Clopidogrel protects against gentamicin-induced nephrotoxicity through targeting oxidative stress, apoptosis, and coagulation pathways.

Gentamicin (Genta)-induced nephrotoxicity poses a significant clinical challenge due to its detrimental effects on kidney function. Clopidogrel (Clop), an antiplatelet drug known for its ability to prevent blood clots by inhibiting platelet aggregation, also has potential effects on oxidative stress and cell death. This study investigates Clop's protective role against Genta-induced nephrotoxicity, emphasizing the importance of the coagulation cascade. The 32 adult male albino rats were randomly assigned to four groups of eight (n = 8). The first group received only the vehicle. Genta was injected intraperitoneally at 100 mg/kg/day for 8 days in the second group. Groups 3 and 4 received oral Clop at 10 and 20 mg/kg/day for 1 week before Genta delivery and throughout the experiment. Renal tissue showed renal function tests, oxidative stress, pro-inflammatory cytokines, apoptotic markers, coagulation profile, and fibrin expression. Clop improved Genta-induced kidney function and histopathology. Clop substantially reduced pro-inflammatory cytokines, oxidative stress indicators, pro-apoptotic proteins, and fibrin protein. Clop also significantly boosted renal tissue anti-inflammatory and anti-apoptotic protein expression. Genta-induced nephrotoxicity involves oxidative stress, apoptosis, and coagulation system activation, according to studies. This study underscores that Genta-induced nephrotoxicity is associated with oxidative stress, apoptosis, and activation of the coagulation system. Clop's protective effects on nephrons are attributed to its anticoagulant, antioxidant, anti-inflammatory, and anti-apoptotic properties, presenting it as a promising therapeutic strategy against Genta-induced kidney damage.

Impact of gervital against histopathological, ultrastructural, and biochemical alterations caused by methotrexate or azathioprine in albino rat testis.

Methotrexate (MTX) and azathioprine (AZA) are chemotherapeutic, immunosuppressive, cytotoxic drugs with reported adverse effects, including oxidative damage to testis. This study aims to evaluate the potential effect of grape seed extract (GSE; gervital) to prevent testicular damage caused by MTX and AZA. Male albino rats were separated into six groups: group I, normal control group; group II, GSE (150 mg/kg/day); group III, MTX (8 mg/kg/week); group IV, AZA (15 mg/kg/day); group V, GSE (150 mg/kg/day) + MTX (8 mg/kg/week); group VI, GSE (150 mg/kg/day) + AZA (15 mg/kg/day). All rats were sacrificed, blood samples were obtained for testosterone analysis, and testis was removed for histological and ultrastructural studies and oxidation measurements. A reduction in relative body and testis weight, along with a significant decrease in testosterone levels, was observed. Histopathological and ultrastructural alterations induced by MTX or AZA included reduced spermatozoa, sloughing, marked reduction of spermatogenic cells, and pyknosis of some nuclei. Significant oxidative stress manifested as reduced glutathione (GSH) levels and catalase (CAT) and superoxide dismutase (SOD) activities, as well as increased malondialdehyde (MDA) levels. GSE administration showed an ameliorative effect on testosterone levels and histopathological and ultrastructural changes. GSE treatment also suppressed the increases in MDA levels and the decreases in GSH levels and CAT and SOD activities. In conclusion, these findings confirm that GSE is an effective antioxidant that protects testis from histopathological and ultrastructural damage induced by MTX and AZA. Therefore, GSE is a promising candidate for future use to minimize and alleviate MTX and AZA risks.

Cinnamaldehyde Mitigates Atherosclerosis Induced by High-Fat Diet via Modulation of Hyperlipidemia, Oxidative Stress, and Inflammation.

Atherosclerosis is a disease in which plaque builds up inside arteries. Cinnamaldehyde (Ci) has many biological properties that include anti-inflammatory and antioxidant activities. Thus, this study was designed to explore the protective effect of Ci against atherosclerosis induced by a high-fat diet (HFD) in Wistar rats. Atherosclerosis was induced by an oral administration of an HFD for 10 weeks. Atherosclerosis-induced rats were supplemented with Ci at a dose of 20 mg/kg bw dissolved in 0.5% dimethyl sulfoxide (DMSO), daily by oral gavage for the same period. Rats were divided into three groups of 10 rats each fed with (a) ND, (b) HFD, and (c) HFD+Ci, daily for 10 weeks. Treatment of rats with Ci significantly reduced the elevated levels of serum total cholesterol (T.Ch), triglycerides (TG), low-density lipoprotein-cholesterol (LDL-Ch), very low-density lipoprotein-cholesterol (VLDL-Ch), and free fatty acids (FFAs) and significantly increased the lowered levels of high-density lipoprotein-cholesterol (HDL-Ch) level. Ci ameliorated the increased cardiovascular risk indices 1 and 2 and the decreased antiatherogenic index. Moreover, Ci reduced the elevated serum creatine kinase (CK), creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), and aspartate aminotransferase (AST) activities. Ci also improved the heart antioxidant activities by decreasing malondialdehyde (MDA) and increasing glutathione S-transferase (GST), superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH), and glutathione peroxidase (Gpx) activities. Furthermore, the supplementation with Ci downregulated the mRNA expression levels of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), interleukin-17 (IL-17), and tumor necrosis factor-α (TNF-α). Thus, Ci successfully elicited a therapeutic impact against atherosclerosis induced by HFD via its hypolipidemic, antioxidant, and anti-inflammatory actions.

Melissa officinalis L. ameliorates oxidative stress and inflammation and upregulates Nrf2/HO-1 signaling in the hippocampus of pilocarpine-induced rats.

Epilepsy is characterized by recurrent epileptic seizures, and its effective management continues to be a therapeutic challenge. Oxidative stress and local inflammatory response accompany the status epilepticus (SE). This study evaluated the effect of Melissa officinalis extract (MOE) on oxidative stress, inflammation, and neurotransmitters in the hippocampus of pilocarpine (PILO)-administered rats, pointing to the involvement of Nrf2/HO-1 signaling. Rats received PILO via intraperitoneal administration and were treated with MOE for 2 weeks. MOE prevented neuronal loss; decreased lipid peroxidation, Cox-2, PGE2, and BDNF; and downregulated glial fibrillary acidic protein in the hippocampus of PILO-treated rats. In addition, MOE enhanced GSH and antioxidant enzymes, upregulated Nrf2 and HO-1 mRNA abundance, and increased the nuclear translocation of Nrf2 in the hippocampus of epileptic rats. Na+/K+-ATPase activity and GABA were increased, and glutamate and acetylcholine were decreased in the hippocampus of epileptic rats treated with MOE. In conclusion, MOE attenuated neuronal loss, oxidative stress, and inflammation; activated Nrf2/HO-1 signaling; and modulated neurotransmitters, GFAP, and Na+/K+-ATPase in the hippocampus of epileptic rats. These findings suggest that M. officinalis can mitigate epileptogenesis, pending further studies to explore the exact underlying mechanisms.

Evaluation of Insulin Resistance Induced Brain Tissue Dysfunction in Obese Dams and their Neonates: Role of Ipriflavone Amelioration.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is associated with activation of liver fibrogenesis and predisposes to cirrhosis and associated morbi-mortality. A high fat high cholesterol diet (HFD) was provided to female albino rats to establish a NASH model. It is well known that the offspring of obese mothers have an increased risk of obesity and diabetes. The present study aimed at evaluating the ameliorative effects of ipriflavone (IP) as a natural food supplement on lipid metabolism, improving insulin sensitivity, reducing oxidative stress and inflammation, modifying metabolic risk factors and/or reduce brain damage, in both neonates and their dams. MATERIALS AND METHODS: The present aim was achieved by evaluating the oxidative stress and antioxidant defense system biomarkers, as thiobarbituric acid reactive substances (TBARS) and reduced glutathione (GSH), catalase, and superoxide dismutase (SOD) activities. In addition, the neurotransmitter acetylcholine (Ach) and acetylcholine esterase (AchE) activities, as well as levels of the apolipoprotein E4 (APOE4); ß-secretase, hyper phosphor-tau and ß-amyloid 42; 3-hydroxy- 3-methyl glutaryl coenzyme A reductase (HMG CoA R)" and COX-II by immunoblotting assays in the brain tissue of neonates and their dams in all the studied groups. RESULTS: A very significant amelioration in acetylcholine and acetylcholine esterase neurotransmitters, Alzheimer's makers (ß-amyloid), antioxidants (reduced glutathione (GSH) contents, catalase (CAT) and superoxide dismutase (SOD); and inflammatory cytokines in NASH model is observed upon administrating ipriflavone (IP) as a natural food supplement. The multifunctional activities of ipriflavone as an antioxidant, anti-inflammatory and anti-insulin resistance drug were discussed and correlated with other investigations. CONCLUSION: Regarding steatohepatitis, the present study confirmed the anti-inflammatory effects of the ipriflavone (IP). Therefore, future studies should focus on hepatic fatty acid uptake, hepatic lipogenesis, and fatty acid oxidation and the role of IP in regulating hepatic fat metabolism. In addition, natural products like IP could be combined with the highly used pharmaceutical drugs to reduce the side effects of nonalcoholic steatohepatitis, and minimize progression of dementia. Moreover, the present study supports further attempts to heal the neural dysfunction via antioxidant and anti-inflammatory cascade activities using ipriflavone (IP).

Association of glycemic status and interferon-γ production with leukocytes and platelet indices alterations in type2 diabetes.

AIMS: The present study aimed to evaluate the correlation between glycemic status and the inflammation biomarkers; leukocytes, platelets indices and interferon gamma (IFN-γ) production in type 2 diabetes mellitus (T2DM) patients regarding diabetic complications. METHODS: Study was conducted on 158 patients allocated as normal healthy subjects (50) and 108 patients diagnosed as T2DM. The diabetic patients were subdivided into six groups according to metformin administration as mono-or dual therapies. RESULTS: The current results exhibited a significant elevation in systolic blood pressure, total and LDL-cholesterol levels and IFN-γ as well as a noticeable decrease in HDL-cholesterol and anti-atherogenic factor values compared to the healthy patients. Leukocytes and neutrophils count, main platelets volume (MPV) and platelet distribution width (PDW) values revealed noticeable elevations in most treated T2DM groups, while a marked depletion was recorded in platelets count compared to healthy subjects. Glycemic control, most treated diabetic patients with metformin mono- and dual therapies showed an ameliorative effect in HbA1c, IFN-γ, MPV, and PDW values compared to recent diabetic ones. CONCLUSION: Diabetes was correlated significantly with dyslipidemia and atherogenic risk in parallel with an increase in IFN-γ production and hematological inflammatory biomarkers; leukocytes, neutrophil/lymphocyte and platelet/lymphocyte ratios, MPV and PDW values. The amelioration in inflammatory biomarkers was associated with improvement in glycemic control.

Gallic acid and p-coumaric acid attenuate type 2 diabetes-induced neurodegeneration in rats.

The brain of diabetics revealed deterioration in many regions, especially the hippocampus. Hence, the present study aimed to evaluate the effects of gallic acid and p-coumaric acid against the hippocampal neurodegeneration in type 2 diabetic rats. Adult male albino rats were randomly allocated into four groups: Group 1 served as control ones and others were induced with diabetes. Group 2 considered as diabetic, and groups 3 and 4 were further orally treated with gallic acid (20 mg/kg b.wt./day) and p-coumaric acid (40 mg/kg b.wt./day) for six weeks. Diabetic rats revealed significant elevation in the levels of serum glucose, blood glycosylated hemoglobin and serum tumor necrosis factor-α, while the level of serum insulin was significantly declined. Furthermore, the brain of diabetic rats showed a marked increase in oxidative stress and a decrease of antioxidant parameters as well as upregulation the protein expression of Bax and downregulation the protein expression of Bcl-2 in the hippocampus. Treatment of diabetic rats with gallic acid and p-coumaric acid significantly ameliorated glucose tolerance, diminished the brain oxidative stress and improved antioxidant status, declined inflammation and inhibited apoptosis in the hippocampus. The overall results suggested that gallic acid and p-coumaric acid may inhibit hippocampal neurodegeneration via their potent antioxidant, anti-inflammatory and anti-apoptotic properties. Therefore, both compounds can be recommended as hopeful adjuvant agents against brain neurodegeneration in diabetics.

Ulva lactuca polysaccharides prevent Wistar rat breast carcinogenesis through the augmentation of apoptosis, enhancement of antioxidant defense system, and suppression of inflammation.

BACKGROUND: Recently, several research studies have been focused on the isolation and function of the polysaccharides derived from different algal species, which revealed multiple biological activities such as antioxidant and antitumor activities. This study assesses the possible breast cancer chemopreventive properties of common seaweeds, sea lettuce, Ulva lactuca (ulvan) polysaccharides using in vitro bioassays on human breast cancer cell line (MCF-7) and an in vivo animal model of breast carcinogenesis. METHODS: Cytotoxic effect of ulvan polysaccharides on MCF-7 was tested in vitro. For an in vivo investigation, a single dose of 25 mg/kg body weight 7,12-dimethylbenz[a]anthracene (DMBA) and ulvan polysaccharides (50 mg/kg body weight every other day) for 10 weeks were administered orally to the Wistar rats. RESULTS: Deleterious histopathological alterations in breast tissues including papillary cyst adenoma and hyperplasia of ductal epithelial lining with intraluminal necrotic materials and calcifications were observed in the DMBA-administered group. These lesions were prevented in the DMBA-administered group treated with ulvan polysaccharides. The immunohistochemical sections depicted that the treatment of DMBA-administered rats with ulvan polysaccharides markedly increased the lowered pro-apoptotic protein, p53, and decreased the elevated anti-apoptotic marker, bcl2, expression in the breast tissue. The elevated lipid peroxidation and the suppressed antioxidant enzyme activities in DMBA-administered control were significantly prevented by the treatment with ulvan polysaccharides. The elevated levels of inflammatory cytokines tumor necrosis factor-α and nitric oxide were significantly ameliorated in DMBA-administered rats treated with ulvan polysaccharides as compared to DMBA-administered control. CONCLUSION: In conclusion, ulvan polysaccharides at the level of initiation and promotion might have potential chemopreventive effects against breast carcinogenesis. These preventive effects may be mediated through the augmentation of apoptosis, suppression of oxidative stress and inflammation, and enhancement of antioxidant defense system.

Cinnamaldehyde potentially attenuates gestational hyperglycemia in rats through modulation of PPARγ, proinflammatory cytokines and oxidative stress.

Cinnamon has a history of use for medicinal purposes and its major benefits have been linked to cinnamaldehyde. The present study aimed to investigate the hypoglycemic action of cinnamaldehyde against fatty-sucrosed diet/streptozotocin (FSD/STZ)-rat model of gestational diabetes. Female albino rats were divided into three groups. Group I fed with normal diet (ND) while group II and III were fed with FSD for eight weeks (five weeks pre-gestational and three weeks gestational). Rats of group III were administered with a daily oral dose of 20mg/kg cinnamaldehyde one week before mating onward. At the 7th day of gestation, FSD-fed rats were injected intraperitoneally with STZ (25mg/kg b.wt.) to induce gestational diabetes. Pre-mating treatment of cinnamaldehyde controls hyperphagia and glucose intolerance during the gestational period than in diabetic rats. It also reduced levels of fructosamine, total cholesterols, triglycerides, leptin, tumor necrosis factor-alpha (TNF-α), malondialdehyde (MDA) and nitric oxide (NO), while it significantly increased levels of high-density lipoprotein (HDL)-cholesterol, adiponectin, liver glycogen, reduced glutathione (GSH) and catalase activity at term pregnancy. In addition, cinnamaldehyde administration up-regulated the mRNA expression of peroxisome proliferated activated receptor-gamma (PPARγ) and also ameliorated the number of viable fetuses, implantation loss sites, fetal glucose and insulin levels. In conclusion, cinnamaldehyde has safe hypoglycemic action on gestational diabetes by potentiating insulin secretion and sensitivity through activating the antioxidant defense system, suppressing pro-inflammatory cytokines production, upregulating PPARγ gene expression and alleviating the reproductive performance.

Consumption of polyphenol-rich Morus alba leaves extract attenuates early diabetic retinopathy: the underlying mechanism.

PURPOSE: Beneficial effects of white mulberry against diabetes mellitus have been reported. However, the molecular mechanisms of how white mulberry can attenuate diabetic retinopathy remain poorly understood. Here, the mechanism underlying the protective effect of Morus alba leaves ethanolic extract on oxidative stress, inflammation, apoptosis, and angiogenesis in diabetic retinopathy was investigated. METHODS: Diabetes was induced by injection of streptozotocin. One week after, M. alba (100 mg/kg) was administrated to the rats daily for 16 weeks. RESULTS: Morus alba extract showed high content of polyphenolics and free radical scavenging activity. Oral M. alba administration significantly attenuated hyperglycemia and weight loss, and decreased sorbitol, fructose, protein kinase C, pro-inflammatory cytokines, and oxidative stress markers in retinas of the diabetic rats. Moreover, M. alba produced marked down-regulation of caspase-3 and Bax, with concomitant up-regulation of Bcl-2 in the diabetic retinas. M. alba also reduced the expression of VEGF in the retina. CONCLUSION: These results indicate that M. alba has protective effect on diabetic retinopathy with possible mechanisms of inhibiting hyperglycemia-induced oxidative stress, apoptosis, inflammation, polyol pathway activation, and VEGF expression in the retina.