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

Nonpsychotropic plant cannabinoids, cannabidivarin (CBDV) and cannabidiol (CBD), activate and desensitize transient receptor potential vanilloid 1 (TRPV1) channels in vitro: potential for the treatment of neuronal hyperexcitability

Epilepsy is the most common neurological disorder, with over 50 million people worldwide affected. Recent evidence suggests that the transient receptor potential cation channel subfamily V member 1 (TRPV1) may contribute to the onset and progression of some forms of epilepsy. Since the two nonpsychotropic cannabinoids cannabidivarin (CBDV) and cannabidiol (CBD) exert anticonvulsant activity in vivo and produce TRPV1-mediated intracellular calcium elevation in vitro, we evaluated the effects of these two compounds on TRPV1 channel activation and desensitization and in an in vitro model of epileptiform activity. Patch clamp analysis in transfected HEK293 cells demonstrated that CBD and CBDV dose-dependently activate and rapidly desensitize TRPV1, as well as TRP channels of subfamily V type 2 (TRPV2) and subfamily A type 1 (TRPA1). TRPV1 and TRPV2 transcripts were shown to be expressed in rat hippocampal tissue. When tested on epileptiform neuronal spike activity in hippocampal brain slices exposed to a Mg2+-free solution using multielectrode arrays (MEAs), CBDV reduced both epileptiform burst amplitude and duration. The prototypical TRPV1 agonist, capsaicin, produced similar, although not identical effects. Capsaicin, but not CBDV, effects on burst amplitude were reversed by IRTX, a selective TRPV1 antagonist. These data suggest that CBDV antiepileptiform effects in the Mg2+-free model are not uniquely mediated via activation of TRPV1. However, TRPV1 was strongly phosphorylated (and hence likely sensitized) in Mg2+-free solution-treated hippocampal tissue, and both capsaicin and CBDV caused TRPV1 dephosphorylation, consistent with TRPV1 desensitization. We propose that CBDV effects on TRP channels should be studied further in different in vitro and in vivo models of epilepsy

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

Simvastatin mitigates diabetic nephropathy by upregulating farnesoid X receptor and Nrf2/HO-1 signaling and attenuating oxidative stress and inflammation in rats

Diabetic nephropathy is one of the complications of diabetes that affects the kidney and can result in renal failure. The cholesterol-lowering drug simvastatin (SIM) has shown promising effects against diabetic nephropathy (DN). This study evaluated the protective role of SIM on DN, pointing to the involvement of farnesoid X receptor (FXR) and Nrf2/HO-1 signaling in attenuating inflammatory response, oxidative injury, and tissue damage in streptozotocin-induced diabetic rats. SIM was supplemented orally for 8 weeks, and samples were collected for analysis. SIM effectively ameliorated hyperglycemia, kidney hypertrophy, body weight loss, and tissue injury and fibrosis in diabetic animals. SIM mitigated oxidative stress (OS), inflammatory response, and cell death, as evidenced by the suppressed malondialdehyde, nitric oxide, myeloperoxidase, NF-kB, TNF-α, IL-1β, CD68, Bax, and caspase-3 in the diabetic kidney. These effects were linked to suppressed Keap1, upregulated FXR, Nrf2, and HO-1, and enhanced antioxidant defenses and Bcl-2. The in silico findings revealed the binding affinity of SIM with NF-kB, caspase-3, Keap1, HO-1, and FXR. In conclusion, SIM protects against DN by attenuating hyperglycemia, kidney injury, fibrosis, inflammation, and OS, and upregulating antioxidants, FXR, and Nrf2/HO-1 signaling

Acetyl-L-Carnitine and Liposomal Co-Enzyme Q10 Attenuate Hepatic Inflammation, Apoptosis, and Fibrosis Induced by Propionic Acid

Propionic acid (PRA) is a metabolic end-product of enteric bacteria in the gut, and it is commonly used as a food preservative. Despite the necessity of PRA for immunity in the body, excessive exposure to this product may result in disruptive effects. The purpose of this study is to examine the hepatoprotective effects of acetyl-L-carnitine (A-CAR) and liposomal-coenzyme Q10 (L-CoQ10) against PRA-induced injury. Liver injury in rats was induced by oral administration of PRA, and A-CAR and L-CoQ10 were administered concurrently with PRA for 5 days. Oxidative stress, inflammatory, apoptotic, and fibrotic biomarkers were analyzed; the histology of liver tissue was assessed as well to further explore any pathological alterations. PRA caused significant increases in the levels of serum liver enzymes and hepatic oxidative stress, inflammatory, and apoptotic biomarker levels, along with histopathological alterations. Concurrent treatment with A-CAR and/or L-CoQ10 with PRA prevented tissue injury and decreased the levels of oxidative stress, proinflammatory cytokines, and apoptotic markers. Additionally, A-CAR and/or L-CoQ10 modulated the expression of high-mobility group box-1, cytokeratin-18, transforming growth factor-beta1, and SMAD3 in liver tissue. In conclusion, A-CAR and/or L-CoQ10 showed hepatoprotective efficacy by reducing oxidative stress, the inflammatory response, apoptosis, and fibrosis in liver tissue

In Situ Thermosensitive Mucoadhesive Nasal Gel Containing Sumatriptan: In Vitro and Ex Vivo Evaluations

The aim of this study was to develop a thermosensitive mucoadhesive (MA) in situ nasal gel for sumatriptan. A 3D response surface methodology (Design of Expert version 11) was employed to formulate nine different formulations. The Pluronic F-127 concentration (X1) and chitosan concentration (X2) were selected as independent factors. The formulas were studied in terms of pH, clarity, drug content, gelation temperature, gelation time, gel strength, MA strength, viscosity, % release after 5 h, and release kinetics. The optimized formulas were studied for % permeated after 5 h and stability in addition to previous tests. The study of the stability of the optimized formula was performed under accelerated conditions (40 ± 2 °C, 75 ± 5% RH) for 3 months. The outcomes of the optimized formula were a clear gel with a gelation temperature of 33 °C and a reasonable gelation time of less than one minute, and the release and permeation during 5 h were 40% and 50%, respectively. The formulated gel decreased the mucociliary clearance (MCC) and thus increased the retention time in the nasal cavity, resulting in enhancing SMT absorption, which could improve the drug efficacy

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-3β 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-α and DNA fragmentation were increased, whereas antioxidant defenses were diminished in the liver of Pb(II)-intoxicated rats. Pb(II) increased hepatic NF-κB and JNK phosphorylation and caspase-3 cleavage, whereas Akt and GSK-3β phosphorylation was decreased. CUR and/or AA ameliorated liver function, prevented tissue injury, and suppressed oxidative stress, DNA damage, NF-κB, JNK and caspase-3. In addition, CUR and/or AA activated Akt and inhibited GSK-3β 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-3β. However, further studies scrutinizing the exact role of Akt/GSK-3β signaling are recommended

Involvement of Nrf2, JAK and COX pathways in acetaminophen-induced nephropathy: Role of some antioxidants

Objectives: Acetaminophen (APAP)-induced nephrotoxicity is detrimental consequence for which there has not been a standardized therapeutic regimen. Although, N-acetylcysteine (NAC) is a well-known antidote used in APAP-induced hepatotoxicity, its benefit in nephrotoxicity caused by APAP is almost lacking. This study aimed to compare the possible protective effect of thymoquinone (TQ), curcumin (CR), and α-lipoic acid (α-LA), either in solo or in combination regimens with that of NAC against APAP-induced renal injury. Design and method: Rats were divided into nine groups; control group, APAP intoxicated group (1000 mg/kg; orally), and the remaining seven groups received, in addition to APAP, oral doses of NAC, TQ, CR, α-LA, CR plus TQ, TQ plus α-LA, or CR plus α-LA. The first dose of the aforementioned antioxidants was given 24 h before APAP, and then the second dose was given 2 h after APAP, whereas the last dose was given 10 h after administration of APAP. Results: Treatment with APAP elevated kidney markers like serum uric acid, urea, and creatinine. In addition, it increased the serum level of tumor necrosis factor alpha (TNF-α), interleukin-1beta (IL-1β) and thiobarbituric acid reactive species (TBARS). Also, the protein expression of renal janus kinase (JAK) and cyclooxygenase (COX)-2 were all upregulated by APAP. In contrast, the expression of Nrf2 and the renal levels of superoxide dismutase and glutathione were downregulated. Treatment with the indicated natural antioxidants resulted in amelioration of the aberrated parameters through exhibiting anti-inflammatory, antioxidant and free radical-scavenging effects with a variable degree. Conclusion: The combined administration of CR and TQ exerted the most potent protection against APAP-induced nephrotoxicity through its anti-inflammatory and free radical-scavenging effects (antioxidant) which were comparable to that of NAC-treatment

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)-α 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.</jats:p

Amelioration of the Protein Expression of Cox2, NFB, and STAT-3 by Some Antioxidants in the Liver of Sodium Fluoride–Intoxicated Rats

The present study aimed to explore the efficiency of N-acetyl cysteine (NACC) or thymoquinone (TMQ) alone or in combination in the downregulation of inflammatory molecule expression and decreasing hepatic injury in response to sodium fluoride (SF). Sodium fluoride upregulated serum alanine and aspartate transferases activities, tumor necrosis factor α and hepatic malondialdehyde and nitric oxide levels, and the expression of cyclooxygenase 2, nuclear factor κB cell, and signal transducer and activator of transcription 3. In contrast, hepatic glutathione level, superoxide dismutase activity, and nuclear factor erythroid 2-related factor 2 expression were decreased. However, the concurrent treatment with antioxidants, alone or in combination, modulated the levels of these parameters. Histopathological examination revealed that SF treatment resulted in focal areas of massive hepatic degeneration and many degenerated hepatocytes, whereas the treatment with TMQ or NACC exhibited moderate improvement in cellular degeneration of the liver with many abnormal cells. Rats receiving a combination of TMQ and NACC showed marked improvement in cellular degeneration of liver with apparently normal hepatic architecture with very few degenerated hepatocytes. The results also revealed that the combination of TMQ and NACC is the most effective regimen in ameliorating SF toxicity, suggesting their efficacy against the toxicity of fluoride compounds. Their activities might be mediated via multiple molecular pathways