Analysis of the Association Between Changes in the GGT/HDL-C Ratio and the Risk of Diabetes Mellitus Based on a Latent Class Growth Mixed Modeling: A Longitudinal Cohort Study of Adults in China.

Objective: Longitudinal cohort analysis was performed to identify the association between changes in the gamma-glutamyl transferase (GGT)/high-density lipoprotein cholesterol (HDL-C) ratio trajectory and the risk of developing diabetes mellitus. Methods: This was a retrospective cohort study. We analyzed the latent trajectory classes of changes in the GGT/HDL-C ratio by applying a latent class mixture model with healthy individuals who underwent medical checkups from January 2017 to December 2021 as the study subjects. To analyze the effect of the GGT/HDL-C ratio trajectory classes on new-onset diabetes mellitus, we then applied a multivariate Cox proportional risk regression model. Statistical analysis was performed using the R-software with the LCMM package. Results: The study cohort comprised 3410 participants. All participants were followed up for 5 years, and 95 developed diabetes (4-year incidence of 2.78%). By applying the latent class mixed model, we categorized participants into three trajectory groups: low-stability group (n = 2253), medium-increase group (n = 941), and high-increase group (n = 216). The Cox proportional risk regression model analysis showed that the hazard ratio (95% confidence interval) for the incidence of diabetes mellitus was 1.73 (1.04-2.87) in the medium-increase group and 3.96 (2.11-7.44) in the high-increase group. Moreover, we calculated the estimated model-based levels and linear slopes of the GGT/HDL-C ratios for each age group between 26 and 85 years at 10-year intervals, respectively. The results indicated the strongest correlation between the GGT/HDL-C ratio slope and diabetes in the 46-55 year age group, with an odds ratio of 1.51 (1.25-1.83). Conclusion: A large increase in the GGT/HDL-C ratio was highly associated with the risk of developing diabetes mellitus. This result suggests that vigilance for changes in the GGT/HDL-C ratio trajectory during community health screening can help identify potential patients with diabetes, enabling early intervention and treatment.

A sensitive benzothiazole fluorescent probe for the detection of γ-glutamyl transpeptidase activity and its application.

A sensitive benzothiazole fluorescent probe (PBZO) for the detection of γ-glutamyl transpeptidase (GGT) activity was developed. Based on the enzymatic hydrolysis of peptide bonds by glutamyl transpeptidase, it can be specifically recognized by PBZO. The PBZO has a good linear relationship with different gradients of GGT activity at the emission wavelength of 560 nm, the Stokes shift reached 215 nm, and the detection limit of GGT activity is 0.1644 U/ml. With the increase of GGT concentration in the probe solution, the color of the solution gradually changed from orange to dark yellow under the 365 nm UV lamp. The same color change was also observed on the probe test paper. In addition, there is a linear relationship between the GGT activity and the R-value of the probe solution. More importantly, the probe has a good recovery rate in serum. Therefore, this probe can be used as a convenient tool for detecting GGT activity.

High level of gamma-glutamyltransferase is a possible risk factor for psoriasis: A nationwide population-based cohort study.

Background Gamma-glutamyl transferase (GGT) has been associated with coronary heart disease, diabetes mellitus, and hypertension, but its association with psoriasis has not yet been elucidated. Aims We conducted this study to determine the association between the risk of psoriasis and the serum GGT. Methods We conducted a nationwide population-based study. A total of 9,939,350 people met the enrolment criteria. The study population was classified into four groups based on GGT levels and the risk of psoriasis was calculated for each group. Results The incidence rates of psoriasis per 1,000 person-years were 2.96105 and 3.68577 in the lowest and highest GGT groups, respectively. After adjusting for age, sex, income, diabetes mellitus, hypertension, dyslipidemia, smoking, alcohol intake, exercise, and body mass index, the highest GGT group showed a significantly increased risk of developing psoriasis (hazard ratio: 1.057, 95% confidence interval: 1.044-1.07). This risk of psoriasis was significantly higher among the old age group (hazard ratio: 1.162, 95% confidence interval: 1.128-1.197) and women (hazard ratio: 1.14, 95% confidence interval: 1.117-1.164). Limitations The limitations of this study included the retrospective design, International Classification of Diseases code-based diagnosis, small hazard ratio, and non-availability of data on covariates. Conclusion The GGT level was found to be an independent risk factor for developing psoriasis.

Alcohol and Periodontal Disease: A Narrative Review.

The scientific literature dealing with alcohol and alcoholic beverages revealed that these drinks possess an adverse impact on periodontal tissues. Additionally, other principal risk factors include tobacco, smoking, poor oral hygiene, etc. It has been observed that among chronic alcoholics, there are further issues, such as mental, social, and physical effects, that promote alcoholism. These people may have weak immunity for defense against pathogenic organisms and bacteria. Thus, chances of gingival bleeding, swollen gums, bad breath, and increased bone loss are there. Different alcoholic beverages in the market cause less salivation; these beverages contain sugars that promote acid production in the oral cavity by pathogens that demineralize the enamel and damage gum and teeth. This chronic alcohol consumption can progress into different types of oral disorders, including cancer, halitosis, and caries, and is also associated with tobacco and smoking. Chronic alcohol consumption can cause alteration of the oral microbiome and increase oral pathogens, which lead to periodontal disease and an environment of inflammation created in the body due to malnutrition, diminished immunity, altered liver condition, brain damage, and gut microbiota alteration. Heavily colored alcoholic beverages produce staining on teeth and, due to less saliva, may cause other toxic effects on the periodontium. Over-dependency on alcohol leads to necrotizing lesions such as necrotizing gingivitis, necrotizing periodontitis, and necrotizing stomatitis. These pathological impairments instigate severe damage to oral structures. Therefore, proper counseling by the attending dental surgeon and related health professionals is urgently required for the patient on the basis that the individual case needs to go away from the regular heavy consumption of alcohol.

Importance of gamma-glutamyl transferase elevation in patients with Fontan-associated liver disease.

AIM: In patients with Fontan-associated liver disease (FALD), gamma-glutamyl transferase (GGT) levels are often elevated, however, its clinical importance is unclear. We investigated the relationship between the clinical course of FALD and GGT levels. METHODS: We enrolled 145 patients with FALD who underwent right-heart catheterization (RHC) and visited our department. Ursodeoxycholic acid (UDCA) was administered to 62 of the patients. Patients with GGT levels <50 and ≥50 U/L were compared. Follow-up RHC was undertaken in 76 patients. Cases in which GGT levels decreased by ≥10% or <50 U/L were defined as improved (n = 33). RESULTS: Patients with GGT levels ≥50 U/L had significantly lower levels of albumin and higher levels of alanine transaminase (ALT) but no significant differences in RHC factors. Over a 4.6-year period, 43.4% showed improvement in GGT levels. Improved cases had significantly lower total bilirubin (1.1 vs. 1.6 mg/dL), AST (22 vs. 28 U/L), and ALT (18 vs. 27 U/L) levels than nonimproved cases (n = 29, p < 0.05), and the change in platelet count (-0.5 vs. -3.0 × 10-4/µL) was significantly lower in the latter (p = 0.03). The improvement rate was significantly higher in UDCA-treated cases (55.2%) with GGT levels ≥50 U/L compared to cases not treated with UDCA (18.2%, p = 0.04). CONCLUSION: In cases of FALD with no improvement in GGT level, the platelet count decreased over time, suggesting progression of fibrosis. Physicians should be aware of the importance of a high GGT level in patients with FALD.

Relationship Between Metabolic Dysfunction-Associated Steatotic Liver Disease and Lipoprotein (a) and Other Biomarkers.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) primarily affects the adult population and is closely related to obesity. The most severe form of MASLD, metabolic dysfunction-associated steatohepatitis (MASH), can progress to liver fibrosis. While lipoprotein(a) (Lp(a)) is known to be associated with cardiovascular disease, its relationship with MASLD remains unclear. This study aims to determine the prevalence of MASLD in ambulatory patients and to explore the association between Lp(a) levels and advanced liver damage. METHODS: This retrospective cross-sectional study included 130 patients older than 18 years seen in a healthcare center in Medellin, Colombia, between April 2023 and May 2024. Sociodemographic, clinical, and specific biomarker data were collected. Patients with cirrhosis, previous liver disease, frequent alcohol consumption, cancer, and other severe conditions were excluded. Continuous variables were analyzed using Student's t-tests or Mann-Whitney tests according to their distribution, and categorical variables were analyzed using contingency tables and chi-square tests. RESULTS: Of the 130 patients, 57.9% (n=73) had MASLD, with a higher prevalence in patients with obesity (80%, n=32). Lp(a) levels were abnormally high in 43.1% (n=31) of patients; however, a weak but significant inverse correlation was found between Lp(a) levels and the Fibrosis-4 (FIB-4) score, which is used to assess the severity of liver fibrosis. Patients with MASLD had significantly lower high-density lipoprotein (HDL) and vitamin D levels, and higher levels of gamma-glutamyl transferase (GGT). CONCLUSIONS: This study highlights the significant prevalence of MASLD in outpatients and its relationship with various biomarkers, including Lp(a), HDL, vitamin D, and GGT. Although the findings suggest a possible utility of Lp(a) as a biomarker in MASLD, longitudinal studies are needed to confirm these associations and clarify their role in liver disease progression. The study's limitations include its cross-sectional nature and potential selection bias, indicating the need for further research to validate these results.

High serum gamma-glutamyltransferase level after hepatitis C virus elimination is a risk factor for the development of hepatocellular carcinoma.

AIM: Gamma-glutamyltransferase (GGT) is known as an oxidative stress marker, induced by alcohol consumption and metabolic disorders, and is reported as a predictor of hepatocellular carcinoma (HCC) development after hepatitis C virus (HCV) elimination. However, it is not clear whether GGT serves simply as a surrogate marker for overlapping metabolic diseases or reflects HCV-specific carcinogenicity. We investigated the association between GGT and hepatocarcinogenesis after achieving a sustained viral response (SVR), accounting for drinking habits or diabetes, and examined predisposing factors associated with GGT levels after SVR. METHODS: This is a prospective, multicenter, and observational study using the database of 1001 patients after HCV eradication with direct-acting antiviral agents. The association of GGT at SVR with cumulative HCC development was examined in a multivariate analysis using Cox proportional hazard models after adjustment for covariates including alcohol and diabetes. The association between oxidative stress markers or genetic factors and GGT levels was analyzed. RESULTS: High GGT levels at SVR were associated with HCC development (HR] 2.38, 95% CI 1.10-5.17). This association was also significant when restricted to patients without alcohol consumption or diabetes (HR 8.38, 95% CI 2.87-24.47). GGT levels were correlated with serum growth differentiation factor 15 levels, a marker of mitochondrial dysfunction. Single-nucleotide polymorphisms of ZNF827 and GDF15 were associated with high GGT levels. CONCLUSIONS: High GGT levels at SVR were associated with HCC development after accounting for alcohol consumption and diabetes. GGT levels are influenced by genetic predisposition and may reflect mitochondrial dysfunction after HCV eradication.

Study of Serum Gamma-Glutamyl Transferase Levels in Patients With Acute Ischemic Stroke.

Background Gamma-glutamyl transferase (GGT) mediates intracellular uptake of glutathione which is a known antioxidant. GGT levels are found to be elevated in conditions of oxidative stress. Ischemic stroke results in anoxic injury, which liberates free radicals, causing glutathione to rise, which may be accompanied by a rise in serum GGT levels. This study aimed to compare serum GGT levels in acute ischemic stroke patients with normal controls and to ascertain the relation of serum GGT levels with National Institute of Health Stroke Scale (NIHSS) scores. Materials and methods This cross-sectional study was carried out in a tertiary care hospital in South India from August 2023 to February 2024. The study included 57 patients who presented with acute ischemic stroke within 24 hours of onset and 57 age- and sex-matched controls. The serum GGT levels of the cases were compared with age- and sex-matched controls using an independent t-test. Mean serum GGT levels were compared among groups with varying NIHSS scores and different locations of infarction using the ANOVA test. Serum GGT levels were also compared based on age, gender, and various comorbidities. Results The mean serum GGT levels were significantly increased (p < 0.0001) in acute ischemic stroke patients, 43.96 ± 28.02 (mean ± SD), when compared to controls, 26.14 ± 5.93 (mean ± SD). The difference in serum GGT levels with NIHSS scores of 5-15 (moderate strokes) with 34.17 ± 18.39 (mean ± SD), 16-20 (moderate-severe strokes) with 46.64 ± 21.95 (mean ± SD), and >21 (severe stroke) with 84.62 ± 39.35 (mean ± SD) was significant (p < 0.00001). Serum GGT levels were not significant while comparing age, gender, location of infarction, type 2 diabetes mellitus, and hypertension. Conclusion Serum GGT levels were significantly elevated in acute ischemic stroke patients within 24 hours of presentation. Serum GGT levels were significantly elevated with increasing severity of stroke as calculated by NIHSS scores at the time of presentation. Serum GGT levels are a potential marker of ischemic stroke and its severity.

A New Assessment of Two Transferase-Based Liver Enzymes in Low- and High-Fibrosis Patients Chronically Infected with Hepatitis B Virus: A Meta-Analysis and Pilot Study.

Background: The detection of fibrosis remains a necessity for the evaluation of hepatitis B virus (HBV)-infected patients, but the most accurate technique is invasive. Current studies aim to develop a novel noninvasive biomarker for fibrosis assessment, but no-one has found the ideal candidate. This study is a meta-analysis combined with a pilot study to investigate the connection between two transferase compounds and the levels of fibrosis. Methods: We studied data from PUBMED, Web of Science, and Scopus, retrieving 28,896 articles. Following PRISMA guidelines, we finally analyzed full-text articles written in English. The excluded items were duplicates, non-article entries, and irrelevant papers. We assessed the variations in alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) levels between patients with high and low levels of fibrosis. Joanna Briggs Institute tools were used to assess article quality. We used R 4.2.2 for statistics. The pilot study included 14 randomly chosen patients with different fibrosis levels. Results: We found significant differences in ALT and GGT levels between patients with high and low fibrosis. The GGT/ALT ratio correlated with the levels of fibrosis and the fibrosis-4 (FIB-4) score. Conclusions: This meta-analysis assessed ALT and GGT levels in chronic HBV patients with fibrosis. The pilot study identified the first association between fibrosis and the GGT/ALT ratio in a Romanian cohort of chronic patients. This brings new ideas for future research.

Glutathione­degrading enzymes in the complex landscape of tumors (Review).

Glutathione (GSH)­degrading enzymes are essential for starting the first stages of GSH degradation. These enzymes include extracellular γ­glutamyl transpeptidase (GGT) and intracellular GSH­specific γ­glutamylcyclotransferase 1 (ChaC1) and 2. These enzymes are essential for cellular activities, such as immune response, differentiation, proliferation, homeostasis regulation and programmed cell death. Tumor tissue frequently exhibits abnormal expression of GSH­degrading enzymes, which has a key impact on the development and spread of malignancies. The present review summarizes gene and protein structure, catalytic activity and regulation of GSH­degrading enzymes, their vital roles in tumor development (including regulation of oxidative and endoplasmic reticulum stress, control of programmed cell death, promotion of inflammation and tumorigenesis and modulation of drug resistance in tumor cells) and potential role as diagnostic biomarkers and therapeutic targets.

TXNDC12 inhibits pancreatic tumor cells ferroptosis by regulating GSH/GGT7 and promotes its growth and metastasis.

Background: Thioredoxin domain-containing protein 12 (TXNDC12) is upregulated in a variety of tumours, including pancreatic cancer (PAAD), and its high expression is closely associated with poor prognosis. However, the regulatory mechanism of TXNDC12 in PAAD has not been reported. The aim of this study is to reveal the precise mechanism of TXNDC12 in regulating PAAD progression. Methods: The expression of TXNDC12 in pan-cancer as well as PAAD was verified by TCGA and GTEx databases, Western blot and RT-qPCR. CCK8 assay, clone formation assay and cell cycle assay were used to observe the effect of TXNDC12 on the proliferation of PAAD cells, the migration and invasion capacities were verified by wound healing assay and Transwell assay. The effect of TXNDC12 on apoptosis of MIA PaCa-2 and PANC-1 cells was detected using Hochest and flow cytometry. Finally, the interaction of TXNDC12 with GGT7 was predicted by STRING database and confirmed by CO-IP assay, the effect of TXNDC12 on ferroptosis through GGT7 was evaluated by GSH assay, MDA assay, ROS assay and Western blot. Results: TXNDC12 is upregulated in PAAD tissues, and patients with high TXNDC12 levels generally have shorter survival times. Knockdown of TXNDC12 significantly inhibited the proliferation, migration and invasion and promoted apoptosis of MIA PaCa-2 and PANC-1 cells. Mechanistically, knockdown of TXNDC12 resulted in a decrease in intracellular GSH content and an increase in GSSG content, as well as elevated levels of pro-ferroptosis factors, such as MDA and ROS. STRING database predicted that TXNDC12 interacts with GGT7, and CO-IP assay was used to validate this result. Finally, the effect of knocking down TXNDC12 on pancreatic cancer cell functions was able to be reversed by overexpression of GGT7. Conclusion: TXNDC12 inhibits ferroptosis in PAAD cells through the GSH/GGT7 axis thereby promoting their development.

Effect of ipragliflozin on liver enzymes in type 2 diabetes mellitus: a meta-analysis of randomized controlled trials.

INTRODUCTION: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is estimated to affect upto 70-80% of people with type 2 diabetes mellitus (T2DM). Although several anti-hyperglycemic drugs have been shown to be effective in such patients, there remains an unmet need for newer drugs. The objective of this meta-analysis was to analyze the effect of ipragliflozin on aspartate aminotransferase (AST), alanine transaminase (ALT), and gamma-glutamyl transpeptidase (GGT) levels in patients with T2DM. METHODS: A literature search on electronic databases was conducted to identify potential randomized clinical trials (RCT) as per predetermined study selection criteria. Mean difference (MD) was calculated using Cochrane review manager. RESULTS: Twelve studies were included in the meta-analysis, including 1349 subjects. Compared to the control group, ipragliflozin as a monotherapy showed a significant reduction in levels of ALT at week 12 (p = 0.02) and at week 24 (p = 0.007), GGT at week 12 (p < 0.00001). Ipragliflozin as an add-on therapy showed significant reduction in levels of AST at week 24 (p < 0.00001), ALT at week 12 (p = 0.002), ALT at week 24 (p < 0.00001), and GGT at week 24 (p < 0.00001). CONCLUSION: Findings suggest the beneficial effects of ipragliflozin on liver enzymes. Further large-scale RCTs are required to confirm ipragliflozin's role for liver-related conditions in T2DM.

Comparative plasma biochemistry analyte data in nesting leatherback (Dermochelys coriacea), foraging green (Chelonia mydas) and foraging and nesting hawksbill (Eretmochelys imbricata) sea turtles in Grenada, West Indies.

Blood biochemistry represents a minimally invasive tool for monitoring sea turtle health, assessing injured sea turtles and supporting conservation strategies. In Grenada, West Indies, plasma biochemical variables were examined in 33 nesting leatherback (Dermochelys coriacea), 49 foraging green (Chelonia mydas), 49 foraging hawksbill (Eretmochelys imbricata) and 12 nesting hawksbill sea turtles sampled between 2017 and 2022. Plasma biochemistry reference intervals are described herein except for nesting hawksbills, which are represented by descriptive statistics due to the low sample size. Select analyte concentrations were positively correlated with curved carapace length in leatherbacks (chloride), green turtles (total protein, albumin and globulin) and foraging hawksbills (total protein, albumin and phosphorus). Cholesterol (7.8 mmol/l ± 1.6 SD) and triglyceride (6.9 mmol/l ± 1.9 SD) concentrations were significantly higher in leatherbacks compared to foraging green turtles, foraging hawksbills and nesting hawksbills (P < 0.001 for all). Cholesterol was significantly higher in nesting hawksbills compared to foraging green turtles (P = 0.050) and foraging hawksbills (P = 0.050). Foraging hawksbills demonstrated significantly higher aspartate transaminase activities than leatherbacks (P = 0.002), green turtles (P = 0.009) and nesting hawksbills (P < 0.001). Biochemical results provide baseline population health data and support guidance for treatments during clinical sea turtle rehabilitation efforts. They also provide insight into species-specific physiologic differences and preludes further studies to better characterize the impacts of life-stage class on biochemistry reference intervals to better support wild sea turtle populations in Grenada.

GGT5: a potential immunotherapy response inhibitor in gastric cancer by modulating GSH metabolism and sustaining memory CD8+ T cell infiltration.

PURPOSE: The variable responses to immunotherapy observed in gastric cancer (GC) patients can be attributed to the intricate nature of the tumor microenvironment. Glutathione (GSH) metabolism significantly influences the initiation and progression of gastric cancer. Consequently, targeting GSH metabolism holds promise for improving the effectiveness of Immune checkpoints inhibitors (ICIs). METHODS: We investigated 16 genes related to GSH metabolism, sourced from the MSigDB database, using pan-cancer datasets from TCGA. The most representative prognosis-related gene was identified for further analysis. ScRNA-sequencing analysis was used to explore the tumor heterogeneity of GC, and the results were confirmed by  Multiplex immunohistochemistry (mIHC). RESULTS: Through DEGs, LASSO, univariate and multivariate Cox regression analyses, and survival analysis, we identified GGT5 as the hub gene in GSH metabolism with the potential to promote GC. Combining CIBERSORT, ssGSEA, and scRNA analysis, we constructed the immune architecture of GC. The subpopulations of T cells were isolated, revealing a strong association between GGT5 and memory CD8+ T cells. Furthermore, specimens from 10 GC patients receiving immunotherapy were collected. mIHC was used to assess the expression levels of GGT5 and memory CD8+ T cell markers. Our results established a positive correlation between GGT5 expression, the enrichment of memory CD8+ T cells, and a suboptimal response to immunotherapy. CONCLUSIONS: Our study identifies GGT5, a hub gene in GSH metabolism, as a potential therapeutic target for inhibiting the response to immunotherapy in GC patients. These findings offer new insights into strategies for optimizing immunotherapy of GC.

GGT5 facilitates migration and invasion through the induction of epithelial-mesenchymal transformation in gastric cancer.

BACKGROUND: Gamma-glutamyltransferase 5 (GGT5), one of the two members in the GGT family (GGT1 and GGT5), plays a crucial role in oxidative regulation, inflammation promotion, and drug metabolism. Particularly in the tumorigenesis of various cancers, its significance has been recognized. Nevertheless, GGT5's role in gastric cancer (GC) remains ambiguous. This study delves into the function and prognostic significance of GGT5 in GC through a series of in vitro experiments. METHODS: Employing online bioinformatics analysis tools such as The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), Kaplan-Meier plotter, and cBioPortal, we explored GGT5 characteristics and functions in GC. This encompassed aberrant expression, prognostic value, genomic alterations and mutations, immune cell infiltration, and associated signaling pathways. Immunohistochemistry was conducted to assess GGT5 expression in GC and adjacent normal tissues. Subsequently, univariate and multivariate logistic regression analyses were applied to investigate the associations between GGT5 and clinical characteristics. CCK8, wound healing, and migration assays were utilized to evaluate the impact of GGT5 on cell viability and migration. Additionally, Gene Set Enrichment Analysis (GSEA) and Western blot analysis were performed to scrutinize the activity of the epithelial-mesenchymal transformation (EMT) signaling pathway under GGT5 regulation. RESULTS: GGT5 exhibits upregulation in gastric cancer, with its overexpression significantly linked to histological differentiation in GC patients (P < 0.05). Multivariate analysis indicates that elevated GGT5 expression is an independent risk factor associated with poorer overall survival in gastric cancer patients (P < 0.05). In vitro experiments reveal that downregulation of GGT5 hampers the proliferation and migration of GC cell lines. Finally, GSEA using TCGA data highlights a significant correlation between GGT5 expression and genes associated with EMT, a finding further confirmed by Western blot analysis. CONCLUSIONS: GGT5 emerges as a promising prognostic biomarker and potential therapeutic target for GC.

The Relationship Between Small Dense Low-Density Lipoprotein Cholesterol and Metabolic Syndrome.

Background: Prior research has established an association between small dense low-density lipoprotein cholesterol (sdLDL-C) and dyslipidemia, serving as a significant marker for predicting cardiovascular diseases. Nevertheless, the connection between sdLDL-C and metabolic syndrome (MetS) remains unclear. Methods: This study retrospectively analyzed 23,187 individuals who underwent health checkups at Taizhou Hospital's health management center. Here, we investigated the relationship between sdLDL-C and MetS, along with its components, utilizing Spearman correlation analysis, receiver operating characteristic (ROC) curve analysis, logistic regression, and mediation analysis. Results: The MetS group exhibited significantly higher level of sdLDL-C compared to the non-MetS group (P<0.001). We observed a strong correlation between sdLDL-C and several key factors: TG (r = 0.711), TC (r = 0.672), LDL-C (r = 0.781), GGT (r = 0.420), and HDL-C (r = -0.417). After adjusting for age and gender, the odds ratio (OR) (95% confidence interval [CI]) for MetS incidence in the second, third, and fourth quartiles versus the first quartile of sdLDL-C concentration were 2.264 (95% CI: 1.851, 2.770), 4.053 (95% CI: 3.350, 4.903), and 9.034 (95% CI: 7.531, 10.837). The optimal cut-off value for diagnosing MetS using sdLDL-C was determined to be 0.98 mmol/L, with an area under the ROC curve (AUC) of 0.716 (95% CI: 0.705, 0.726). Additionally, mediation analysis revealed that sdLDL-C mediated a 12.8% correlation between GGT and TG concentration. Conclusion: The sdLDL-C is correlated with MetS and it can successfully mediate the relationship between GGT and TG. Our data suggests that sdLDL-c and GGT are suitable parameters for preventing and monitoring MetS.

NR1H4 disease: rapidly progressing neonatal intrahepatic cholestasis and early death.

BACKGROUND: Clinical studies on progressive familial intrahepatic cholestasis (PFIC) type 5 caused by mutations in NR1H4 are limited. METHODS: New patients with biallelic NR1H4 variants from our center and all patients from literature were retrospectively analyzed. RESULTS: Three new patients were identified to be carrying five new variants. Liver phenotypes of our patients manifests as low-γ-glutamyl transferase cholestasis, liver failure and related complications. One patient underwent liver transplantation (LT) and survived, and two other patients died without LT. Nine other patients were collected through literature review. Twelve out of 13 patients showed neonatal jaundice, with the median age of onset being 7 days after birth. Reported clinical manifestations included cholestasis (13/13, 100%), elevated AFP (11/11, 100%), coagulopathy (11/11, 100%), hypoglycemia (9/13, 69%), failure to thrive (8/13, 62%), splenomegaly (7/13, 54%), hyperammonemia (7/13, 54%), and hepatomegaly (6/13, 46%). Six of 13 patients received LT at a median age of 6.2 months, and only one patient died of acute infection at one year after LT. Other 7 patients had no LT and died with a median age of 5 months (range 1.2-8). There were 8 patients with homozygous genotype and 5 patients with compound heterozygous genotype. In total, 13 different variants were detected, and 5 out of 12 single or multiple nucleotides variants were located in exon 5. CONCLUSIONS: We identified three newly-diagnosed patients and five novel mutations. NR1H4-related PFIC typically cause progressive disease and early death. LT may be the only lifesaving therapy leading to cure.

The discovery of GGT1 as a novel gene for ischemic stroke conferring protection against disease risk in non-smokers and non-abusers of alcohol.

OBJECTIVES: Increased plasma gamma-glutamyl transferase (GGT1) has been identified as a robust and independent risk factor for ischemic stroke (IS), but the molecular mechanisms of the enzyme-disease association are unclear. The present study investigated whether polymorphisms in the GGT1 gene contribute to IS susceptibility. MATERIALS AND METHODS: DNA samples obtained from 1288 unrelated individuals (600 IS patients and 688 controls) were genotyped for common single nucleotide polymorphisms of GGT1 using the MassArray-4 platform. RESULTS: The rs5751909 polymorphism was significantly associated with decreased risk of ischemic stroke regardless sex and age (Pperm ≤ 0.01, dominant genetic model). The haplotype rs4820599A-rs5760489A-rs5751909A showed strong protection against ischemic stroke (OR 0.53, 95 %CI 0.36 - 0.77, Pperm ≤ 0.0001). The protective effect of SNP rs5751909 in the stroke phenotype was successfully replicated in the UK Biobank, SiGN, and ISGC cohorts (P ≤ 0.01). GGT1 polymorphisms showed joint (epistatic) effects on the risk of ischemic stroke, with some known IS-associated GWAS loci (e.g., rs4322086 and rs12646447) investigated in our population. In addition, SNP rs5751909 was found to be strongly associated with a decreased risk of ischemic stroke in non-smokers (OR 0.54 95 %CI 0.39-0.75, Pperm = 0.0002) and non-alcohol abusers (OR 0.43 95 %CI 0.30-0.61, Pperm = 2.0 × 10-6), whereas no protective effects of this SNP against disease risk were observed in smokers and alcohol abusers (Pperm < 0.05). CONCLUSIONS: We propose mechanisms underlying the observed associations between GGT1 polymorphisms and ischemic stroke risk. This pilot study is the first to demonstrate that GGT1 is a novel susceptibility gene for ischemic stroke and provides additional evidence of the genetic contribution to impaired redox homeostasis underlying disease pathogenesis.

Hepatogenic photosensitization in lambs supplemented with different levels of extruded urea in Brachiaria spp. pastures in the Brazilian Cerrado: Case report.

The aim was to report cases and risk factors for hepatogenous photosensitization in lambs kept on Brachiaria spp. pastures and supplemented with levels of extruded urea (EU). The herd consisted of 69 Texel crossbred lambs with known parentage (fathers and mothers adapted to the consumption of forage of the genus Brachiaria), randomly divided into 5 groups and distributed in individual paddocks for each group. The animals were supplemented with increasing levels of EU (Amireia® 200S): 0, 6, 12, 18, and 24 g of EU per 100 kg-1 of body weight (BW). The concentration of protodioscin was estimated in the mixed pastures of Brachiaria spp. (cv. Marandu and cv. Basilisk), structural components (leaf, stem, and dead material), samples of each cultivar, and in the months of December (2018), February, and April (2019). The animals were examined daily, and when behavioral changes were identified, they underwent clinical examinations and anamnesis. Weighing was performed every 14 days, followed by necropsy and serum biochemical analysis, including gamma-glutamyltransferase (GGT). The highest concentrations of protodioscin (p < 0.0001) were found in the pastures used by animals supplemented without extruded urea (7.07 ± 0.56), in the Basilisk cultivar (11.35 ± 0.06), in the leaf blade components (2.08 ± 0.05), and thatch (2.20 ± 0.00), and in the month of April (7.34 ± 0.29) (the month with the lowest rainfall), respectively. Fourteen (20.29%) cases of photosensitization were observed in lambs, of which six recovered, and eight died. Serum GGT levels ranged from 42.2 to 225 IU/L; however, in animals that died, values ranged from 209.4 to 225 IU/L. The use of levels 12 g and 18 g per 100 kg-1 of body weight of extruded urea may contribute to the lower occurrence of photosensitization, as the animals selected pastures with lower protodioscin content, presenting a smaller number of cases.