Search Results (49)

The enzyme γ-glutamyl transpeptidase (GGT), located on the surface of cellular membranes, hydrolyzes extracellular glutathione (GSH) to guarantee the recycling of cysteine and maintain intracellular redox homeostasis. High expression levels of GGT on tumor cells are associated with increased cell proliferation and resistance against chemotherapy. Therefore, GGT inhibitors have potential as adjuvants in treating GGT-positive tumors; however, most have been abandoned during clinical trials due to toxicity. Recent studies indicate marine-derived ovothiols as more potent non-competitive GGT inhibitors, inducing a mixed cell-death phenotype of apoptosis and autophagy in GGT-overexpressing cell lines, such as the chronic B leukemic cell HG-3, while displaying no toxicity towards non-proliferative cells. In this work, we characterize the activity of two synthetic ovothiol analogs, L-5-sulfanylhistidine and iso-ovothiol A, in GGT-positive cells, such as HG-3 and HL-60 cells derived from acute promyelocytic leukemia. The two compounds inhibit the activity of membrane-bound GGT, without altering cell vitality nor inducing cytotoxic autophagy in HG-3 cells. We provide evidence that a portion of L-5-sulfanylhistidine enters HG-3 cells and acts as a redox regulator, contributing to the increase in intracellular GSH. On the other hand, ovothiol A, which is mostly sequestered by external membrane-bound GGT, induces intracellular ROS increase and the consequent autophagic pathways. These findings provide the basis for developing ovothiol derivatives as adjuvants in treating GGT-positive tumors’ chemoresistance. Full article

γ-Glutamyl transpeptidase (GGT) is overexpressed in a variety of diseases, making it an important diagnostic criterion for diseases. Herein, a new fluorescence probe based on naphthalimide (Glu-MDA) was developed and employed for the rapid detection of GGT in tumor cells or samples. Alkynylated naphthalimide is the fluorescent core for excellent fluorescence response. The covalent bridging of self-immolative short linkers reduces the steric hindrance between probes and enzyme cleavage sites, which leads to improved enzymatic reaction kinetics. Glu-MDA shows a rapid response and excellent selectivity with a detection limit of 0.044 U/L. This allows the efficient detection of GGT levels in solution and cells. Simultaneously, the construction of Glu-MDA pre-stained test strips provided an innovative strategy for the qualitative detection of GGT activity, helping to detect GGT faster, more portably, and cost-effectively in various scenarios. Full article

The liver of hens bears a very heavy workload in handling lipogenesis as well as carbohydrate, protein, and other nutrient metabolism to maintain a high laying rate. D-glucuronolactone (DGL) is a naturally occurring chemical metabolite produced from glucose and exhibits a hepatoprotective effect as a food ingredient. This study aimed to evaluate the effect of DGL on production performance, egg quality, and liver health in laying hens during their peak period. Four hundred and eighty Hy-Line brown hens (aged 42 weeks), with comparable high-laying performance, were randomly assigned to four groups, with each group consisting of eight replicates. The control group was fed a basal diet, while the treatment groups were supplemented with DGL at 70, 140, and 280 mg/kg in the basal diet, respectively. The results indicated that DGL supplementation significantly increases the laying rate and egg mass of hens (p < 0.05). The brown color of the eggshell was significantly deepened by DGL administration (p < 0.05). Additionally, DGL supplementation significantly decreased the serum levels of aspartate aminotransferase and γ-glutamyl transpeptidase (p < 0.05). The liver index, liver fat, and triglyceride levels in the liver had also significantly decreased (p < 0.05). Liver histopathological results showed that the control group exhibited yellow coloration with large gaps and numerous vacuolar cells, while DGL supplementation improved the compactness of liver parenchyma. Antioxidant activity was enhanced, showing a significant increase in the activity of total antioxidant capacity and catalase in the liver (p < 0.05). The inflammatory response was alleviated, with a significant decrease in expressions of interleukin-β, tumor necrosis factor-α, interferon-α, interleukin-6, and interleukin-8 genes in the liver (p < 0.05). Moreover, DGL supplementation significantly reduced cell apoptosis-related genes, including factor-related apoptosis, Caspase 7, and BCL2 associated X protein in the liver (p < 0.05). Overall, these findings indicate that dietary DGL enhanced the laying performance of hens by maintaining liver health, with the best results achieved at a dose of 280 mg/kg in this trial. Full article

Background and Aim: Controlling the hepatic inflammation of metabolic dysfunction-associated steatotic liver disease (MASLD) is important to prevent serious condition. Pemafibrate, a selective peroxisome proliferator-activated receptor-α modulator, has demonstrated effectiveness at a standard dose (0.2 mg daily). The aim of this study is to evaluate the effectiveness of pemafibrate dose escalation from 0.2 mg to 0.4 mg daily in patients with MASLD who are refractory to standard-dose therapy. Methods: This study included patients with MASLD who had a persistent elevation of alanine aminotransferase (ALT) levels despite more than one year of standard-dose pemafibrate therapy (0.2 mg daily). All patients underwent dose escalation to 0.4 mg once daily. Hepatic inflammation was assessed using serum ALT levels, hepatic function was evaluated with the albumin–bilirubin score, and hepatic fibrosis was estimated using Mac-2 binding protein glycosylation isomer (M2BPGi) levels. A one-year treatment period was investigated, including six months before dose escalation and six months after dose escalation. Results: Eleven patients were included. The median treating period with standard-dose pemafibrate was 3.2 years. Weight did not show significant change throughout the observation period. Regarding the hepatobiliary enzyme, the aspartate aminotransferase, ALT, and γ-glutamyl transpeptidase levels significantly improved six months after the dose escalation. Specifically, ALT improved in all patients, and the ALT levels normalized in four patients (36%). The lipid profiles, the albumin–bilirubin score, and M2BPGi did not significantly change after the dose escalation. Conclusions: The dose escalation of pemafibrate from 0.2 mg to 0.4 mg daily may improve hepatic inflammation in patients with MASLD refractory to standard-dose therapy. Full article

Reynoutria ciliinervis (Nakai) Moldenke (R. ciliinervis) root, a traditional Chinese medicine, was found to exhibit remarkable pharmacological properties through a series of comprehensive investigations. Our study commenced with a qualitative phytochemical analysis that identified 12 bioactive compounds within the plant. Subsequently, utilizing ultraviolet-visible spectrophotometry, the methanol extract emerged as the optimal solvent extract, which was abundant in diverse classes of compounds such as carbohydrates, phenolics, steroids, alkaloids, phenolic acids, and tannins. In vitro antioxidant assays underscored the exceptional free radical scavenging, metal ion chelation, hydrogen peroxide scavenging, singlet oxygen quenching, and β-carotene bleaching capabilities of the methanol extract, significantly outperforming other solvent extracts. Further ultra high-performance liquid chromatography–electrospray ionization–quadrupole time of flight–mass spectrometry analysis revealed the presence of 45 compounds, predominantly anthraquinones and phenolics, in the methanol extract. The extract demonstrated robust stability under various conditions, including high temperatures, varying pH levels, and simulated gastrointestinal digestion as well as efficacy in inhibiting the oxidation in edible oils. Acute toxicity tests in mice confirmed the safety of the methanol extract and provided a valuable dosage reference for future studies. Importantly, high-dose methanol extract exhibited a significant pre-protective effect against D-galactosamine-induced liver injury in rats, as evidenced by reduced alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transpeptidase, malondialdehyde levels, and elevated catalase and albumin levels. These findings suggest a potential role for the methanol extract of R. ciliinervis root in treating oxidative stress-related disorders, highlighting the plant’s immense medicinal potential. Our research offers a thorough evaluation of the bioactive components, antioxidant properties, stability, and liver-protecting effects of the methanol extract, setting the stage for deeper investigation and potential clinical applications. Full article

Lentinula edodes (L. edodes) is a globally popular edible mushroom because of its characteristic sulfur-containing flavor compounds. However, the formation of the volatile sulfur-containing compounds in the mycelium of L. edodes has not been studied. We found that there were also sulfur-containing aroma compounds in the mycelium of L. edodes, and the content and composition varied at different stages of mycelial growth and development. The γ-glutamyl-transpeptidase (GGT) and cysteine sulfoxide lyase (C-S lyase) related to the generation of sulfur compounds showed the highest activities in the 15-day sample. Candidate genes for the metabolism of volatile sulfur compounds in mycelium were screened using transcriptome analysis, including encoding the GGT enzyme, C-S lyase, fatty acid oxidase, HSP20, and P450 genes. The expression patterns of Leggt3 and Leccsl3 genes were consistent with the measured activities of GGT and C-S lyase during the cultivation of mycelium and molecular dynamics simulations showed that they could stably bind to the substrate. Our findings provide insights into the formation of sulfur-containing flavor compounds in L. edodes. The mycelium of L. edodes is suggested for use as material for the production of sulfur-containing flavor compounds. Full article

Introduction: Chronic hepatitis C (CHC) is a clinical and pathological syndrome with various causes and is characterized by varying degrees of hepatocellular necrosis and inflammation. It is a significant cause of liver transplantation and liver-related death worldwide. The hepatic manifestations of CHC are typically characterized by slowly progressing liver fibrosis, which is a non-specific and often disproportionate response to tissue damage. A large majority of HCV patients have extrahepatic manifestations with varying degrees of severity. HCV infection is a risk factor for cardiovascular disease and diabetes mellitus, which increases insulin resistance, oxidative stress, and iron overload and causes chronic systemic inflammation. HCV infection is treated using direct-acting antivirals (DAAs) with cure rates of over 95 percent, minimal side effects, and shorter therapeutic courses. Despite the effective elimination of the virus, it seemed pertinent to understand to what extent HCV clearance eliminates or attenuates all the systemic alterations already induced by the virus during infection and chronicity. Objectives: Our study aimed to determine whether eliminating HCV with DAAs alters the severity of liver disease (liver stiffness and liver fibrosis stage by TE) and the metabolic/cellular profile of patients with CHC. Materials and methods: A group of 329 CHC patients from a Gastroenterology and Hepatology outpatient department were prospectively studied. Of these, 134 were also studied with DAAs. The liver fibrosis stage was evaluated by transient elastography (TE) using a FibroScan^® device, and two groups were established for the analysis of liver stiffness (LS): mild and moderate stiffness (fibrosis F1 and F2; F1/2) and severe stiffness (fibrosis and cirrhosis F3 and F4; F3/4). Metabolic/cellular parameters were evaluated before and after antiviral treatment using standard methods: alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyl-transpeptidase (γ-GT), haptoglobin (Hp), total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TG), free iron (Fe), transferrin saturation (TS), total iron binding capacity (TIBC), ferritin (Ft), glycemia, insulin, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and platelets count. The results were statistically analyzed using SPSS 24.0 for Windows. Results: Comparing the fibrosis stage before and after DAAs treatment, we verify a reduction in LS in 85.7% of patients and an improvement in liver fibrosis stage in 22.2% of them after DAAs treatment. Before DAAs treatment, patients showed a 2.410 risk for higher fibrosis stages (F3/4). Comparing metabolic/cellular parameters before and after DAAs treatment, patients showed lower ALP, AST, ALT, γGT, TG, Fe, TIBC, and Ft values and higher TC, LDL, and Hp values after treatment. As such, HCV elimination reduces iron overload and insulin resistance. On the other hand, it caused dyslipidemia, raising total cholesterol and LDL to levels outside the reference values. The improvement in the liver fibrosis stage by TE was mainly associated with higher baseline platelet count and HDL values and lower insulin resistance. Conclusions: With this study, we were able to contribute to the knowledge of the effects of HCV elimination with DAAs on liver disease and metabolic profile to improve the quality of treatment and follow-up of these patients after HCV elimination. Full article

Intense physical activity can induce metabolic changes that modify specific biochemical biomarkers. In this scenario, the purpose of our study was to evaluate how intense physical activity can affect oxidative metabolism. Following this, fifteen professional basketball players and fifteen sedentary controls were recruited and subjected to two samplings of serum and urine in the pre-season (September) and two months after the start of the competitive season (November). Our results have shown an increase in athletes compared to controls in CK and LDH in September (respectively, p-value 0.003 and p-value < 0.001) and in November (both p-value < 0.001), whereas ALT is increased only in November (p-value 0.09). GGT serum levels were decreased in athletes compared to controls in both months (in September p-value 0.001 and in November p-value < 0.001). A gene expression analysis, carried out using RT-PCR, has revealed that IL-2, IL-6, IL-8, xCT and GCLM are increased in athletes in both months (p-value < 0.0001), while IL-10 and CHAC1 are increased only in September if compared to the controls (respectively, p-value 0.040 and p-value < 0.001). In conclusion, physical activity creates an adaptation of the systems involved in oxidative metabolism but without causing damage to the liver or kidney. This information could be of help to sports doctors for the prevention of injuries and illnesses in professional athletes for the construction of the athlete’s passport. Full article

Background: To summarize available evidence in the literature on the impacts of CoQ₁₀ supplementation on metabolic, biochemical, and performance outcomes in athletes. Methods: Six databases, Cochrane Library (33 articles), PubMed (90 articles), Scopus (55 articles), Embase (60 articles), SPORTDiscus (1056 articles), and Science Direct (165 articles), were researched. After applying the eligibility criteria, articles were selected for peer review independently as they were identified by June 2022. The protocol for this systematic review was registered on PROSPERO (CRD42022357750). Results: Of the 1409 articles found, 16 were selected for this systematic review. After CoQ₁₀ supplementation, a decrease in oxidative stress markers was observed, followed by higher antioxidant activity. On the other hand, lower levels of liver damage markers (ALT); Aspartate aminotransferase (AST); and Gamma-glutamyl transpeptidase (γGT) were identified. Finally, we found a reduction in fatigue indicators such as Creatine Kinase (CK) and an increase in anaerobic performance. Conclusions: This systematic review concludes that supplementation with orally administered CoQ₁₀ (30–300 mg) was able to potentiate plasma antioxidant activity and anaerobic performance, reducing markers linked to oxidative stress and liver damage in athletes from different modalities aged 17 years old and older. Full article

Schizandrae Fructus (SF), fruits of Schisandra chinensis (Turcz.) Baill. and Hoveniae Semen cum Fructus (HSCF), the dried peduncle of Hovenia dulcis Thunb., have long been used for alcohol detoxification in the traditional medicine of Korea and China. In the current study, we aimed to evaluate the potential synergistic hepatoprotective effect of a combination mixture (MSH) comprising fermented SF pomace (fSFP) and HSCF hot water extracts at a 1:1 (w:w) ratio against ethanol-induced liver toxicity. Subacute ethanol-mediated hepatotoxicity was induced by the oral administration of ethanol (5 g/kg) in C57BL/6J mice once daily for 14 consecutive days. One hour after each ethanol administration, MSH (50, 100, and 200 mg/kg) was also orally administered daily. MSH administration significantly reduced the serum activities of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and γ-glutamyl transpeptidase. Histological observation indicated that MSH administration synergistically and significantly decreased the fatty changed region of hepatic parenchyma and the formation of lipid droplet in hepatocytes. Moreover, MSH significantly attenuated the hepatic triglyceride accumulation through reducing lipogenesis genes expression and increasing fatty acid oxidation genes expression. In addition, MSH significantly inhibited protein nitrosylation and lipid peroxidation by lowering cytochrome P450 2E1 enzyme activity and restoring the glutathione level, superoxide dismutase and catalase activity in liver. Furthermore, MSH synergistically decreased the mRNA level of tumor necrosis factor-α in the hepatic tissue. These findings indicate that MSH has potential for preventing alcoholic liver disease through inhibiting hepatic steatosis, oxidative stress, and inflammation. Full article

Schizandrae Fructus (SF) and Hoveniae Semen cum Fructus (HSCF) have long been used as medicinal herbs for treating various diseases in Asian traditional medicine. In the current study, we investigated the protective effect of fermented SF pomace and HSCF extract 1:1 (w:w) combination mixture (MSH) against carbon tetrachloride (CCl₄)-induced acute liver injury mice. After MSH (50–200 mg/kg) oral administration for 7 consecutive days, animals were injected intraperitoneally with CCl₄ (0.5 mL/kg). Histopathological observation revealed that administration of MSH synergistically decreased the degeneration of hepatocytes and the infiltration of inflammatory cells induced by CCl₄. Moreover, MSH administration reduced the activities of alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transpeptidase in serum, and mitigated apoptotic cell death in hepatic parenchyma. In addition, MSH alleviated CCl₄-mediated lipid peroxidation by restoring endogenous antioxidants capacities including glutathione contents, superoxide dismutase, and catalase activities. In vitro assessments using tert-butyl hydroperoxide-induced oxidative stress in HepG2 cells revealed that MSH protects hepatocytes by lowering ROS generation and lipid peroxidation via upregulating the transcriptional activity of nuclear factor erythroid-2-related factor 2 and the expression of antioxidant genes. Furthermore, MSH synergistically attenuated the expression of proinflammatory cytokines in CCl₄-injured liver and lipopolysaccharide-stimulated RAW 264.7 cells. Taken together, these findings suggest that MSH has the potential to prevent acute liver damage by effectively suppressing oxidative stress and inflammation. Full article

Pemafibrate, a novel selective peroxisome proliferator-activated receptor modulator, has beneficial effects on lipid metabolism. However, its effects on glucose metabolism in individuals with type 2 diabetes (T2DM) remain to be fully clarified. This was a subanalysis of the PARM-T2D study, a multicenter prospective observational study on the use of pemafibrate versus conventional therapy for 52 weeks in subjects with T2DM complicated with hypertriglyceridemia. The subanalysis included participants who did not change their treatment for diabetes and did not receive insulin or insulin secretagogues during the study period. Changes in glucose metabolism markers, including homeostatic model assessment (HOMA2) scores and disposition index, were assessed. A total of 279 participants (141 in the pemafibrate group; 138 in the control group) met the criteria for the subanalysis. There were no significant changes in HbA1c during the 52-week study period in both groups. However, the pemafibrate group showed significant improvements versus the control group for insulin resistance assessed by HOMA2-R (−0.15 versus 0.08; estimated treatment difference −0.23 (95% confidence interval −0.44, −0.02); p = 0.03) and maintenance of β-cell function assessed by disposition index (0.015 versus −0.023; estimated treatment difference 0.037 (95% confidence interval 0.005, 0.069); p = 0.02). Correlation analyses showed that improvements in HOMA2-R and disposition index were significantly associated with improvements in lipid abnormalities and γ-glutamyl transpeptidase. In conclusion, pemafibrate reduced insulin resistance and maintained β-cell function in subjects with T2DM and hypertriglyceridemia, presumably by improving lipid profiles and lipid-related hepatocyte stress. Full article

Bovine milk γ-glutamyltransferase (BoGGT) can produce γ-glutamyl peptides using L-glutamine as a donor substrate, and the transpeptidase activity is highly dependent on both γ-glutamyl donors and acceptors. To explore the molecular mechanism behind the donor and acceptor substrate preferences for BoGGT, molecular docking and molecular dynamic simulations were performed with L-glutamine and L-γ-glutamyl-p-nitroanilide (γ-GpNA) as donors. Ser450 is a crucial residue for the interactions between BoGGT and donors. BoGGT forms more hydrogen bonds with L-glutamine than γ-GpNA, promoting the binding affinity between BoGGT and L-glutamine. Gly379, Ile399, and Asn400 are crucial residues for the interactions between the BoGGT intermediate and acceptors. The BoGGT intermediate forms more hydrogen bonds with Val-Gly than L-methionine and L-leucine, which can promote the transfer of the γ-glutamyl group from the intermediate to Val-Gly. This study reveals the critical residues responsible for the interactions of donors and acceptors with the BoGGT and provides a new understanding of the substrate selectivity and catalytic mechanism of GGT. Full article

Background: Both pemafibrate and sodium glucose cotransporter-2 (SGLT2) inhibitor can decrease serum transaminase levels in patients with non-alcoholic fatty liver disease (NAFLD) complicated with dyslipidemia and type 2 diabetes mellitus (T2DM), respectively. However, the effectiveness of combined therapy has been rarely reported. Methods: This is a two-center retrospective observational study. NAFLD patients complicated with T2DM treated with pemafibrate for >1 year were included, in whom prior treatment with SGLT2 inhibitor > 1 year failed to normalize serum alanine aminotransferase (ALT) levels. Hepatic inflammation, function, and fibrosis were assessed by ALT, albumin-bilirubin (ALBI) score, and Mac-2 binding protein glycosylation isomer (M2BPGi) levels, respectively. Results: Seven patients were included. The median duration of prior treatment with SGLT2 inhibitors was 2.3 years. During the one year before starting pemafibrate therapy, the therapy did not significantly change hepatic enzymes. All patients received pemafibrate 0.1 mg twice daily without dose escalations. During one year of pemafibrate therapy, triglyceride, aspartate aminotransferase, ALT, γ-glutamyl transpeptidase, ALBI score, and M2BPGi levels significantly improved (p < 0.05), although weight or hemoglobin A1c did not significantly change. Conclusions: One year of pemafibrate therapy improves markers of hepatic inflammation, function, and fibrosis in NAFLD patients in whom long-term SGLT2 inhibitor therapy failed to normalize serum ALT. Full article

Neutral/negatively charged nanoparticles are beneficial to reduce plasma protein adsorption and prolong their blood circulation time, while positively charged nanoparticles easily transverse the blood vessel endothelium into a tumor and easily penetrate the depth of the tumor via transcytosis. Γ-Glutamyl transpeptidase (GGT) is overexpressed on the external surface of endothelial cells of tumor blood vessels and metabolically active tumor cells. Nanocarriers modified by molecules containing γ-glutamyl moieties (such as glutathione, G-SH) can maintain a neutral/negative charge in the blood, as well as can be easily hydrolyzed by the GGT enzymes to expose the cationic surface at the tumor site, thus achieving good tumor accumulation via charge reversal. In this study, DSPE-PEG2000-GSH (DPG) was synthesized and used as a stabilizer to generate paclitaxel (PTX) nanosuspensions for the treatment of Hela cervical cancer (GGT-positive). The obtained drug-delivery system (PTX-DPG nanoparticles) was 164.6 ± 3.1 nm in diameter with a zeta potential of −9.85 ± 1.03 mV and a high drug-loaded content of 41.45 ± 0.7%. PTX-DPG NPs maintained their negative surface charge in a low concentration of GGT enzyme (0.05 U/mL), whereas they showed a significant charge-reversal property in the high-concentration solution of GGT enzyme (10 U/mL). After intravenous administration, PTX-DPG NPs mainly accumulated more in the tumor than in the liver, achieved good tumor-targetability, and significantly improved anti-tumor efficacy (68.48% vs. 24.07%, tumor inhibition rate, p < 0.05 in contrast to free PTX). This kind of GGT-triggered charge-reversal nanoparticle is promising to be a novel anti-tumor agent for the effective treatment of such GGT-positive cancers as cervical cancer. Full article