Hepatic Oxidative Stress Markers Research Articles

Trans-chalcone ameliorates CCl4-induced acute liver injury by suppressing endoplasmic reticulum stress, oxidative stress and inflammation

BackgroundAcute liver injury serves as a crucial marker for detecting liver damage due to toxic, viral, metabolic, and autoimmune exposures. Due to the response to adverse external stimuli and various cellular homeostasis, Endoplasmic reticulum stress (ERS), Oxidative stress, and Inflammation have great potential for treating liver injury. Trans-chalcones (TC) is a polyphenolic compound derived from a natural plant with anti-oxidative and anti-inflammatory abilities. Here, TC was aimed to attenuate liver injury by triggering ER stress, oxidative stress, inflammation, and apoptosis. A single dose of carbon tetrachloride (CCl4) 1 mL/kg was administered intraperitoneally into C57BL6 mice to construct an in vivo NAFLD model, whereas AML12 cells were treated with lipopolysaccharides (LPS) to construct an in vitro NAFLD model. The mice used in the experiment were randomly assigned to two groups: a 12-hour set and a 24-hour set. Forty-nine mice were randomly divided into seven groups, the control group (Group I), TC group (Group II) 10 mg/kg TC, negative control group (Group III) CCl4, TC + CCl4 groups (Groups IV−VI), mice were subcutaneously treated with (5, 10, and 20) mg/kg of TC for three consecutive days before the CCl4 injection and the positive control group (Group VII) received 10 mg/kg Silymarin. After the experiment, serum transaminase, liver histological pathology, hepatic expression levels ERS, oxidative stress, and inflammation-related markers were assessed. TC pre-treatment significantly alleviates the expression of ER stress, oxidative stress, inflammatory cytokines, and apoptosis in both in vivo and in vitro models of liver injury. TC treatment significantly reduced serum transaminase levels (ALT and AST), and improved liver histopathological scores. TC administration also led to a reduction in MDA levels and the suppression of ROS generated by CCl4 in hepatic tissue, which contributed to an increase in GSH levels. The protective effect of TC on the liver injury mouse model was achieved by inhibiting hepatocyte apoptosis. Moreover, TC pre-treatment dramatically decreased the protein levels of ER stress indicators such as CHOP, Bip, Ero-Lα, IRE1α, PERK, Calnexin, and PDI when compared to the CCl4-only treated group. TC exerts hepatoprotective effects against CCl4-induced acute liver injuries in mice by modulating ERS, oxidative stress, and inflammation. These results suggest that TC pre-treatment at a dose of (20 mg/kg BW) was as effective as silymarin (10 mg/kg) in preventing CCl4-induced acute liver injury. Further investigations are necessary to elucidate the precise molecular mechanisms underlying the hepatoprotective effects of TC and to explore its therapeutic potential in clinical trials.

Supplementation with cysteine improved metabolic syndrome in rats by increasing antioxidant potential in the liver and adipose tissue, as well as decreasing hepatic NF-κB expression

Insulin resistance is a key characteristic of metabolic syndrome (MetS). The hepatic nuclear factor- κB (NF-κB) signaling pathway plays a crucial role in insulin resistance and the development of type 2 diabetes. Our study aimed to examine the impact of cysteine (Cys) on various biochemical and histopathological parameters in the liver and kidney, hepatic NF-kβ expression, oxidative stress, inflammation, glycation, carbonyl stress markers, and insulin resistance. The study involved four groups of rats, each consisting of seven rats: a control group, a MetS group, and two similar groups receiving Cys treatment. Metabolic syndrome was induced in rats by administering a 40% sucrose solution, while, the treated groups received 50 mg/L Cys in their drinking water. Various factors, including body weight, hepatic NF-kβ expression, levels of antioxidants, anti-glycation, oxidative stress, carbonyl stress, inflammatory, anti-glycation, and glycation markers were assessed in blood and tissues. Liver and kidney function parameters and metabolic profiles were measured. Finally, liver tissue was also evaluated by a pathologist. The results showed that Cys reduced hepatic NF-kβ expression, oxidative stress, inflammation, glycation and carbonyl stress markers, as well as liver fatty content, blood sugar levels, insulin resistance, cardiovascular risk index, and body weight. The treatment also mitigated histopathological liver changes and acute hepatitis (p < 0.001). Cysteine exhibited anti-obesity and anti-atherosclerotic effects, improved β-cell function, insulin sensitivity, and lipid metabolism, and enhanced liver and kidney function, as well as prevented acute hepatitis by restoring the GSH/GSSG ratio, hepatic NF-kβ signaling, and carbonyl stress.

The Oxidative Stress Markers' Protective Influence of Sea Buckthorn and Grape Extracts in Atorvastatin-Treated Hyperlipidemic Rats.

Free radicals and reactive oxygen species initiate when the oxidative stress arises. (1) Background: The effect of natural molecules on oxidative stress in hyperlipidemic rats, taking statins, was observed. (2) Methods: One hundred and twelve white Wistar rats, males and females, were divided into seven: Group I received 20 mg of atorvastatin while groups II and III received a combination of 20 mg of atorvastatin and 100 mg of Sea buckthorn and grape extract. Groups IV and V received 100 mg of Sea buckthorn and grape extract, while groups VI and VII received only high-fat diet (HFD) and normal rodents' fodder. After two and six months, rats were euthanized, and blood was gathered to measure the main paraclinical values and total antioxidant capacity (TAC). Also, the liver and kidney were stored for the organs' cytoarchitecture. For statistics, two-way analysis of variance (ANOVA), was performed. (3) Results: HFD produced hyperlipidemia, accompanied by augmented serum and hepatic oxidative stress markers, in addition to a reduction in antioxidant enzyme activities and glutathione levels. Polyphenolic substances proven efficient against HFD caused oxidative stress. (4) Conclusions: Atorvastatin heightened the histological injuries caused by the fatty diet, but these were diminished by taking atorvastatin in combination with 100 mg/kg of plant extracts.

P-Coumaric acid pronounced protective effect against potassium bromate-induced hepatic damage in Swiss albino mice.

Potassium bromate (KBrO3) is a common dietary additive, pharmaceutical ingredient, and significant by-product of water disinfection. p-coumaric acid (PCA) is a naturally occurring nutritional polyphenolic molecule with anti-inflammatory and antioxidant activities. The goal of the current investigation was to examine the protective effects of p-coumaric acid against the liver damage caused by KBrO3. The five groups of animals-control, KBrO3 (100 mg/kg bw), treatment with KBrO3 along with Silymarin (100 mg/kg bw), KBrO3, followed by PCA (100 mg/bw, and 200 mg/kg bw) were randomly assigned to the animals. Mice were slaughtered, and blood and liver tissues were taken for assessment of the serum biochemical analysis for markers of liver function (alanine transaminase, aspartate transaminase, alkaline phosphatase, albumin, and protein), lipid markers and antioxidant markers (TBARS), glutathione peroxidase [GSH-Px], glutathione (GSH), and markers of hepatic oxidative stress (CAT), (SOD), as well as histological H&E stain, immunohistochemical stain iNOS, and COX-2 as markers of inflammatory cytokines. PCA protects against acute liver failure by preventing the augmentation of blood biochemical markers and lipid profiles. In mice liver tissues, KBrO3 increases lipid indicators and depletes antioxidants, leading to an increase in JNK, ERK, and p38 phosphorylation. Additionally, PCA inhibited the production of pro-inflammatory cytokines and reduced the histological alterations in KBrO3-induced hepatotoxicity. Notably, PCA effectively mitigated KBrO3-induced hepatic damage by obstructing the TNF-α/NF-kB-mediated inflammatory process signaling system. Additionally, in KBrO3-induced mice, PCA increased the intensities of hepatic glutathione (GSH), SOD, GSH-Px, catalase, and GSH activities. Collectively, we demonstrate the molecular evidence that PCA eliminated cellular inflammatory conditions, mitochondrial oxidative stress, and the TNF-α/NF-κB signaling process, thereby preventing KBrO3-induced hepatocyte damage.

Biochemical investigation into the influence of telfairia occidentalis on hepatic oxidative stress markers and pro-inflammatory biomarkers induced by streptozotocin

In rat models of diabetes, this research examined the biochemical impact of Telfairia occidentalis (TO) on pro-inflammatory biomarkers and hepatic oxidative stress markers caused by streptozotocin (STZ). There were five experimental groups: G 1 (Normal control) received 0.5 ml of distilled water; G 2 through 5 received 10% fructose for 14 days, after which STZ was administered intraperitoneally once. After the diagnosis of diabetes was confirmed, rats in groups 3 (TO1), 4 (TO2), and 5 (MET) were given 200 mg/kg b.w. TO, 300 mg/kg b.w. TO, and 300 mg/kg b.w. Metformin, respectively, for 28 days. The findings show that STZ significantly (p&lt;0.05) increased malondialdehyde (MDA) levels in diabetic rats relative to the control group and significantly (p&lt;0.05) decreased the activities of liver antioxidant enzymes such as catalase (CAT), reduced glutathione (GSH), glutathione S-transferase (GST), glutathione peroxidase (GPx), and superoxide dismutase (SOD). On the other hand, administration of TO (200 mg/kg and 300 mg/kg) and Metformin (300 mg/kg) resulted in a significant (p&lt;0.05) increase in antioxidant enzyme activities and a significant (p&lt;0.05) decrease in MDA levels. Furthermore, the inflammatory biomarkers myeloperoxidase (MPO), interleukin-1beta (IL-1β), tumor necrosis factor-alpha (TNF-α), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) as well as the apoptotic marker caspase-3 were significantly (p&lt;0.05) elevated upon STZ induction; however, these elevations were significantly (p&lt;0.05) attenuated upon TO administration, mirroring the effects of Metformin. In conclusion, Telfairia occidentalis significantly reduces the oxidative stress markers, inflammatory reactions brought on by STZ, and liver antioxidant status in diabetic rats. These results point to TO's possible therapeutic benefit in reducing diabetes-related liver problems via regulating oxidative and inflammatory pathways.

Strength Training Protects High-Fat-Fed Ovariectomized Mice against Insulin Resistance and Hepatic Steatosis.

Menopause is characterized by a reduction in sex hormones in women and is associated with metabolic changes, including fatty liver and insulin resistance. Lifestyle changes, including a balanced diet and physical exercise, are necessary to prevent these undesirable changes. Strength training (ST) has been widely used because of the muscle and metabolic benefits it provides. Our study aims to evaluate the effects of ST on hepatic steatosis and insulin resistance in ovariectomized mice fed a high-fat diet (HFD) divided into four groups as follows: simulated sedentary surgery (SHAM-SED), trained simulated surgery (SHAM-EXE), sedentary ovariectomy (OVX-SED), and trained ovariectomy (OVX-EXE). They were fed an HFD for 9 weeks. ST was performed thrice a week. ST efficiently reduced body weight and fat percentage and increased lean mass in OVX mice. Furthermore, ST reduced the accumulation of ectopic hepatic lipids, increased AMPK phosphorylation, and inhibited the de novo lipogenesis pathway. OVX-EXE mice also showed a better glycemic profile, associated with greater insulin sensitivity identified by the euglycemic-hyperinsulinemic clamp, and reduced markers of hepatic oxidative stress compared with sedentary animals. Our data support the idea that ST can be indicated as a non-pharmacological treatment approach to mitigate metabolic changes resulting from menopause.

Hepatoprotective Effect of Merlot Grape Pomace Extract against Acetaminophen-Induced Damage in Mouse

This study investigated the benefits of Merlot grape pomace extract (EBUM) in experimental acetaminophen-induced intoxication. Swiss mice received the respective treatments for 7 days: Control (saline), Silymarin (100 mg/Kg), EBUM: 100 mg/Kg and 500 mg/Kg. On the seventh day, the acetaminophen control,Silymarin and EBUM received a single dose of acetaminophen 500 mg/kg. After 24 hours, the mice were sacrificed, the blood and liver were collected for analysis of serum transaminases (ALT and AST), bilirubin, hepatic markers of oxidative stress and histopathological analysis. EBUM was able to prevent acetaminophen-induced hepatic necrosis with a significant reduction (p&lt;0.0001) in ALT and AST, bilirubin, as well as a significant increase in hepatic GSH and CAT levels. The histological data are consistent with the transaminase results, showing less liver damage in the treated groups when compared to the acetaminophen group. The results allow us to infer that EBUM has a hepatoprotective effect against intoxication caused by acetaminophen in animal model, proving to be a therapeutic alternative in preventing drug-induced liver damage.

Afriplex GRTTM extract attenuates hepatic steatosis in an in vitro model of NAFLD.

Currently, it is acknowledged that vitamin E, insulin sensitizers and anti-diabetic drugs are used to manage non-alcoholic fatty liver disease (NAFLD), however, these therapeutic interventions harbour adverse side effects. Pioglitazone, an anti-diabetic drug, is currently the most effective therapy to manage NAFLD. The use of natural medicines is widely embraced due to the lack of evidence of their negative side effects. Rooibos has been previously shown to decrease inflammation and oxidative stress in experimental models of diabetes, however, this is yet to be explored in a setting of NAFLD. This study was aimed at investigating the effects of an aspalathin-rich green rooibos extract (Afriplex GRTTM) against markers of hepatic oxidative stress, inflammation and apoptosis in an in vitro model of NAFLD. Oleic acid [1 mM] was used to induce hepatic steatosis in C3A liver cells. Thereafter, the therapeutic effect of Afriplex GRTTM, with or without pioglitazone, was determined by assessing its impact on cell viability, changes in mitochondrial membrane potential, intracellular lipid accumulation and the expression of genes and proteins (ChREBP, SREBF1, FASN, IRS1, SOD2, Caspase-3, GSTZ1, IRS1 and TNF-α) that are associated with the development of NAFLD. Key findings showed that Afriplex GRTTM added to the medium alone or combined with pioglitazone, could effectively block hepatic lipid accumulation without inducing cytotoxicity in C3A liver cells exposed oleic acid. This positive outcome was consistent with effective regulation of genes involved in insulin signaling, as well as carbohydrate and lipid metabolism (IRS1, SREBF1 and ChREBP). Interestingly, in addition to reducing protein levels of an inflammatory marker (TNF-α), the Afriplex GRTTM could ameliorate oleic acid-induced hepatic steatotic damage by decreasing the protein expression of oxidative stress and apoptosis related markers such as GSTZ1 and caspase-3. Afriplex GRTTM reduced hepatic steatosis in oleic acid induced C3A liver cells by modulating SREBF1, ChREBP and IRS-1 gene expression. The extract may also play a role in alleviating inflammation by reducing TNF-α expression, suggesting that additional experiments are required for its development as a suitable therapeutic option against NAFLD. Importantly, further research is needed to explore its antioxidant role in this model.

The hepatotoxicity of γ-radiation synthesized 5-fluorouracil nanogel versus 5-fluorouracil in rats model.

The clinical use of 5-fluorouracil (5-FU), a routinely used chemotherapy medication, has a deleterious impact on the liver. Therefore, it is necessary to find a less harmful alternative to minimize liver damage. This study was designed to see how 5-fluorouracil nanogel influenced 5-FU-induced liver damage in rats. To induce liver damage, male albino rats were injected intraperitoneally with 5-FU (12.5mg/kg) three doses/week for 1month. The histopathological examination together with measuring the activities of serum alanine and aspartate aminotransferase enzymes (ALT and AST) were used to evaluate the severity of liver damage besides, hepatic oxidative stress and antioxidant markers were also measured. The hepatic gene expression of heme oxygenase-1 (HO-1), nuclear factor erythroid 2-related factor 2 (Nrf2) and its inhibitor Kelch-like ECH-associated protein-1(Keap-1) in addition to hepatic inflammatory mediators including tumor necrosis factor-α (TNF- α) and interleukins (IL-1β, IL-6) were detected. 5-Fu nanogel effectively attenuated 5-FU-induced liver injury by improving the hepatic structure and function (ALT and AST) besides the suppression of the hepatic inflammatory mediators (TNF- α, IL-1β and IL-6). Additionally, 5-FU nanogel alleviated the impaired redox status and restored the antioxidant system via maintaining the cellular homeostasis Keap-1/Nrf2/HO-1 pathway. Consequently, 5-Fu nanogel exhibited lower liver toxicity compared to 5-FU, likely due to the alleviation of hepatic inflammation and the regulation of the cellular redox pathway.

Assessment of antiarthritic potential of Asparagus dumosus using formaldehyde and CFA-induced arthritic models in rats via modulation of oxidative stress biomarkers and mRNA expression of IL-1b, IL-6, RANKL, OPG, TNF-α and COX-2.

Medicinal plants play a pivotal role in the prevention of chronic non-communicable diseases including arthritis. Despite the traditional use of Asparagus dumosus in arthritis, it has not been studied yet for its effectiveness in arthritis. This study was aimed to explore the antiarthritic potential of A. dumosus in formaldehyde and complete Freund's adjuvant (CFA)-induced arthritic rats. Body weight, arthritic index, hepatic oxidative stress, hematological, biochemical and inflammatory markers were assessed using ELISA, whilst qRT-PCR studies were carried out for the mRNA expression of IL-1b, IL-6, RANKL, OPG, TNF-α and COX-2 genes. GCMS and HPLC analysis were performed to identify the secondary metabolites of A. dumosus. From day 8 to 28 post-administration of formaldehyde and CFA, oral administration of A. dumosus (600, 300 and 150mg/kg) showed a noteworthy improvement (p < 0.001) in the body weights, immune organ weights, serum levels of rheumatoid (RA) factor, C-reactive protein, TNF-α and IL-6 levels in arthritic rats similar to the effect of piroxicam and methotrexate. Subsequently, the administration of A. dumosus to formaldehyde and CFA-challenged rats, caused a marked decrease (p < 0.001) in the mRNA expression of IL-1b, IL-6, OPG, RANKL, TNF-α and COX-2 genes in treated rats. Likewise, when assessed for antioxidant potential, A. dumosus produced a pronounced (p < 0.001) reduction in malondialdehyde (MDA) levels and hydrogen peroxide (H2O2) production, whilst a dose-dependent (p < 0.001) increase in catalase (CAT) and superoxide dismutase (SOD) activities was recorded. GCMS profiling of A. dumosus presented benzaldehyde, 3-hydroxy-4-methoxy-, 1-decanol and undecane as plant compositions, whereas HPLC fingerprinting displayed quercetin, benzaldehyde, 3-hydroxy-4-methoxy-, gallic acid and cinnamic acid as plants constituents. These results depict that A. dumosus possesses anti-arthritic effect mediated possibly through attenuation of arthritic indices, chronic inflammatory and oxidative stress biomarkers along with down-regulation in the mRNA expression of arthritic candid genes.

Impact of Cannabidiol oil and prednisolone on liver enzymes, oxidative stress markers and liver histology in cadmium induced toxicity in male Wistar rats

Background: This study aimed to ascertain the effect of cannabidiol (CBD) oil and prednisolone on serum liver enzyme markers and hepatic oxidative stress markers on cadmium-induced toxicity in male Wistar rats. Forty (40) male Wistar rats weighing between 150g to 200g were assigned into 8 groups (A-H) of five animals each. Group 1 served as control, Groups 2-8 received 1mg/kg body weight of prednisolone; 1.5mg/kg bw of cadmium; 1mg/kg bw of prednisolone + 0.2mg/kg bw of CBD-oil; 0.2mg/kg bw of CBD-oil + 2mg/kg bw of cadmium; 3mg/kg bw of prednisolone + 2mg/kg of cadmium; 0.1mg/kg bw of CBD-oil and 0.2mg/kg bw of CBD-oil respectively. The administration was done using an orogastric tube (gavage) for 14 days. Results revealed a significant decrease in the concentration of aspartate aminotransferase (AST) in all treated groups compared to control. Furthermore, serum alanine aminotransferase (ALT) showed a significant (p&lt;0.05) decrease in all treated groups compared to control. There was a significant decrease in the concentration of alkaline phosphatase (ALP) in treated groups compared to the control. Liver catalase significantly increased in rats fed with pred +cadmium compared to control and other treated groups. Liver superoxide dismutase (SOD) significantly decreased in (p&lt;0.05) the group treated with cadmium compared to the control and prednisolone groups. Liver malondialdehyde concentration did not reveal any significant change (p&gt;0.05). Liver glutathione peroxidase significantly decreased in treated groups than in control. Liver-reduced glutathione significantly decreased across treated groups than the control. Histology of the liver revealed degeneration of hepatocytes and vascular congestion in groups treated with prednisolone, prednisolone+ cadmium, and CBD oil (0.2mg/kg). We conclude that CBD oil, prednisolone, and Cadmium administration at different doses decreased the concentration of serum liver enzyme and oxidative stress markers but caused local inflammation of the liver. If this study is applicable to humans, CBD-oil and prednisolone should be cautiously taken as they may likely present adverse effects, especially in people with liver disease.

The Hepatotoxicity of Nigella sativa Oil Linked to the Route of Administration

Background: Even Nigella sativa oil (NSO) has several pharmacological effects; the route of administration is critical to obtain the desired activity in which intraperitoneal injection (IP) of oil recruits macrophages and induces inflammation. Objective: The current study aimed to determine the best administration route of NSO in rats either oral or IP. Methods: The components of NSO, routine blood analyses, hepatic oxidative stress and proinflammatory parameters, and liver histopathological study were evaluated. Results: NSO contained 32.14% E,E,Z- 1, 3 , 12- nonadecatriene- 5, 14 diol, 25% thymoquinone (TQ) and 3.74% dimethyl sulfoxide (DMSO). In addition, the rats who received IP injection of NSO showed an increase in hepatic enzymes, lipid profiles, oxidative stress, and inflammatory markers. This was associated with hepatic up-regulation of the A disintegrin and metalloproteinase 17 (ADAM- 17) genes, which are corroborated by a reduction in hepatic tissue inhibitor of metalloproteinase 3 (TIMP-3) concentration. These indications were seen in rats given a small amount of DMSO (NSO vehicle), indicating that NSO-oral delivery was safer than IP. Conclusion: NSO-IP administration promotes the hepatic oxidative stress-inflammation axis; thus, NSO is a generally safe chemical, especially when administered orally to experimental animals.

Studying the actions of sage and thymoquinone combination on metabolic syndrome induced by high-fat diet in rats.

High-fat diet is one of the most imperative risk factors for cardiovascular disorders. Thymoquinone (TQ) is one of the active pharmacological components of Nigella sativa (black cumin). Salvia officinalis L. (sage) has been demonstrated to have diverse pharmacological actions. The main objective of this study was to determine the effects of sage and TQ combination on hyperglycemia, oxidative stress, blood pressure, and lipid profile in rats fed with a high-fat diet (HFD). Wistar male rats were divided into five groups; normal diet (ND) and HFD, in which rats were fed with a normal diet or HFD for 10 weeks, respectively. In HFD + sage group, animals were administered sage essential oil (0.052 ml/kg) orally along with HFD. In HFD + TQ group, rats were administered TQ (50 mg/kg) orally with HFD. In HF + sage + TQ group, animals received sage + TQ along with HFD. Blood glucose (BGL) and Fast serum insulin (FSI) levels, oral glucose tolerance test, blood pressure, liver function tests, plasma, and hepatic oxidative stress markers, antioxidant enzymes, and glutathione content, and lipid profile were measured. Sage and TQ combination decreased the final body weight, weight gain, BGL, FSI, and Homeostasis Model Assessment-Insulin Resistance (HOMA-IR). The combination also lowered systolic and diastolic arterial pressures and liver function enzymes. The combination deterred lipid peroxidation, advanced protein oxidation product, and nitric oxide amplification, as well as restoring the superoxide dismutase, catalase activities, and glutathione content in plasma and hepatic tissue. Sage and TQ combination reduced the plasma total cholesterol (TC), triglyceride (TG), and low-density lipoprotein (LDL) levels and amplified high-density lipoprotein (HDL). The results of the current study verified that sage essential oil, together with TQ exhibited hypoglycemic, hypolipidemic, and antioxidant actions and thus could be a valuable addition to diabetes management.

Oliveria decumbens Extract Exhibits Hepatoprotective Effects Against Bile Duct Ligation-Induced Liver Injury in Rats by Reducing Oxidative Stress

Background: Cholestasis is described as a disease in which bile flow from the liver is reduced or stopped, and due to its oxidative effects, irreversible consequences may occur. Objectives: Due to the remarkable antioxidant properties of Oliveria decumbens (OD) and the contribution of oxidants to the progression of bile duct ligation (BDL)-induced cholestasis, this research aimed to examine how the OD ethanolic extract affected liver damage and oxidant-antioxidant balance markers in BDL-induced cholestasis. Methods: Forty male Wistar rats weighing 200 - 250 g were used. Cholestasis was induced using the BDL approach. The rats were categorized into four groups: Group 1, sham-control (SC); group 2, cholestatic; group 3, SC + OD; and group 4, cholestatic + OD. A dose of OD ethanolic extract was administered orally (500 mg/kg/day) to rats for seven days. Seven days following surgery, the rats’ blood samples were collected; after sacrifice, a part of the liver tissue was isolated. A histopathological examination was performed, while the rest was stored at -70°C in liquid nitrogen. Heparin-containing tubes were used to gather blood samples. In plasma and hepatic tissue, biochemical tests, histopathological evaluations, and oxidative stress markers staining levels were performed. Results: Our findings showed that OD could effectively reduce liver injury by reducing the activity of liver function enzymes (AST and ALP). At the same time, it did not affect total bilirubin and protein. Bile duct ligation-induced hepatic markers of protein oxidation (PCO) and reactive nitrogen species (NO) were significantly decreased by OD, and it also promoted liver antioxidant capacity by enhancing superoxide dismutase (SOD) activities. Moreover, OD treatment prevented liver bile duct proliferative changes in histopathologic analysis. Conclusions: Our study confirmed that OD exerts substantial hepatoprotective activities against BDL-induced cholestasis by improving liver damage markers and regulating oxidative stress. It may be a beneficial therapeutic agent for managing cholestasis. Bioassay-guided isolation and identification of bioactive OD secondary metabolites can further direct the discovery of potential natural-based drug candidates.

Assessment of the Hepatotoxicity of Intratracheally Instilled Silver Nanoparticles in Hypertensive Mice

Background: Silver nanoparticles (AgNPs) are extensively used in numerous engineering and biomedical fields. Inhaled nanoparticles can induce lung inflammation and translocate into secondary organs including the liver. However, the possible impact of these nanoparticles on the liver received only scant attention, especially following intratracheal (i.t.) instillation in an animal model of hypertension. Aims and Objectives: Here, we evaluated the hepatotoxicity and mechanism of action of polyethylene glycol (PEG)-coated AgNPs in a mouse model of hypertension. Materials and Methods: Mice were made hypertensive (HT) by inserting osmotic minipump infusing angiotensin II (ANG II) or vehicle (control) normotensive (NT). Either saline (control) or PEG-AgNPs (0.5 mg/kg) were i.t. instilled on days 7, 14, 21 and 28 post-ANG II or vehicle infusion. Twenty-four hours after the last exposure (day 29), lung histopathology and several markers of liver function, inflammation, oxidative stress, DNA damage and apoptosis were evaluated in all mice. Results: In comparison with either saline-treated HT group or PEG-AgNPs-treated NT group, lung histology of PEG-AgNPs-treated HT mice showed more focal areas of widening of interalveolar septae with inflammatory cells consisting mainly in macrophages and neutrophil polymorphs. In PEG-AgNPs-treated HT mice, the activities of lactate dehydrogenase, aspartate transaminase, alanine transaminase, gamma-glutamyl transferase and alkaline phosphatase in plasma were increased, compared with either saline-treated HT or PEG-AgNPs-treated NT mice. Similarly, markers of hepatic oxidative stress (lipid peroxidation, glutathione and catalase), inflammation (interleukin [IL]-6, IL-1 β and tumour necrosis factor α), DNA damage (8-hydroxy-2′-deoxyguanosine) and apoptosis (cleaved caspase-3) were significantly increased in PEG-AgNPs-treated HT mice, compared with either saline-treated HT or PEG-AgNPs-treated NT mice. Conclusion: Our data provide novel evidence on the aggravation of liver damage following pulmonary administration of PEG-AgNPs in hypertension through mechanisms involving inflammation oxidative stress, DNA damage and apoptosis.

MiR-139 Protects Liver Tissue Damage and Oxidative Stress in Diabetic Mice by Up-Regulating (Silent Mating Type Information Regulation 2 Homolog-1) SIRT1

Diabetes affects human health. This study aimed to investigate the molecular regulation mechanism of miR-139 on liver injury and oxidative stress in diabetic mice. The diabetic mice were divided into miR-139 inhibitor group, si-SIRT group, miR-139 mimic group, and the mRNA expression and protein level of miR-139 and SIRT1 were analyzed, respectively. Bioinformatics revealed the relationship between miR-139 and SIRT1. In addition, histological analysis and oxidation reaction indicators were performed on mouse livers induced by high glucose. After induction, a mouse diabetes model was established with highly expressed ALT. Bioinformatics found that miR-139 negatively regulated SIRT1. Furthermore, markers of hepatic oxidative stress were increased and blood glucose levels decreased in mice overexpressing miR-139. Up-regulation of miR-139 can protect the liver tissue of diabetic mice from oxidative stress injury by inhibiting the expression of SIRT1, and si-SIRT treatment reversed the increased blood glucose level and oxidative stress injury caused by the reduction of miR-139.

Preventive effect of salmon sperm DNA on acute carbon tetrachloride-induced liver injury in mice through Nrf2/ARE and mitochondrial apoptosis pathway.

Liver injury refers to the damage of liver function, which will seriously harm the body's health if it is not prevented and treated in time. Sporadic researches have reported that ingestion of DNA has a hepatoprotective effect, but its effect and mechanism were not clarified. The purpose of this study was to explore the preventive effect and mechanism of salmon sperm DNA on acute liver injury in mice induced by carbon tetrachloride (CCl4). Six-week-old ICR (Institute of Cancer Research) male mice were used to establish a liver injury model by injecting with 4% CCl4, silymarin, and three different concentrations of DNA solutions were given to mice by gavage for 14 days. The histological and pathological changes in the liver were observed. The levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum and the levels of oxidative and antioxidant markers such as malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and glutathione (GSH) in liver tissue were determined. The levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were detected by enzyme-linked immunosorbent assay (ELISA), and hepatic oxidative stress and apoptosis-related markers were determined by western blotting. The results showed that compared with the model group, the DNA test group significantly improved the liver pathological changes and the level of liver function, regulated liver oxidative stress, reduced hepatocyte apoptosis, and decreased the levels of inflammatory factors such as TNF-α and IL-6. Compared with the silymarin group, the high dose of DNA was even more effective in preventing liver injury. In conclusion, salmon sperm DNA has a potential protective effect against acute liver injury induced by CCl4, which is achieved by regulating the Nrf2/ARE (nuclear factor erythroid 2 (NF-E2)-related factor 2/antioxidant responsive element) oxidative stress pathway and mitochondrial apoptosis pathway.

Punicalagin Protects against the Development of Methotrexate-Induced Hepatotoxicity in Mice via Activating Nrf2 Signaling and Decreasing Oxidative Stress, Inflammation, and Cell Death.

Despite its effectiveness in treating inflammatory diseases and various malignancies, methotrexate (MTX) is well known to cause hepatotoxicity, which involves increased oxidative stress and inflammation, limiting its clinical use. Herein, we looked into the effect of punicalagin (PU), a polyphenolic molecule having a variety of health-promoting attributes, on MTX-induced hepatotoxicity in mice. PU (25 and 50 mg/kg/day) was given orally to the mice for 10 days, while a single dose of MTX (20 mg/kg) was injected intraperitoneally (i.p.) at day 7. The MTX-induced liver damage was demonstrated by remarkably higher transaminases (ALT and AST), ALP, and LDH, as well as significant histological alterations in hepatic tissues. MTX-injected mice also demonstrated increases in hepatic oxidative stress markers, including malondialdehyde (MDA) and nitric oxide (NO), with a concordant drop in glutathione (GSH) content and superoxide dismutase (SOD) and catalase (CAT) activities. PU significantly attenuated the MTX-induced serum transaminases, ALP and LDH elevations, and hepatic oxidative stress measures and boosted antioxidant defenses in the liver. Moreover, the liver of MTX-treated mice showed increases in NF-κB p65 expression, pro-inflammatory cytokine (IL-6 and TNF-α) levels, and pro-apoptotic protein (caspase-3 and Bax) expression, whereas Bcl-2 and Nrf2 expressions were reduced, which were all attenuated by PU treatment. Collectively, PU inhibits oxidative damage, inflammation, and apoptosis and upregulates Nrf2 in the liver of MTX-induced mice. Thus, these findings suggest that PU may have great therapeutic potential for the prevention of MTX-induced hepatotoxicity, pending further exploration in upcoming studies.

Methanolic Moringa oleifera leaf extract protects against epithelial barrier damage and enteric bacterial translocation in intestinal I/R: Possible role of caspase 3.

Background: Activation of caspase 3 has been implicated in the pathogenesis of I/R injury in various organs, but there is a paucity of data on its role in IIRI. Also, no reports were found on the beneficial role of methanolic Moringa oleifera leaf extract (MMOLE) in IIRI. This study investigated the involvement of caspase 3 in IIRI, and the impact of MMOLE in IIRI. Methods: Male Wistar rats were randomized into five groups; the sham-operated group that was sham-operated and received 0.5 ml of distilled water for 7 days prior to sham surgery, and the IIRI, febuxostat (FEB) +IIRI, low dose MMOLE (LDMO)+IIRI, and high dose MMOLE (HDMO)+IIRI groups that underwent I/R and also received 0.5 ml of distilled water, 10 mg/kg of febuxostat, 200 mg/kg of MMOLE, and 400 mg/kg of MMOLE respectively for 7 days prior to I/R. Markers of hepatic function, oxidative stress, and inflammation as well as enteric bacterial translocation and histoarchitecture integrity of intestinal and hepatic tissues were evaluated. The bioactive components of MMOLE were also determined by GC-MS. Results: As revealed by GC-MS, the active bioactive components of MMOLE were thiosemicarbazone, hydrazine, 1,3-dioxolane, octanoic acid, 1,3-benzenediamine, 9-octadecenoic acid, oleic acid, nonadecanoic acid, 3-undecanone, phosphonic acid, and cyclopentanecarboxylic acid. MMOLE alleviated IIRI-induced rise in intestinal and hepatic injury markers, malondialdehyde, TNF-α, IL-6, and myeloperoxidase activities. MMOLE improved IIRI-induced suppression of reduced glutathione, thiol and non-thiol proteins, and superoxide dismutase, catalase and glutathione peroxidase activities. These were associated with suppression of IIRI-induced caspase 3 activity and bacterial translocation. Histopathological evaluation revealed that MMOLE attenuated IIRI-induced alterations in intestinal and hepatic histoarchitecture integrity. MMOLE also militated against increased absolute and relative intestinal and hepatic weight, intestinal and hepatic injuries, epithelial mucosal barrier dysfunction, and enteric bacterial translocation associated with IIRI by downregulating oxidative stress-mediated activation of caspase 3. Conclusion: IIRI is associated with a rise in caspase 3 activity. Also, MMOLE confers protection against IIRI, possibly due to its constituent bioactive molecules, especially hydrazine, 9-octadecenoic acid, 1,3-dioxolane, oleic acid, and nonadecanoic acid.

Metformin, pioglitazone, dapagliflozin and their combinations ameliorate manifestations associated with NAFLD in rats via anti-inflammatory, anti-fibrotic, anti-oxidant and anti-apoptotic mechanisms

Non-alcoholic fatty liver disease (NAFLD) is an important health threat that is strongly linked to components of metabolic syndrome, particularly the low-grade inflammatory changes. Significantly, several of the available anti-diabetic drug classes demonstrate a considerable anti-inflammatory effect, and hence might be of benefit for NAFLD patients. In this study, we used a rat model of diet-induced NAFLD to examine the potential effect of metformin, pioglitazone, dapagliflozin and their combinations on NAFLD manifestations. Rats were fed an atherogenic diet containing 1.25 % cholesterol, 0.5 % cholic acid and 60 % cocoa butter for 6 weeks causing a number of metabolic and hepatic alterations including insulin resistance, dyslipidemia, systemic inflammation, increased hepatic oxidative stress and lipid peroxidation, hepatic steatosis, lobular inflammation, as well as increased markers of liver inflammation and hepatocyte apoptosis. Drug treatment, which started at the third week of NAFLD induction and continued for three weeks, not only ameliorated the observed metabolic impairment, but also functional and structural manifestations of NAFLD. Specifically, anti-diabetic drug treatment reversed markers of systemic and hepatic inflammation, oxidative stress, hepatic fibrosis, and hepatocyte apoptosis. Our findings propose that anti-diabetic drugs with a potential anti-inflammatory effect can ameliorate the manifestations of NAFLD, and thus may provide a therapeutic option for such a condition that is closely associated with metabolic diseases. The detailed pharmacology of these classes in aspects linked to the observed impact on NAFLD requires to be further investigated and translated into clinical studies for tailored therapy specifically targeting NAFLD.