Melissa officinalis extract palliates redox imbalance and inflammation associated with hyperthyroidism-induced liver damage by regulating Nrf-2/ Keap-1 gene expression in γ-irradiated rats.

BACKGROUND: Melissa officinalis (MO) is a well-known medicinal plant species used in the treatment of several diseases; it is widely used as a vegetable, adding flavour to dishes. This study was designed to evaluate the therapeutic effect of MO Extract against hyperthyroidism induced by Eltroxin and γ-radiation. METHODS: Hyperthyroidism was induced by injecting rats with Eltroxin (100 µg/kg/ day) for 14 days and exposure to γ-radiation (IR) (5 Gy single dose). The hyperthyroid rats were orally treated with MO extract (75 mg/kg/day) at the beginning of the second week of the Eltroxin injection and continued for another week. The levels of thyroid hormones, liver enzymes and proteins besides the impaired hepatic redox status and antioxidant parameters were measured using commercial kits. The hepatic gene expression of 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), Monocyte chemoattractant protein-1 (MCP-1) and fibrogenic markers such as transforming growth factor-beta1 (TGF-ß1) were determined. RESULTS: MO Extract reversed the effect of Eltroxin + IR on rats and attenuated the thyroid hormones. Moreover, it alleviated hyperthyroidism-induced hepatic damage by inhibiting the hepatic enzymes' activities as well as enhancing the production of proteins concomitant with improving cellular redox homeostasis by attenuating the deranged redox balance and modulating the Nrf2/Keap-1 pathway. Additionally, MO Extract alleviated the inflammatory response by suppressing the TNF- α and MCP-1 and prevented hepatic fibrosis via Nrf2-mediated inhibition of the TGF-ß1/Smad pathway. CONCLUSION: Accordingly, these results might strengthen the hepatoprotective effect of MO Extract in a rat model of hyperthyroidism by regulating the Nrf-2/ Keap-1 pathway.

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

INTRODUCTION: 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. METHODS: To induce liver damage, male albino rats were injected intraperitoneally with 5-FU (12.5 mg/kg) three doses/week for 1 month. 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-1ß, IL-6) were detected. RESULTS: 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-1ß 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. CONCLUSION: 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.

Melissa officinalis extract suppresses endoplasmic reticulum stress-induced apoptosis in the brain of hypothyroidism-induced rats exposed to γ-radiation.

The purpose of this study was to demonstrate the neuroprotective effect of Melissa officinalis extract (MEE) against brain damage associated with hypothyroidism induced by propylthiouracil (PTU) and/or γ-radiation (IR) in rats. Hypothyroidism induction and/or exposure to IR resulted in a significant decrease in the serum levels of T3 and T4 associated with increased levels of lipid peroxidation end product, malondialdehyde (MDA), and nitrites (NO) in the brain tissue homogenate. Also, hypothyroidism and /or exposure to IR markedly enhance the endoplasmic reticulum stress by upregulating the gene expressions of the protein kinase RNA-like endoplasmic reticulum kinase (PERK), activated transcription factor 6 (ATF6), endoplasmic reticulum-associated degradation (ERAD), and CCAAT/enhancer-binding protein homologous protein (CHOP) in the brain tissue homogenate associated with a proapoptotic state which indicated by the overexpression of Bax, BCl2, and caspase-12 that culminates in brain damage. Meanwhile, the PTU and /or IR-exposed rats treated with MEE reduced oxidative stress and ERAD through ATF6. Also, the MEE treatment prevented the Bax and caspase-12 gene expression from increasing. This treatment in hypothyroid animals was associated with neuronal protection as indicated by the downregulation in the gene expressions of the microtubule-associated protein tau (MAPT) and amyloid precursor protein (APP) in the brain tissue. Furthermore, the administration of MEE ameliorates the histological structure of brain tissue. In conclusion, MEE might prevent hypothyroidism-induced brain damage associated with oxidative stress and endoplasmic reticulum stress.

ß-sitosterol attenuates high- fat diet-induced hepatic steatosis in rats by modulating lipid metabolism, inflammation and ER stress pathway.

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic hepatic disorder. The naturally occurring phytosterol; ß-sitosterol has antiobesogenic and anti-diabetic properties. The purpose of this study was to explore the role of ß-sitosterol in preventing hepatic steatosis induced by a high-fat diet (HFD) in rats. In the current study, to induce NAFLD in the female Wister rats, an HFD was administered to them for 8 weeks. The pathogenic severity of steatosis in rats receiving an HFD diet was dramatically decreased by oral administration of ß-sitosterol. After administering ß-sitosterol to HFD-induced steatosis for three weeks, several oxidative stress-related markers were then assessed. We showed that ß-sitosterol reduced steatosis and the serum levels of triglycerides, transaminases (ALT and AST) and inflammatory markers (IL-1ß and iNOS) compared to HFD-fed rats. Additionally, ß-sitosterol reduced endoplasmic reticulum stress by preventing the overexpression of inositol-requiring enzyme-1 (IRE-1α), X-box binding protein 1(sXBP1) and C/EBP homologous protein (CHOP) genes which, showing a function in the homeostatic regulation of protein folding. Also, it was found that the expression of the lipogenic factors; peroxisome proliferator-activated receptor (PPAR-α), sterol regulatory element binding protein (SREBP-1c) and carnitine palmitoyltransferase-1(CPT-1), which are involved in the regulation of the fatty acid oxidation process, may be regulated by ß-sitosterol. It can be concluded that ß-sitosterol may prevent NAFLD by reducing oxidative stress, endoplasmic reticulum stress and inflammatory responses, which supports the possibility of using ß-sitosterol as an alternative therapy for NAFLD. Together, ß-sitosterol may be an option for NAFLD prevention.

ß-Sitosterol mitigates hepatocyte apoptosis by inhibiting endoplasmic reticulum stress in thioacetamide-induced hepatic injury in γ-irradiated rats.

The endoplasmic reticulum (ER) controls many biological functions besides maintaining the function of liver cells. Various studies reported the role of the ER stress and UPR signaling pathway in various liver diseases via triggering hepatocytes apoptosis. This study aims to investigate the suppressive effect of ß-sitosterol (ßS) on apoptosis associated with liver injury and ER stress. METHODS: Liver damage in rats was induced by TAA (150 mg/kg I.P twice a week/3 weeks) and γ-irradiation (single dose 3.5 Gy) and treated with ßS (20 mg/kg daily for 30 days). Serum aminotransferase activity, lipid profile and lipid metabolic factors were measured beside liver oxidative stress and inflammatory markers. Moreover, the hepatic expression of ER stress markers (inositol-requiring enzyme 1 alpha (IRE1α), X-box-binding protein 1 (XBP1) and CCAAT/enhancer binding protein homologous protein (CHOP) and apoptotic markers were detected together with histopathological examination. RESULTS: ßS diminished the aminotransferase activity, the oxidative stress markers as well as the inflammatory mediators. Furthermore, ßS lowered the circulating TG and TC and the hepatic lipotoxicity via the suppression of lipogenesis (Srebp-1c) and improved the ß-oxidation (Pparα and Cpt1a) together with the mitochondrial biogenesis (Pgc-1 α). Moreover, the upregulated levels of ER stress markers were reduced upon treatment with ßS, which consequently attenuated hepatic apoptosis. CONCLUSION: ßS relieves hepatic injury, ameliorates mitochondrial biogenesis, and reduces lipotoxicity and apoptosis via inhibition of CHOP and ER stress response.

Bisphenol-A/Radiation mediated inflammatory response activates EGFR/KRAS/ERK1/2 signaling pathway leads to lung carcinogenesis incidence.

BACKGROUND: Bisphenol (BPA) and ionizing radiation exposure (IR) are potent oxidants that cause free radical induction, leading to signaling pathway activation that alters cell growth. Due to the insufficient knowledge of the impact of BPA and IR on the lungs, the current study determined the impact of BPA and IR on the lung tissue of adult female Wistar rats. METHODS: Forty Wister female rats were used in this study and were randomly divided into four groups. The rats received BPA (150 mg/kg body weight/day for 6 weeks) and were exposed to IR at 2 Gy/week up to 12 Gy for 6 weeks. RESULTS: It was found that BPA and IR possess a harmful effect on the lungs via induction of oxidative stress, confirmed by increasing levels of malondialdehyde (MDA), nitric oxide, myeloperoxidase (MPO), and lactate dehydrogenase (LDH). Exposure to BPA and IR activates inflammatory cytokines TNF-α, IL-6, IL-1ß, growth factors such as TGF-ß, and gastrin-releasing peptides. BPA/IR exposures induced phosphorylated expression p-ERK1/2 and p-MEK1/2 associated with triggering of the GPER/EGFR/KRAS signaling factors, resulting in matrix metalloproteinase-2 and 9 overexpression and the development of lung tumors. Our findings support the causal role of two deleterious environmental pollutants BPA and IR, via the cytotoxicity in the respiratory system in the form of severe lung damage resulting in cancerous cells.