Reno-protective effect of nicorandil and pentoxifylline against potassium dichromate-induced acute renal injury via modulation p38MAPK/Nrf2/HO-1 and Notch1/TLR4/NF-κB signaling pathways.

BACKGROUND: Occupational and environmental exposure to chromium compounds such as potassium dichromate (PDC) (K2Cr2O7) has emerged as a potential aetiologic cause for renal disease through apoptotic, and inflammatory reactions. The known potent antioxidants such as nicorandil (NIC) and/or pentoxifylline (PTX) were studied for their possible nephroprotective effect in PDC-treated rats. METHODS: Forty male Wistar rats were divided into five groups; control, PDC group, NIC+PDC, PTX+PDC group, and combination+PDC group. Nephrotoxicity was evaluated histopathologically and biochemically. Invasive blood pressure, renal function parameters urea, creatinine, uric acid and albumin, glomerular filtration rate markers Cys-C, Kim-1 and NGAL, inflammatory markers IL-1ß, IL-6, TNF-α, TGF-ß, COX-II, p38MAPK, NF-κB and TLR4, oxidative stress SOD, GSH, MDA, MPO, HO-1 and Nrf2 and apoptotic mediators Notch1 and PCNA were evaluated. Besides, renal cortical histopathology was assayed as well. RESULTS: PDC led to a considerable increase in indicators for kidney injury, renal function parameters, invasive blood pressure, oxidative stress, and inflammatory markers. They were markedly reduced by coadministration of PDC with either/or NIC and PTX. The NIC and PTX combination regimen showed a more significant improvement than either medication used alone. Our results demonstrated the nephroprotective effect of NIC, PTX, and their combined regimen on PDC-induced kidney injury through suppression of oxidative stress, apoptosis, and inflammatory response. CONCLUSION: Renal recovery from PDC injury was achieved through enhanced MAPK/Nrf2/HO-1 and suppressed Notch1/TLR4/NF-κB signaling pathways. This study highlights the role of NIC and PTX as effective interventions to ameliorate nephrotoxicity in patients undergoing PDC toxicity.

Relationship between vitamin D and coronary artery disease in Egyptian patients.

BACKGROUND: Previous studies have reported conflicting results about the association of vitamin D (VD) level with coronary artery disease (CAD). We aimed to study the association of VD with atherosclerotic CAD in Egyptian individuals. RESULTS: We prospectively enrolled 188 consecutive CAD patients with a median age of 55(50-62) years; 151(80.3%) were male. All patients were diagnosed by cardiac catheterization and were compared with 131 healthy controls. VD levels were measured in serum samples of all participants. Compared to controls, CAD patients had a significantly lower median VD level, 14.65 (9.25-21.45) versus 42.0 (32.0-53.0) ng/mL, p < 0.001. VD was correlated with the number of diseased coronary arteries and lipid profile (total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides, p < 0.001 for each). By multivariate analyses, VD was an independent predictor of CAD [OR 1.22 (95% CI 1.07-1.4), p = 0.003, optimal cut-off value 30 ng/mL (AUC 0.92, sensitivity 81% and specificity 81.4%), p < 0.001], and the number of diseased coronary arteries, p < 0.001, especially three-vessel disease [OR 0.83 (95% CI 0.72-0.95), p = 0.008]. CONCLUSIONS: We have shown that low VD should be considered a non-traditional risk factor for CAD in Egyptian individuals. Low VD was correlated with coronary atherosclerosis, especially in patients with multivessel effects.

The teratogenic effect of pregabalin on heart, liver and kidney in rats: a light microscopic, electron microscopic and immunohistochemical study.

BACKGROUND: Pregabalin (PGB) was approved as new anti-epileptic drugs with little information about its teratogenic effect. AIM OF THE WORK: to evaluate the developmental toxicity of PGB. MATERIALS AND METHODS: 60 pregnant albino rats were divided into three groups. PGB (500 mg/kg body weight/day) was given to group II, PGB (1250 mg/kg body weight/day) was given to Group III and no medications were given to group I. The pups were normally delivered. Liver, kidney and heart specimens were prepared for histological, immunohistochemical, and morphometric studies. RESULTS: A dose of 500 mg of PGB had minimal toxic effects in the form of mild collagen deposition and moderate positive caspase-3 immunoexpression. PGB dose of 1250 mg/kg induced gross toxic effects in form of degenerated cardiac myofibres, ruptured blood vessels, vacuolations in the renal cortex, fibrosis and strong positive caspase-3 immunoexpression. CONCLUSION: PGB at dose of 500 mg/kg revealed minimal toxic changes. PGB cause embryotoxicity in a dose-dependent manner, as the higher dose induced more degenerative changes.

Naproxen as a potential candidate for promoting rivastigmine anti-Alzheimer activity against aluminum chloride-prompted Alzheimer's-like disease in rats; neurogenesis and apoptosis modulation as a possible underlying mechanism.

BACKGROUND AND AIM: Alzheimer's disease (AD) is one of the leading causes of dependence and disability among the elderly worldwide. The traditional anti-Alzheimer medication, rivastigmine, one of the cholinesterase inhibitors (ChEIs), fails to achieve a definitive cure. We tested the hypothesis that naproxen administration to the rivastigmine-treated aluminum chloride (AlCl3) Alzheimer's rat model could provide an additive neuroprotective effect compared to rivastigmine alone. MATERIALS AND METHODS: The studied groups were control (Cont), AlCl3 treated (Al), rivastigmine treated (RIVA), naproxen treated (Napro), and combined rivastigmine and naproxen treated (RIVA + Napro). Rats' memory, spatial learning, and cognitive behavior were assessed followed by evaluation of hippocampal acetylcholinesterase (AChE) activity. Hippocampal and cerebellar histopathology were thoroughly examined. Activated caspase-3 and the neuroepithelial stem cells marker; nestin expressions were immunohistochemically assayed. RESULTS: AD rats displayed significantly impaired memory and cognitive function, augmented hippocampal AChE activity; massive neurodegeneration associated with enhanced astrogliosis, apoptosis, and impaired neurogenesis. Except for the enhancement of neurogenesis and suppression of apoptosis, the combination therapy had no additional neuroprotective benefit over rivastigmine-only therapy. CONCLUSION: Naproxen's efficacy was established by its ability to function at the cellular level, improved neurogenesis, and decreased, apoptosis without having an additional mitigating impact on cognitive impairment in rivastigmine-treated AD rats.

Adipose tissue-derived mesenchymal stem cells reduce endometriosis cellular proliferation through their anti-inflammatory effects.

OBJECTIVE: Endometriosis is a chronic debilitating inflammatory condition characterized by the presence of endometrial tissues outside the uterine cavity. Pelvic soreness and infertility are the usual association. Due to the poor effectiveness of the hormone therapy and the high incidence of recurrence following surgical excision, there is no single effective option for management of endometriosis. Mesenchymal stem cells (MSCs) are multipotent stromal cells studied for their broad immunoregulatory and anti-inflammatory properties; however, their efficiency in endometriosis cases is still a controversial issue. Our study aim was to evaluate whether adipose tissue-derived MSCs (AD-MSCs) could help with endometriosis through their studied anti-inflammatory role. METHODS: Female Wistar rats weighting 180 to 250 g were randomly divided into two groups: group 1, endometriosis group; established by transplanting autologous uterine tissue into rats' peritoneal cavities and group 2, stem cell treated group; treated with AD-MSCs on the 5th day after induction of endometriosis. The proliferative activity of the endometriosis lesions was evaluated through Ki67 staining. Quantitative estimation of interferon γ, tumor necrosis factor-α, interleukin (IL)-6, IL-1ß, IL-10, and transforming growth factor ß expression, as well as immunohistochemical detection of CD68 positive macrophages, were used to assess the inflammatory status. RESULTS: The size and proliferative activity of endometriosis lesions were significantly reduced in the stem cell treated group. Stem cells efficiently mitigated endometriosis associated chronic inflammatory reactions estimated through reduction of CD68 positive macrophages and the expression of the proinflammatory cytokines. CONCLUSION: Stem cell therapy can be considered a novel remedy in endometriosis possibly through its anti-inflammatory and antiproliferative properties.

Valproate attenuates hypertonic glycerol-induced rhabdomyolysis and acute kidney injury.

BACKGROUND AND AIM: The current study investigated the effects of treatment with 300 mg/kg valproic acid on rhabdomyolysis and acute kidney injury induced by intramuscular injection of hypertonic glycerol in rats. METHODS: Four groups of male wistar rats: control and hypertonic glycerol, valproic acid and valproic acid + hypertonic glycerol treated groups were used. Blood urea nitrogen, serum creatinine, creatinine kinase (CK) and CK MB, myoglobin and renal reduced glutathione (GSH) levels were measured. Histopathological examination of the kidneys was carried out to evaluate the degree of renal injury in each group. The expression of interleukin-1 beta "IL-1ß" in renal tissue was detected using immunohistochemistry. RESULTS: Hypertonic glycerol administration led to severe renal tubular damage with a significant elevation of blood urea nitrogen, serum creatinine, creatinine kinase, CK MB and myoglobin levels and overexpression of IL-1ß compared to control group. Valproic acid administration attenuated both the muscle injury and the acute kidney injury induced by hypertonic glycerol, estimated through a significant reduction of creatinine kinase, myoglobin, and serum creatinine. Valproic acid administration caused a significant increase in GSH in the hypertonic glycerol + valproic acid group compared to the hypertonic glycerol group. A significant decrease in tubular necrosis grade, and expression of IL-1ß in hypertonic glycerol + valproic acid group compared to the hypertonic glycerol group was observed. CONCLUSION: This study demonstrates, for the first time to the best of our knowledge, that valproic acid could ameliorate the rhabdomyolysis and the related acute kidney injury in rats.

Lisofylline mitigates cardiac inflammation in a mouse model of obesity through improving insulin secretion and activating cardiac AMPK signaling pathway.

Obesity has emerged as a leading cause of death in the last few decades, mainly due to associated cardiovascular diseases. Obesity, inflammation, and insulin resistance are strongly interlinked. Lisofylline (LSF), an anti-inflammatory agent, demonstrated protection against type 1 diabetes, as well as reduced obesity-induced insulin resistance and adipose tissue inflammation. However, its role in mitigating cardiac inflammation associated with obesity is not well studied. Mice were divided into 4 groups; the first group was fed regular chow diet, the second was fed regular chow diet and treated with LSF, the third was fed high fat diet (HFD), and the fourth was fed HFD and treated with LSF. Cardiac inflammation was interrogated via expression levels of TNF α, interleukins 6 and 10, phosphorylated STAT4 and lipoxygenases 12 and 12/15. Apoptosis and expression of the survival gene, AMPK, were also evaluated. We observed that LSF alleviated obesity-induced cardiac injury indirectly by improving both pancreatic ß-cell function and insulin sensitivity, as well as, directly via upregulation of cardiac AMPK expression and downregulation of cardiac inflammation and apoptosis. LSF may represent an effective therapy targeting obesity-induced metabolic and cardiovascular complications.

The Novel Potential Therapeutic Utility of Montelukast in Alleviating Autistic Behavior Induced by Early Postnatal Administration of Thimerosal in Mice.

BACKGROUND AND AIM: Thimerosal (THIM) is a mercury-containing preservative widely used in many biological and medical products including many vaccines. It has been accused of being a possible etiological factor for some neurodevelopmental disorders such as autistic spectrum disorders (ASDs). In our study, the potential therapeutic effect of montelukast, a leukotriene receptor antagonist used to treat seasonal allergies and asthma, on THIM mice model (ASDs model) was examined. METHODOLOGY: Newborn mice were randomly distributed into three groups: (Group 1) Control (Cont.) group received saline injections. (Group 2) THIM-treated (THIM) group received THIM intramuscular (IM) at a dose of 3000 µg Hg/kg on postnatal days 7, 9, 11, and 15. (Group 3) Montelukast-treated (Monte) group received THIM followed by montelukast sodium (10 mg/kg/day) intraperitoneal (IP) for 3 weeks. Mice were evaluated for growth development, social interactions, anxiety, locomotor activity, and cognitive function. Brain histopathology, alpha 7 nicotinic acetylcholine receptors (α7nAChRs), nuclear factor kappa B p65 (NF-κB p65), apoptotic factor (Bax), and brain injury markers were evaluated as well. RESULTS: THIIM significantly impaired social activity and growth development. Montelukast mitigated THIM-induced social deficit probably through α7nAChRs upregulation, NF-κB p65, Bax, and brain injury markers downregulation, thus suppressing THIM-induced neuronal toxicity and inflammation. CONCLUSION: Neonatal exposure to THIM can induce growth retardation and abnormal social interactions similar to those observed in ASDs. Some of these abnormalities could be ameliorated by montelukast via upregulation of α7nAChRs that inhibited NF-κB activation and significant suppression of neuronal injury and the associated apoptosis.

Astaxanthin alleviates oxidative stress insults-related derangements in human vascular endothelial cells exposed to glucose fluctuations.

Glycemic fluctuations may play a critical role in the pathogenesis of diabetic complications, such as cardiovascular disease. We investigated whether the oxycarotenoid astaxanthin can reduce the detrimental effects of fluctuating glucose on vascular endothelial cells. Human umbilical venous endothelial cells were incubated for 3 days in media containing 5.5mM glucose, 22 mM glucose, or 5.5mM glucose alternating with 22 mM glucose in the absence or presence of astaxanthin or N-acetyl-L-cysteine (NAC). Constant high glucose increased reactive oxygen species (ROS) generation, but such an effect was more pronounced in fluctuating glucose. This was associated with up-regulated p22(phox) expression and down-regulated peroxisome proliferator activated receptor-γ coactivator (PGC-1α) expression. Astaxanthin inhibited ROS generation, p22(phox) up-regulation, and PGC-1α down-regulation by the stimuli of glucose fluctuation. Fluctuating glucose, but not constant high glucose, significantly decreased the endothelial nitric oxide synthase (eNOS) phosphorylation level at Ser-1177 without affecting total eNOS expression, which was prevented by astaxanthin as well as by the anti-oxidant NAC. Transferase-mediated dUTP nick end labeling (TUNEL) showed increased cell apoptosis in fluctuating glucose. Glucose fluctuation also resulted in up-regulating gene expression of pro-inflammatory mediators, interleukin-6 and intercellular adhesion molecule-1. These adverse changes were subdued by astaxanthin. The phosphorylation levels of c-Jun N-terminal kinase (JNK) and p38 were significantly increased by glucose fluctuations, and astaxanthin significantly inhibited the increase in JNK and p38 phosphorylation. Taken together, our results suggest that astaxanthin can protect vascular endothelial cells against glucose fluctuation by reducing ROS generation.