Fennel seeds extract prevents fructose-induced cardiac dysfunction in a rat model of metabolic syndrome via targeting abdominal obesity, hyperuricemia and NF-κß inflammatory pathway.

BACKGROUND: Metabolic syndrome (MetS) is commonly associated with increased risk of cardiac disease that affects a large number of world populations. OBJECTIVE: This research attempted to investigate the efficacy of fennel seeds extract (FSE) in preventing development of cardiac dysfunction in rats on fructose enriched diet for 3 months, as a model of MetS. MATERIALS & METHODS: Thirty adult Wistar male rats (160-170 g) were assigned into 5 groups including control, vehicle, FSE (200 mg/kg BW) and fructose (60%) fed rats with and without FSE. Following the last treatment, blood pressure, ECG and heart rate were measured. Next, blood and cardiac tissues were taken for biochemical and histological investigations. RESULTS: Feeding fructose exhibited characteristic features of MetS involving, hypertension, abnormal ECG, elevated heart rate, serum glucose, insulin, lipids and insulin resistance, accompanied by abdominal obesity, cardiac hypertrophy and hyperuricemia. Fructose fed rats also showed significant reduction in cardiac antioxidants (GSH, SOD, CAT) with elevation in oxidative stress indices (NADPH oxidase, O2.-, H2O2, MDA, PCO), NF-κß, pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6), adhesion molecules (ICAM-1, VCAM-1) and serum cardiac biomarkers (AST, LDH, CK-MB, cTn-I). Histopathological changes evidenced by destruction of cardiac myofibrils, cytoplasmic vacuolization, and aggregation of inflammatory cells were also detected. Consumption of FSE showed high ability to alleviate fructose-induced hypertension, ECG abnormalities, cardiac hypertrophy, metabolic alterations, oxidative stress, inflammation and histological injury. CONCLUSION: Findings could suggest FSE as a complementary supplement for preventing MetS and associated cardiac outcomes. However, well controlled clinical studies are still needed.

Ameliorative Effect of Thymoquinone and Thymoquinone Nanoparticles against Diazinon-Induced Hepatic Injury in Rats: A Possible Protection Mechanism.

The health benefits of thymoquinone (TQ) have been a significant focus of numerous studies. However, more research is needed to ascertain whether its nano-form can effectively treat or prevent chronic diseases. In this study, we investigated how thymoquinone and its nanoparticles can mitigate liver damage induced by diazinon in male Wistar rats and explored the intracellular mechanisms involved. Forty-two Wistar male rats (n = 42) were randomly allotted into seven groups. Group 1 served as the control. Group 2 (vehicle) consisted of rats that received corn oil via a gastric tube daily. In Group 3 (TQ), rats were given a daily oral administration of TQ (40 mg/kg bw). Group 4 (thymoquinone nanoparticles, NTQ) included rats that received NTQ (0.5 mg/kg bw) orally for 21 days. Group 5 (DZN) involved rats that were administered diazinon (DZN, 15 mg/kg bw) orally. In Group 6 (TQ + DZN), rats first received TQ orally, followed by DZN. Group 7 (NTQ + DZN) consisted of rats receiving NTQ orally, then DZN. After 21 days of treatment, the rats were euthanized. After oral administration of DZN, liver enzymes were significantly elevated (p < 0.05). Additionally, there were noticeable increases in oxidative injury markers, such as nitric oxide, malondialdehyde, redox oxygen radicals, and overall increases in hydrogen peroxide and liver protein carbonyl concentrations. This was accompanied by the upregulation of apoptotic markers (Bax, caspase9, caspase 3, bax/Bcl2 ratio), inflammatory cytokines (TNF-α, IL-6), and DNA damage. There was also a noteworthy decrease (p < 0.05) in the activities of antioxidant enzymes and anti-apoptotic markers. However, the oral administration of thymoquinone or its nanoparticle form mitigated these diazinon complications; our histopathological findings corroborated our biochemical and molecular observations. In conclusion, the significant antioxidant properties of thymoquinone, or its nanoparticle form, in tandem with the downregulation of apoptotic markers and inflammatory cytokines, provided a protective effect against hepatic dysfunction caused by diazinon.

Comparative study between effects of ginkgo biloba extract and extract loaded on gold nanoparticles on hepatotoxicity induced by potassium bromate.

In human organs, potassium bromate (KBrO3) produces toxicity. The main causes of KBrO3 hepatotoxicity are the formation of reactive oxygen species (ROS) and DNA damage. The purpose of this study is to show how ginkgo biloba extract (GBE) and extract loaded with nanogold particles (GBE@AuNPs) affect hepatotoxicity caused by KBrO3. The rats were separated into eight groups: control (group I), GBE (group II), AuNPs (group III), GBE@AuNPs (group IV), KBrO3 (group V), KBrO3 and GBE (group VI), KBrO3 and AuNPS (group VII), and KBrO3 and GBE@AuNPs (group VIII). KBrO3 generated DNA damage spots in a comet assay, which were associated with increased inflammatory indicators (IL-6), decreased anti-apoptotic Bcl-2, and increased apoptotic markers (Bax and caspase-3). The inflammatory, apoptotic, and ultrastructural alterations in liver tissue produced by KBrO3 were reduced in treated groups VI, VII, or VIII. The hepatotoxic effects of KBrO3 were reduced when GBE, AuNPs, or GBE@AuNPs were used; the particular GBE@AuNPs were the most effective.

Potassium bromate-induced nephrotoxicity and potential curative role of metformin loaded on gold nanoparticles.

Potassium bromate (KBrO3) is classified by the International Agency for Research on Cancer as a carcinogenic compound, where it causes renal tumors. The present study investigated the potential curative effect of metformin loaded on gold nanoparticles (MET AuNPs) in attenuating KBrO3-induced nephrotoxicity. Rats were divided into eight groups (control, MET, AuNPs, MET AuNPs, KBrO3, KBrO3/MET, KBrO3/AuNPS, and KBrO3/MET AuNPs). KBrO3 administration resulted in a significant elevation in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total protein (TP), albumin (Alb), total bilirubin (TB), direct bilirubin (DB), total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), creatinine, urea, uric acid. Also, KBrO3 significantly increased renal malondialdehyde (MDA), protein carbonyl (PC), and nitric oxide (NO) levels and reduced the activities of antioxidant molecules superoxide dismutase (SOD), catalase (CAT), glutathione-S-transferase (GST), and Reduced glutathione (GSH). It also caused damaged DNA spots in comet assay and increased inflammatory IL-6 and apoptotic markers (caspase 3, Bax) while antiapoptotic Bcl-2 was significantly reduced. MET, AuNPS, MET AuNPS reduced the extent of renal damage induced by KBrO3 as indicated by decreased (AST, ALT, ALP, Alb, TP, TB, DB, creatinine, urea, uric, Lipid profile). MET, AuNPS, MET AuNPS showed a good curative effect against KBrO3-induced nephrotoxicity and MET AuNPS group showed better results compared with monotherapy.

Genetic variability of CYP2D6, CYP3A4 and CYP3A5 among the Egyptian population.

Aim: This study investigated major allelic variants of CYP2D6, CYP3A4 and CYP3A5 in Egyptians, an Arabic population for which there is little information regarding these important pharmacogenes. Patients & methods:CYP2D6*2, *4, *5, *10, *41 and gene copy number variation, as well as CYP3A4*22 and CYP3A5*3 were determined with commercially available TaqMan assays in 145 healthy study participants. Results: The CYP2D6 alleles identified suggest that the prevalence of poor metabolizers is low as none were found among the 145 subjects investigated. The frequency for CYP3A5 nonexpressers was 74.5% and the CYP3A4*22 allele frequency was low at 2.0%. Conclusion: These preliminary findings indicate that pharmacogene variation in Egyptians is different from those of other Middle Eastern/Arabic populations and warrants further investigation.

Myrtle (Myrtus communis) leaf extract suppresses hepatotoxicity induced by monosodium glutamate and acrylamide through obstructing apoptosis, DNA fragmentation, and cell cycle arrest.

A large number of plant extracts have demonstrated to provide health benefits and mitigate several disease conditions. However, at the molecular and cellular levels, few studies have been conducted. The present work was designed to study the effect of Myrtus communis leaf extract (ME) (300 mg/kg bw) against hepatotoxicity induced by monosodium glutamate (MSG) (100 mg/kg bw), and acrylamide (ACR) (20 mg/kg bw) in male rats and determining its molecular and cellular mechanisms. The data showed that the treatment with MSG and/or ACR induced significant changes in numerous biomarkers (Bcl-2 and the programmed cell death protein-1) related to liver damage, as recorded by genotoxicity, apoptosis, and histopathological changes. On the other side, the oral administration of ME (300 mg/kg bw) improved the hepatic conditions as confirmed by the improvement in cell viability, programmed cell death, and histopathological alterations. It can be concluded that the consumption of ME might be useful for minimizing the occurred hepatotoxicity through up-regulation of the key apoptotic regulators as well as the improvement of DNA content and cell cycle restoration. Graphical abstract.

Baker's Yeast Induces Apoptotic Effects and Histopathological Changes on Skin Tumors in Mice.

The current study investigates the apoptotic effect of Baker's yeast (S. cerevisiae) on chemically-induced skin cancer in mice. Intra-tumoral treatment with yeast caused: increases in Ca2+ in skin homogenate, modulated the intrinsic/extrinsic pathways by downregulating Bcl-2 and FasL, upregulating Bax, and increased the expression of cytochrome-c and caspases 9, 8, and 3. Histopathological changes were detected, including mild dysplasia, atypia, tumor regression, and absence of basaloid cell proliferation. No toxic effects were detected, as examined by histopathological, biochemical, and body weight analysis. These results show that yeast exerts anti-skin cancer activity, suggesting its possible use for treatment of human skin cancer.

Epigallocatechin-3-gallate protects against diabetic cardiomyopathy through modulating the cardiometabolic risk factors, oxidative stress, inflammation, cell death and fibrosis in streptozotocin-nicotinamide-induced diabetic rats.

The potential protective effect of epigallocatechin-3-gallate (EGCG) on type 2 diabetes-induced heart injury was investigated. A rat model of diabetes was achieved by injection of nicotinamide (100mg/kg, i.p), 20min before the administration of streptozotocin (55mg/kg, i.p.). After confirmation of diabetes, EGCG (2mg/kg, p.o.) was administrated on alternate days for one month. Treatment of diabetic rats with EGCG showed a remarkable reduction in glucose, glycosylated hemoglobin, HOMA-IR and lipid profile levels with an elevation in insulin levels, indicating its antihyperglycemic and antidyslipidemic actions. EGCG treatment also suppressed the increase in the levels of superoxide, 4-hydroxynonenal and protein carbonyl, whereas it increased the content of glutathione and the activities of superoxide dismutase and catalase in heart of diabetic rats, indicating its antioxidant capacity. In addition, EGCG improved heart function of diabetic rats as evidenced by a remarkable reduction in troponin T level and creatine kinase-MB, lactate dehydrogenase and aspartate aminotransferase activities in the serum. Oral administration of EGCG for one month after diabetes induction significantly protected the increase in serum levels of pro-inflammatory cytokines (IL-1 ß, IL-6 and TNF-α) and adhesion molecules (ICAM-1 and VCAM-1), suggesting its anti-inflammatory potential. Furthermore, EGCG hampered the mitochondrial apoptotic pathway through increasing Bcl-2 level and decreasing p53, Bax, cytochrome c and caspase-3 and 9 levels in hearts of diabetic rats, indicating its anti-apoptotic action. Diabetic rats treated with EGCG also exhibited decreased level of DNA damage in the myocardium. The histological examinations indicated the cardioprotective effect of EGCG against harmful impact of diabetes. Therefore, these findings suggest that EGCG has a protective effect on the heart affected by type 2 diabetes and recommend it as a complementary supplement for diabetic patients.

Melatonin reduces oxidant damage and promotes mitochondrial respiration: implications for aging.

Melatonin has a number of properties as a consequence of which it could be beneficial to animals as they age. Of particular interest are its ubiquitous actions as a direct and indirect antioxidant and free radical scavenger. Besides directly detoxifying a variety of reactive oxygen and reactive nitrogen species, at least one product that is formed as a result of these interactions is also a potent free radical scavenger. Thus, the product that is formed when melatonin detoxifies hydrogen peroxide, that is, N1-acetyl-N2-formyl-5-methoxykynuramine is an efficient scavenger, at least equivalent to melatonin itself. This antioxidant cascade increases the ability of melatonin to resist oxidative damage. Other actions of melatonin, such as stimulation of antioxidative enzymes also improves its status as an antioxidant. Finally, recent observations documenting melatonin's ability to stimulate electron transport and ATP production in the inner-mitochondrial membrane also has relevance for melatonin as an agent that could alter processes of aging. These findings, coupled with diminished melatonin production in advanced age, has prompted scientists to consider melatonin in the context of aging. As of this writing there is no definitive evidence to prove that melatonin alters the rate of aging, although data relating to melatonin deferring some age-related degenerative conditions is accumulating rapidly.

Chemical and physical properties and potential mechanisms: melatonin as a broad spectrum antioxidant and free radical scavenger.

Melatonin was found to be a potent free radical scavenger in 1993. Since then over 800 publications have directly or indirectly confirmed this observation. Melatonin scavenges a variety of reactive oxygen and nitrogen species including hydroxyl radical, hydrogen peroxide, singlet oxygen, nitric oxide and peroxynitrite anion. Based on the analyses of structure-activity relationships, the indole moiety of the melatonin molecule is the reactive center of interaction with oxidants due to its high resonance stability and very low activation energy barrier towards the free radical reactions. However, the methoxy and amide side chains also contribute significantly to melatonin's antioxidant capacity. The N-C=O structure in the C3 amide side chain is the functional group. The carbonyl group in the structure of N-C=O is key for melatonin to scavenge the second reactive species and the nitrogen in the N-C=O structure is necessary for melatonin to form the new five membered ring after melatonin's interaction with a reactive species. The methoxy group in C5 appears to keep melatonin from exhibiting prooxidative activity. If the methoxy group is replaced by a hydroxyl group, under some in vitro conditions, the antioxidant capacity of this molecule may be enhanced. However, the cost of this change are decreased lipophility and increased prooxidative potential. Therefore, in in vivo studies the antioxidant efficacy of melatonin appears to be superior to its hydroxylated counterpart. The mechanisms of melatonin's interaction with reactive species probably involves donation of an electron to form the melatoninyl cation radical or through an radical addition at the site C3. Other possibilities include hydrogen donation from the nitrogen atom or substitution at position C2, C4 and C7 and nitrosation. Melatonin also has the ability to repair damaged biomolecules as shown by the fact that it converts the guanosine radical to guanosine by electron transfer. Unlike the classical antioxidants, melatonin is devoid of prooxidative activity and all known intermediates generated by the interaction of melatonin with reactive species are also free radical scavengers. This phenomenon is defined as the free radical scavenging cascade reaction of the melatonin family. Due to this cascade, one melatonin molecule has the potential to scavenge up to 4 or more reactive species. This makes melatonin very effective as an antioxidant. Under in vivo conditions, melatonin is often several times more potent than vitamin C and E in protecting tissues from oxidative injury when compared at an equivalent dosage (micromol/kg). Future research in the field of melatonin as a free radical scavenger might be focused on: 1), signal transduction and antioxidant enzyme gene expression induced by melatonin and its metabolites, 2), melatonin levels in tissues and in cells, 3), melatonin structure modifications, 4), melatonin and its metabolites in plants and, 5), clinical trials using melatonin to treat free radical related diseases such as Alzheimer's, Parkinson's, stroke and heart disease.