosing with LY3509754 was poorly tolerated. [ABSTRACT FROM AUTHOR]

The purpose of this investigation was to study how supplementing nutritional nano-selenium (NNSe) in diets containing all-plant-protein (APP) ingredients affects the physiological properties associated with stress resistance and post-stress recovery in common carp (Cyprinus carpio). Therefore, two basal diets with equal crude protein content were formulated: the FM-Control diet contained 35 % fishmeal (FM), and the APP-Control diet contained merely plant-protein constituents. Three additional diets were also prepared by supplementing NNSe in the APP-Control diet at levels of 1 (NNSe1), 2 (NNSe2), and 3 (NNSe3) mg/Kg. One hundred and fifty fish (average weight, 30.63 ± 0.61 g) were randomly allocated to five groups in triplicate tanks and fed the experimental diets for 60 days. The best growth performance and feed efficiency (FE) among the NNSe-supplemented groups were recorded in the NNSe3 and FM-Control groups (P < 0.05). The highest liver glutathione peroxidase (GPx) activity was detected in the FM-Control group, followed by the NNSe3 group (P < 0.05). Also, the highest and lowest liver malondialdehyde (MDA) contents were found in the FM-Control and the NNSe3 groups, respectively (P < 0.05). Following the 60-day feeding trial, the fish were challenged with acute crowding stress by reducing water volume to confine fish at the density of 200 kg/m3 for 45 min, and their blood samples were obtained at 0, 2, 4, 8, 12, and 24 h after stress to compare post-stress recovery between different groups. At most time intervals after stress, plasma levels of cortisol, glucose, lactate, alkaline phosphatase (ALP), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) of the NNSe3 group were equal to or lower than values measured for the FM-Control group. The results suggest that NNSe at 3 mg/Kg enhances stress resistance and post-stress recovery in carp fed all-plant-protein diets.

Aim. Investigate the effect of additional therapy of atorvastatin, essential phospholipids and their combination on activity of aminotransferases in RA patients with NAFLD. Materials and Methods. We investigated 126 RA patients and 30 in control. 77 RA patients with NAFLD were divided into three groups. I: 25 RA patients received 10 mg of atorvastatin per day. II: 26 RA patients received essential phospholipids 1800 mg per day. III: 26 RA patients received essential phospholipids 1800 mg per day and atorvastatin 10 mg per day for 6 months. The results. In the I group, a transient increase in ALT and AST activity was observed to 35.11±3.501 U/l and 30.51±2.19 U/l, respectively, and a spontaneous decrease in elevated transaminases was recorded after 6 months of atorvastatin use. In the II group, a decrease in ALT by 25.6% was observed compared to the indicators before treatment, and they remained unchanged even after 6 months. After 3 months of complex use of atorvastatin and essential phospholipids, ALT activity decreased by 33.8% and AST decreased by 8.2%, which was not observed in RA patients with NAFLD of groups I and II. Conclusions. Use essential phospholipids 600 mg three times a day and atorvastatin 10 mg per day for 6 months in addition to antirheumatic therapy in RA patients with NAFLD allows to avoid a transient increase in aminotransferases, reduce the severity of hepatotoxic reactions, and avoid stopping or canceling antirheumatic therapy.