Evaluation of Renal Gene Expression of Protein Kinase C (PKC) Isoforms in Diabetic and Nondiabetic Proliferative Glomerular Diseases

The protein kinase C (PKC) family consists of 13 members categorized as conventional or novel depending on whether diacylglycerol, calcium, or phosphatidylserine is required for activation. High glucose leads to activation of different forms of PKC across tissue types, thus determining the kind of diabetes-induced organ damage. PKC β was reported to have a positive role in B-lymphocyte activity through activation of NF-κB, leading to various immune disorders. We examined renal expression of two PKC isoforms α and β in renal biopsies of patients with diabetic nephropathy, lupus nephritis (LN) (Class 3-4), and mesangioproliferative glomerulonephritis (MPGN) to explore the role of each isoform in different glomerular diseases. PKC α and β gene expression was studied by quantitative real-time reverse transcription-PCR in 20 patients with type 2 diabetes and proteinuria (serum creatinine 2.04 ± 0.85 mg/dl, 24-h urinary protein 3.61 ± 1.75 g, eGFR 37.85 ± 17.89 ml/min/1.73 m2), 20 patients with proliferative LN (serum creatinine 1.67 ± 1.50 mg/dl, 24-h urinary protein 4.46 ± 5.01 g, eGFR 69.62 ± 40.93 ml/min/1.73 m2), and 20 patients with MPGN (serum creatinine 3.32 ± 2.79 mg/dl, 24-h urinary protein 4.65 ± 4.11 g, eGFR 32.62 ± 29.56 ml/min/1.73 m2). Normal tissues from the normal pole of four kidneys removed because of renal tumor served as controls. PKC α gene expression was significantly increased in diabetic kidneys compared to LN and MPGN (316.95 ± 152.94 µg/ml vs. 185.97 ± 32.13 and 195.46 ± 46.45 µg/ml, p < 0.05). PKC β gene expression was significantly increased in the LN and MPGN groups compared to the diabetic nephropathy group (41.01 ± 14.03 and 39.93 ± 16.41 µg/ml, respectively, vs. 18.20 ± 4.91 µg/ml, p < 0.05). Significant correlation was noted between the PKC α gene concentrations and proteinuria in diabetic patients. Renal expression of PKC α and β genes in control tissues were significantly lower compared to diabetic kidneys, LN, and MPGN groups (32.31 ± 0.36 and 4.67 ± 2.41 µg/ml, respectively, p < 0.001). The study revealed enhanced renal gene expression of both PKC isoforms α and β in diabetic kidney tissues, LN, and MPGN, but in different patterns. PKC α gene expression was significantly increased in diabetic patients with chronic kidney disease. The increased expression of the PKC β gene in LN and MPGN highlights its role in regulation of the immune system. This may represent potential therapeutic targets for prevention of progressive kidney injury in diabetic and proliferative glomerular diseases

Pulmonary prophylactic impact of melatonin and/or quercetin: A novel therapy for inflammatory hypoxic stress in rats

The study aims to compare, through histological and biochemical studies, the effects of quercetin, melatonin and their combination in regulation of immuno-inflammatory mediators and heat shock protein expressions in sodium nitrite induced hypoxia in rat lungs. The results revealed that NaNO2 injection caused a significant decrease in Hb in rats, while serum levels of TNF-α, IL-6 and CRP, VEGF and HSP70 were elevated compared to the control group. Administration of melatonin, quercetin or their combination before NaNO2 injection markedly reduced these parameters. Histopathological examination of the lung tissue supported these biochemical findings. The study suggests that melatonin and/or quercetin are responsible for lung tissue protection in hypoxia by downregulation of immuno-inflammatory mediators and heat shock protein expressions. Pre-treatment of hypoxic animals with a combination of melatonin and quercetin was effective in modulating most of the studied parameters to near-normal levels

Evaluation of Antiulcer and Cytotoxic Potential of the Leaf, Flower, and Fruit Extracts of Calotropis procera

Calotropis procera is traditionally used for treating many diseases including ulcers and tumors. It was thus deemed of interest to investigate and compare the antiulcer and cytotoxic activities of C. procera leaf, flower, and fruit extracts in an attempt to verify its traditional uses. Phytochemical studies on the fruits, flowers, and leaves of C. procera, collected from the desert of Saudi Arabia, led to the isolation of one new lignan 7′-methoxy-3′-O-demethyl-tanegool-9-O-β-D-glucopyranoside and five known compounds from the flowers, four compounds from leaves, and a flavonoid glycoside and a lignan glycoside from the fruits. The structures of compounds were determined by spectroscopic techniques. Ethanol extracts of the three parts of C. procera were evaluated for their antiulcer activity and we found that the leaf extract possessed a powerful antiulcer activity which could be considered as a promising drug candidate. All the extracts and the isolated compounds were evaluated for their cytotoxic activity against MCF-7, HCT-116, HepG-2, and A-549 human cancer cell lines. Compound 2 was highly active on all the cell lines, whereas compounds 5 and 11 were more selective on colon and liver cell lines. Compound 10 demonstrated a significant activity on liver and lung cancer cell lines

Curcumin and nano-curcumin mitigate copper neurotoxicity by modulating oxidative stress, inflammation, and akt/gsk-3β signaling

Copper (Cu) is essential for multiple biochemical processes, and copper sulphate (CuSO4) is a pesticide used for repelling pests. Accidental or intentional intoxication can induce multiorgan toxicity and could be fatal. Curcumin (CUR) is a potent antioxidant, but its poor systemic bioavailability is the main drawback in its therapeutic uses. This study investigated the protective effect of CUR and N-CUR on CuSO4-induced cerebral oxidative stress, inflammation, and apoptosis in rats, pointing to the possible involvement of Akt/GSK-3β. Rats received 100 mg/kg CuSO4 and were concurrently treated with CUR or N-CUR for 7 days. Cu-administered rats exhibited a remarkable increase in cerebral malondialdehyde (MDA), NF-κB p65, TNF-α, and IL-6 associated with decreased GSH, SOD, and catalase. Cu provoked DNA fragmentation, upregulated BAX, caspase-3, and p53, and decreased BCL-2 in the brain of rats. N-CUR and CUR ameliorated MDA, NF-κB p65, and pro-inflammatory cytokines, downregulated pro-apoptotic genes, upregulated BCL-2, and enhanced antioxidants and DNA integrity. In addition, both N-CUR and CUR increased AKT Ser473 and GSK-3β Ser9 phosphorylation in the brain of Cu-administered rats. In conclusion, N-CUR and CUR prevent Cu neurotoxicity by attenuating oxidative injury, inflammatory response, and apoptosis and upregulating AKT/GSK-3β signaling. The neuroprotective effect of N-CUR was more potent than CUR

Nano-curcumin prevents copper reproductive toxicity by attenuating oxidative stress and inflammation and improving Nrf2/HO-1 signaling and pituitary-gonadal axis in male rats

Copper is essential for several cellular processes and is an important catalytic factor for many proteins. However, excess copper can provoke oxidative stress and reproductive toxicity. This study evaluated the effect of liposomal nano-curcumin (N-CUR) and CUR on testicular oxidative injury, inflammation, and apoptosis, and altered steroidogenesis and Nrf2/HO-1 signaling induced by copper sulfate (CuSO4). Rats received CuSO4 and N-CUR or CUR via oral gavage for 7 days. CuSO4 induced histopathological changes and altered pituitary-gonadal axis manifested by decreased serum gonadotropins and testosterone. Testicular steroidogenesis genes (StAR, 3β-HSD, CYP17A1, and 17β-HSD) and androgen receptor (AR) were downregulated in rats that received CuSO4. N-CUR and CUR prevented testicular tissue injury, increased circulating FSH, LH, and testosterone, and upregulated testicular steroidogenesis genes and AR. Additionally, N-CUR and CUR decreased testicular MDA, NO, NF-κB, iNOS, TNF-α, Bax, and caspase-3 while enhanced Bcl-2, Nrf2, and the antioxidants GSH, HO-1, SOD, and catalase. In conclusion, N-CUR and CUR prevented CuSO4-induced reproductive toxicity in male rats by suppressing oxidative injury and inflammatory response and boosting steroidogenesis, sex hormones, and Nrf2/HO-1 signaling. N-CUR was more effective in ameliorating tissue injury, oxidative stress, inflammation, and apoptosis and enhancing steroidogenesis and Nrf2/HO-1 than the native form

Quercetin and Idebenone Ameliorate Oxidative Stress, Inflammation, DNA damage, and Apoptosis Induced by Titanium Dioxide Nanoparticles in Rat Liver

Titanium dioxide nanoparticles (TiO 2 -NPs) are extensively used in a wide range of applications; however, many reports have investigated their nanotoxicological effect at the molecular level either in vitro or in vivo systems. The defensive roles of quercetin (Qur) or idebenone (Id) against the hepatotoxicity induced by TiO 2 -NPs were evaluated in the current study. The results showed that the coadministration of Qur or Id to rats intoxicated with TiO 2 -NPs markedly ameliorated the elevation in hepatic malondialdehyde (MDA), serum alanine amino-transferase (ALT), glucose, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), immunoglobin G (IgG), and C-reactive protein (CRP) levels compared to their levels in TiO 2 -NPs-treated rats. The aforementioned antioxidants also effectively modulated the changes in the levels of serum vascular endothelial growth factor (VEGF), nitric oxide (NO), hepatic DNA breakage, caspase-3, and inhibition of drug metabolizing enzymes (cytochrome P450s; CYP4502E12E1) in rat livers induced by TiO 2 -NPs toxicity. The histopathological examination of the liver section showed that TiO 2 -NPs caused severe degeneration of most hepatocytes with an increase in collagen in the portal region, while treatment with the antioxidants in question improved liver architecture. These outcomes supported the use of Qur and Id as protective agents against the hepatotoxicity induced by TiO 2 -NPs and other hepatotoxic drugs

Liposomal Resveratrol and/or Carvedilol Attenuate Doxorubicin-Induced Cardiotoxicity by Modulating Inflammation, Oxidative Stress and S100A1 in Rats

Doxorubicin (DOX) is a cytotoxic anthracycline antibiotic and one of the important chemotherapeutic agents for different types of cancers. DOX treatment is associated with adverse effects, particularly cardiac dysfunction. This study examined the cardioprotective effects of carvedilol (CAR) and/or resveratrol (RES) and liposomal RES (LIPO-RES) against DOX-induced cardiomyopathy, pointing to their modulatory effect on oxidative stress, inflammation, S100A1 and sarco/endoplasmic reticulum calcium ATPase2a (SERCA2a). Rats received CAR (30 mg/kg) and/or RES (20 mg/kg) or LIPO-RES (20 mg/kg) for 6 weeks and were challenged with DOX (2 mg/kg) twice per week from week 2 to week 6. DOX-administered rats exhibited a significant increase in serum creatine kinase-MB (CK-MB), troponin-I and lactate dehydrogenase (LDH) along with histological alterations, reflecting cardiac cell injury. Cardiac toll-like receptor 4 (TLR-4), inducible nitric oxide synthase (iNOS), tumor necrosis factor (TNF)-&alpha; and interleukin (IL)-6 protein expression were up-regulated, and lipid peroxidation was increased in DOX-administered rats. Treatment with CAR, RES or LIPO-RES as well as their alternative combinations ameliorated all observed biochemical and histological alterations with the most potent effect exerted by CAR/LIPO-RES. All treatments increased cardiac antioxidants, and the expression of S100A1 and SERCA2a. In conclusion, the present study conferred new evidence on the protective effects of CAR and its combination with either RES or LIPO-RES on DOX-induced inflammation, oxidative stress and calcium dysregulation

Curcumin Ameliorates Lead-Induced Hepatotoxicity by Suppressing Oxidative Stress and Inflammation, and Modulating Akt/GSK-3β Signaling Pathway

Lead (Pb) is a toxic heavy metal pollutant with adverse effects on the liver and other body organs. Curcumin (CUR) is the principal curcuminoid of turmeric and possesses strong antioxidant and anti-inflammatory activities. This study explored the protective effect of CUR on Pb hepatotoxicity with an emphasis on oxidative stress, inflammation and Akt/GSK-3&beta; signaling. Rats received lead acetate and CUR and/or ascorbic acid (AA) for seven days and samples were collected for analyses. Pb(II) induced liver injury manifested by elevated serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH), as well as histopathological alterations, including massive hepatocyte degeneration and increased collagen deposition. Lipid peroxidation, nitric oxide, TNF-&alpha; and DNA fragmentation were increased, whereas antioxidant defenses were diminished in the liver of Pb(II)-intoxicated rats. Pb(II) increased hepatic NF-&kappa;B and JNK phosphorylation and caspase-3 cleavage, whereas Akt and GSK-3&beta; phosphorylation was decreased. CUR and/or AA ameliorated liver function, prevented tissue injury, and suppressed oxidative stress, DNA damage, NF-&kappa;B, JNK and caspase-3. In addition, CUR and/or AA activated Akt and inhibited GSK-3&beta; in Pb(II)-induced rats. In conclusion, CUR prevents Pb(II) hepatotoxicity via attenuation of oxidative injury and inflammation, activation of Akt and inhibition of GSK-3&beta;. However, further studies scrutinizing the exact role of Akt/GSK-3&beta; signaling are recommended