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-1ß) 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.

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, 3ß-HSD, CYP17A1, and 17ß-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.

The Potential Protective Effect of Curcumin and α-Lipoic Acid on N-(4-Hydroxyphenyl) Acetamide-induced Hepatotoxicity Through Downregulation of α-SMA and Collagen III Expression.

BACKGROUND AND OBJECTIVES: N-(4-hydroxyphenyl) acetamide (NHPA) is the most commonly used analgesic and antipyretic agent worldwide; however, it remains the leading cause of drug-induced acute liver failure. This study explored the potential impact of curcumin (Curc) and/or α-lipoic acid (Lip acid) on liver damage induced by NHPA overdose. MATERIALS AND METHODS: Male Wistar rats were intoxicated with a single oral dose of NHPA (1000 mg/kg) and treated with Curc (200 mg/kg p. o.) and/or Lip acid (100 mg/kg i. p.). These treatments were given in 2 doses at 2 hours and 10 hours post-NHPA-administration. Animals were sacrificed 24 hours post-NHPA-administration. RESULTS: Treatment with Curc and/or Lip acid showed effective reduction of NHPA-induced liver injury, demonstrated by reducing serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, as well as hepatic nitric oxide and malondialdehyde. Curc and/or Lip acid treatments counteracted these changes. They also ameliorated NHPA-induced centrilobular hepatocellular necrosis, evidenced by histopathological examination. Moreover, Curc and Lip acid reduced the expression of alpha-smooth muscle actin and collagen III, upregulated by NHPA intoxication in response to oxidative stress and inflammation. DISCUSSION AND CONCLUSION: Curc and Lip acid can be considered as promising natural therapies against liver injury, induced by NHPA, through their antioxidant and antifibrotic actions.

Nano-Resveratrol: A Promising Candidate for the Treatment of Renal Toxicity Induced by Doxorubicin in Rats Through Modulation of Beclin-1 and mTOR.

Background: Although doxorubicin (DXR) is one of the most used anticancer drugs, it can cause life-threatening renal damage. There has been no effective treatment for DXR-induced renal damage until now. Aim: This work aims at examining the potential impact of nano-resveratrol (N-Resv), native resveratrol (Resv), and their combination with carvedilol (Card) against DXR-induced renal toxicity in rats and to investigate the mechanisms through which these antioxidants act to ameliorate DXR nephrotoxicity. Method: DXR was administered to rats (2 mg/kg, i.p.) twice weekly over 5 weeks. The antioxidants in question were taken 1 week before the DXR dose for 6 weeks. Results: DXR exhibited an elevation in serum urea, creatinine, renal lipid peroxide levels, endoglin expression, kidney injury molecule-1 (KIM-1), and beclin-1. On the other hand, renal podocin and mTOR expression and GSH levels were declined. In addition, DNA fragmentation was markedly increased in the DXR-administered group. Treatment with either Resv or N-Resv alone or in combination with Card ameliorated the previously measured parameters. Conclusion: N-Resv showed superior effectiveness relative to Resv in most of the measured parameters. Histopathological examination revealed amelioration of renal structural and cellular changes after DXR by Card and N-Resv, thus validating the previous biochemical and molecular results.

L-Ascorbic Acid and Curcumin Prevents Brain Damage Induced via Lead Acetate in Rats: Possible Mechanisms.

Lead acetate (lead ac.) is a widespread ecological toxicant that can cause marked neurotoxicity and decline in brain functions. This study aimed to evaluate the possible neuroprotective role of L-ascorbic acid (ASCR) and curcumin (CRCM) alone or together against lead ac.-induced neurotoxicity. Rats were injected with lead ac. then treated orally with ASCR and CRCM alone or in combination for 7 days. Lead ac. caused elevation in brain tumor necrosis factor-α, interleukin-6, caspase-3, and malondialdehyde levels, while superoxide dismutase, reduced glutathione as well as the expression of brain-derived neurotrophic factor, cAMP response element-binding, and Beclin1 were downregulated. Expressions of C/EBP homologous protein and mammalian Target of rapamycin kinase were upregulated in brain tissues matched with the control group. Histopathological examination supported the previously mentioned parameters, the administration of the antioxidants in question modulated all the altered previous parameters. The combination regimen achieved the superlative results in the antagonizing lead ac.-induced neurotoxicity via its antioxidant and antiapoptotic activities.

Curcumin and Nano-Curcumin Mitigate Copper Neurotoxicity by Modulating Oxidative Stress, Inflammation, and Akt/GSK-3ß 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-3ß. 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-3ß 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-3ß signaling. The neuroprotective effect of N-CUR was more potent than CUR.

Nano-Curcumin Prevents Cardiac Injury, Oxidative Stress and Inflammation, and Modulates TLR4/NF-κB and MAPK Signaling in Copper Sulfate-Intoxicated Rats.

Copper (Cu) is essential for a plethora of biological processes; however, its high redox reactivity renders it potentially toxic. This study investigated the protective effect of curcumin (CUR) and nano-CUR (N-CUR) against Cu cardiotoxicity, emphasizing the role of oxidative stress, TLR4/NF-κB and mitogen-activated protein kinase (MAPK) signaling and cell death in rats. Rats received 100 mg/kg copper sulfate (CuSO4), a pesticide used for repelling pests, and were concurrently treated with CUR or N-CUR for 7 days. Cu caused cardiac injury manifested by elevated serum cardiac troponin I (cTnI), creatine kinase (CK)-MB, and lactate dehydrogenase (LDH), as well as histopathological alterations. Cardiac malondialdehyde (MDA), NF-κB p65, TNF-α, and IL-6 were increased, and reduced glutathione (GSH), superoxide dismutase (SOD) and catalase were decreased in Cu-treated rats. CUR and N-CUR prevented cardiac tissue injury, decreased serum cTnI, CK-MB, and LDH, and cardiac MDA, NF-κB p65, TNF-α, and IL-6, and enhanced cellular antioxidants. CUR and N-CUR downregulated TLR4 and AP-1, and decreased the phosphorylation levels of p38 MAPK, JNK, and ERK1/2. In addition, CUR and N-CUR increased cardiac Bcl-2 and BAG-1, decreased Bax and caspase-3, and prevented DNA fragmentation. In conclusion, N-CUR prevents Cu cardiotoxicity by attenuating oxidative injury, inflammatory response, and apoptosis, and modulating TLR4/NF-κB and MAPK signaling. The cardioprotective effect of N-CUR was more potent than the native form.

Turmeric and vitamin C mitigate testicular atrophy induced by lead diacetate via regulation of GRP-78/17ß-HSD pathways in rat's model.

Occupational and ecological contacts to lead persist as a universal concern. Lead alters most of the physiological processes via enhancing oxidative stress. Thus, this study was purposed to assess the influence of turmeric (TMRC) and/or vitamin C (VIT-C) on Lead diacetate (Lead diAC)-induced testicular atrophy with an emphasis on oxidative stress, inflammation, BAX/STAR and GRP-78/17ß-HSD signalling. Rats were injected with Lead diAC and then treated with TMRC and/or VIT-C orally for 1 week. Lead diAC decreased serum testosterone and testicular glutathione levels. It also decreased superoxide dismutase activity. On the contrary, levels of malondialdehyde, tumour necrosis factor-α, IL-1ß and caspase-3 were increased. mRNA levels and protein expressions of GRP-78 and BAX were upregulated, while the expression of both steroidogenic acute regulatory protein and 17ß-HSD were downregulated. DNA fragmentation was increased as well. These changes were further confirmed by histopathological findings. Supplementation with TMRC and/or VIT-C ameliorated all of the above parameters. In Conclusion: TMRC or VIT-C specially in combination group prevents Lead diAC testicular damage via reduction of oxidative injury as well as inflammation, downregulation of GRP-78/BAX and upregulation of 17ß-HSD and STAR expression as well as improvement in the histological architecture of the testis.

Chitosan nanoparticles as a promising candidate for liver injury induced by 2-nitropropane: Implications of P53, iNOS, VEGF, PCNA, and CD68 pathways.

The current article was designed to assess the role of chitosan nanoparticles (CNPs) in the management of hepatic injury induced by the hepatocarcinogen 2-nitropropane (2-NP). Rats were divided into three groups. The first group served as a control, the second group was injected with 2-NP, while the third group was treated with CNPs 1 h before 2-NP injection every other day for 4 weeks. The 2-NP injection upregulated serum AST and ALT activities, as well as hepatic TNF- α, IL-6, and MDA levels and the expression of vascular endothelial growth factor (VEGF) and caspase-3, whereas GSH contents and SOD activity were decreased. Immunohistochemistry investigations revealed that the hepatic protein expression of collagen I, inducible nitric oxide synthetase, proliferating cell nuclear antigen, cluster of differentiation, and p53 were upregulated. hematoxylin and eosin (H&E) and Masson's trichrome stains supported the previous parameters, and CNPs ameliorated most of the previous biochemical parameters. CNPs achieved promising results in the limitation of 2-NP hepatotoxicity.

Antioxidant, antiapoptotic, and antifibrotic effects of the combination of liposomal resveratrol and carvedilol against doxorubicin-induced cardiomyopathy in rats.

The use of the cytotoxic antibiotic doxorubicin (DOXR) is limited by its dose-dependent cardiotoxicity. The aim of this study was to evaluate the cardioprotective effect of the combination of carvedilol (CARD) and liposomal resveratrol (LIPO RESV) against DOXR-induced cardiomyopathy in rats. The results of the present study showed that DOXR administration significantly increased heart weight/body weight ratio by 35.6%, creatine kinase-MB (CK-MB) by 40.6%, troponin-I levels by 85%, and decreased reduced glutathione level and superoxide dismutase activity by 47% and 52%, respectively compared to the control group. Moreover, cardiac caspase-3 protein expression was upregulated by 51.6% vs the control group. In contrast, treatment of DOXR-administered rats with CARD, RESV, or LIPO RESV and their combination for 6 weeks improved all the above-mentioned measured parameters. In conclusion, concomitant administration of CARD and LIPO RESV exerted additive pharmacological effects in some measured parameters against DOXR-induced cardiomyopathy and this may be a useful cardioprotective strategy.

Role of α-tocopherol and Lactobacillus plantarum in the alleviation of mercuric chloride-induced testicular atrophy in rat's model: Implication of molecular mechanisms.

The present work was aimed to evaluate the protective effects of alpha-tocopherol (α-toco) and/or Lactobacillus plantarum (LCB) against testicular atrophy induced by mercuric chloride (MCH). Rats were injected with 5 mg/kg MCH for 5 days consecutively, then treated with 100 mg/kg α-toco and 6 × 1010 CFU 1.8701/kg LCB alone or together for 3 weeks. The MCH elevated serum TNF-α, IL- 6, caspase-3, and testicular malondialdehyde. However, serum testosterone, dehydroepiandrosterone, testicular messenger RNA of a steroidogenic acute regulatory protein, 17-ß-hydroxysteroid dehydrogenase, 3ß-hydroxysteroid dehydrogenase, glutathione level, and superoxide dismutase activity were decreased. Protein expression of Nrf2 was downregulated whereas that of Bax and DNA fragmentation was upregulated in the testicular tissues. Treatment with α-toco and LCB ameliorated the deviated biochemical parameters and improved tissue injury. It was concluded that the combination of LCB and α-toco achieved promising results in the amelioration of MCH-induced testicular atrophy. Nrf2, Bax expressions, and DNA fragmentation are involved in the testicular atrophy induced by MCH.

Role of some natural anti-oxidants in the down regulation of Kim, VCAM1, Cystatin C protein expression in lead acetate-induced acute kidney injury.

BACKGROUND: Lead is a dangerous systemic toxicant and can provoke life-threatening renal injury. The plan of this study was to evaluate the potential impact of curcumin (CRMN) and L-ascorbic acid (L-ascb) alone or together to counteract lead acetate (Pb-acetate)-induced renal damage in rats and to find out the underlying mechanisms of action of these nutraceuticals. METHODS: Pb-acetate (100 mg/kg/day, i.p.) was injected in male rats along with L-ascb (250 mg/kg/day) and/or CRMN (200 mg/kg/day) orally for 7 days. RESULTS: Pb-acetate administration increased serum urea, creatinine and uric acid. Renal tissue showed a marked depletion in reduced glutathione level and superoxide dismutase activity and elevation in nitric oxide and malondialdehyde levels. Serum C-reactive protein and IL-1ß levels were elevated. Up-regulation of the expression of kidney injury molecule, vascular adhesion molecule-1 and Cystatin C were noticed after Pb-acetate administration. DNA fragmentation was also increased in renal tissues. Histopathological examination revealed a destructed partial layer of Bowman's capsule, proximal and distal convoluted tubules. Treatment with the aforementioned antioxidants ameliorated most of the altered measured biomarker levels. CONCLUSION: Interestingly, the combination of L-ascb and CRMN showed the superlative protective effect against Pb-acetate-induced nephrotoxicity.

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.

Prophylactic administration of carnosine and melatonin abates the incidence of apoptosis, inflammation, and DNA damage induced by titanium dioxide nanoparticles in rat livers.

Although titanium dioxide nanoparticles (TDO-ns) are extensively used in the food, medicine, and cosmetic industries, discussions about the possible hazards of nanomaterials are just beginning to emerge. This study aimed to detect the inflammatory stress, oxidative stress, and apoptotic cell death induced in the livers of rats exposed to TDO-ns (600 mg/kg, particle size ≤ 100 nm). Furthermore, the modulation of these toxic effects by two potent naturally occurring antioxidants, carnosine (Carno) or melatonin (Melato), was evaluated. The co-administration of carnosine or melatonin to rats intoxicated with TDO-ns significantly attenuated the increases in serum tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP), immunoglobulin G (IgG), vascular endothelial growth factor (VEGF), nitric oxide (NO), and alanine aminotransferase (ALT) levels. The two agents markedly ameliorated hepatic DNA damage and the alterations in hepatic malondialdehyde (MDA), glutathione (GSH), cytochrome P450, caspase-3, total phospholipid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, sphingomyelin, and triglyceride (TG) levels. These results support the use of Carno or Melato as prophylactic agents against TDO-ns-induced liver damage.

Carnosine and L-arginine attenuate the downregulation of brain monoamines and gamma aminobutyric acid; reverse apoptosis and upregulate the expression of angiogenic factors in a model of hemic hypoxia in rats.

PURPOSE: The purpose of the present study was to investigate the preventive effect of L-arginine (ARG) and carnosine (CAR) on hypoxia-induced neurotoxicity in rats. The impact on neuro-inflammation, apoptosis, angiogenesis, and the brain levels of monoamines and GABA were investigated. METHODS: Rats were divided into the following: normal control, hypoxia model induced by sodium nitrite (75 mg/kg s.c), and hypoxic rats pre-treated with CAR (250 mg/kg), ARG (200 mg/kg), and their combination. RESULTS: Data revealed that hypoxia induced significant elevation of hypoxia inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and its receptor reflecting the stimulation of angiogenesis. Hypoxia also resulted in increased inflammatory mediators-including nuclear factor kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6). In addition, hypoxia initiates cerebral apoptosis as revealed by increased caspase-3 and BAX with reduced Bcl-2. These changes were associated with reduced brain levels of GABA and monoamines including noradrenaline (NADR), dopamine (DOP), and serotonin (SER). Pre-treatment with ARG and/or CAR significantly mitigated the neural changes induced by hypoxia and attenuated the elevated levels of NF-κB, TNF-α, IL-6, caspase-3, and BAX, while ameliorated the reduced levels of Bcl-2, NADR, DOP, SER, and GABA, with the best improvement observed with the combination. Further elevation of the angiogenic markers was observed indicating their role in boosting oxygen delivery to brain. CONCLUSION: CAR, ARG, and, importantly, their combination could effectively protect against hypoxia-induced neurotoxicity, via their angiogenic, anti-inflammatory, and anti-apoptotic properties in addition to reversing the effect on GABA and monoamines.

Curcumin and Selenium Prevent Lipopolysaccharide/Diclofenac-Induced Liver Injury by Suppressing Inflammation and Oxidative Stress.

Diclofenac (DCL), an anti-inflammatory drug used to reduce pain and inflammation, ranks in the top causes of drug-induced liver injury. The inflammatory stress induced by inflammagens is implicated in DCL-induced liver injury. Curcumin (CUR) and selenium (Se) possess anti-inflammatory effects; therefore, this study evaluated their protective potential against lipopolysaccharide (LPS)/DCL-induced liver injury. Rats received CUR and/or Se for 7 days followed by a single intravenous administration of LPS 2 h before a single injection of DCL and two other doses of CUR and/or Se 2 and 8 h after DCL. Administration of nontoxic doses of LPS and DCL resulted in liver damage evidenced by the significantly elevated liver function markers in serum. LPS/DCL-induced liver injury was confirmed by histological alterations, increased lipid peroxidation and nitric oxide, and diminished glutathione and superoxide dismutase. CUR and/or Se prevented liver injury, histological alterations, and oxidative stress and boosted antioxidant defenses in LPS/DCL-induced rats. In addition, CUR and/or Se reduced serum C-reactive protein, liver pro-inflammatory cytokines, and the expression of TLR4, NF-κB, JNK, and p38, and upregulated heme oxygenase-1 (HO-1). In conclusion, CUR and/or Se mitigated LPS/DCL-induced liver injury in rats by suppressing TLR4 signaling, inflammation, and oxidative stress and boosting HO-1 and other antioxidants. Therefore, CUR and Se can hinder the progression and severity of liver injury during acute inflammatory episodes.

Arctium lappa Root Extract Prevents Lead-Induced Liver Injury by Attenuating Oxidative Stress and Inflammation, and Activating Akt/GSK-3ß Signaling.

Arctium lappa L (A. lappa) is a popular medicinal plant with promising hepatoprotective activity. This study investigated the protective effect of A. lappa root extract (ALRE) on lead (Pb) hepatotoxicity, pointing to its ability to modulate oxidative stress, inflammation, and protein kinase B/Akt/glycogen synthase kinase (GSK)-3ß signaling. Rats received 50 mg/kg lead acetate (Pb(Ac)2) and 200 mg/kg ALRE or vitamin C (Vit. C) for 7 days, and blood and liver samples were collected. Pb(Ac)2 provoked hepatotoxicity manifested by elevated serum transaminases and lactate dehydrogenase, and decreased total protein. Histopathological alterations, including distorted lobular hepatic architecture, microsteatotic changes, congestion, and massive necrosis were observed in Pb(II)-induced rats. ALRE ameliorated liver function and prevented all histological alterations. Pb(II) increased hepatic lipid peroxidation (LPO), nitric oxide (NO), caspase-3, and DNA fragmentation, and serum C-reactive protein, tumor necrosis factor-α, and interleukin-1ß. Cellular antioxidants, and Akt and GSK-3ß phosphorylation levels were decreased in the liver of Pb(II)-induced rats. ALRE ameliorated LPO, NO, caspase-3, DNA fragmentation and inflammatory mediators, and boosted antioxidant defenses in Pb(II)-induced rats. In addition, ALRE activated Akt and inhibited GSK-3ß in the liver of Pb(II)-induced rats. In conclusion, ALRE inhibits liver injury in Pb(II)-intoxicated rats by attenuating oxidative injury and inflammation, and activation of Akt/GSK-3ß signaling pathway.

Curcumin Ameliorates Lead-Induced Hepatotoxicity by Suppressing Oxidative Stress and Inflammation, and Modulating Akt/GSK-3ß 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-3ß 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-3ß 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-3ß 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-3ß. However, further studies scrutinizing the exact role of Akt/GSK-3ß signaling are recommended.

Mitigation of acetamiprid - induced renotoxicity by natural antioxidants via the regulation of ICAM, NF-kB and TLR 4 pathways.

BACKGROUND: Acetamiprid (ACMP) is a member of the neonicotinoid group of insecticides. It is extensively used worldwide. The misuse of ACMP creates danger hazards to human and animal. METHODS: ACMP induced renal damage evidenced by an increase in kidney injury biomarkers. So the goal of this work is to clarify the reno protective effect of Quercetin (Qrctn) and/or Nano-glutathione (N-Gluta) solely or in combination to counterbalance the danger effect of ACMP. All treatments with the previous agents were coadministered orally with ACMP for one month. RESULTS: ACMP ingestion caused a significant rise in serum creatinin, urea, and uric acid, TNF α along with renal cystatin C, lipid peroxidation and nitric oxide with the concomitant decline in the levels of reduced glutathione and IL-10 levels. Protein expression of ICAM was upregulated as well as mRNA expression of NF-κB while mRNA expression of Nrf2 was down-regulated. Immune histochemistry of TLR 4 revealed strong immune reaction. The administration of Qrctn or N-Gluta either individually or together modulated all the preceding aforementioned parameters. CONCLUSION: Fascinatingly Qrctn and N-Gluta combination was the most powerful regimen to frustrate ACMP reno-toxicity and may be deliberate as a hopeful applicant for renal therapy.

Inhibition of NF-κB and the oxidative stress -dependent caspase-3 apoptotic pathway by betaine supplementation attenuates hepatic injury mediated by cisplatin in rats.

BACKGROUND: Cisplatin is a major anti-cancer drug commonly used in the treatment of various cancers; nevertheless, the associated hepatotoxicity has limited its clinical application. The aim of this investigation is to test the impact of betaine supplementation on cisplatin-induced hepatotoxicity. METHODS: Animals were allocated into four groups; normal control group (control betaine group (250 mg/kg/day, po for twenty six days), cisplatin group (single injection of 7 mg/kg, ip) and betaine + cisplatin group (received betaine for twenty one days before cisplatin injection and daily after cisplatin for five days). RESULTS: Cisplatin-induced liver injury was confirmed by increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Cisplatin elevated lipid peroxides, and reduced the concentrations of reduced glutathione (GSH), glutathione peroxidase (GSH-Px), catalase and superoxide dismutase (SOD) in hepatic tissues. Cisplatin increased the inflammatory mediators; nitrite and tumor necrosis factor-α (TNF- α) in hepatic tissues. Increased gene expressions of the apoptotic marker, caspase-3 and nuclear factor-kappa B (NF-κB) were observed in hepatic tissues of cisplatin-treated rats. All these changes were further confirmed by histopathological findings in cisplatin group. Pre-treatment with betaine reduced serum aminotransferases (ALT and AST), and lowered hepatic concentrations of lipid peroxides, nitrite and TNF-α while increased SOD, GSH, catalase, and GSH-Px concentrations. Moreover, the histological and immunohistochemical changes were improved. CONCLUSION: The suppression of NF-κß-mediated inflammation, oxidative stress, and caspase-3 induced apoptosis are possible mechanisms to the observed hepatoprotective effect of betaine.