Hepatoprotective potential of taxifolin in type 2 diabetic rats: modulation of oxidative stress and Bcl2/Bax/Caspase-3 signaling pathway.

BACKGROUND: Diabetes mellitus (DM) is a global metabolic problem. Several factors including hyperglycemia, oxidative stress, and inflammation play significant roles in the development of DM complications. Apoptosis is also an essential event in DM pathophysiology, -with B-cell lymphoma 2 (Bcl-2) and Bcl-2 associated X (Bax) determining apoptotic susceptibility. The present study aimed to elucidate the protective effects of two doses of taxifolin (TXF) on liver damage in diabetic rats and explore the possible mechanisms of action. METHODS AND RESULTS: DM was induced in eighteen rats through intraperitoneal injections of 50 mg/kg streptozotocin and 110 mg/kg nicotinamide. Diabetic rats received daily oral intubation of 25 and 50 mg/kg TXF for 3 months. In the untreated diabetic group, there was a significant increase in fasting and postprandial glucose levels, glycosylated hemoglobin A1C (HbA1c), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6), while insulin and adiponectin levels decreased significantly. Both TXF doses mitigated hyperglycemia, regulated cytokine production, and increased insulin level. Gene expressions and protein levels of Bax, caspase 3, and cytochrome c were significantly increased, while Bcl-2 was significantly decreased in the livers of diabetic rats, effects that were significantly ameliorated after TXF treatment. The results of the TUNEL assay supported the apoptotic pathway. Additionally, TXF significantly decreased lipid peroxidation and enhanced antioxidant enzyme activity in diabetic rats. Liver enzymes and histopathological changes also showed improvement. CONCLUSIONS: TXF mitigated diabetes-associated hepatic damage by reducing hyperglycemia, oxidative stress, inflammation, and modulating anti-/pro-apoptotic genes and proteins. A dose of 50 mg/kg TXF was more effective than 25 mg/kg and is recommended for consumption.

Umbelliferone attenuates diabetic cardiomyopathy by suppression of JAK/STAT signaling pathway through amelioration of oxidative stress and inflammation in rats.

Umbelliferone (UMB), 7-hydroxycoumarin, is a naturally occurring coumarin derivative that has a plethora of biological and therapeutic activities. The focus of this research was to elucidate the curative effects of two different doses of UMB on diabetic cardiomyopathy (DCM) in a type 2 diabetic rat model induced by 50 mg/kg body weight of streptozotocin (STZ). Diabetic rats orally received 10 or 30 mg/kg of UMB daily for 8 weeks. Compared to the nontreated diabetic group, both UMB treatment doses significantly decreased glucose levels, glycated hemoglobin (HbA1c), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), creatine kinase MB (CK-MB), cardiovascular risk indices, and oxidative stress by reducing malondialdehyde (MDA) and increasing the activity of the antioxidant enzymes. The hypercholesterolemia and hypertriglyceridemia also dramatically decreased in diabetic groups with UMB treatments accompanied by an improvement in insulin, and insulin sensitivity indices (HOMA-IR and QUICKI). Furthermore, the cardiac gene expressions and protein levels of Janus kinase2 (JAK2), signal transducer and activator of transcription3 (STAT3), and transforming growth factor beta1 (TGF-ß1) were also markedly downregulated in a dose-dependent manner by UMB treatments. Finally, the biochemical results were assured by the reduction of histological alterations in cardiac tissues. In conclusion, UMB is a propitious substance for the treatment of DCM by virtuousness of its antihyperglycemic, antihyperlipidemic, antioxidant, and anti-inflammatory properties through modulating the JAK/STAT signaling pathway that may be the underlying mechanism in UMB action.

Eltroxin and Hesperidin mitigate testicular and renal damage in hypothyroid rats: amelioration of oxidative stress through PPARγ and Nrf2/HO-1 signaling pathway.

BACKGROUND: Thyroid hormones (THs) regulate growth, development and function of different tissues. Hypothyroidism is a common clinical disorder characterized by deficiency in THs and adversely affects the development and functions of several organs. This work aimed to investigate the ameliorative effect of eltroxin (ELT), a hypothyroidism medication, and hesperidin (HSP), a flavonoid, against testicular and renal toxicity in hypothyroid rats. Twenty-four rats were divided into four groups and treated orally for 12 weeks. Group I (control), group II (hypothyroidism) received 20 mg/kg carbimazole (CBZ), group III received CBZ and 0.045 mg/kg ELT, and group IV received CBZ and 200 mg/kg HSP. RESULTS: CBZ administration induced biochemical and histopathological changes in testis and kidney. Co-administration of ELT or HSP significantly (P < 0.05) ameliorated THs, reduced urea and creatinine while raised follicle stimulating hormone (FSH), Luteinizing hormone (LH), and testosterone in serum. Testicular and renal malondialdehyde level as a lipid peroxidation indicator, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) were significantly (P < 0.05) decreased while glutathione content, glutathione peroxidase, and glutathione-s-transferase activities were significantly (P < 0.05) increased. The histopathological changes were also diminished. Decreased mRNA and protein expressions of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and peroxisome proliferator-activated receptor gamma(PPARγ) in hypothyroid rats were up-regulated after ELT or HSP treatment. CONCLUSIONS: ELT and HSP showed antioxidant and anti-inflammatory effects against CBZ-induced testicular and renal toxicity, and these effects may be promoted via activating Nrf2/HO-1 and PPARγ signaling pathways.

Evaluation of MMP-13 and Micro RNA-138 as prognostic biomarkers for breast cancer in Egyptian women patients.

BACKGROUND: Elevated serum levels of MMP-13 are linked to tumor growth and metastasis, while miR-138 dysregulation is observed in breast cancer cases. The aim of this study is to investigate the expression of miR-138 and MMP-13 levels as potential biomarkers for the prognosis of breast cancer. PATIENTS AND METHOD: In this retrospective case-control study, 119 female subjects were recruited and divided into three groups. MMP-13 level was measured using Enzyme Linked Immunosorbent Assay (ELISA), while real-time PCR technique was employed to quantify miR-138 expression. RESULTS: Both non-metastatic and metastatic groups showed significantly higher levels of serum MMP-13 compared to other groups. MMP-13 levels are significantly increased among patients with advanced tumor size, lymph node metastasis, and triple-negative breast cancer cases. An inverse significant association between MMP-13 levels and response to treatment was observed. Expression of miR-138 underwent a significant down-regulation in breast cancer patients, and a statistically significant association was established between miR-138 expression and triple-negative breast cancer cases. A positive association was detected between the increase in miR-138 expression and the good response to treatment. The expression of miR-138 was inversely correlated with the MMP-13 levels. CONCLUSION: MMP-13 levels were significantly higher in breast cancer, especially in advanced cases, suggesting its role in promoting tumor invasion and metastasis. MiR-138 was down-regulated in breast cancer, especially in triple-negative breast cancer patients, rendering it a promising biomarker for triple-negative breast cancer. Modulation of miR-138 expression and MMP-13 levels may represent therapeutic targets for breast cancer.

Antioxidant Properties of Teucrium polium Extract Contribute to Neurochemical and Brain Structural Modulations in Nicotine-Induced Mice.

INTRODUCTION: Tobacco use is a major global health issue linked to psychiatric illnesses and high mortality rates. Nicotine, the primary compound absorbed during smoking, causes harm to various organs, particularly the brain. The current study examined the modulatory effect of Teucrium polium extract (TPE) on nicotine-induced biochemical and histological changes in the brains of mice. METHODS: Twenty-four mice were divided into four groups and were treated for three weeks. Group one was the control; Group two received 100 mg/kg TPE orally; Group three was subcutaneously injected with 2.5 mg/kg nicotine, and Group four received both nicotine and TPE. RESULTS: The brain tissue of the nicotine-induced group showed histopathological alterations and oxidative stress as indicated by increased lipid peroxidation and nitric oxide levels concomitant with decreased glutathione content and superoxide dismutase activity. DNA fragmentation was also detected by comet assay. Treatment with TPE significantly decreased oxidative stress and DNA fragmentation while increasing antioxidant biomarkers. Histopathological changes were also diminished. CONCLUSION: Through the antioxidant activity of TPE, it protected against nicotine-induced neurotoxicity in mice by impacting oxidative stress, DNA fragmentation, and brain histopathological changes.

Royal Jelly and Chlorella vulgaris Mitigate Gibberellic Acid-Induced Cytogenotoxicity and Hepatotoxicity in Rats via Modulation of the PPARα/AP-1 Signaling Pathway and Suppression of Oxidative Stress and Inflammation.

Gibberellic acid (GA3) is a well-known plant growth regulator used in several countries, but its widespread use has negative effects on both animal and human health. The current study assesses the protective effect of royal jelly (RJ) and Chlorella vulgaris (CV) on the genotoxicity and hepatic injury induced by GA3 in rats. Daily oral administration of 55 mg/kg GA3 to rats for 6 constitutive weeks induced biochemical and histopathological changes in the liver via oxidative stress and inflammation. Co-administration of 300 mg/kg RJ or 500 mg/kg CV with GA3 considerably ameliorated the serum levels of AST (aspartate aminotransferase), ALT (alanine aminotransferase), ALP (alkaline phosphatase), γGT (gamma-glutamyl transferase), total bilirubin, and albumin. Lowered malondialdehyde, tumor necrosis factor α (TNF-α), and nuclear factor κB (NF-κB) levels along with elevated SOD (superoxide dismutase), CAT (catalase), and GPx (glutathione peroxidase) enzyme activities indicated the antioxidant and anti-inflammatory properties of both RJ and CV. Also, they improved the histological structure and reduced cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expressions along with up-regulating peroxisome proliferator activated receptor α (PPARα) and down-regulating activator protein 1 (AP-1) gene expression. Additionally, chromosomal abnormalities and mitotic index were nearly normalized after treatment with RJ and CV. In conclusion, RJ and CV can protect against GA3-induced genotoxicity and liver toxicity by diminishing oxidative stress and inflammation, and modulating the PPARα/AP-1 signaling pathway.

Mesenchymal stem cells ameliorate oxidative stress, inflammation, and hepatic fibrosis via Nrf2/HO-1 signaling pathway in rats.

Liver fibrosis occurs in most types of chronic liver diseases and can develop into cirrhosis and liver failure. Bone marrow-derived mesenchymal stem cells (BMSCs) showed promising effects in the treatment of fibrosis. This study evaluated the possible role of Nrf2/HO-1 signaling in the ameliorative effect of BMSCs against carbon tetrachloride (CCl4)-induced liver fibrosis, oxidative stress, and inflammation in rats. Hepatic fibrosis was induced by subcutaneous injection of CCl4 twice per week for 6 consecutive weeks and rat BMSCs were administered intravenously. After 4 weeks, the rats were sacrificed, and samples were collected for analysis. CCl4-intoxicated rats showed elevated serum transaminases, ALP, γGT, bilirubin and pro-inflammatory cytokines, and decreased albumin. Hepatic NF-κB p65 and malondialdehyde (MDA) were significantly increased, and cellular antioxidants were decreased in CCl4-intoxicated rats. BMSCs ameliorated liver function markers, suppressed MDA, NF-κB p65, and inflammatory cytokines, and enhanced antioxidants in the liver of CCl4-intoxicated rats. BMSCs were engrafted within the liver tissue and prevented histological alterations and collagen accumulation induced by CCl4. In addition, BMSCs upregulated hepatic Nrf2 and HO-1 expression in CCl4-intoxicated rats. In conclusion, this study provides evidence that BMSCs suppress oxidative stress, inflammation, and liver fibrosis through a mechanism involving activation of the Nrf2/HO-1 signaling.

Hesperidin protects against chemically induced hepatocarcinogenesis via modulation of Nrf2/ARE/HO-1, PPARγ and TGF-ß1/Smad3 signaling, and amelioration of oxidative stress and inflammation.

Hesperidin is a plant-derived bioflavonoid with promising antitumor efficacy, though the underlying mechanisms of action remain poorly elucidated. Thus, we evaluated the in vivo chemopreventive effect of hesperidin against diethylnitrosamine (DEN)-induced hepatocarcinogenesis. We demonstrated the modulatory effect of hesperidin on Nrf2/ARE/HO-1, PPARγ and TGF-ß1/Smad3 signaling. Hepatocarcinogenesis was initiated with DEN and promoted with carbon tetrachloride (CCl4). DEN/CCl4-induced rats were treated with 50 and 100 mg/kg hesperidin throughout the experiment. The results revealed that hesperidin significantly reduced circulating liver function marker enzymes, bilirubin, tumor markers and tumor necrosis factor alpha. Hesperidin prevented liver morphological damage, proliferating cell nuclear antigen (PCNA) expression and oxidative stress as evidenced by the reduced lipid peroxidation and enhanced antioxidant defenses. Liver NF-κB and TGF-ß1 expression, and Smad3 phosphorylation were significantly up-regulated in DEN/CCl4-induced rats. Hesperidin dramatically abolished NF-κB and TGF-ß1/Smad3 signaling as well as collagen deposition in the liver of DEN/CCl4-induced rats. In addition, hesperidin markedly up-regulated the expression of Nrf2, HO-1 and PPARγ in the liver of DEN/CCl4-induced rats. In conclusion, hesperidin can inhibit hepatocarcinogenesis by suppressing oxidative stress, inflammation, cell proliferation, TGF-ß1/Smad3 signaling and collagen deposition. These effects are suggested to be mediated by activating Nrf2/ARE/HO-1 and PPARγ pathways.