Hepatic Glutathione S-transferase Research Articles

Differential Hepatic Expression of miRNA in Response to Aflatoxin B1 Challenge in Domestic and Wild Turkeys.

Aflatoxin B1 (AFB1) is a major foodborne mycotoxin that poses a significant economic risk to poultry due to a greater degree of susceptibility compared to other agricultural species. Domesticated turkeys (Meleagris gallopavo) are especially sensitive to AFB1; however, wild turkeys (M. g. silvestris) are more resistant. A lack of functional isoforms of hepatic glutathione S-transferases (GSTs), an enzyme that plays a role in the detoxification of aflatoxin, is suspected as the reason for the increased sensitivity. Previous studies comparing the gene expression of domesticated and wild turkeys exposed to AFB1 identified hepatic genes responding differentially to AFB1, but could not fully explain the difference in response. The current study examined differences in the expression of microRNAs (miRNAs) in the livers of wild and domesticated turkeys fed dietary AFB1 (320 μg/kg in feed). Short-read RNA sequencing and expression analysis examined both domesticated and wild turkeys exposed to AFB1 compared to controls. A total of 25 miRNAs was identified as being significantly differentially expressed (DEM) in pairwise comparisons. The majority of these have mammalian orthologs with known dysregulation in liver disease. The largest number of DEMs occurred between controls, suggesting an underlying difference in liver potential. Sequences of the DEMs were used to identify potential miRNA binding sites in target genes, resulting in an average of 4302 predicted target sites per DEM. These DEMs and gene targets provide hypotheses for future investigations into the role of miRNAs in AFB1 resistance.

Upregulation of Hepatic Glutathione S-Transferase Alpha 1 Ameliorates Metabolic Dysfunction-Associated Steatosis by Degrading Fatty Acid Binding Protein 1.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common metabolic disease of the liver, characterized by hepatic steatosis in more than 5% of hepatocytes. However, despite the recent approval of the first drug, resmetirom, for the management of metabolic dysfunction-associated steatohepatitis, decades of target exploration and hundreds of clinical trials have failed, highlighting the urgent need to find new druggable targets for the discovery of innovative drug candidates against MASLD. Here, we found that glutathione S-transferase alpha 1 (GSTA1) expression was negatively associated with lipid droplet accumulation in vitro and in vivo. Overexpression of GSTA1 significantly attenuated oleic acid-induced steatosis in hepatocytes or high-fat diet-induced steatosis in the mouse liver. The hepatoprotective and anti-inflammatory drug bicyclol also attenuated steatosis by upregulating GSTA1 expression. A detailed mechanism showed that GSTA1 directly interacts with fatty acid binding protein 1 (FABP1) and facilitates the degradation of FABP1, thereby inhibiting intracellular triglyceride synthesis by impeding the uptake and transportation of free fatty acids. Conclusion: GSTA1 may be a good target for the discovery of innovative drug candidates as GSTA1 stabilizers or enhancers against MASLD.

Can environmental factors increase oxidative responses in fish exposed to polycyclic aromatic hydrocarbons (PAHs)?

Relations among polycyclic aromatic hydrocarbons (PAHs), biomarkers of oxidative stress (lipid peroxidation, glutathione, and glutathione S-transferase activity), and the possible influence of environmental factors (temperature, pH, and salinity) were assessed in situ for specimens of Ramnogaster arcuata, a native estuarine fish. PAH levels found in the muscular tissue of R. arcuata ranged from 0.7 to 293.4 ng g−1 wet weight with petrogenic and pyrolytic inputs. Lipid peroxidation in the liver showed positive correlations (P < 0.05) with total PAHs (r = 0.66), 3-ring (r = 0.66) and 4-ring PAHs (r = 0.52) and glutathione in muscle (r = 0.58). Significant positive correlations (P < 0.05) were also evidenced between muscular glutathione with total (r = 0.62) and 3-ring PAHs (r = 0.75). Hepatic glutathione S-transferase negatively correlated with 4-ring PAHs (r = −0.58). These correlations suggest that lipid peroxidation and muscular glutathione could be good biomarkers for complex mixtures of PAHs, and hepatic glutathione S-transferase could be a suitable biomarker for 4-ring PAHs. Furthermore, significant correlations (P < 0.05) of environmental factors with PAH levels and biomarkers were observed, especially pH with 3-ring PAHs (r = −0.65), lipid peroxidation (r = −0.6), glutathione in the liver (r = −0.73) and muscle (r = −0.75); and temperature with 2-ring PAHs (r = −0.75) and glutathione in muscle (r = 0.51). The data suggest an influence of physicochemical parameters which could be driving a shift in PAH toxicity in R. arcuata. These results are essential for an integrated understanding of ecotoxicology and could help to predict environmental effects in present and future scenarios of ocean warming and acidification.

Ameliorating the impairment of glucose utilization in a high-fat diet-induced obesity model through the consumption of Tucum-do-Cerrado (Bactris Setosa Mart.).

We evaluated the effect of Tucum-do-Cerrado on glucose metabolism homeostasis and its relationship with redox-inflammatory responses in a high-fat (HF) diet-induced obesity model. The HF diet increased energy intake, feed efficiency, body weight, muscle and hepatic glycogen, insulin, homeostatic model assessment of insulin resistance (HOMA IR) and beta (β)-cell function, and gut catalase (CAT) activity, and decreased food intake, hepatic glutathione reductase (GR), glutathione peroxidase (GPX), glutathione S-transferase (GST), and superoxide dismutase (SOD) activities, hepatic phosphoenolpyruvate carboxykinase 1 (Pck1), and intestinal solute carrier family 5 member 1 (Slc5a1) mRNA levels compared with the control diet. However, the HF diet with Tucum-do-Cerrado decreased hepatic glycogen, and increased hepatic GR activity, hepatic Slc2a2 mRNA levels and serum Tnfa compared with the HF diet. Tucum-do-Cerrado decreased muscle glycogen, intestinal CAT and GPX activities, muscle PFK-1 and HK activities, and increased hepatic protein (CARB) and intestinal lipid (MDA) oxidation, hepatic GST activity, serum antioxidant potential, hepatic phosphofructokinase-1 (PFK-1) activity, intestinal solute carrier family 2 member 2 (Slc2a2), tumor necrosis factor (Tnf), interleukin-1 beta (Il1b), muscle protein kinase AMP-activated alpha 1 (Prkaa1), solute carrier family 2 member 2 (Slc2a2) mRNA levels, and serum interleukin-6 (IL-6) levels, regardless of diet type. Tucum-do-Cerrado consumption may ameliorate impaired glucose utilization in a HF diet-induced obesity model by increasing liver and muscle glucose uptake and oxidation. These data suggest that Tucum-do-Cerrado consumption improves muscle glucose oxidation in non-obese and obese rats. This response may be related to the improvement in the total antioxidant capacity of rats.

Hexane insoluble fraction from purple rice extract improves steatohepatitis and fibrosis via inhibition of NF-κB and JNK signaling.

Nonalcoholic fatty liver disease (NAFLD) is fatty liver mainly related to metabolic syndrome. NAFLD with inflammation and hepatocellular damage is defined as nonalcoholic steatohepatitis (NASH), which can progress to cirrhosis and hepatocellular carcinoma. We have previously reported that a hexane insoluble fraction from an anthocyanin-rich purple rice ethanolic extract (PRE-HIF) can suppress prostate carcinogenesis. However, the extract's effect on NASH has not yet been established. In the present study, we investigated the chemopreventive effect of a PRE-HIF on NASH and liver fibrosis using a connexin 32 (Cx32) dominant negative transgenic (Cx32ΔTg) rat NASH model. Seven-week-old male Cx32ΔTg rats were fed a control diet, a high-fat diet (HFD), or an HFD with 1% PRE-HIF and intraperitoneal administration of dimethylnitrosamine for 17 weeks. Histological findings of NASH such as fat deposition, lobular inflammation, hepatocyte ballooning injury, and bridging fibrosis were observed in the HFD group but not in the control group, and all histological parameters were significantly improved by PRE-HIF treatment. Corresponding to the histological changes, increased expression of inflammatory cytokine mRNAs (TNF-α, IL-6, IL-18, IFN-γ, IL-1β, TGF-β1, TIMP1, TIMP2, COL1A1), along with and activation of nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK) signaling were observed in the HFD group, which was significantly decreased by PRE-HIF. The number and area of hepatic precancerous glutathione S-transferase placental form-positive foci tended to be decreased by PRE-HIF. These results indicate that intake of purple rice as a dietary supplement may reduce steatohepatitis, liver injury, and fibrosis in NASH by inactivation of NF-κB or JNK.

Carbon nanofibers caused oxidative stress and disrupted anti-predator responses in common spiny loach

Carbon nanofibers, recently recognized pollutants, have been heavily used among the nanomaterials in many industries. Due to the poor suspension-stability, carbon nanofibers tend to sediment at the bottom of waterbodies and hence can be consumed by the bottom-dwellers. The current investigation evaluates the impact of carbon nanofibers at concentrations between 0.1 and 10 mg L−1 on the common bottom dweller spiny loach Lepidocephalichthys thermalis inhabiting Indian rivers. Carbon nanofiber exposure elevated the activities of the hepatic antioxidant enzymes superoxide dismutase, catalase, peroxidase and glutathione S-transferase, as oxidative stress markers. The fish behaviour patterns were examined by testing the effect of carbon nanofibers on predator recognition ability using kairomones, conspecific alarm cues, and dietary cues. The carbon nanofiber-exposed fish showed a loss of predator-recognition abilities. The results collectively demonstrated the carbon nanofiber driven hepatic oxidative damage and impaired predator-recognition ability in L. thermalis. The investigation, first of its kind, highlights the toxic potential of the carbon nanofibers on benthic fishes.

Changes in hepatic thiol contents and regulation of glutathione S-transferase by high-fructose diet: Effects of kefir and some probiotic bacteria

In this study, thiol/disulfide homeostasis in the liver tissues of high-fructose-fed rats was investigated in conjunction with the changes in the main hepatic detoxification enzyme, glutathione S-transferase (GST). Additionally, the effects of well-known probiotics namely Kefir, Lactobacillus helveticus, and Lactobacillus plantarum supplementation on the thiol/disulfate contents and GST activity and gene expression levels were analyzed. Fructose, administered as a 20% solution in drinking water for 15 weeks, developed an animal model of metabolic syndrome in male Wistar rats. Kefir, L. helveticus, and L. plantarum supplementations were given by gastric gavage once a day during the final 6-weeks. The changes in hepatic GST were determined with kinetic-optimized spectrophotometric enzyme assays and qRT-PCR. Total thiol, native thiol, and disulfide levels were analyzed using (5,5-dithio-bis-(2-nitrobenzoic acid) as a chromogenic agent. High-fructose consumption reduced total and native thiol contents while increasing disulfide levels in the liver tissues of rats. Kefir and L. plantarum normalized the thiol levels and all probiotics reduced disulfide contents. High fructose augmented total GST activity but reduced the GST-Mu isoform. L. helveticus and L. plantarum normalized the total and GST-Mu activity, respectively. These results demonstrated a shift toward disulfide formation in the hepatic tissues of rats fed with high fructose. A possible reason would be the increase in total GST activity that uses the free glutathione, the main native thiol source in cells, as a substrate. Besides, probiotics such as Kefir, L. helveticus, and L. plantarum have an improving effect on thiol/disulfide homeostasis as well as main detoxification enzymes.&#x0D;

Comparisons between human and rodent hepatic glutathione S-Transferase activities reveal sex and species differences

Glutathione S-transferases (GSTs) are conjugating enzymes involved in drug metabolism, antioxidant defence, and cell signalling. Herein, we investigated hepatic GST conjugation in several mouse and rat strains, including both sexes, with a direct comparison to humans. Using general and isoform-selective substrates, all mouse strains had significantly greater activities than humans for total cytosolic GST, GST-M, GST-T, and microsomal GST activities. Some strains had significantly greater GST-P activities compared to humans. Sex differences between males and females were evident in all strains for total cytosolic GST, GST-M, and GST-P, and sex differences in GST-T and microsomal GST activities within strains were noted. All rats had significantly greater activities than humans for GST-M and GST-T; only some strains were significantly greater than humans for GST-P, total cytosolic GST, and microsomal GST. Sex differences within strains showed significantly greater GST-M and GST-T activities in males compared to females. Select strains showed sex differences for total cytosolic and microsomal GST activities; there were no sex differences in GST-P activities. Significant differences in glutathione conjugation between humans and rodents exist, including sex differences. This highlights the need for careful animal selection in pre-clinical studies where GSTs are the primary metabolic pathway.

Alexander Munn

An immunohistochemical study of glutathione S-transferase (GST) expression in hepatocellular carcinoma and cholangiocarcinoma is described. Unlike most animal models of hepatic malignancy pi class GST was not consistently overexpressed in...

Enriched Riceberry Bran Oil Exerts Chemopreventive Properties through Anti-Inflammation and Alteration of Gut Microbiota in Carcinogen-Induced Liver and Colon Carcinogenesis in Rats.

Simple SummaryRice bran oil is gaining popularity around the world due to its ability to improve lipid profiles. Recent in vitro studies have shown that the active compounds in colored rice bran oil exhibited anti-cancer properties in various cell lines. However, there has been a limited number of animal studies focusing on the anti-carcinogenic action of rice bran oil. In this study, Riceberry bran oil (RBBO) extracted from the bran of a Thai-pigmented rice variety, namely Riceberry, was investigated for its inhibitory mechanism on the early stages of liver and colorectal carcinogenesis using the dual carcinogens-induced rat model. RBBO was able to inhibit the biomarkers of rat liver cancer and colon cancer by forcing cells to undergo apoptosis, reducing inflammation, and changing the profiles of bacteria and their metabolites. These findings suggest that RBBO could be a promising source of high-value chemopreventive agents in terms of both cancer prevention and treatment.Riceberry has recently been acknowledged for its beneficial pharmacological effects. Riceberry bran oil (RBBO) exhibited anti-proliferation activity in various cancer cell lines. However, animal studies of RBBO on anti-carcinogenicity and its molecular inhibitory mechanism have been limited. This study purposed to investigate the chemopreventive effects of RBBO on the carcinogen-induced liver and colorectal carcinogenesis in rats. Rats were injected with diethylnitrosamine (DEN) and 1,2-dimethylhydrazine (DMH) and further orally administered with RBBO equivalent to 100 mg/kg body weight of γ-oryzanol 5 days/week for 10 weeks. RBBO administration suppressed preneoplastic lesions including hepatic glutathione S-transferase placental form positive foci and colorectal aberrant crypt foci. Accordingly, RBBO induced hepatocellular and colorectal cell apoptosis and reduced pro-inflammatory cytokine expression. Interestingly, RBBO effectively promoted the alteration of gut microbiota in DEN- and DMH-induced rats, as has been shown in the elevated Firmicutes/Bacteroidetes ratio. This outcome was consistent with an increase in butyrate in the feces of carcinogen-induced rats. The increase in butyrate reflects the chemopreventive properties of RBBO through the mechanisms of its anti-inflammatory properties and cell apoptosis induction in preneoplastic cells. This would indicate that RBBO containing γ-oryzanol, phytosterols, and tocols holds significant potential in the prevention of cancer.

Influence of dietary Plukenetia conophora seed on growth performance, hepatic antioxidant status, blood chemistry, fillet quality, fatty acid, and oxidative stability of Clarias gariepinus

This study assessed the effects of dietary supplementation of Plukenetia conophora seed (PCS) on growth performance, blood chemistry, hepatic antioxidant status, fillet fatty acids, and physicochemical properties of Clarias gariepinus. Two hundred and seventy post-juvenile Clarias gariepinus (14.2 ± 1.4 g, BW) were randomly assigned to either T1, a control diet without PCS; T2, diet containing 2.5% PCS; or T3, diet containing 5% PCS, and were fed the different diets for 70 d. Each treatment consisted of six replicates with 15 fish per replicate. Diet had no effect (P > 0.05) on feed intake, hepatosomatic index, viscerosomatic index and survival rate of C. gariepinus. Body weight gain and specific growth rate increased (P < 0.05) as the level of PCS increased in diet. The T3 C. gariepinus had lower (P < 0.05) feed conversion ratio compared with the control C. gariepinus. Leucocytes, serum LDL-cholesterol and total cholesterol were higher (P < 0.05) in the control C. gariepinus compared with the T2 and T3 C. gariepinus. Hepatic glutathione peroxidase, superoxide dismutase, and catalase increased (P < 0.05) with increase in PCS levels in diet. Hepatic glutathione S-transferase was higher (P < 0.05) in the control C. gariepinus compared with the supplemented C. gariepinus. The percentage of C18:3n-3, C22:5n3 and C22:6n-3 was higher (P < 0.05) while that of C18:2n-6 and C20:4n-6 was lower (P < 0.05) in the fillet of C. gariepinus fed on 2.5% and 5% PCS compared with the control C. gariepinus. Dietary PCS had no effect on fillet pH, chemical composition, carbonyl concentration, water holding capacity, color coordinates, and TBARS values in C. gariepinus. These results evince that dietary inclusion of PCS enhanced fillet n-3 polyunsaturated fatty acids and growth performance without instigating fillet oxidative spoilage in C. gariepinus.

Effects of Chinese gallnut tannic acid on growth performance, blood parameters, antioxidative status, intestinal histomorphology, and cecal microbial shedding in broilers challenged with aflatoxin B1.

The objective of the present study was to investigate the effects of tannic acid (TA) on growth performance, blood parameters, antioxidant capacity, and intestinal health in broilers challenged with aflatoxin B1 (AFB1). A total of 480 broilers aged 1 d were randomly allotted into four treatments: 1) CON, control diet; 2) AF, CON + 60 μg/kg AFB1 of feed during days 1 to 21, CON + 120 μg/kg AFB1 of feed during days 22 to 42; 3) TA1, AF + 250 mg/kg TA; and 4) TA2, AF + 500 mg/kg TA. Average daily gain (ADG) and average daily feed intake (ADFI) were increased in the TA1 during days 1 to 21, days 22 to 42, and days 1 to 42 compared with CON and AF treatments (P < 0.05). Broilers fed the TA2 diet had greater ADG and ADFI than those fed the CON and AF diets during the finisher and the whole period (P < 0.05). Administration of TA decreased the relative weight of liver and kidney compared with broilers fed the AF diet on day 42 (P < 0.05). The blood activity of alanine transferase (ALT) and gamma-glutamyl transferase (GGT) was increased in the AF treatment compared with the CON (P < 0.05). Broilers fed the TA1 decreased the ALT content on day 21, and the level of ALT and GGT was decreased in the TA2 compared with the AF group on day 42 (P < 0.05). The activity of total superoxide dismutase (T-SOD) and glutathione peroxidase (GSH-Px) in plasma, and the hepatic glutathione S-transferase (GST) was decreased in the AF group compared with the CON group (P < 0.05). The TA decreased plasma malondialdehyde concentration, and increased plasma T-SOD, GSH-Px, total antioxidant capacity, and hepatic GST activity compared with the AF (P < 0.05). The crypt depth of the jejunum was decreased in the TA1 treatment on day 21, and the villus height of the ileum was increased in the TA2 group on day 42 compared with the AF treatment (P < 0.05). The cecal Lactobacillus counts on day 21 were tended to increase in the TA treatments compared with the AF (P = 0.061). In conclusion, dietary inclusion of 250 and 500 mg/kg TA could improve the growth, antioxidant capacity, and partially protected the intestinal health of broilers challenged with AFB1.

Growth performance and hepatic antioxidants responses to early thermal conditioning in broiler chickens.

There are little data about antioxidants' status responses to early thermal conditioning (TC) on broiler chickens. Therefore, the present study was conducted to investigate the different time ages of thermal conditioning on antioxidants responses and the growth rate of broiler chicks. A total of two hundred forty-one-day-old male broiler chicks (Cobb 500) weighed on average 51.5±0.5g were randomly distributed into four equal groups (60 chicks each), and chicks of each group were ranked in five replicates. The first group reared under the ambient temperature, while the second, third and fourth groups (TC3, TC5 and TC7) were subjected to early-age thermal conditioning at 39°C for 6h on the third, fifth and seventh day of age respectively. Broilers were fed ad-libitum, and drinking water was a free choice during the experimental period. At the end of the experimental period that lasted 5weeks, all experimental groups were exposed to heat challenge at 36°C for 6h. Early-age thermal conditioning did not affect growth performance. Plasma corticosterone elevation in TC5 (as a post-challenge response) was the lowest among the experimental groups. Hepatic malondialdehyde significantly increased in TC5 and TC7 groups both at the post-conditioning stage and at the end of the experimental period. Hepatic glutathione, glutathione S-transferases, catalase and superoxide dismutase significantly decreased by early-age thermal conditioning compared with non-conditioned broilers. Microscopic examination of the liver sections from broilers chickens in TC5 and TC7 groups showed all the basic features of normal liver tissue, while the control and TC3 groups showed few necrotic areas. It could be concluded that early-age thermal conditioning at 39°C for 6h on the fifth day of age could improve the antioxidant defence system of broilers without any adverse effects on growth performance.

The combined impact of decabromodiphenyl ether and high fat exposure on non-alcoholic fatty liver disease in vivo and in vitro

Non-alcoholic fatty liver disease (NAFLD) is considered a public health concern. Decabromodiphenyl ether (BDE-209) and high fat (HF) exposure cause liver injury, yet the combined impact on NAFLD development remains unclear. HepG2 cells were incubated with BDE-209 or/and HF reagent (Csodium oleate/Csodium palmitate = 2/1) for establishing the in vitro model, while C57BL/6 mice fed BDE-209 or/and HF diet (HFD) was the in vivo model. Oil Red O staining and the determination of triglyceride, malondialdehyde, and reactive oxygen species (ROS) contents proved the elevated lipid accumulation and oxidative stress by the mixture of BDE-209 and HF in HepG2 cells, consistent in C57BL/6 mice. Importantly, the action analysis showed the synergistic effect between BDE-209 and HF, suggesting that the population preferring the HFD is more susceptible to BDE-209 to aggravate the progression of NAFLD. Further, the increased protein expression of sterol regulatory element-binding protein 1, fatty acid synthase, and stearoyl-CoA desaturase 1 was considered to be responsible for hepatic steatosis. The impairment of antioxidant system was reflected by the lower hepatic superoxide dismutase and glutathione transferase activities and reduced glutathione level, explaining the detected excessive ROS production. Besides, using high content analysis, the decline of mitochondrial mass and membrane potential, which was closed to the NAFLD pathogenesis, was also demonstrated in HepG2 cells.

Characterization of Cytosolic Glutathione S-Transferases Involved in the Metabolism of the Aromatase Inhibitor, Exemestane.

Exemestane (EXE) is a hormonal therapy used to treat estrogen receptor-positive breast cancer by inhibiting the final step of estrogen biosynthesis catalyzed by the enzyme aromatase. Cysteine conjugates of EXE and its active metabolite 17β-dihydro-EXE (DHE) are the major metabolites found in both the urine and plasma of patients taking EXE. The initial step in cysteine conjugate formation is glutathione conjugation catalyzed by the glutathione S-transferase (GST) family of enzymes. The goal of the present study was to identify cytosolic hepatic GSTs active in the GST-mediated metabolism of EXE and 17β-DHE. Twelve recombinant cytosolic hepatic GSTs were screened for their activity against EXE and 17β-DHE, and glutathionylated EXE and 17β-DHE conjugates were detected by ultra-performance liquid chromatography tandem mass spectrometry. GST α (GSTA) isoform 1, GST μ (GSTM) isoform 3 and isoform 1 were active against EXE, whereas only GSTA1 exhibited activity against 17β-DHE. GSTM1 exhibited the highest affinity against EXE with a Michaelis-Menten constant (KM) value that was 3.8- and 7.1-fold lower than that observed for GSTA1 and GSTM3, respectively. Of the three GSTs, GSTM3 exhibited the highest intrinsic clearance against EXE (intrinsic clearance = 0.14 nl·min-1·mg-1). The KM values observed for human liver cytosol against EXE (46 μM) and 17β-DHE (77 μM) were similar to those observed for recombinant GSTA1 (53 and 30 μM, respectively). Western blot analysis revealed that GSTA1 and GSTM1 composed 4.3% and 0.57%, respectively, of total protein in human liver cytosol; GSTM3 was not detected. These data suggest that GSTA1 is the major hepatic cytosolic enzyme involved in the clearance of EXE and its major active metabolite, 17β-DHE. SIGNIFICANCE STATEMENT: Most previous studies related to the metabolism of the aromatase inhibitor exemestane (EXE) have focused mainly on phase I metabolic pathways and the glucuronidation phase II metabolic pathway. However, recent studies have indicated that glutathionylation is the major metabolic pathway for EXE. The present study is the first to characterize hepatic glutathione S-transferase (GST) activity against EXE and 17β-dihydro-EXE and to identify GST α 1 and GST μ 1 as the major cytosolic GSTs involved in the hepatic metabolism of EXE.

Telomerase activator-65 and pomegranate peel improved the health status of the liver in aged rats; multi-targets involved.

Objective(s):This study was undertaken to investigate the efficacy of telomerase activator-65 (Ta-65) and pomegranate peel against aging-induced deteriorations in the liver. Materials and Methods: The rats were divided into four groups: control, aged, aged rats treated with Ta-65, and pomegranate orally for two months.Results:Aging significantly increased the serum levels of total protein, globulins, and protein carbonyl and reduced the insulin-like growth factor 1 (IGF-1). It also elevated the hepatic malondialdehyde and decreased the hepatic glutathione S-transferase (GST) activity. Aging elevated the expression of thioredoxin reductase1, telomerase reverse transcriptase, and cytochrome 3a1 in the liver; it increased the p53 protein level and elevated the activity of caspase-3 in the liver indicating the occurrence of apoptosis. The architecture of the liver deteriorated in the aged rats, as shown by both light and electron microscopy examinations. The liver of the aged rats had many apoptotic hepatocytes with shrunken nuclei. Many hepatocytes had dilated rough endoplasmic reticulum, many lysosomes, and many fat droplets. Administration of Ta-65 and pomegranate to the aged rats normalized most of the previous biochemical parameters and improved the liver architecture. Conclusion:Ta-65 and pomegranate have anti-aging activity through targeting multiple cellular pathways. It is also noteworthy that Ta-65 was superior to pomegranate in its alleviative effects.

Protective Role of Vanillic Acid against Diethylnitrosamine- and 1,2-Dimethylhydrazine-Induced Hepatocarcinogenesis in Rats.

This study aimed to evaluate the cancer chemopreventive activity of vanillic acid (VA) in diethylnitrosamine- and 1,2-dimethylhydrazine-induced liver and colon carcinogenesis in rats. VA did not induce the formation of hepatic glutathione S-transferase placental form (GST-P) positive foci and colonic aberrant crypt foci, demonstrating no carcinogenic activity. VA (75 mg kg−1 body weight) could significantly reduce the number and areas of hepatic GST-P positive foci when administered before carcinogen injections, but no such effect was seen when it was administered after carcinogen injection. No protection was seen in the colon when VA was treated before or after carcinogen injection. Immunohistochemical studies demonstrated the decreased expression of proliferating cell nuclear antigen and the induction of apoptosis. Mechanistic studies showed that VA significantly induced the expression of GSTA-5 and Nrf-2 genes, which are associated with the detoxification system. Likewise, the antiproliferative effect was noticed by the reduction of Cyclin D1 expression. The apoptotic activity may be due to the upregulation of Caspase-3 and Bad levels and downregulation of the Bcl-2 level. These data suggest that VA exhibited significant protection against diethylnitrosamine- and 1,2-dimethylhydrazine-induced hepatocarcinogenesis, which might be related to the induction of the detoxifying enzyme, the reduction of proliferation and the induction of apoptosis.

Antioxidant effects of gum arabic on gentamycin-induced hepatotoxicity in rats

Background Gum arabic (GA) is an exudate obtained from Acacia senegal and A. seyal, and it contains a large amount of nonviscous soluble fiber. Experimental studies revealed its strong antioxidant properties. Gentamycin-induced hepatotoxicity has been reported in experimental animals. Gentamycin induces hepatoxicity mainly by generating free radicals and enhancing oxidative stress. Aim This study aimed to investigate the involvement of oxidative stress and the alteration of the oxidant–antioxidant balance in gentamycin-induced hepatotoxicity. In addition, this study explored the possible protection that can be afforded by GA, given its antioxidant potential. Materials and methods Forty adult male Albino rats’ weighing was used in this study. The animals were randomly divided into four groups. Group I served as control, which received normal mouse diet. Group II orally received GA through a gastric feeding tube for 8 days. Group III received a daily intraperitoneal injection of gentamycin. Group IV received gentamycin intraperitoneally plus orally for 8 days. Results The results of this study revealed significant elevation of serum alanine transaminase, hepatic malondialdehyde level, glutathione peroxidase, and glutathione S-transferase activities and reduction of hepatic Reduced Glutathione (GSH) and glutathione reductase activities in gentamycin-treated animals. Administration of GA with gentamycin intake restored the altered parameters to their normal values, whereas hepatic glutathione peroxidase and glutathione S-transferase activities were enhanced further. Conclusion This study demonstrated the antioxidant effect of GA and its protective role against gentamycin-induced hepatocyte injury. More studies are warranted to further reveal the underlying mechanisms of the antioxidant properties of GA, especially at the structural and molecular levels.

Spirulina platensis Alleviated the Oxidative Damage in the Gills, Liver, and Kidney Organs of Nile Tilapia Intoxicated with Sodium Sulphate.

Simple SummaryNile tilapia (Oreochromis niloticus) are expected to suffer from oxidative stress induced by sodium sulphate in the ecosystem. Herein, we proposed that dietary Spirulina platensis could relieve the impacts of sodium sulphate on tilapia. The hepatic antioxidative and related activities were decreased under sodium sulphate exposure. However, dietary S. platensis alleviated the tissue antioxidative overexpression compared to the sodium sulphate and control groups. This study implies that natural dietary antioxidants can be applied in aquatic organisms to alleviate the features induced by toxicants and xenobiotics.The current study aimed at assessing the recuperative roles of dietary Spirulina platensis on the antioxidation capacity of Nile tilapia (Oreochromis niloticus) exposed to sodium sulphate for eight weeks. In brief, fish were allocated into four groups with three triplicates per group, where a group fed on a commercial basal diet served as control, a group was intoxicated with sodium sulphate (SS) 5.8 mg/L, another group was fed a diet supplemented with 1% S. platensis (SP), and the last group was fed 1% SP and concomitantly intoxicated with 5.8 mg/L sodium sulphate (SP/SS). Tissue antioxidative indices of each fish were measured as follows: glutathione peroxidase (GSH-Px) activity in muscles, catalase (CAT) and superoxide dismutase (SOD) activities in gills, and total antioxidant capacity (T-AOC) in the liver and kidney. Moreover, the expression of hepatic SOD, GSH-Px, and glutathione-S-transferase (GST) genes was also determined. It was found that tissue CAT, SOD, and GSH-Px activities as well as the T-AOC levels were significantly decreased in the SS group (p < 0.05). Moreover, there was a significant downregulation of hepatic SOD, GSH-Px, and GST genes in SS-exposed fish (p < 0.05). Interestingly, simultaneous dietary supplementation with SP provided a marked attenuation of the tissue antioxidative parameters when compared with the SS and control groups. To conclude, the present study exemplifies that dietary SP supplementation could be a beneficial abrogation of SS-induced tissue oxidative stress in the exposed fish.

Diazinon exposure produces histological damage, oxidative stress, immune disorders and gut microbiota dysbiosis in crucian carp (Carassius auratus gibelio).

Diazinon is a common organophosphate pesticide widely used to control parasitic infections in agriculture. Excessive use of diazinon can have adverse effects on the environment and aquatic animal health. In the present study, the toxic effects of diazinon on the histology, antioxidant, innate immune and intestinal microbiota community composition of crucian carp (Carassius auratus gibelio) were investigated. The results showed that diazinon at the tested concentration (300μg/L) induced gill and liver histopathological damages. Hepatic total superoxide dismutase (T-SOD), catalase (CAT), and glutathione S-transferase (GST) activities significantly decreased (P<0.05) by 32.47%, 65.33% and 37.34%, respectively. However, the liver tissue malondialdehyde (MDA) content significantly (P<0.05) increased by 138.83%. The 300μg/L diazinon significantly (P<0.05) downregulated the gene expression of TLR4, MyD88, NF-kB p100 and IL-8 but had no significant effect TNF-α (P=0.8239). In addition, the results demonstrated that diazinon exposure could affect the intestinal microbiota composition and diversity. Taken together, the results of this study indicated that diazinon exposure can cause damage to crucian carp, induce histopathological damage in gill and liver tissues, oxidative stress in the liver, and innate immune disorders and alter intestinal microbiota composition and diversity.