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Sample records for pacap ameliorates oxidative

  1. Influence of PACAP on oxidative stress and tissue injury following small-bowel autotransplantation.

    PubMed

    Ferencz, Andrea; Racz, Boglarka; Tamas, Andrea; Reglodi, Dora; Lubics, Andrea; Nemeth, Jozsef; Nedvig, Klara; Kalmar-Nagy, Karoly; Horvath, Ors Peter; Weber, Gyorgy; Roth, Erzsebet

    2009-02-01

    Tissue injury caused by cold preservation and reperfusion remains an unsolved problem during small-bowel transplantation. Pituitary adenylate cyclase-activating polypeptide (PACAP) is present and plays a central role in the intestinal physiology. This study investigated effect of PACAP-38 on the oxidative stress and tissue damage in autotransplanted intestine. Sham-operated, ischemia/reperfusion, and autotransplanted groups were established in Wistar rats. In ischemia/reperfusion groups, 1 h (group A), 2 h (group B), and 3 h (group C) ischemia followed by 3 h of reperfusion was applied. In autotransplanted groups, total orthotopic intestinal autotransplantation was performed. Grafts were preserved in University of Wisconsin (UW) solution and in UW containing 30 microg PACAP-38 for 1, 2, 3, and 6 h. Reperfusion lasted 3 h in all groups. Endogenous PACAP-38 concentration was measured by radioimmunoassay. To determine oxidative stress parameters, malondialdehyde, reduced glutathione, and superoxide dismutase were measured in tissue samples. Tissue damage was analyzed by qualitative and quantitative methods on hematoxylin/eosin-stained sections. Concentration of endogenous PACAP-38 significantly decreased in groups B and C compared to sham-operated group. Preservation solution containing PACAP-38 ameliorated bowel tissue oxidative injury induced by cold ischemia and reperfusion. Histological results showed that preservation caused destruction of the mucous, submucous, and muscular layers, which were further deteriorated by the end of reperfusion. In contrast, PACAP-38 significantly protected the intestinal structure. Ischemia/reperfusion decreased the endogenous PACAP-38 concentration in the intestinal tissue. Administration of PACAP-38 mitigated the oxidative injury and histological lesions in small-bowel autotransplantation model.

  2. Protective Effects of Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Against Oxidative Stress in Zebrafish Hair Cells.

    PubMed

    Kasica, Natalia; Podlasz, Piotr; Sundvik, Maria; Tamas, Andrea; Reglodi, Dora; Kaleczyc, Jerzy

    2016-11-01

    Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic neuropeptide, with known antiapoptotic functions. Our previous in vitro study has demonstrated the ameliorative role of PACAP-38 in chicken hair cells under oxidative stress conditions, but its effects on living hair cells is now yet known. Therefore, the aim of the present study was to investigate in vivo the protective role of PACAP-38 in hair cells found in zebrafish (Danio rerio) sense organs-neuromasts. To induce oxidative stress the 5-day postfertilization (dpf) zebrafish larvae were exposed to 1.5 mM H2O2 for 15 min or 1 h. This resulted in an increase in caspase-3 and p-38 MAPK level in the hair cells as well as in an impairment of the larvae basic behavior. To investigate the ameliorative role of PACAP-38, the larvae were incubated with a mixture of 1.5 mM H2O2 and 100 nM PACAP-38 following 1 h preincubation with 100 nM PACAP-38 only. PACAP-38 abilities to prevent hair cells from apoptosis were investigated. Whole-mount immunohistochemistry and confocal microscopy analyses revealed that PACAP-38 treatment decreased the cleaved caspase-3 level in the hair cells, but had no influence on p-38 MAPK. The analyses of basic locomotor activity supported the protective role of PACAP-38 by demonstrating the improvement of the fish behavior after PACAP-38 treatment. In summary, our in vivo findings demonstrate that PACAP-38 protects zebrafish hair cells from oxidative stress by attenuating oxidative stress-induced apoptosis.

  3. Presence of endogenous PACAP-38 ameliorated intestinal cold preservation tissue injury.

    PubMed

    Ferencz, Andrea; Weber, Gyorgy; Helyes, Zsuzsanna; Hashimoto, Hitoshi; Baba, Akemichi; Reglodi, Dora

    2010-11-01

    Cold preservation tissue injury remains an unsolved problem during small intestinal transplantation. Pituitary adenylate cyclase-activating polypeptide (PACAP) plays a central role in the intestinal physiology. The aim of our study was to compare the cold ischemic injury in wild-type and PACAP-38 deficient mice after small bowel cold storage. Cold ischemia was produced with small bowel preservation in a University of Wisconsin solution at 4°C in wild-type (n = 35) mice for 1 h (GI), for 3 h (GII), and for 6 h (GIII); and in PACAP-38 deficient (n = 35) mice for 1 h (GIV), for 3 h (GV), and for 6 h (GVI). Small bowel biopsies were collected after laparotomy (Control) and at the end of the ischemia periods. To determine oxidative stress parameters, malondialdehyde (MDA), reduced glutathione (GSH), and superoxide dismutase (SOD) were measured. Tissue damage was analyzed by qualitative and quantitative methods on hematoxylin/eosin-stained sections. In PACAP-38 deficient animals, tissue lipid peroxidation was elevated. These changes were significant after 6 h (153.04 ± 7.2) compared to sham-operated (110.44 ± 5.5) and compared to wild-type results (120.0 ± 1.1 µmol/g, p < 0.05). Meanwhile, the capacity and activity of the endogenous antioxidant system decreased significantly after 3 and 6 h preservation (GSH: 808.7 ± 5.2; 720.4 ± 8.7 vs. 910.4 ± µmol/g; SOD: 125.1 ± 1.4; 103.3 ± 1.9 vs. 212.11 ± 5.8 IU/g). Qualitative and quantitative histological results showed destruction of the mucous, submucous layers, and crypts in PACAP-38 deficient mice compared to wild-type tissues. These processes depended on the time of the cold preservation periods. Our present study showed that the presence of PACAP-38 in the small bowel tissue has a key role in the protection against intestinal cold preservation injury.

  4. The induction of nitric oxide-mediated relaxation of human isolated pulmonary arteries by PACAP

    PubMed Central

    Cardell, Lars Olaf; Hjert, Ola; Uddman, Rolf

    1997-01-01

    The effects of pituitary adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP) were analysed in human isolated circular segments of pulmonary arteries. Guinea-pig pulmonary arteries were used for comparison. The responses obtained were analysed in relation to the vascular endothelium and the nitric oxide (NO) synthase inhibitor NG-monomethyl L-arginine (L-NMMA).PACAP and VIP induced concentration-dependent relaxations of precontracted pulmonary arteries. The maximal dilator response (Imax,%) and the potency (pEC50 value) were the same for both peptides, and there were no differences in the effects obtained on human and guinea-pig segments. PACAP and VIP were both more potent that acetylcholine (ACh).Removal of the vascular endothelium abolished the PACAP induced dilator response in pulmonary arteries from both species. The VIP induced dilatation was unaffected, whereas the response to ACh was abolished. L-NMMA given before PACAP inhibited the dilatation. Furthermore, L-NMMA also reversed the dilatation already induced by PACAP and excess concentrations of L-arginine restored the dilator response of the L-NMMA treated arteries.PACAP is a potent dilator of human pulmonary arteries. Although the dilator effect seems to be similar in amplitude to the one induced by VIP, the present results suggest differences in the underlying mechanisms of action (endothelium-dependency) between the two peptides. PMID:9134222

  5. Rapid tachyphylaxis to hemodynamic effects of PACAP-27 after inhibition of nitric oxide synthesis

    NASA Technical Reports Server (NTRS)

    Whalen, E. J.; Travis, M. D.; Johnson, A. K.; Lewis, S. J.

    1999-01-01

    The vasodilator effects of pituitary adenylate cyclase-activating polypeptide (PACAP)-27 are subject to tachyphylaxis in rats treated with the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME). We examined whether this tachyphylaxis could be prevented by administration of the putative endothelium-derived nitrosyl factor S-nitroso-L-cysteine (L-SNC) and whether L-SNC may exert its effects via increases in cGMP levels in vascular smooth muscle. Five doses of PACAP-27 (2 nmol/kg iv) produced pronounced vasodilator responses in saline-treated rats. These responses were not subject to tachyphylaxis. The first injection of PACAP-27 (2 nmol/kg iv) in L-NAME-treated (50 micromol/kg iv) rats produced vasodilator responses similar to those in saline-treated rats, whereas subsequent injections produced progressively smaller responses. The injection of L-SNC (1,200 nmol/kg iv) before each injection of PACAP-27 prevented tachyphylaxis to the Gs protein-coupled receptor agonist in L-NAME-treated rats, whereas equihypotensive doses of the NO donor sodium nitroprusside (100 micrograms/kg iv) did not. The injection of the membrane-permeant cGMP analog 8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphate (8-CPT-cGMP; 30 micromol/kg iv) to L-NAME-treated rats restored resting hemodynamic values to pre-L-NAME levels but did not prevent the development of tachyphylaxis to PACAP-27. These results suggest that nitrosyl factors prevent the development of tachyphylaxis to the hemodynamic actions of PACAP-27. These nitrosyl factors may act independently of their ability to generate cGMP in vascular smooth muscle.

  6. Nitric oxide and receptors for VIP and PACAP in cutaneous active vasodilation during heat stress in humans.

    PubMed

    Kellogg, Dean L; Zhao, Joan L; Wu, Yubo; Johnson, John M

    2012-11-01

    VPAC2 receptors sensitive to vasoactive intestinal polypeptide (VIP) and pituitary adenylyl cyclase activating polypeptide (PACAP), PAC1 receptors sensitive to PACAP, and nitric oxide (NO) generation by NO synthase (NOS) are all implicated in cutaneous active vasodilation (AVD) through incompletely defined mechanisms. We hypothesized that VPAC2/PAC1 receptor activation and NO are synergistic and interdependent in AVD and tested our hypothesis by examining the effects of VPAC2/PAC1 receptor blockade with and without NOS inhibition during heat stress. The VPAC2/PAC1 antagonist, pituitary adenylate cyclase activating peptide 6-38 (PACAP6-38) and the NOS inhibitor, N(G)-nitro-l-arginine methyl ester (l-NAME) were administered by intradermal microdialysis. PACAP6-38, l-NAME, a combination of PACAP6-38 and l-NAME, or Ringer's solution alone were perfused at four separate sites. Skin blood flow was monitored by laser-Doppler flowmetry at each site. Body temperature was controlled with water-perfused suits. Blood pressure was monitored by Finapres, and cutaneous vascular conductance (CVC) calculated (CVC = laser-Doppler flowmetry/mean arterial pressure). The protocol began with a 5- to 10-min baseline period without antagonist perfusion, followed by perfusion of PACAP6-38, l-NAME, or combined PACAP6-38 and l-NAME at the different sites in normothermia (45 min), followed by 3 min of whole body cooling. Whole body heating was then performed to induce heat stress and activate AVD. Finally, 58 mM sodium nitroprusside were perfused at all sites to effect maximal vasodilation for normalization of blood flow data. No significant differences in CVC (normalized to maximum) were found among Ringer's PACAP6-38, l-NAME, or combined antagonist sites during normothermia (P > 0.05 among sites) or cold stress (P > 0.05 among sites). CVC responses at all treated sites were attenuated during AVD (P < 0.05 vs. Ringer's). Attenuation was greater at l-NAME and combined PACAP6-38- and l

  7. PACAP stimulation of maturational gonadotropin secretion in goldfish involves extracellular signal-regulated kinase, but not nitric oxide or guanylate cyclase, signaling.

    PubMed

    Chang, John P; Sawisky, Grant R; Mitchell, Gabriel; Uretsky, Aubrey D; Kwong, Patrick; Grey, Caleb L; Meints, Amanda N; Booth, Morgan

    2010-01-01

    In goldfish, nitric oxide synthase (NOS) immunoreactivity is present in gonadotropes and extracellular signal-regulated protein kinase (ERK) mediates GnRH stimulation of gonadotropin release and synthesis. In this study, we tested the possible involvement of nitric oxide (NO) and ERK in mediating PACAP-stimulated maturational gonadotropin (GTH-II) release from primary cultures of dispersed goldfish pituitary cells. In static incubation experiments, PACAP-induced GTH-II release was unaffected by two inhibitors of NOS synthase, AGH and 1400W; whereas addition of a NO donor, SNAP, elevated GTH-II secretion. In perifusion experiments, neither NOS inhibitors (AGH, 1400W and 7-Ni) nor NO scavengers (PTIO and rutin hydrate) attenuated the GTH-II response to pulse applications of PACAP. In addition, the GTH-II responses to PACAP and the NO donor SNP were additive while PTIO blocked SNP action. Although dibutyryl cGMP increased GTH-II secretion in static incubation, inhibition of guanylate cyclase (GC), a known down-stream target for NO signaling, did not reduce the GTH-II response to pulse application of PACAP. On the other hand, GTH-II responses to PACAP in perifusion were attenuated in the presence of two inhibitors of ERK kinase (MEK), U 0126 and PD 98059. These results suggest that although increased availability of NO and cGMP can lead to increased GTH-II secretion, MEK/ERK signaling, rather than NOS/NO/GC activation, mediates PACAP action on GTH-II release in goldfish.

  8. Ameliorative Effects of PACAP against Cartilage Degeneration. Morphological, Immunohistochemical and Biochemical Evidence from in Vivo and in Vitro Models of Rat Osteoarthritis

    PubMed Central

    Giunta, Salvatore; Castorina, Alessandro; Marzagalli, Rubina; Szychlinska, Marta Anna; Pichler, Karin; Mobasheri, Ali; Musumeci, Giuseppe

    2015-01-01

    Osteoarthritis (OA); the most common form of degenerative joint disease, is associated with variations in pro-inflammatory growth factor levels, inflammation and hypocellularity resulting from chondrocyte apoptosis. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide endowed with a range of trophic effects in several cell types; including chondrocytes. However; its role in OA has not been studied. To address this issue, we investigated whether PACAP expression is affected in OA cartilage obtained from experimentally-induced OA rat models, and then studied the effects of PACAP in isolated chondrocytes exposed to IL-1β in vitro to mimic the inflammatory milieu of OA cartilage. OA induction was established by histomorphometric and histochemical analyses. Changes in PACAP distribution in cartilage, or its concentration in synovial fluid (SF), were assessed by immunohistochemistry and ELISA. Results showed that PACAP abundance in cartilage tissue and SF was high in healthy controls. OA induction decreased PACAP levels both in affected cartilage and SF. In vitro, PACAP prevented IL-1β-induced chondrocyte apoptosis, as determined by MTT assay; Hoechst staining and western blots of apoptotic-related proteins. These changes were also accompanied by decreased i-NOS and COX-2 levels, suggesting an anti-inflammatory effect. Altogether, these findings support a potential role for PACAP as a chondroprotective agent for the treatment of OA. PMID:25782157

  9. Ameliorative effects of PACAP against cartilage degeneration. Morphological, immunohistochemical and biochemical evidence from in vivo and in vitro models of rat osteoarthritis.

    PubMed

    Giunta, Salvatore; Castorina, Alessandro; Marzagalli, Rubina; Szychlinska, Marta Anna; Pichler, Karin; Mobasheri, Ali; Musumeci, Giuseppe

    2015-03-13

    Osteoarthritis (OA); the most common form of degenerative joint disease, is associated with variations in pro-inflammatory growth factor levels, inflammation and hypocellularity resulting from chondrocyte apoptosis. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide endowed with a range of trophic effects in several cell types; including chondrocytes. However; its role in OA has not been studied. To address this issue, we investigated whether PACAP expression is affected in OA cartilage obtained from experimentally-induced OA rat models, and then studied the effects of PACAP in isolated chondrocytes exposed to IL-1β in vitro to mimic the inflammatory milieu of OA cartilage. OA induction was established by histomorphometric and histochemical analyses. Changes in PACAP distribution in cartilage, or its concentration in synovial fluid (SF), were assessed by immunohistochemistry and ELISA. Results showed that PACAP abundance in cartilage tissue and SF was high in healthy controls. OA induction decreased PACAP levels both in affected cartilage and SF. In vitro, PACAP prevented IL-1β-induced chondrocyte apoptosis, as determined by MTT assay; Hoechst staining and western blots of apoptotic-related proteins. These changes were also accompanied by decreased i-NOS and COX-2 levels, suggesting an anti-inflammatory effect. Altogether, these findings support a potential role for PACAP as a chondroprotective agent for the treatment of OA.

  10. Pituitary Adenylate Cyclase-Activating Polypeptide Ameliorates Experimental Acute Ileitis and Extra-Intestinal Sequelae

    PubMed Central

    Schulze, Silvia; Fischer, André; Grundmann, Ursula; Alutis, Marie; Kühl, Anja A.; Tamas, Andrea; Toth, Gabor; Dunay, Miklos P.; Göbel, Ulf B.; Reglodi, Dora; Bereswill, Stefan

    2014-01-01

    Background The neuropeptide Pituitary adenylate cyclase-activating polypeptide (PACAP) plays pivotal roles in immunity and inflammation. So far, potential immune-modulatory properties of PACAP have not been investigated in experimental ileitis. Methodology/Principal Findings Mice were perorally infected with Toxoplasma (T.) gondii to induce acute ileitis (day 0) and treated daily with synthetic PACAP38 from day 1 to 6 post infection (p.i.; prophylaxis) or from day 4 to 6 p.i. (therapy). Whereas placebo-treated control mice suffered from acute ileitis at day 7 p.i. and succumbed to infection, intestinal immunopathology was ameliorated following PACAP prophylaxis. PACAP-treated mice exhibited increased abundance of small intestinal FOXP3+ cells, but lower numbers of ileal T lymphocytes, neutrophils, monocytes and macrophages, which was accompanied by less ileal expression of pro-inflammatory cytokines such as IL-23p19, IL-22, IFN-γ, and MCP-1. Furthermore, PACAP-treated mice displayed higher anti-inflammatory IL-4 concentrations in mesenteric lymph nodes and liver and higher systemic anti-inflammatory IL-10 levels in spleen and serum as compared to control animals at day 7 p.i. Remarkably, PACAP-mediated anti-inflammatory effects could also be observed in extra-intestinal compartments as indicated by reduced pro-inflammatory mediator levels in spleen (TNF-α, nitric oxide) and liver (TNF-α, IFN-γ, MCP-1, IL-6) and less severe histopathological sequelae in lungs and kidneys following prophylactic PACAP treatment. Strikingly, PACAP prolonged survival of T. gondii infected mice in a time-of-treatment dependent manner. Conclusion/Significance Synthetic PACAP ameliorates acute small intestinal inflammation and extra-intestinal sequelae by down-regulating Th1-type immunopathology, reducing oxidative stress and up-regulating anti-inflammatory cytokine responses. These findings provide novel potential treatment options of inflammatory bowel diseases. PMID:25238233

  11. CGRP and Migraine: Could PACAP Play a Role Too?

    PubMed Central

    Kaiser, Eric A.; Russo, Andrew F.

    2013-01-01

    Migraine is a debilitating neurological disorder that affects about 12% of the population. In the past decade, the role of the neuropeptide calcitonin gene-related peptide (CGRP) in migraine has been firmly established by clinical studies. CGRP administration can trigger migraines, and CGRP receptor antagonists ameliorate migraine. In this review, we will describe multifunctional activities of CGRP that could potentially contribute to migraine. These include roles in light aversion, neurogenic inflammation, peripheral and central sensitization of nociceptive pathways, cortical spreading depression, and regulation of nitric oxide production. Yet clearly there will be many other contributing genes that could act in concert with CGRP. One candidate is pituitary adenylate cyclase-activating peptide (PACAP), which shares some of the same actions as CGRP, including the ability to induce migraine in migraineurs and light aversive behavior in rodents. Interestingly, both CGRP and PACAP act on receptors that share an accessory subunit called receptor activity modifying protein-1 (RAMP1). Thus, comparisons between the actions of these two migraine-inducing neuropeptides, CGRP and PACAP, may provide new insights into migraine pathophysiology. PMID:24210136

  12. Neuroprotection by endogenous and exogenous PACAP following stroke☆

    PubMed Central

    Chen, Yun; Samal, Babru; Hamelink, Carol R.; Xiang, Charlie C.; Chen, Yong; Chen, Mei; Vaudry, David; Brownstein, Michael J.; Hallenbeck, John M.; Eiden, Lee E.

    2014-01-01

    We investigated the effects of PACAP treatment, and endogenous PACAP deficiency, on infarct volume, neurological function, and the cerebrocortical transcriptional response in a mouse model of stroke, middle cerebral artery occlusion (MCAO). PACAP-38 administered i.v. or i.c. v. 1 h after MCAO significantly reduced infarct volume, and ameliorated functional motor deficits measured 24 h later in wild-type mice. Infarct volumes and neurological deficits (walking faults) were both greater in PACAP-deficient than in wild-type mice, but treatment with PACAP reduced lesion volume and neurological deficits in PACAP-deficient mice to the same level of improvement as in wild-type mice. A 35,546-clone mouse cDNA microarray was used to investigate cortical transcriptional changes associated with cerebral ischemia in wild-type and PACAP-deficient mice, and with PACAP treatment after MCAO in wild-type mice. 229 known (named) transcripts were increased (228) or decreased (1) in abundance at least 50% following cerebral ischemia in wild-type mice. 49 transcripts were significantly up-regulated only at 1 h post- MCAO (acute response transcripts), 142 were up-regulated only at 24 h post-MCAO (delayed response transcripts) and 37 transcripts were up- regulated at both times (sustained response transcripts). More than half of these are transcripts not previously reported to be altered in ischemia. A larger percentage of genes up-regulated at 24 hr than at 1 hr required endogenous PACAP, suggesting a more prominent role for PACAP in later response to injury than in the initial response. This is consistent with a neuroprotective role for PACAP in late response to injury, i.e., even when administered 1 hr or more after MCAO. Putative injury effector transcripts regulated by PACAP include β-actin, midline 2, and metallothionein 1. Potential neuroprotective transcripts include several demonstrated to be PACAP-regulated in other contexts. Prominent among these were transcripts encoding the

  13. PACAP38 increases vesicular monoamine transporter 2 (VMAT2) expression and attenuates methamphetamine toxicity

    PubMed Central

    Guillot, TS; Richardson, JR; Wang, MZ; Li, YJ; Taylor, TN; Ciliax, BJ; Zachrisson, O; Mercer, A; Miller, GW

    2008-01-01

    Pituitary adenylyl cyclase activating polypeptide, 38 amino acids (PACAP38) is a brain-gut peptide with diverse physiological functions and is neuroprotective in several models of neurological disease. In this study, we show that systemic administration of PACAP38, which is transported across the blood-brain barrier, greatly reduces the neurotoxicity of methamphetamine (METH). Mice treated with PACAP38 exhibited an attenuation of striatal dopamine loss after METH exposure as well as greatly reduced markers of oxidative stress. PACAP38 treatment also prevented striatal neuroinflammation after METH administration as measured by overexpression of glial fibrillary acidic protein (GFAP), an indicator of astrogliosis, and glucose transporter 5 (GLUT5), a marker of microgliosis. In PACAP38 treated mice, the observed protective effects were not due to an altered thermal response to METH. Since the mice were not challenged with METH until 28 days after PACAP38 treatment, this suggests the neuroprotective effects are mediated by regulation of gene expression. At the time of METH administration, PACAP38 treated animals exhibited a preferential increase in the expression and function of the vesicular monoamine transporter (VMAT2). Genetic reduction of VMAT2 has been shown to increase the neurotoxicity of METH, thus we propose that the increased expression of VMAT2 may underlie the protective actions of PACAP38 against METH. The ability of PACAP38 to increase VMAT2 expression suggests that PACAP38 signaling pathways may constitute a novel therapeutic approach to treat and prevent disorders of dopamine storage. PMID:18533255

  14. PACAP and VIP signaling in chondrogenesis and osteogenesis.

    PubMed

    Juhász, Tamás; Helgadottir, Solveig Lind; Tamás, Andrea; Reglődi, Dóra; Zákány, Róza

    2015-04-01

    Skeletal development is a complex process regulated by multifactorial signaling cascades that govern proper tissue specific cell differentiation and matrix production. The influence of certain regulatory peptides on cartilage or bone development can be predicted but are not widely studied. In this review, we aimed to assemble and overview those signaling pathways which are modulated by PACAP and VIP neuropeptides and are involved in cartilage and bone formation. We discuss recent experimental data suggesting broad spectrum functions of these neuropeptides in osteogenic and chondrogenic differentiation, including the canonical downstream targets of PACAP and VIP receptors, PKA or MAPK pathways, which are key regulators of chondro- and osteogenesis. Recent experimental data support the hypothesis that PACAP is a positive regulator of chondrogenesis, while VIP has been reported playing an important role in the inflammatory reactions of surrounding joint tissues. Regulatory function of PACAP and VIP in bone development has also been proved, although the source of the peptides is not obvious. Crosstalk and collateral connections of the discussed signaling mechanisms make the system complicated and may obscure the pure effects of VIP and PACAP. Chondro-protective properties of PACAP during oxidative stress observed in our experiments indicate a possible therapeutic application of this neuropeptide.

  15. Increased behavioral and neuronal responses to a hallucinogenic drug in PACAP heterozygous mutant mice.

    PubMed

    Hazama, Keisuke; Hayata-Takano, Atsuko; Uetsuki, Kazuki; Kasai, Atsushi; Encho, Naoki; Shintani, Norihito; Nagayasu, Kazuki; Hashimoto, Ryota; Reglodi, Dora; Miyakawa, Tsuyoshi; Nakazawa, Takanobu; Baba, Akemichi; Hashimoto, Hitoshi

    2014-01-01

    Accumulating evidence from human genetic studies implicates the pituitary adenylate cyclase-activating polypeptide (PACAP) gene as a risk factor for psychiatric disorders, including schizophrenia and stress-related diseases. Mice with homozygous disruption of the PACAP gene display profound behavioral and neurological abnormalities that are ameliorated with the atypical antipsychotic and dopamine D2 and serotonin (5-HT)2 antagonist risperidone and the 5-HT2 receptor antagonist ritanserin; however, the underlying mechanisms remain unknown. Here, we investigated if PACAP heterozygous mutant (PACAP(+/-)) mice, which appear behaviorally normal, are vulnerable to aversive stimuli. PACAP(+/-) mice were administered a 5-HT2 receptor agonist, (±)-2,5-dimethoxy-4-iodoamphetamine (DOI), a hallucinogenic drug, and their responses were compared with the littermate wild-type mice. After DOI injection, PACAP(+/-) mice showed increased head-twitch responses, while their behavior was normal after saline. DOI induced deficits in sensorimotor gating, as determined by prepulse inhibition, specifically in PACAP(+/-) mice. However, other 5-HT2 receptor-dependent responses, such as corticosterone release and hypothermia, were similarly observed in PACAP(+/-) and wild-type mice. c-Fos expression analysis, performed in various brain regions, revealed that the DOI-induced increase in the number of c-Fos-positive cells was more pronounced in 5-HT2A receptor-negative cells in the somatosensory cortex in PACAP(+/-) mice compared with wild-type mice. These results indicate that PACAP(+/-) mice exhibit specific vulnerability to DOI-induced deficits in cortical sensory function, such as exaggerated head-twitch responses and sensorimotor gating deficits. Our findings provide insight into the neural mechanisms underlying impaired behavioral responses in which 5-HT2 receptors are implicated.

  16. Increased Behavioral and Neuronal Responses to a Hallucinogenic Drug in PACAP Heterozygous Mutant Mice

    PubMed Central

    Kasai, Atsushi; Encho, Naoki; Shintani, Norihito; Nagayasu, Kazuki; Hashimoto, Ryota; Reglodi, Dora; Miyakawa, Tsuyoshi; Nakazawa, Takanobu; Baba, Akemichi; Hashimoto, Hitoshi

    2014-01-01

    Accumulating evidence from human genetic studies implicates the pituitary adenylate cyclase-activating polypeptide (PACAP) gene as a risk factor for psychiatric disorders, including schizophrenia and stress-related diseases. Mice with homozygous disruption of the PACAP gene display profound behavioral and neurological abnormalities that are ameliorated with the atypical antipsychotic and dopamine D2 and serotonin (5-HT)2 antagonist risperidone and the 5-HT2 receptor antagonist ritanserin; however, the underlying mechanisms remain unknown. Here, we investigated if PACAP heterozygous mutant (PACAP+/−) mice, which appear behaviorally normal, are vulnerable to aversive stimuli. PACAP+/− mice were administered a 5-HT2 receptor agonist, (±)-2,5-dimethoxy-4-iodoamphetamine (DOI), a hallucinogenic drug, and their responses were compared with the littermate wild-type mice. After DOI injection, PACAP+/− mice showed increased head-twitch responses, while their behavior was normal after saline. DOI induced deficits in sensorimotor gating, as determined by prepulse inhibition, specifically in PACAP+/− mice. However, other 5-HT2 receptor-dependent responses, such as corticosterone release and hypothermia, were similarly observed in PACAP+/− and wild-type mice. c-Fos expression analysis, performed in various brain regions, revealed that the DOI-induced increase in the number of c-Fos-positive cells was more pronounced in 5-HT2A receptor-negative cells in the somatosensory cortex in PACAP+/− mice compared with wild-type mice. These results indicate that PACAP+/− mice exhibit specific vulnerability to DOI-induced deficits in cortical sensory function, such as exaggerated head-twitch responses and sensorimotor gating deficits. Our findings provide insight into the neural mechanisms underlying impaired behavioral responses in which 5-HT2 receptors are implicated. PMID:24586556

  17. PACAP induces neurite outgrowth in cultured trigeminal ganglion cells and recovery of corneal sensitivity after flap surgery in rabbits.

    PubMed

    Fukiage, Chiho; Nakajima, Takeshi; Takayama, Yoshiko; Minagawa, Yoko; Shearer, Thomas R; Azuma, Mitsuyoshi

    2007-02-01

    To evaluate the ability of pituitary adenylate cyclase-activating polypeptide (PACAP) to induce growth of neuronal processes in cultured trigeminal ganglion cells, and to accelerate neurite outgrowth and recovery of corneal sensitivity after creation of a corneal flap in a rabbit model of laser-assisted in situ keratomileusis (LASIK) surgery. Animal study. The cDNA of rabbit PACAP was sequenced, and the expression of PACAP receptors in the trigeminal ganglia from rabbits was quantified by quantitative real-time polymerase chain reaction. Trigeminal ganglion cells were isolated from rabbits and cultured for 48 hours with or without PACAP27 (bioactive N-terminal peptide from PACAP). Cells were stained with antibody against neurofilaments, and neurite outgrowth was quantified by cell counting. In the rabbit LASIK model, a corneal flap with a planned thickness of 130 microm and 8.5 mm diameter was created with a microkeratome. The rabbits then received eyedrops containing PACAP27 four times a day for eight weeks, and corneal sensitivity was measured. Neurite outgrowth was assessed by staining histologic sections of the flap area for cholinesterase. The deduced amino acid sequence of PACAP in rabbit was identical to that of human. PACAP receptor, PAC1, was highly expressed in trigeminal ganglia from newborn and adult rabbits. PACAP27 at 1 microM induced growth of neuronal processes in cultured primary trigeminal ganglion cells. In the LASIK model, extensions of neuronal processes from amputated nerve trunks in cornea were observed after administration of eyedrops containing 1 or 10 microM PACAP27. The 10 microM PACAP27 treatment also greatly accelerated recovery of corneal sensitivity. PACAP may be a candidate drug for ameliorating dry eye after LASIK surgery.

  18. Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) Signalling Exerts Chondrogenesis Promoting and Protecting Effects: Implication of Calcineurin as a Downstream Target

    PubMed Central

    Juhász, Tamás; Matta, Csaba; Katona, Éva; Somogyi, Csilla; Takács, Roland; Gergely, Pál; Csernoch, László; Panyi, Gyorgy; Tóth, Gábor; Reglődi, Dóra; Tamás, Andrea; Zákány, Róza

    2014-01-01

    Pituitary adenylate cyclase activating polypeptide (PACAP) is an important neurotrophic factor influencing differentiation of neuronal elements and exerting protecting role during traumatic injuries or inflammatory processes of the central nervous system. Although increasing evidence is available on its presence and protecting function in various peripheral tissues, little is known about the role of PACAP in formation of skeletal components. To this end, we aimed to map elements of PACAP signalling in developing cartilage under physiological conditions and during oxidative stress. mRNAs of PACAP and its receptors (PAC1,VPAC1, VPAC2) were detectable during differentiation of chicken limb bud-derived chondrogenic cells in micromass cell cultures. Expression of PAC1 protein showed a peak on days of final commitment of chondrogenic cells. Administration of either the PAC1 receptor agonist PACAP 1-38, or PACAP 6-38 that is generally used as a PAC1 antagonist, augmented cartilage formation, stimulated cell proliferation and enhanced PAC1 and Sox9 protein expression. Both variants of PACAP elevated the protein expression and activity of the Ca-calmodulin dependent Ser/Thr protein phosphatase calcineurin. Application of PACAPs failed to rescue cartilage formation when the activity of calcineurin was pharmacologically inhibited with cyclosporine A. Moreover, exogenous PACAPs prevented diminishing of cartilage formation and decrease of calcineurin activity during oxidative stress. As an unexpected phenomenon, PACAP 6-38 elicited similar effects to those of PACAP 1-38, although to a different extent. On the basis of the above results, we propose calcineurin as a downstream target of PACAP signalling in differentiating chondrocytes either in normal or pathophysiological conditions. Our observations imply the therapeutical perspective that PACAP can be applied as a natural agent that may have protecting effect during joint inflammation and/or may promote cartilage regeneration

  19. Pituitary adenylate cyclase activating peptide (PACAP) immunoreactivity and mRNA expression in the duck gastrointestinal tract.

    PubMed

    Mirabella, N; Squillacioti, C; Colitti, M; Germano, G; Pelagalli, A; Paino, G

    2002-06-01

    The presence and distribution of pituitary adenylate cyclase activating peptide (PACAP) immunoreactivity were studied in the duck gastrointestinal tract using immunohistochemistry and radioimmunoassays. Expression and distribution of PACAP mRNA were also studied using reverse transcriptase polymerase chain reaction (RT-PCR) and hybridization techniques. In addition, a partial coding sequence (cds) of the duck growth hormone-releasing hormone (GRF)/PACAP gene was identified. The presence of both PACAP-38 and PACAP-27 was demonstrated, the former being the predominant form. PACAP immunoreactivity was found in neurons and fibers of the enteric nervous system (ENS), in endocrine cells and in the gut associated lymphoid tissue (GALT). Double immunostaining showed that PACAP is almost completely colocalized with vasoactive intestinal peptide (VIP) in the ENS. Moreover, PACAP was also found in nitric oxide synthase (NOS)-containing neurons and nerve fibers. Radioimmunoassay (RIA) performed on denervated gut showed that more than one-half of the duodenal PACAP is extrinsic in origin. RT-PCR, Northern blot analysis and in situ hybridization confirmed the immunohistochemical data. The findings of the present study suggest that, in birds, PACAP may have multiple roles in regulating gastrointestinal functions.

  20. Oxidative Stress in Lead and Cadmium Toxicity and Its Amelioration

    PubMed Central

    Patra, R. C.; Rautray, Amiya K.; Swarup, D.

    2011-01-01

    Oxidative stress has been implicated to play a role, at least in part, in pathogenesis of many disease conditions and toxicities in animals. Overproduction of reactive oxygen species and free radicals beyond the cells intrinsic capacity to neutralize following xenobiotics exposure leads to a state of oxidative stress and resultant damages of lipids, protein, and DNA. Lead and cadmium are the common environmental heavy metal pollutants and have widespread distribution. Both natural and anthropogenic sources including mining, smelting, and other industrial processes are responsible for human and animal exposure. These pollutants, many a times, are copollutants leading to concurrent exposure to living beings and resultant synergistic deleterious health effects. Several mechanisms have been explained for the damaging effects on the body system. Of late, oxidative stress has been implicated in the pathogenesis of the lead- and cadmium-induced pathotoxicity. Several ameliorative measures to counteract the oxidative damage to the body system aftermath or during exposure to these toxicants have been assessed with the use of antioxidants. The present review focuses on mechanism of lead- and cadmium-induced oxidate damages and the ameliorative measures to counteract the oxidative damage and pathotoxicity with the use of supplemented antioxidants for their beneficial effects. PMID:21547215

  1. PACAP Is Protective in a Rat Model of Retinopathy of Prematurity.

    PubMed

    Kvarik, Timea; Mammel, Barbara; Reglodi, Dora; Kovacs, Krisztina; Werling, Dora; Bede, Brigitta; Vaczy, Alexandra; Fabian, Eszter; Toth, Gabor; Kiss, Peter; Tamas, Andrea; Ertl, Tibor; Gyarmati, Judit; Atlasz, Tamas

    2016-10-01

    The oxygen-induced retinopathy (OIR) is a well-established rodent model of retinopathy of prematurity (ROP), which is one of the most common causes of childhood visual impairment affecting preterm babies. Pituitary adenylate cyclase-activating polypeptide (PACAP) is known to have neuroprotective effects. Several studies have revealed the presence of PACAP and its receptors in the retina and reported its protective effects in ischemic and diabetic retinopathy. In this study, we investigated whether PACAP administration can influence the vascular changes in the rat OIR model. OIR was generated by placing the animals in daily alternating 10/50 oxygen concentrations from postnatal day (PD) 0 to PD14 then returned them to room air. Meanwhile, animals received PACAP or saline intraperitoneally or intravitreally from PD1 to PD8 or on PD11, PD14, and PD17, respectively. On PD19 ± 1, the retinas were isolated and the vessels were visualized by isolectin staining. The percentage of avascular to whole retinal areas and the number of branching points were measured. Change in cytokine expression was also determined. Intravitreal treatment with PACAP remarkably reduced the extent of avascular area compared to the non- and saline-treated OIR groups. Intraperitoneal PACAP injection did not influence the vascular extent. Retinal images of room-air controls did not show vascular alterations. No changes in the number of vessel branching were observed after treatments. Alterations in cytokine profile after local PACAP injection further supported the protective role of the peptide. This is the first study to examine the effects of PACAP in ROP. Although the exact mechanism is still not revealed, the present results show that PACAP treatment can ameliorate the vascular changes in the animal model of ROP.

  2. Ischemia/reperfusion-induced Kidney Injury in Heterozygous PACAP-deficient Mice.

    PubMed

    Laszlo, E; Varga, A; Kovacs, K; Jancso, G; Kiss, P; Tamas, A; Szakaly, P; Fulop, B; Reglodi, D

    2015-09-01

    Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide with very diverse distribution and functions. Among others, PACAP is a potent cytoprotective peptide due to its antiapoptotic, anti-inflammatory, and antioxidant actions. This also has been shown in different kidney pathologies, including ischemia/reperfusion-induced kidney injury. Similar protective effects of the endogenous PACAP are confirmed by the increased vulnerability of PACAP-deficient mice to different harmful stimuli. Kidneys of homozygous PACAP-deficient mice have more severe damages in renal ischemia/reperfusion and kidney cell cultures isolated from these mice show increased sensitivity to renal oxidative stress. In our present study we raised the question of whether the partial lack of the PACAP gene is also deleterious, i.e. whether heterozygous PACAP-deficient mice also display more severe damage after renal ischemia/reperfusion. Mice underwent 45 or 60 minutes of ischemia followed by 2 weeks reperfusion. Histological evaluation of the kidneys was performed and individual histopathological parameters were graded. Furthermore, we investigated apoptotic markers, cytokine expression, and the activity of superoxide dismutase (SOD) enzyme 24 hours after 60 minutes of renal ischemia/reperfusion. We found no difference between the intact kidneys of wild-type and heterozygous mice, but marked differences could be observed following ischemia/reperfusion. Heterozygous PACAP-deficient mice had more severe histological alterations, with significantly higher histopathological scores for most of the tested parameters. Higher level of the proapoptotic pp38 MAPK and of some proinflammatory cytokines, as well as lower activity of the antioxidant SOD could be found in these mice. In conclusion, the partial lack of the PACAP gene results in worse outcomes in cases of renal ischemia/reperfusion, confirming that PACAP functions as an endogenous protective factor in the kidney.

  3. Quercetin Treatment Ameliorates Systemic Oxidative Stress in Cirrhotic Rats

    PubMed Central

    Vieira, Emanuelle Kerber; Bona, Silvia; Di Naso, Fábio Cangeri; Porawski, Marilene; Tieppo, Juliana; Marroni, Norma Possa

    2011-01-01

    Our aim was to investigate whether the antioxidant quercetin protects against liver injury and ameliorates the systemic oxidative stress in rats with common bile duct ligation. Secondary biliary cirrhosis was induced through 28 days of bile duct obstruction. Animals received quercetin (Q) after 14 days of obstruction. Groups of control (CO) and cirrhotic (CBDL) animals received a daily 50 mg/kg body weight i.p. injection of quercetin (CO + Q; CBDL + Q) or vehicle (CO; CBDL). Quercetin corrected the reduction in superoxide dismutase (SOD), catalase CAT, and glutathione peroxidase GPx activities and prevented the increase of thiobarbituric acid reactive substances (TBARS), aminotransferases, and alkaline phosphatase in cirrhotic animals. Quercetin administration also corrected the reduced total nitrate concentration in the liver and prevented liver fibrosis and necrosis. These effects suggest that quercetin might be a useful agent to preserve liver function and prevent systemic oxidative stress. PMID:21991520

  4. PACAP/PAC1R signaling modulates acetylcholine release at neuronal nicotinic synapses

    PubMed Central

    Pugh, Phyllis C.; Jayakar, Selwyn S.; Margiotta, Joseph F.

    2009-01-01

    Neuropeptides collaborate with conventional neurotransmitters to regulate synaptic output. Pituitary adenylate cyclase-activating polypeptide (PACAP) co-localizes with acetylcholine in presynaptic nerve terminals, is released by stimulation, and enhances nicotinic acetylcholine receptor- (nAChR-) mediated responses. Such findings implicate PACAP in modulating nicotinic neurotransmission, but relevant synaptic mechanisms have not been explored. We show here that PACAP acts via selective high-affinity G-protein coupled receptors (PAC1Rs) to enhance transmission at nicotinic synapses on parasympathetic ciliary ganglion (CG) neurons by rapidly and persistently increasing the frequency and amplitude of spontaneous, impulse-dependent nicotinic excitatory postsynaptic currents (sEPSCs). Of the canonical adenylate cyclase (AC) and phospholipase-C (PLC) transduction cascades stimulated by PACAP/PAC1R signaling, only AC-generated signals are critical for synaptic modulation since the increases in sEPSC frequency and amplitude were mimicked by 8-Bromo-cAMP, blocked by inhibiting AC or cAMP-dependent protein kinase (PKA), and unaffected by inhibiting PLC. Despite its ability to increase agonist-induced nAChR currents, PACAP failed to influence nAChR-mediated impulse-independent miniature EPSC amplitudes (quantal size). Instead, evoked transmission assays reveal that PACAP/PAC1R signaling increased quantal content, indicating it modulates synaptic function by increasing vesicular ACh release from presynaptic terminals. Lastly, signals generated by the retrograde messenger, nitric oxide- (NO-) are critical for the synaptic modulation since the PACAP-induced increases in spontaneous EPSC frequency, amplitude and quantal content were mimicked by NO donor and absent after inhibiting NO synthase (NOS). These results indicate that PACAP/PAC1R activation recruits AC-dependent signaling that stimulates NOS to increase NO production and control presynaptic transmitter output at neuronal

  5. Involvement of PACAP/ADNP signaling in the resistance to cell death in malignant peripheral nerve sheath tumor (MPNST) cells.

    PubMed

    Castorina, Alessandro; Giunta, Salvatore; Scuderi, Soraya; D'Agata, Velia

    2012-11-01

    Malignant peripheral nerve sheath tumors (MPNSTs) are sarcomas able to grow under conditions of metabolic stress caused by insufficient nutrients or oxygen. Both pituitary adenylate cyclase-activating polypeptide (PACAP) and activity-dependent neuroprotective protein (ADNP) have glioprotective potential. However, whether PACAP/ADNP signaling is involved in the resistance to cell death in MPNST cells remains to be clarified. Here, we investigated the involvement of this signaling system in the survival response of MPNST cells against hydrogen peroxide (H(2)O(2))-evoked death both in the presence of normal serum (NS) and in serum-starved (SS) cells. Results showed that ADNP levels increased time-dependently (6-48 h) in SS cells. Treatment with PACAP38 (10(-9) to 10(-5) M) dose-dependently increased ADNP levels in NS but not in SS cells. PAC(1)/VPAC receptor antagonists completely suppressed PACAP-stimulated ADNP increase and partially reduced ADNP expression in SS cells. NS-cultured cells exposed to H(2)O(2) showed significantly reduced cell viability (~50 %), increased p53 and caspase-3, and DNA fragmentation, without affecting ADNP expression. Serum starvation significantly reduced H(2)O(2)-induced detrimental effects in MPNST cells, which were not further ameliorated by PACAP38. Altogether, these finding provide evidence for the involvement of an endogenous PACAP-mediated ADNP signaling system that increases MPNST cell resistance to H(2)O(2)-induced death upon serum starvation.

  6. Ontogeny of the VIP system in the gastro-intestinal tract of the Axolotl, Ambystoma mexicanum: successive appearance of co-existing PACAP and NOS.

    PubMed

    Badawy, Gamal; Reinecke, Manfred

    2003-03-01

    Evidence for the presence and potential co-existence of vasoactive intestinal polypeptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP) and nitric oxide synthase (NOS) in gastro-intestinal endocrine cells and/or nerve fibers is conflicting and very few results exist on development. This immunofluorescence study aims to clarify the appearance and localization of VIP, PACAP and NOS in the gastro-intestinal tract of the Axolotl, Ambystoma mexicanum, during ontogeny. VIP-immunoreactivity appeared in nerve fibers as early as on day 3 after hatching likely indicating a particular role, such as a trophic action, of VIP in very early development. PACAP-immunoreactivity was observed 3 days later within the VIP-immunoreactive (-IR) fibers. From this time on, VIP- and PACAP-immunoreactivity exhibited complete co-existence. VIP/PACAP-IR fibers were found throughout the gastro-intestinal tract. They were most prominent in the myenteric plexus and the muscle layers and less frequent in the submucosa. NOS-immunoreactivity appeared as late as at the 1st (64 days) juvenile stage in a subpopulation of the VIP/PACAP-IR fibers that contacted submucosal arteries. We found only very few VIP/PACAP-IR perikarya, indicating that part of the VIP/PACAP-IR fibers is of extrinsic origin. On day 12 and in the 1st and 2nd (104 days) juvenile stage, infrequent PACAP-IR entero-endocrine cells were noted, while neither VIP- nor NOS-immunoreactivity occurred in endocrine cells at any stage of development. The complete coexistence of neuronal PACAP- and VIP-immunoreactivities and their very early appearance in ontogeny may suggest important and coordinated roles of both peptides in the control of Axolotl gastro-intestinal activity, while the VIP/ PACAP/NOS-IR fibers may be involved in the regulation of submucosal blood flow.

  7. Tachyphylaxis to PACAP-27 after inhibition of NO synthesis: a loss of adenylate cyclase activation

    NASA Technical Reports Server (NTRS)

    Whalen, E. J.; Johnson, A. K.; Lewis, S. J.

    1999-01-01

    The vasodilator effects of pituitary adenylate cyclase activating polypeptide (PACAP-27) are subject to tachyphylaxis in rats treated with the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). This study examined whether this tachyphylaxis is due to the loss of vasodilator potency of cAMP generated by activation of the G(s) protein-coupled PACAP receptors. Five successive treatments with PACAP-27 (2 nmol/kg iv) produced pronounced vasodilator responses in saline-treated rats that were not subject to tachyphylaxis. The first injection of PACAP-27 (2 nmol/kg iv) in L-NAME (50 micromol/kg iv)-treated rats produced vasodilator responses of similar magnitude to those in saline-treated rats, whereas four subsequent injections produced progressively and markedly smaller responses. The hemodynamic effects of the membrane-permeable cAMP analog 8-(4-chlorophenylthiol)-cAMP (8-CPT-cAMP; 5-15 micromol/kg iv) were similar in L-NAME-treated rats and in L-NAME-treated rats that had received the five injections of PACAP-27. In addition, five injections of 8-CPT-cAMP (10 micromol/kg iv) produced pronounced vasodilator responses in saline- and L-NAME-treated rats that were not subject to the development of tachyphylaxis. These results suggest that a loss of biological potency of cAMP is not responsible for tachyphylaxis to PACAP-27 in L-NAME-treated rats. This tachyphylaxis may be due to the inability of the G(s) protein-coupled PACAP receptor to activate adenylate cyclase.

  8. Dietary Iron Oxide Nanoparticles Delay Aging and Ameliorate Neurodegeneration in Drosophila.

    PubMed

    Zhang, Yi; Wang, Zhuyao; Li, Xiaojiao; Wang, Lu; Yin, Min; Wang, Lihua; Chen, Nan; Fan, Chunhai; Song, Haiyun

    2016-02-17

    Dietary iron oxide nanoparticles are shown to ameliorate neurodegeneration in a Drosophelia Alzheimer's disease model. Iron oxide nanoparticles can mimic catalase and can decompose reactive oxygen species (ROS). This has potential therapeutic uses for aging, metabolic disorders, and neurodegenerative diseases, in which increased production of ROS is closely implicated. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. Manganese-induced oxidative stress in two ontogenetic stages of chamomile and amelioration by nitric oxide.

    PubMed

    Kováčik, Jozef; Babula, Petr; Hedbavny, Josef; Švec, Pavel

    2014-02-01

    Impact of manganese (Mn(2+)) excess (100, 500 and 1000 μM over 7 days) on two ontogenetic stages (7-week-old plants and 7-day-old seedlings) of Matricaria chamomilla was compared. Mn excess depressed growth of seedlings (but not germination) and stimulated oxidative stress (ROS and lipid peroxidation) in both plants and seedlings. Growth inhibition could be evoked by higher Mn uptake and higher translocation factor in seedlings than in plants. Total thiols staining revealed elevation in almost all treatments. In 7-week-old plants, activity of peroxidases increased slightly and rather decreased under high Mn doses. Superoxide rather than hydrogen peroxide contributed to visualized ROS presence. Fluorescence of nitric oxide (NO) showed stimulation in plants but decrease in seedlings. Impact of exogenous nitric oxide donor (sodium nitroprusside/SNP) was therefore tested and results showed amelioration of 1000 μM Mn-induced oxidative stress in seedlings (decrease in H2O2 and increase in NO content while antioxidative enzyme activities were variably affected) concomitantly with depleted Mn accumulation. It is concluded that NO participates in tolerance to Mn excess but negative effects of the highest SNP dose were also observed. Extensive fluorescence microscopy is also explanatively discussed. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  10. Examination of PACAP-Like Immunoreactivity in Urogenital Tumor Samples.

    PubMed

    Tamas, Andrea; Javorhazy, Andras; Reglodi, Dora; Sarlos, Donat Peter; Banyai, Daniel; Semjen, David; Nemeth, Jozsef; Lelesz, Beata; Fulop, Daniel Balazs; Szanto, Zalan

    2016-06-01

    Numerous studies investigated the localization of pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptors in different tumors and described the effects of analogs on tumor growth to show its potential role in oncogenesis. Recently, our research group has found significantly lower levels of PACAP27-like immunorreactivity (LI) and PACAP38-LI in different human samples of primary small cell lung cancer and colon cancer compared to normal healthy tissues. There are only few human studies showing the presence of PACAP and its receptors in urogenital tumors; therefore, the aim of the present study was to compare PACAP-LI in different healthy and pathological human samples from urogenital organs (kidney, urinary bladder, prostate, testis) with radioimmunoassay (RIA) method. Similar to our earlier observations, the PACAP27-LI was significantly lower compared to PACAP38-LI in all samples. We did not find significant alterations in PACAP-LI between healthy and tumoral samples from the urinary bladder and testis. On the other hand, we found significantly lower PACAP38-LI level in kidney tumors compared with healthy tissue samples, and we showed higher PACAP27-LI in prostatic cancer compared to samples from benign prostatic hyperplasia. These data indicate that PACAP levels of different tissue samples are altered under pathological conditions suggesting a potential role of PACAP in the development of different urogenital tumors.

  11. PACAP38: Emerging Drug Target in Migraine and Cluster Headache.

    PubMed

    Vollesen, Anne Luise Haulund; Ashina, Messoud

    2017-05-01

    Here, we review the role of pituitary adenylate cyclase-activating peptide-38 (PACAP38) in migraine and cluster headache (CH). Mounting evidence implicates signaling molecule PACAP38 in the pathophysiology of migraine. Human provocation studies show PACAP38 induces migraine attacks in migraine patients without aura and marked and sustained dilation of extracerebral arteries. PACAP38 selectively targets the PAC1 receptor making this receptor a promising candidate for targeted migraine therapy. Randomized clinical trials are warranted to pursue this possible treatment pathway. PACAP38 provocation studies in CH could elucidate possible involvement of PACAP38 in CH pathophysiology and predict efficacy of PACAP38 antagonists in this primary headache. © 2017 American Headache Society.

  12. Examination of calcium-binding protein expression in the inner ear of wild-type, heterozygous and homozygous pituitary adenylate cyclase-activating polypeptide (PACAP)-knockout mice in kanamycin-induced ototoxicity.

    PubMed

    Nemeth, A; Szabadfi, K; Fulop, B; Reglodi, D; Kiss, P; Farkas, J; Szalontai, B; Gabriel, R; Hashimoto, H; Tamas, A

    2014-01-01

    Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide with diverse biological effects. It also occurs and exerts protective effects in sensory organs; however, little is known about its effects in the auditory system. Recently, we have shown that PACAP protects cochlear cells against oxidative-stress-induced apoptosis and homozygous PACAP-deficient animals show stronger expression of Ca(2+)-binding proteins in the hair cells of the inner ear, but there are no data about the consequences of the lack of endogenous PACAP in different ototoxic insults such as aminoglycoside-induced toxicity. In this study, we examined the effect of kanamycin treatment on Ca(2+)-binding protein expression in hair cells of wild-type, heterozygous and homozygous PACAP-deficient mice. We treated 5-day-old mice with kanamycin, and 2 days later, we examined the Ca(2+)-binding protein expression of the hair cells with immunohistochemistry. We found stronger expression of Ca(2+)-binding proteins in the hair cells of control heterozygous and homozygous PACAP-deficient mice compared with wild-type animals. Kanamycin induced a significant increase in Ca(2+)-binding protein expression in wild-type and heterozygous PACAP-deficient mice, but the baseline higher expression in homozygous PACAP-deficient mice did not show further changes after the treatment. Elevated endolymphatic Ca(2+) is deleterious for the cochlear function, against which the high concentration of Ca(2+)-buffers in hair cells may protect. Meanwhile, the increased immunoreactivity of Ca(2+)-binding proteins in the absence of PACAP provide further evidence for the important protective role of PACAP in ototoxicity, but further investigations are necessary to examine the exact role of endogenous PACAP in ototoxic insults.

  13. [On PACAP-aggravated experimental acute pancreatitis].

    PubMed

    Chen, Youdai; Zhou, Zongguang; Chen, Youqin; Wang, Zhao; Gao, Hongkai; Zheng, Xuelian

    2004-12-01

    The role of PACAP (pituitary adenylate cyclase activating polypeptide), a peptidergic transmitter, in the pathogenesis of acute pancreatitis is not yet clear. This experiment was conducted to examine the action of exogenous PACAP on rat pancreas and on the course of experimental acute pancreatitis. The results showed that 5-30 microg/kg of PACAP slightly raised the serum amylase level, induced pancreatic edema (23.88% +/- 2.532%-25.86% +/- 1.974% of experiment groups versus 29.21% +/- 5.657% of control group), inflammatory cell infiltration, vacuolization of acinar cells, and occasionally fatty and parenchymal necroses. 15-30 microg/kg of PACAP aggravated cerulein-induced acute pancreatitis; the pancreatic edema became more marked (13.45% +/- 2.045%-17.66% +/- 4.652% of expreiment groups versus 21.83% +/- 3.013% of cerulein group, P<0.05), the serum amylase level became higher; and ascites, pancreatic bleeding, fatty and parenchymal necroses, and extensive vacuolization of acinar cells appeared. For sodium taurocholate-induced pancreatitis, 5-10 microg/kg of PACAP mildly attenuated the pancreatic edema, reduced the serum amylase level (1986.91 +/- 710.97-2944.33 +/- 1182.47 IU/L vs 3690.87 +/- 2277.99 IU/L, P<0.05), whereas it caused multifocal hemorrhage and prominent necrosis in pancreas. Except the cerulein-induced pancreatitis groups, other groups were found to have reduced pancreatic functional capillary density (FCD); when pancreatic edema was taken into consideration and calibrated FCD was introduced (FCD weighted against pancreatic wet/dry ratio), all groups revealed increases in pancreatic functional capillaries when compared with normal control. In conclusion, PACAP is proinflammatory in the pathogenesis of acute pancreatitis, PACAP plus cerulein can induce acute hemorrhagic/necrotizing pancreatitis, and the action of PACAP on cerulein-induced panceatitis may differ from that on sodium taurocholate-induced one. In this experiment, pancreatic FCD was

  14. Effect of PACAP in Central and Peripheral Nerve Injuries

    PubMed Central

    Tamas, Andrea; Reglodi, Dora; Farkas, Orsolya; Kovesdi, Erzsebet; Pal, Jozsef; Povlishock, John T.; Schwarcz, Attila; Czeiter, Endre; Szanto, Zalan; Doczi, Tamas; Buki, Andras; Bukovics, Peter

    2012-01-01

    Pituitary adenylate cyclase activating polypeptide (PACAP) is a bioactive peptide with diverse effects in the nervous system. In addition to its more classic role as a neuromodulator, PACAP functions as a neurotrophic factor. Several neurotrophic factors have been shown to play an important role in the endogenous response following both cerebral ischemia and traumatic brain injury and to be effective when given exogenously. A number of studies have shown the neuroprotective effect of PACAP in different models of ischemia, neurodegenerative diseases and retinal degeneration. The aim of this review is to summarize the findings on the neuroprotective potential of PACAP in models of different traumatic nerve injuries. Expression of endogenous PACAP and its specific PAC1 receptor is elevated in different parts of the central and peripheral nervous system after traumatic injuries. Some experiments demonstrate the protective effect of exogenous PACAP treatment in different traumatic brain injury models, in facial nerve and optic nerve trauma. The upregulation of endogenous PACAP and its receptors and the protective effect of exogenous PACAP after different central and peripheral nerve injuries show the important function of PACAP in neuronal regeneration indicating that PACAP may also be a promising therapeutic agent in injuries of the nervous system. PMID:22942712

  15. Altered Gene Expression of RNF34 and PACAP Possibly Involved in Mechanism of Exercise-Induced Analgesia for Neuropathic Pain in Rats.

    PubMed

    Yamaoka, Shintaro; Oshima, Yusuke; Horiuchi, Hideki; Morino, Tadao; Hino, Masayuki; Miura, Hiromasa; Ogata, Tadanori

    2017-09-13

    Despite the availability of several modalities of treatment, including surgery, pharmacological agents, and nerve blocks, neuropathic pain is often unresponsive and sometimes progresses to intractable chronic pain. Although exercise therapy is a candidate for treatment of neuropathic pain, the mechanism underlying its efficacy has not been elucidated. To clarify the molecular mechanism for pain relief induced by exercise, we measured Rnf34 and Pacap mRNA levels in the spinal cord dorsal horn of SNL rats, a model of neuropathic pain. SNL model rats exhibited stable mechanical hyperalgesia for at least 6 weeks. When the rats were forced to exercise on a treadmill, mechanical and thermal hyperalgesia were significantly ameliorated compared with the non-exercise group. Accordingly, gene expression level of Rnf34 and Pacap were also significantly altered in the time course analysis after surgery. These results suggest that exercise therapy possibly involves pain relief in SNL rats by suppressing Rnf34 and Pacap expression in the spinal cord.

  16. Cerium oxide nanoparticle treatment ameliorates peritonitis-induced diaphragm dysfunction.

    PubMed

    Asano, Shinichi; Arvapalli, Ravikumar; Manne, Nandini D P K; Maheshwari, Mani; Ma, Bing; Rice, Kevin M; Selvaraj, Vellaisamy; Blough, Eric R

    2015-01-01

    The severe inflammation observed during sepsis is thought to cause diaphragm dysfunction, which is associated with poor patient prognosis. Cerium oxide (CeO2) nanoparticles have been posited to exhibit anti-inflammatory and antioxidative activities suggesting that these particles may be of potential use for the treatment of inflammatory disorders. To investigate this possibility, Sprague Dawley rats were randomly assigned to the following groups: sham control, CeO2 nanoparticle treatment only (0.5 mg/kg iv), sepsis, and sepsis+CeO2 nanoparticles. Sepsis was induced by the introduction of cecal material (600 mg/kg) directly into the peritoneal cavity. Nanoparticle treatment decreased sepsis-associated impairments in diaphragmatic contractile (P(o)) function (sham: 25.6±1.6 N/cm(2) vs CeO2: 23.4±0.8 N/cm(2) vs Sep: 15.9±1.0 N/cm(2) vs Sep+CeO2: 20.0±1.0 N/cm(2), P<0.05). These improvements in diaphragm contractile function were accompanied by a normalization of protein translation signaling (Akt, FOXO-1, and 4EBP1), diminished proteolysis (caspase 8 and ubiquitin levels), and decreased inflammatory signaling (Stat3 and iNOS). Histological analysis suggested that nanoparticle treatment was associated with diminished sarcolemma damage and diminished inflammatory cell infiltration. These data indicate CeO2 nanoparticles may improve diaphragmatic function in the septic laboratory rat.

  17. Accelerated retinal aging in PACAP knock-out mice.

    PubMed

    Kovács-Valasek, Andrea; Szabadfi, Krisztina; Dénes, Viktória; Szalontai, Bálint; Tamás, Andrea; Kiss, Péter; Szabó, Aliz; Setalo, Gyorgy; Reglődi, Dóra; Gábriel, Robert

    2017-02-13

    Pituitary adenylate cyclase activating polypeptide (PACAP) is a neurotrophic and neuroprotective peptide. PACAP and its receptors are widely distributed in the retina. A number of reports provided evidence that PACAP is neuroprotective in retinal degenerations. The current study compared retina cell type-specific differences in young (3-4months) and aged adults (14-16months), of wild-type (WT) mice and knock-out (KO) mice lacking endogenous PACAP production during the course of aging. Histological, immunocytochemical and Western blot examinations were performed. The staining for standard neurochemical markers (tyrosine hydroxylase for dopaminergic cells, calbindin 28 kDa for horizontal cells, protein kinase Cα for rod bipolar cells) of young adult PACAP KO retinas showed no substantial alterations compared to young adult WT retinas, except for the specific PACAP receptor (PAC1-R) staining. We could not detect PAC1-R immunoreactivity in bipolar and horizontal cells in young adult PACAP KO animals. Some other age-related changes were observed only in the PACAP KO mice only. These alterations included horizontal and rod bipolar cell dendritic sprouting into the photoreceptor layer and decreased ganglion cell number. Also, Müller glial cells showed elevated GFAP expression compared to the aging WT retinas. Furthermore, Western blot analyses revealed significant differences between the phosphorylation state of ERK1/2 and JNK in KO mice, indicating alterations in the MAPK signaling pathway. These results support the conclusion that endogenous PACAP contributes to protection against aging of the nervous system.

  18. Intermedin ameliorates IgA nephropathy by inhibition of oxidative stress and inflammation.

    PubMed

    Wang, Yanhong; Tian, Jihua; Guo, Haixiu; Mi, Yang; Zhang, Ruijing; Li, Rongshan

    2016-05-01

    IgA nephropathy (IgAN) is the most frequent form of glomerulonephritis worldwide. The role of oxidative stress and inflammation in the pathogenesis of IgAN has been reported. Intermedin (IMD) is a newly discovered peptide that is closely related to adrenomedullin. We have recently reported that IMD can significantly reduce renal ischemia/reperfusion injury by diminishing oxidative stress and suppressing inflammation. The present study was designed to explore whether IMD ameliorates IgAN via oxidative stress- and inflammation-dependent mechanisms. Our results showed that IMD administration resulted in the prevention of albuminuria and ameliorated renal pathomorphological changes. These findings were associated with (1) decreased renal TGF-β1 and collagen IV expression, (2) an increased SOD level and reduced MDA level, (3) the inhibition of the renal activation of NF-κB p65 and (4) the downregulation of the expression of inflammatory factors (TNF-α, MCP-1 and MMP-9) in the kidney. These results indicate that IMD in the kidney protects against IgAN by reducing oxidative stress and suppressing inflammation.

  19. Amelioration of cyclophosphamide induced myelosuppression and oxidative stress by cinnamic acid.

    PubMed

    Patra, Kartick; Bose, Samadrita; Sarkar, Shehnaz; Rakshit, Jyotirmoy; Jana, Samarjit; Mukherjee, Avik; Roy, Abhishek; Mandal, Deba Prasad; Bhattacharjee, Shamee

    2012-02-05

    Cinnamic acid (C9H8O2), is a major constituent of the oriental Ayurvedic plant Cinnamomum cassia (Family: Lauraceae). This phenolic acid has been reported to possess various pharmacological properties of which its antioxidant activity is a prime one. Therefore it is rational to hypothesize that it may ameliorate myelosuppression and oxidative stress induced by cyclophosphamide, a widely used chemotherapeutic agent. Commercial cyclophosphamide, Endoxan, was administered intraperitoneally to Swiss albino mice (50mg/kg) pretreated with 15, 30 and 60mg/kg doses of cinnamic acid orally at alternate days for 15days. Cinnamic acid pre-treatment was found to reduce cyclophosphamide induced hypocellularity in the bone marrow and spleen. This recovery was also reflected in the peripheral blood count. Amelioration of hypocellularity could be correlated with the modulation of cell cycle phase distribution. Cinnamic acid pre-treatment reduced bone marrow and hepatic oxidative stress as evident by lipid peroxidation and activity assays of antioxidant enzymes such as superoxide dismutase, catalase and glutathione-S-transferase. The present study indicates that cinnamic acid pretreatment has protective influence on the myelosuppression and oxidative stress induced by cyclophosphamide. This investigation is an attempt and is the first of its kind to establish cinnamic acid as an agent whose consumption provides protection to normal cells from the toxic effects of a widely used anti-cancer drug. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  20. Sesamin ameliorates oxidative liver injury induced by carbon tetrachloride in rat.

    PubMed

    Lv, Dan; Zhu, Chang-Qing; Liu, Li

    2015-01-01

    Sesamin is naturally occurring lignan from sesame oil with putative antioxidant property. The present study was designed to investigate the protective role of sesamin against carbon tetrachloride induced oxidative liver injury. Male Wistar albino rats (180-200 g) were divided in to 5 groups (n=6). Hepatotoxicity was induced by the administration of CCl4 (0.1 ml/100 g bw., 50% v/v with olive oil) intraperitoneally. Sesamin was administered in two different dose (5 and 10 ml/kg bw) to evaluate the hepatoprotective activity. Sesamin significantly reduced the elevated serum liver marker enzymes (P<0.0001). Reduction of TBARS (P<0.01 and P<0.001) followed by enhancement of GSH., SOD and catalase (P<0.0001) in liver homogenate in sesamin treated groups shows the amelioration of oxidative stress induced by CCl4. Histopathological report also supported the hepatoprotection offered by sesamin. Sesamin effects in both the dose were in comparable to reference standard drug silymarin. From these above findings it has been concluded that sesamin ameliorate the oxidative liver injury in terms of reduction of lipid peroxidation and enhancement of liver antioxidant enzymes.

  1. Sesamin ameliorates oxidative liver injury induced by carbon tetrachloride in rat

    PubMed Central

    Lv, Dan; Zhu, Chang-Qing; Liu, Li

    2015-01-01

    Sesamin is naturally occurring lignan from sesame oil with putative antioxidant property. The present study was designed to investigate the protective role of sesamin against carbon tetrachloride induced oxidative liver injury. Male Wistar albino rats (180-200 g) were divided in to 5 groups (n=6). Hepatotoxicity was induced by the administration of CCl4 (0.1 ml/100 g bw., 50% v/v with olive oil) intraperitoneally. Sesamin was administered in two different dose (5 and 10 ml/kg bw) to evaluate the hepatoprotective activity. Sesamin significantly reduced the elevated serum liver marker enzymes (P<0.0001). Reduction of TBARS (P<0.01 and P<0.001) followed by enhancement of GSH., SOD and catalase (P<0.0001) in liver homogenate in sesamin treated groups shows the amelioration of oxidative stress induced by CCl4. Histopathological report also supported the hepatoprotection offered by sesamin. Sesamin effects in both the dose were in comparable to reference standard drug silymarin. From these above findings it has been concluded that sesamin ameliorate the oxidative liver injury in terms of reduction of lipid peroxidation and enhancement of liver antioxidant enzymes. PMID:26191289

  2. Honey supplementation in spontaneously hypertensive rats elicits antihypertensive effect via amelioration of renal oxidative stress.

    PubMed

    Erejuwa, Omotayo O; Sulaiman, Siti A; Ab Wahab, Mohd S; Sirajudeen, Kuttulebbai N S; Salleh, Salzihan; Gurtu, Sunil

    2012-01-01

    Oxidative stress is implicated in the pathogenesis and/or maintenance of elevated blood pressure in hypertension. This study investigated the effect of honey on elevated systolic blood pressure (SBP) in spontaneously hypertensive rats (SHR). It also evaluated the effect of honey on the amelioration of oxidative stress in the kidney of SHR as a possible mechanism of its antihypertensive effect. SHR and Wistar Kyoto (WKY) rats were randomly divided into 2 groups and administered distilled water or honey by oral gavage once daily for 12 weeks. The control SHR had significantly higher SBP and renal malondialdehyde (MDA) levels than did control WKY. The mRNA expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and glutathione S-transferase (GST) were significantly downregulated while total antioxidant status (TAS) and activities of GST and catalase (CAT) were higher in the kidney of control SHR. Honey supplementation significantly reduced SBP and MDA levels in SHR. Honey significantly reduced the activities of GST and CAT while it moderately but insignificantly upregulated the Nrf2 mRNA expression level in the kidney of SHR. These results indicate that Nrf2 expression is impaired in the kidney of SHR. Honey supplementation considerably reduces elevated SBP via amelioration of oxidative stress in the kidney of SHR.

  3. Cellular localization of pituitary adenylate cyclase-activating peptide (PACAP) following traumatic brain injury in humans.

    PubMed

    van Landeghem, Frank K H; Weiss, Thorsten; Oehmichen, Manfred; von Deimling, Andreas

    2007-06-01

    The pituitary adenylate cyclase-activating peptide (PACAP) is involved in many processes of the developing and mature central nervous system, such as proliferation, differentiation, apoptosis, neurotransmission, inflammation and neuroprotection. Alternative posttranslational processing of PACAP results in two biologically active, amidated 27- and 38-amino acid peptides termed PACAP27 and PACAP38. In the present study, we examined whether traumatic brain injury (TBI) affects cellular immunopositivity for PACAP27 and PACAP38. Patients (n = 55) were classified into three groups dependent on their survival time (under 24 h, between 24 h and 7 days and between 7 days and 99 days postinjury). PACAP27 and PACAP38 were expressed by neurons and glial cells in normal human neocortex (n = 10). Following TBI, the total number of PACAP27- and PACAP38-positive cells was significantly decreased for a prolonged survival period within the traumatized neocortex. In the pericontusional cortex, the number of cells expressing PACAP27 and PACAP38 was significantly increased at all survival times examined. Triple immunofluorescence examinations revealed a significant increase in the absolute numbers of GFAP-positive reactive astrocytes as well as a decrease in the CNP-positive oligodendrocytes, each coexpressing PACAP27 or PACAP38 in the contusional and pericontusional cortex. We hypothesize that the increase of glial PACAP immunoreactivity may be interpreted as part of a complex endogenous neuroprotective response in the pericontusional regions, but the precise role of PACAP following TBI is yet to be determined.

  4. PACAP suppresses dry eye signs by stimulating tear secretion

    PubMed Central

    Nakamachi, Tomoya; Ohtaki, Hirokazu; Seki, Tamotsu; Yofu, Sachiko; Kagami, Nobuyuki; Hashimoto, Hitoshi; Shintani, Norihito; Baba, Akemichi; Mark, Laszlo; Lanekoff, Ingela; Kiss, Peter; Farkas, Jozsef; Reglodi, Dora; Shioda, Seiji

    2016-01-01

    Dry eye syndrome is caused by a reduction in the volume or quality of tears. Here, we show that pituitary adenylate cyclase-activating polypeptide (PACAP)-null mice develop dry eye-like symptoms such as corneal keratinization and tear reduction. PACAP immunoreactivity is co-localized with a neuronal marker, and PACAP receptor (PAC1-R) immunoreactivity is observed in mouse infraorbital lacrimal gland acinar cells. PACAP eye drops stimulate tear secretion and increase cAMP and phosphorylated (p)-protein kinase A levels in the infraorbital lacrimal glands that could be inhibited by pre-treatment with a PAC1-R antagonist or an adenylate cyclase inhibitor. Moreover, these eye drops suppress corneal keratinization in PACAP-null mice. PACAP eye drops increase aquaporin 5 (AQP5) levels in the membrane and pAQP5 levels in the infraorbital lacrimal glands. AQP5 siRNA treatment of the infraorbital lacrimal gland attenuates PACAP-induced tear secretion. Based on these results, PACAP might be clinically useful to treat dry eye disorder. PMID:27345595

  5. Oxidative stress in streptozocin-diabetic rats: Amelioration by mulberry (Morus Indica L.) leaves.

    PubMed

    Andallu, Bondada; Kumar, Av Vinay; Varadacharyulu, N Ch

    2012-12-22

    OBJECTIVE: To investigate amelioration of oxidative stress by mulberry (Morus indica L.) leaves in streptozocin (STZ)-diabetic rats, as the leaves of mulberry (Morus indica L.) of Moraceae, are reported to be rich in a number of bioactive principles, i.e. antioxidant vitamins, flavonoids and moracins that can fight against oxidative stress in diabetes. METHOD: Normal wistar albino rats and STZ-diabetic rats were treated with dried mulberry leaf powder at 25% in the diet for a period of 8 weeks. The antioxidant role of mulberry was assessed by determining the effect of the leaves on hepatic lipid peroxidation, a marker of oxidative stress and the activity of hepatic antioxidant enzymes and serum antioxidant vitamins in comparison with untreated normal and diabetic rats. RESULTS: Increased oxidative stress as shown by increased lipid peroxidation and increased activity of catalase (CAT) in hepatic tissue, decreased serum ascorbic acid (vitamin C) and tocopherol (vitamin E) in diabetic rats were countered by mulberry leaves. In addition, decreased activities of hepatic antioxidant enzymes, i.e. glucose-6-phosphate dehydrogenase (G6PDH), glutathione peroxidase (GPx), glutathinone-S-tranferase (GST) and superoxide dismutase (SOD) were significantly increased by 34%, 61%, 19% and 53% respectively in mulberry leaves-treated diabetic rats as compared with diabetic control rats. CONCLUSION: Treatment with mulberry leaves protected STZ-diabetic rats from lipid peroxidation and elevated the activities of defense enzymes. This study reveals ameliorating effect of mulberry leaves on oxidative stress in diabetic rats by the synergistic action of a number of bioactive compounds present in mulberry leaves.

  6. Reduction of cerebral infarction in rats by biliverdin associated with amelioration of oxidative stress.

    PubMed

    Deguchi, Kentaro; Hayashi, Takeshi; Nagotani, Shoko; Sehara, Yoshihide; Zhang, Hanzhe; Tsuchiya, Atsushi; Ohta, Yasuyuki; Tomiyama, Koji; Morimoto, Nobutoshi; Miyazaki, Masahiro; Huh, Nam-Ho; Nakao, Atsunori; Kamiya, Tatsushi; Abe, Koji

    2008-01-10

    Biliverdin (BV), one of the byproducts of heme catalysis through heme oxygenase (HO) system, is a scavenger of reactive oxygen species (ROS). We hypothesized that BV treatment could protect rat brain cells from oxidative injuries via its anti-oxidant efficacies. Cerebral infarction was induced by transient middle cerebral artery occlusion (tMCAO) for 90 min, followed by reperfusion. BV or vehicle was administered intraperitoneally immediately after reperfusion. The size of the cerebral infarction 2 days after tMCAO was evaluated by 2,3,5-triphenyltetrazolium chloride (TTC) stain. Superoxide generation 4 h after tMCAO was determined by detection of oxidized hydroethidine. In addition, the oxidative impairment of neurons were immunohistochemically assessed by stain for lipid peroxidation with 4-hydroxy-2-nonenal (4-HNE) and damaged DNA with 8-hydroxy-2'-deoxyguanosine (8-OHdG). BV treatment significantly reduced infarct volume of the cerebral cortices associated with less superoxide production and decreased oxidative injuries of brain cells. The present study demonstrated that treatment with BV ameliorated the oxidative injuries on neurons and decreased brain infarct size in rat tMCAO model.

  7. Diallyl disulfide ameliorates gentamicin-induced oxidative stress and nephropathy in rats.

    PubMed

    Pedraza-Chaverrí, José; González-Orozco, Ana E; Maldonado, Perla D; Barrera, Diana; Medina-Campos, Omar N; Hernández-Pando, Rogelio

    2003-07-18

    Experimental evidences suggest a role of reactive oxygen species in gentamicin-induced nephropathy in rats. Therefore, we investigated if diallyl disulfide, a garlic-derived compound with antioxidant properties, has a renoprotective effect in this experimental model. Four groups of rats were studied: (1) control, (2) gentamicin treated subcutaneously with gentamicin (70 mg/kg/12 h/4 days), (3) diallyl disulfide treated intragastrically with diallyl disulfide (50 mg/kg/24 h/4 days), and (4) gentamicin + diallyl disulfide treated with gentamicin + diallyl disulfide. Gentamicin induced (a) nephrotoxicity, (b) increase in renal oxidative stress, and (c) decrease in the activity of manganese superoxide dismutase, glutathione peroxidase, and glutathione reductase. Diallyl disulfide ameliorated these changes induced by gentamicin. The mechanism by which diallyl disulfide has a renoprotective effect in gentamicin-induced acute renal failure in rats may be related, at least in part, to the amelioration in the oxidative stress and the preservation in the activity of the antioxidant enzymes in kidney.

  8. Hydroxycitric acid ameliorates inflammation and oxidative stress in mouse models of multiple sclerosis

    PubMed Central

    Goudarzvand, Mahdi; Afraei, Sanaz; Yaslianifard, Somaye; Ghiasy, Saleh; Sadri, Ghazal; Kalvandi, Mustafa; Alinia, Tina; Mohebbi, Ali; Yazdani, Reza; Azarian, Shahin Khadem; Mirshafiey, Abbas; Azizi, Gholamreza

    2016-01-01

    Hydroxycitric acid (HCA) is derived primarily from the Garcinia plant and is widely used for its anti-inflammatory effects. Multiple sclerosis can cause an inflammatory demyelination and axonal damage. In this study, to validate the hypothesis that HCA exhibits therapeutic effects on multiple sclerosis, we established female C57BL/6 mouse models of multiple sclerosis, i.e., experimental autoimmune encephalomyelitis, using Complete Freund's Adjuvant (CFA) emulsion containing myelin oligodendrocyte glycoprotein (35–55). Treatment with HCA at 2 g/kg/d for 3 weeks obviously improved the symptoms of nerve injury of experimental autoimmune encephalomyelitis mice, decreased serum interleulin-6, tumor necrosis factor alpha, nitric oxide, and malondialdehyde levels, and increased superoxide dismutase and glutathione reductase activities. These findings suggest that HCA exhibits neuroprotective effects on multiple sclerosis-caused nerve injury through ameliorating inflammation and oxidative stress. PMID:27904492

  9. Early Neurobehavioral Development of Mice Lacking Endogenous PACAP.

    PubMed

    Farkas, Jozsef; Sandor, Balazs; Tamas, Andrea; Kiss, Peter; Hashimoto, Hitoshi; Nagy, Andras D; Fulop, Balazs D; Juhasz, Tamas; Manavalan, Sridharan; Reglodi, Dora

    2017-04-01

    Pituitary adenylate cyclase activating polypeptide (PACAP) is a multifunctional neuropeptide. In addition to its diverse physiological roles, PACAP has important functions in the embryonic development of various tissues, and it is also considered as a trophic factor during development and in the case of neuronal injuries. Data suggest that the development of the nervous system is severely affected by the lack of endogenous PACAP. Short-term neurofunctional outcome correlates with long-term functional deficits; however, the early neurobehavioral development of PACAP-deficient mice has not yet been evaluated. Therefore, the aim of the present study was to describe the postnatal development of physical signs and neurological reflexes in mice partially or completely lacking PACAP. We examined developmental hallmarks during the first 3 weeks of the postnatal period, during which period most neurological reflexes and motor coordination show most intensive development, and we describe the neurobehavioral development using a complex battery of tests. In the present study, we found that PACAP-deficient mice had slower weight gain throughout the observation period. Interestingly, mice partially lacking PACAP weighed significantly less than homozygous mice. There was no difference between male and female mice during the first 3 weeks. Some other signs were also more severely affected in the heterozygous mice than in the homozygous mice, such as air righting, grasp, and gait initiation reflexes. Interestingly, incisor teeth erupted earlier in mice lacking PACAP. Motor coordination, shown by the number of foot-faults on an elevated grid, was also less developed in PACAP-deficient mice. In summary, our results show that mice lacking endogenous PACAP have slower weight gain during the first weeks of development and slower neurobehavioral development regarding a few developmental hallmarks.

  10. Propofol ameliorates doxorubicin-induced oxidative stress and cellular apoptosis in rat cardiomyocytes

    SciTech Connect

    Lai, H.C.; Yeh, Y.C.; Wang, L.C.; Ting, C.T.; Lee, W.L.; Lee, H.W.; Wang, K.Y.; Wu, A.; Su, C.S.; Liu, T.J.

    2011-12-15

    Background: Propofol is an anesthetic with pluripotent cytoprotective properties against various extrinsic insults. This study was designed to examine whether this agent could also ameliorate the infamous toxicity of doxorubicin, a widely-used chemotherapeutic agent against a variety of cancer diseases, on myocardial cells. Methods: Cultured neonatal rat cardiomyocytes were administrated with vehicle, doxorubicin (1 {mu}M), propofol (1 {mu}M), or propofol plus doxorubicin (given 1 h post propofol). After 24 h, cells were harvested and specific analyses regarding oxidative/nitrative stress and cellular apoptosis were conducted. Results: Trypan blue exclusion and MTT assays disclosed that viability of cardiomyocytes was significantly reduced by doxorubicin. Contents of reactive oxygen and nitrogen species were increased and antioxidant enzymes SOD1, SOD2, and GPx were decreased in these doxorubicin-treated cells. Mitochondrial dehydrogenase activity and membrane potential were also depressed, along with activation of key effectors downstream of mitochondrion-dependent apoptotic signaling. Besides, abundance of p53 was elevated and cleavage of PKC-{delta} was induced in these myocardial cells. In contrast, all of the above oxidative, nitrative and pro-apoptotic events could be suppressed by propofol pretreatment. Conclusions: Propofol could extensively counteract oxidative/nitrative and multiple apoptotic effects of doxorubicin in the heart; hence, this anesthetic may serve as an adjuvant agent to assuage the untoward cardiac effects of doxorubicin in clinical application. -- Highlights: Black-Right-Pointing-Pointer We evaluate how propofol prevents doxorubicin-induced toxicity in cardiomyocytes. Black-Right-Pointing-Pointer Propofol reduces doxorubicin-imposed nitrative and oxidative stress. Black-Right-Pointing-Pointer Propofol suppresses mitochondrion-, p53- and PKC-related apoptotic signaling. Black-Right-Pointing-Pointer Propofol ameliorates apoptosis and

  11. Tetramethylpyrazine identified by a network pharmacology approach ameliorates methotrexate-induced oxidative organ injury.

    PubMed

    Zhang, Bo; Lu, Cheng; Bai, Ming; He, Xiaojuan; Tan, Yong; Bian, Yanqin; Xiao, Cheng; Zhang, Ge; Lu, Aiping; Li, Shao

    2015-12-04

    Tetramethylpyrazine (TMP) is one of the active constituents extracted from a frequently used herb, Ligusticum wallichii Franchat (Chuan-Xiong in Chinese), in traditional Chinese medicine. TMP can exert multiple pharmacological actions such as anti-inflammatory, anti-oxidative damage, anti-platelet and neuroprotective effects, and its applications deserve further explored. This study aimed to determine the new role of TMP identified by a network pharmacology approach to alleviate the methotrexate (MTX)-induced oxidative injury and characterize their mechanism of combinational actions. A network pharmacology-based screening strategy is applied for target profile prediction and pharmacological characterization of herbal compounds, which is used to guide the following in vitro and in vivo experiments. The effect of herbal compounds identified by network pharmacology approaches to reduce the toxicity of MTX was assessed by MTX-induced rat toxicity model. The potential targets of TMP in this study were evaluated using standard protocols provided by Cerep, Inc. This strategy identified TMP from Ligusticum wallichii Franchat as a potent compound for ameliorating the oxidative organ injury of MTX. According to the predicted target profiles of TMP, a possible mechanism of the abrogation of MTX-induced toxicity is that TMP could upregulate cAMP by inhibiting phosphodiesterase (PDE) 10A2 activity. Another novel finding is that the competitive binding and antagonistic effects of TMP on adenosine receptor 2A and 2B appear to play important roles in the TMP-mediated reversal of MTX-induced hepatic injury. TMP identified by a network pharmacology approach could ameliorate MTX-induced oxidative organ injury. This study provides important evidence for the preclinical evaluation of TMP and MTX as a novel combinatorial remedy. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  12. PACAP induces plasticity at autonomic synapses by nAChR-dependent NOS1 activation and AKAP-mediated PKA targeting.

    PubMed

    Jayakar, Selwyn S; Pugh, Phyllis C; Dale, Zack; Starr, Eric R; Cole, Samantha; Margiotta, Joseph F

    2014-11-01

    Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic neuropeptide found at synapses throughout the central and autonomic nervous system. We previously found that PACAP engages a selective G-protein coupled receptor (PAC1R) on ciliary ganglion neurons to rapidly enhance quantal acetylcholine (ACh) release from presynaptic terminals via neuronal nitric oxide synthase (NOS1) and cyclic AMP/protein kinase A (PKA) dependent processes. Here, we examined how PACAP stimulates NO production and targets resultant outcomes to synapses. Scavenging extracellular NO blocked PACAP-induced plasticity supporting a retrograde (post- to presynaptic) NO action on ACh release. Live-cell imaging revealed that PACAP stimulates NO production by mechanisms requiring NOS1, PKA and Ca(2+) influx. Ca(2+)-permeable nicotinic ACh receptors composed of α7 subunits (α7-nAChRs) are potentiated by PKA-dependent PACAP/PAC1R signaling and were required for PACAP-induced NO production and synaptic plasticity since both outcomes were drastically reduced following their selective inhibition. Co-precipitation experiments showed that NOS1 associates with α7-nAChRs, many of which are perisynaptic, as well as with heteromeric α3*-nAChRs that generate the bulk of synaptic activity. NOS1-nAChR physical association could facilitate NO production at perisynaptic and adjacent postsynaptic sites to enhance focal ACh release from juxtaposed presynaptic terminals. The synaptic outcomes of PACAP/PAC1R signaling are localized by PKA anchoring proteins (AKAPs). PKA regulatory-subunit overlay assays identified five AKAPs in ganglion lysates, including a prominent neuronal subtype. Moreover, PACAP-induced synaptic plasticity was selectively blocked when PKA regulatory-subunit binding to AKAPs was inhibited. Taken together, our findings indicate that PACAP/PAC1R signaling coordinates nAChR, NOS1 and AKAP activities to induce targeted, retrograde plasticity at autonomic synapses. Such

  13. Targeting the transcription factor Nrf2 to ameliorate oxidative stress and inflammation in chronic kidney disease.

    PubMed

    Ruiz, Stacey; Pergola, Pablo E; Zager, Richard A; Vaziri, Nosratola D

    2013-06-01

    Oxidative stress and inflammation are mediators in the development and progression of chronic kidney disease (CKD) and its complications, and they are inseparably linked as each begets and amplifies the other. CKD-associated oxidative stress is due to increased production of reactive oxygen species (ROS) and diminished antioxidant capacity. The latter is largely caused by impaired activation of Nrf2, the transcription factor that regulates genes encoding antioxidant and detoxifying molecules. Protective effects of Nrf2 are evidenced by amelioration of oxidative stress, inflammation, and kidney disease in response to natural Nrf2 activators in animal models, while Nrf2 deletion amplifies these pathogenic pathways and leads to autoimmune nephritis. Given the role of impaired Nrf2 activity in CKD-induced oxidative stress and inflammation, interventions aimed at restoring Nrf2 may be effective in retarding CKD progression. Clinical trials of the potent Nrf2 activator bardoxolone methyl showed significant improvement in renal function in CKD patients with type 2 diabetes. However, due to unforeseen complications the BEACON trial, which was designed to investigate the effect of this drug on time to end-stage renal disease or cardiovascular death in patients with advanced CKD, was prematurely terminated. This article provides an overview of the role of impaired Nrf2 activity in the pathogenesis of CKD-associated oxidative stress and inflammation and the potential utility of targeting Nrf2 in the treatment of CKD.

  14. Role of curcuminoids in ameliorating oxidative modification in β-thalassemia/Hb E plasma proteome.

    PubMed

    Weeraphan, Churat; Srisomsap, Chantragan; Chokchaichamnankit, Daranee; Subhasitanont, Pantipa; Hatairaktham, Suneerat; Charoensakdi, Ratiya; Panichkul, Narumol; Siritanaratkul, Noppadol; Fucharoen, Suthat; Svasti, Jisnuson; Kalpravidh, Ruchaneekorn W

    2013-03-01

    Thalassemic patients often exhibit high levels of oxidative stress and iron overload, which can lead to hazardous complications. Curcuminoids, extracted from the spice turmeric, are known to have antioxidant and iron-chelating properties and have been proposed as a potential upstream therapy of thalassemia. Here we have applied proteomic techniques to study the protein profile and oxidative damage in the plasma of β-thalassemia/Hb E patients before and after treatment with curcuminoids. In this study, 10 β-thalassemia/Hb E patients were treated with 500 mg curcuminoids daily for 12 months. The plasma protein profile and protein carbonyl content were determined at baseline, 6 and 12 months using two-dimensional fluorescence difference gel electrophoresis and carbonyl immunoblotting, respectively. Other hematological, clinical, and biochemical parameters were also analyzed. Twenty-six spots, identified as coagulation factors and proteins involved in iron homeostasis, showed significantly decreased intensity in thalassemic plasma, compared to those of normal subjects. Treatment with curcuminoids up-regulated the plasma levels of these proteins and reduced their oxidative damage. Serum non-transferrin bound iron, platelet factor-3 like activity, oxidative stress parameters and antioxidant enzymes were also improved after curcuminoids treatment. This study is the first proteomic study of plasma in the thalassemic state and also shows the ameliorating role of curcuminoids towards oxidative stress and iron overload in the plasma proteome.

  15. Role of hydrotherapy in the amelioration of oxidant-antioxidant status in rheumatoid arthritis patients.

    PubMed

    Mateen, Somaiya; Moin, Shagufta; Khan, Abdul Q; Zafar, Atif; Fatima, Naureen; Shahzad, Sumayya

    2017-06-14

    Rheumatoid arthritis (RA) is an inflammatory autoimmune disease. Reactive oxygen species (ROS) are involved in the pathophysiology of RA. Moderate intensity exercises have been reported to have anti-oxidant and anti-inflammatory effects. The aim of this study was to evaluate the effect of hydrotherapy on oxidant-antioxidant status in RA patients. Forty RA patients and 30 age- and sex-matched healthy controls were included in this study. RA patients were subdivided into two groups: the first group (n = 20) received treatment with conventional RA drugs, while the second group (n = 20) received hydrotherapy along with the conventional drugs for a period of 12 weeks. Disease Activity Score of 28 joints (DAS-28), ROS level, protein oxidation, lipid peroxidation, DNA damage and the activities of antioxidant enzymes were evaluated before and after 12 weeks of treatment. RA patients showed a significant change in the oxidative stress biomarkers (ROS, P < 0.01; ferric reducing antioxidant potential, P < 0.001; malondialdehyde, P < 0.01; protein carbonyl, P < 0.001; tail length, P < 0.05) and decrease in the activities of anti-oxidant enzymes (superoxide dismutase [SOD], P < 0.01; glutathione peroxidase [GPx], P < 0.001). Conventional drug treatment has not produced any significant change in these parameters. However, cotreatment of drugs with hydrotherapy has decreased protein, lipid and DNA oxidation by increasing the activities of antioxidant enzymes (SOD and GPx). Our results indicate that hydrotherapy along with drugs has reduced the severity of disease (DAS-28) by ameliorating the oxidant-antioxidant status in RA patients. Thus, in addition to conventional drugs, RA patients should be advised to have hydrotherapy (moderate intensity exercise) in their treatment regimen. © 2017 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.

  16. Sesamin Ameliorates High-Fat Diet-Induced Dyslipidemia and Kidney Injury by Reducing Oxidative Stress.

    PubMed

    Zhang, Ruijuan; Yu, Yan; Deng, Jianjun; Zhang, Chao; Zhang, Jinghua; Cheng, Yue; Luo, Xiaoqin; Han, Bei; Yang, Haixia

    2016-05-09

    The study explored the protective effect of sesamin against lipid-induced renal injury and hyperlipidemia in a rat model. An animal model of hyperlipidemia was established in Sprague-Dawley rats. Fifty-five adult Sprague-Dawley rats were divided into five groups. The control group was fed a standard diet, while the other four groups were fed a high-fat diet for 5 weeks to induce hyperlipidemia. Three groups received oral sesamin in doses of 40, 80, or 160 mg/(kg·day). Seven weeks later, the blood lipids, renal function, antioxidant enzyme activities, and hyperoxide levels in kidney tissues were measured. The renal pathological changes and expression levels of collagen type IV (Col-IV) and α-smooth muscle actin (α-SMA) were analyzed. The administration of sesamin improved the serum total cholesterol, triglyceride, low-density lipoprotein cholesterol, apolipoprotein-B, oxidized-low-density lipoprotein, and serum creatinine levels in hyperlipidemic rats, while it increased the high-density lipoprotein cholesterol and apolipoprotein-A levels. Sesamin reduced the excretion of 24-h urinary protein and urinary albumin and downregulated α-SMA and Col-IV expression. Moreover, sesamin ameliorated the superoxide dismutase activity and reduced malondialdehyde levels in kidney tissue. Sesamin could mediate lipid metabolism and ameliorate renal injury caused by lipid metabolism disorders in a rat model of hyperlipidemia.

  17. Sesamin Ameliorates High-Fat Diet–Induced Dyslipidemia and Kidney Injury by Reducing Oxidative Stress

    PubMed Central

    Zhang, Ruijuan; Yu, Yan; Deng, Jianjun; Zhang, Chao; Zhang, Jinghua; Cheng, Yue; Luo, Xiaoqin; Han, Bei; Yang, Haixia

    2016-01-01

    The study explored the protective effect of sesamin against lipid-induced renal injury and hyperlipidemia in a rat model. An animal model of hyperlipidemia was established in Sprague-Dawley rats. Fifty-five adult Sprague-Dawley rats were divided into five groups. The control group was fed a standard diet, while the other four groups were fed a high-fat diet for 5 weeks to induce hyperlipidemia. Three groups received oral sesamin in doses of 40, 80, or 160 mg/(kg·day). Seven weeks later, the blood lipids, renal function, antioxidant enzyme activities, and hyperoxide levels in kidney tissues were measured. The renal pathological changes and expression levels of collagen type IV (Col-IV) and α-smooth muscle actin (α-SMA) were analyzed. The administration of sesamin improved the serum total cholesterol, triglyceride, low-density lipoprotein cholesterol, apolipoprotein-B, oxidized-low-density lipoprotein, and serum creatinine levels in hyperlipidemic rats, while it increased the high-density lipoprotein cholesterol and apolipoprotein-A levels. Sesamin reduced the excretion of 24-h urinary protein and urinary albumin and downregulated α-SMA and Col-IV expression. Moreover, sesamin ameliorated the superoxide dismutase activity and reduced malondialdehyde levels in kidney tissue. Sesamin could mediate lipid metabolism and ameliorate renal injury caused by lipid metabolism disorders in a rat model of hyperlipidemia. PMID:27171111

  18. Protective effect of potato peel powder in ameliorating oxidative stress in streptozotocin diabetic rats.

    PubMed

    Singh, Nandita; Kamath, Vasudeva; Rajini, P S

    2005-06-01

    The potential of dietary potato peel (PP) powder in ameliorating oxidative stress (OS) and hyperglycemia was investigated in streptozotocin (STZ)-induced diabetic rats. In a 4-week feeding trial, incorporation of potato peel powder (5 and 10%) in the diet of diabetic rats was found to significantly reduce the plasma glucose level and also reduce drastically the polyuria of STZ diabetic rats. The total food intake was significantly reduced in the diabetic rats fed 10% PP powder compared to the control diabetic rats. However, the body weight gain over 28 days was nearly four times greater in PP powder supplemented diabetic rats (both at 5 and 10%) compared to the control diabetic rats. PP powder in the diet also decreased the elevated activities of serum transaminases (ALT and AST) and nearly normalized the hepatic MDA and GSH levels as well as the activities of specific antioxidant enzymes in liver of diabetic rats. The result of these studies clearly establishes the modulatory propensity of PP against diabetes induced alterations. Considering that potato peels are discarded as waste and not effectively utilized, these results suggest the possibility that PP waste could be effectively used as an ingredient in health and functional food to ameliorate certain disease states such as diabetes.

  19. Ameliorative effect of Phytocee™ Cool against carbon tetrachloride-induced oxidative stress.

    PubMed

    Joseph, Joshua Allan; Ayyappan, Usha Parackal Thachappully; Sasidharan, Suja Rani; Mutyala, Sridhar; Goudar, Krishnagouda Shankargouda; Agarwal, Amit

    2014-10-01

    Antioxidants from natural sources have a major role in reversing the effects of oxidative stress and promoting health, growth and productivity in animals. This study was undertaken to investigate the possible antioxidant activity and hepatoprotective effects of Phytocee™ Cool on carbon tetrachloride (CCl4) induced oxidative stress and liver damage in rats. Animals were pretreated with Phytocee™ Cool for 10 days and were challenged with CCl4 (1:1 v/v) in olive oil on the 10(th) day. After 24 h of CCl4 administration blood was collected and markers of hepatocellular damage aspartate aminotransferase (AST), alanine aminotransferase (ALT) were evaluated. Rats were sacrificed and oxidative stress in liver was estimated using malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD) and catalase. CCl4 caused a significant increase in serum AST, ALT, hepatic MDA and GSH levels, whereas the SOD and catalase activities were decreased. Phytocee™ Cool pretreatment attenuated the MDA, AST ALT levels and increased the activities of SOD and catalase. Phytocee™ Cool demonstrated antioxidant potential and hepatoprotective effects and plausibly be used in the amelioration of oxidative stress.

  20. Ameliorative effect of Phytocee™ Cool against carbon tetrachloride-induced oxidative stress

    PubMed Central

    Joseph, Joshua Allan; Ayyappan, Usha Parackal Thachappully; Sasidharan, Suja Rani; Mutyala, Sridhar; Goudar, Krishnagouda Shankargouda; Agarwal, Amit

    2014-01-01

    Background: Antioxidants from natural sources have a major role in reversing the effects of oxidative stress and promoting health, growth and productivity in animals. Objective: This study was undertaken to investigate the possible antioxidant activity and hepatoprotective effects of Phytocee™ Cool on carbon tetrachloride (CCl4) induced oxidative stress and liver damage in rats. Materials and Methods: Animals were pretreated with Phytocee™ Cool for 10 days and were challenged with CCl4 (1:1 v/v) in olive oil on the 10th day. After 24 h of CCl4 administration blood was collected and markers of hepatocellular damage aspartate aminotransferase (AST), alanine aminotransferase (ALT) were evaluated. Rats were sacrificed and oxidative stress in liver was estimated using malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD) and catalase. Results: CCl4 caused a significant increase in serum AST, ALT, hepatic MDA and GSH levels, whereas the SOD and catalase activities were decreased. Phytocee™ Cool pretreatment attenuated the MDA, AST ALT levels and increased the activities of SOD and catalase. Conclusion: Phytocee™ Cool demonstrated antioxidant potential and hepatoprotective effects and plausibly be used in the amelioration of oxidative stress. PMID:25276070

  1. Hesperidin ameliorates heavy metal induced toxicity mediated by oxidative stress in brain of Wistar rats.

    PubMed

    Khan, Mohammad Haaris Ajmal; Parvez, Suhel

    2015-01-01

    Cadmium (Cd) induces neurotoxicity owing to its highly deleterious capacity to cross the blood brain barrier (BBB). Recent studies have provided insights on antioxidant properties of bioflavonoids which have emerged as potential therapeutic and nutraceutical agents. The aim of our study was to examine the hypothesis that hesperidin (HP) ameliorates oxidative stress and may have mitigatory effects in the extent of heavy metal-induced neurotoxicity. Cd (3mg/kg body weight) was administered subcutaneously for 21 days while HP (40 mg/kg body weight) was administered orally once every day. The results of the current investigation demonstrate significant elevated levels of oxidative stress markers such as lipid peroxidation (LPO) and protein carbonyl (PC) along with significant depletion in the activity of non-enzymatic antioxidants like glutathione (GSH) and non-protein thiol (NP-SH) and enzymatic antioxidants in the Cd treated rats' brain. Activity of neurotoxicity biomarkers such as acetylcholinesterase (AchE), monoamine oxidase (MAO) and total ATPase were also altered significantly and HP treatment significantly attenuated the altered levels of oxidative stress and neurotoxicity biomarkers while salvaging the antioxidant sentinels of cells to near normal levels thus exhibiting potent antioxidant and neuroprotective effects on the brain tissue against oxidative damage in Cd treated rodent model.

  2. C-phycocyanin ameliorates doxorubicin-induced oxidative stress and apoptosis in adult rat cardiomyocytes.

    PubMed

    Khan, Mahmood; Varadharaj, Saradhadevi; Shobha, Jagdish C; Naidu, Madireddi U; Parinandi, Narasimham L; Kutala, Vijay Kumar; Kuppusamy, Periannan

    2006-01-01

    Doxorubicin (DOX), a potent antineoplastic agent, poses limitations for its therapeutic use due to the associated risk of developing cardiomyopathy and congestive heart failure. The cardiotoxicity of doxorubicin is associated with oxidative stress and apoptosis. We have recently shown that Spirulina, a blue-green alga with potent antioxidant properties, offered significant protection against doxorubicin-induced cardiotoxicity in mice. The aim of the present study was to establish the possible protective role of C-phycocyanin, one of the active ingredients of Spirulina, against doxorubicin-induced oxidative stress and apoptosis. The study was carried out using cardiomyocytes isolated from adult rat hearts. Doxorubicin significantly enhanced the formation of reactive oxygen species (ROS) in cells as measured by the 2',7'-dichlorodihydrofluorescein diacetate and dihydroethidium fluorescence. The doxorubicin-induced reactive oxygen species formation was significantly attenuated in cells pretreated with C-phycocyanin. It was further observed that the doxorubicin-induced DNA fragmentation and apoptosis, as assayed by TUNEL assay and flow cytometry coupled with BrdU-FITC/propidium iodide staining, were markedly attenuated by C-phycocyanin. C-phycocyanin also significantly attenuated the doxorubicin-induced increase in the expression of Bax protein, release of cytochrome c, and increase in the activity of caspase-3 in cells. In summary, C-phycocyanin ameliorated doxorubicin-induced oxidative stress and apoptosis in cardiomyocytes. This study further supports the crucial role of the antioxidant nature of C-phycocyanin in its cardioprotection against doxorubicin-induced oxidative stress and apoptosis.

  3. Inosine ameliorates the effects of hemin-induced oxidative stress in broilers.

    PubMed

    Seaman, Christen; Moritz, Joseph; Falkenstein, Elizabeth; Van Dyke, Knox; Casotti, Giovanni; Klandorf, Hillar

    2008-12-01

    The objective of these studies was to determine whether inosine, a precursor of the antioxidant uric acid, can ameliorate hemin-induced oxidative stress. Dietary inclusion of inosine was begun either before or after hemin-induced oxidative stress. Broilers (4 weeks) were divided into four treatment groups (Control, Hemin, Inosine, Hemin/Inosine). Throughout the study control birds (n=10) were injected daily with a buffer solution, while hemin birds (n=10) were injected daily (i.p.) with a 20 mg/kg body weight hemin buffer solution. Leukocyte oxidative activity (LOA) and concentrations of plasma uric acid (PUA) were measured. Results from the first study showed that hemin birds had increased levels of LOA (P=0.0333) and lower PUA (P=0.1174). On day 10, control and hemin birds were subdivided into inosine birds (n=5) and hemin/inosine birds (n=5). These birds were given 0.6 M/kg of feed/day of dry inosine. Plasma concentrations of uric acid and LOA were then measured on day 15. Results showed that inosine raised concentrations of PUA (P=0.0001) and lowered LOA (P=0.0044) as induced by hemin. In the second study pretreatment of broilers with hemin prevented the increase in LOA induced by hemin (P=0.0001). These results show that modulating the concentrations of uric acid can markedly affect oxidative stress.

  4. Resveratrol-enhanced autophagic flux ameliorates myocardial oxidative stress injury in diabetic mice

    PubMed Central

    Wang, Bo; Yang, Qing; Sun, Yuan-yuan; Xing, Yi-fan; Wang, Ying-bin; Lu, Xiao-ting; Bai, Wen-wu; Liu, Xiao-qiong; Zhao, Yu-xia

    2014-01-01

    Autophagic dysfunction is observed in diabetes mellitus. Resveratrol has a beneficial effect on diabetic cardiomyopathy. Whether the resveratrol-induced improvement in cardiac function in diabetes is via regulating autophagy remains unclear. We investigated the mechanisms underlying resveratrol-mediated protection against heart failure in diabetic mice, with a focus on the role of sirtuin 1 (SIRT1) in regulating autophagic flux. Diabetic cardiomyopathy in mice was induced by streptozotocin (STZ). Long-term resveratrol treatment improved cardiac function, ameliorated oxidative injury and reduced apoptosis in the diabetic mouse heart. Western blot analysis revealed that resveratrol decreased p62 protein expression and promoted SIRT1 activity and Rab7 expression. Inhibiting autophagic flux with bafilomycin A1 increased diabetic mouse mortality and attenuated resveratrol-induced down-regulation of p62, but not SIRT1 activity or Rab7 expression in diabetic mouse hearts. In cultured H9C2 cells, redundant or overactive H2O2 increased p62 and cleaved caspase 3 expression as well as acetylated forkhead box protein O1 (FOXO1) and inhibited SIRT1 expression. Sirtinol, SIRT1 and Rab7 siRNA impaired the resveratrol amelioration of dysfunctional autophagic flux and reduced apoptosis under oxidative conditions. Furthermore, resveratrol enhanced FOXO1 DNA binding at the Rab7 promoter region through a SIRT1-dependent pathway. These results highlight the role of the SIRT1/FOXO1/Rab7 axis in the effect of resveratrol on autophagic flux in vivo and in vitro, which suggests a therapeutic strategy for diabetic cardiomyopathy. PMID:24889822

  5. Camel milk ameliorates hyperglycaemia and oxidative damage in type-1 diabetic experimental rats.

    PubMed

    Meena, Sunita; Rajput, Yudhishthir S; Pandey, Amit K; Sharma, Rajan; Singh, Raghvendar

    2016-08-01

    This study was designed to assess anti-diabetic potential of goat, camel, cow and buffalo milk in streptozotocin (STZ) induced type 1 diabetic albino wistar rats. A total of 48 rats were taken for the study where one group was kept as non-diabetic control group (8 rats) while others (40 rats) were made diabetic by STZ (50 mg/kg of body weight) injection. Among diabetic rats, a control group (8 rats) was kept and referred as diabetic control whereas other four groups (8 rats each) of diabetic rats were fed on 50 ml of goat or camel or cow or buffalo milk for 4 weeks. All the rats (non-diabetic and diabetic) were maintained on standard diet for four weeks. STZ administration resulted in enhancement of glucose, total cholesterol, triglyceride, low density lipoprotein, HbA1c and reduction in high density lipoprotein in plasma and lowering of antioxidative enzymes (catalase, glutathione peroxidase and superoxide dismutase) activities in pancreas, kidney, liver and RBCs, coupled with enhanced levels of TBARS and protein carbonyls in pancreas, kidney, liver and plasma. OGTT carried out at the end of 4 week milk feeding indicated that all milks helped in early maintenance of glucose level. All milks reduced atherogenic index. In camel milk fed diabetic group, insulin concentration enhanced to level noted for non-diabetic control while goat, cow and buffalo milk failed to restore insulin level. HbA1c level was also restored only in camel milk fed diabetic group. The level of antioxidative enzymes (catalase, GPx and SOD) in pancreas enhanced in all milk fed groups. Camel milk and to a reasonable extent goat milk reduced formation of TBARS and PCs in tissues and blood. It can be concluded that camel milk ameliorates hyperglycaemia and oxidative damage in type-1 diabetic experimental rats. Further, only camel milk completely ameliorated oxidative damage in pancreas and normalised insulin level.

  6. Quercetin, a Flavonoid Antioxidant, Ameliorated Procarbazine-Induced Oxidative Damage to Murine Tissues.

    PubMed

    Olayinka, Ebenezer Tunde; Ore, Ayokanmi; Adeyemo, Oluwatobi Adewumi; Ola, Olaniyi Solomon; Olotu, Olaoluwa Oluwaseun; Echebiri, Roseline Chinonye

    2015-04-28

    Procarbazine (PCZ) (indicated in Hodgkin's disease), is an alkylating agent known to generate free radicals in vivo, while Quercetin (QCT) is a flavonoid antioxidant with proven free radical scavenging capacity. This study investigated the protective effects of QCT on PCZ-induced oxidative damage in the rat. Male Wistar rats (160-180 g) were randomized into five groups (n = 5/group): I (control), II PCZ-treated (2 mg/kg body weight (bw) for seven days); III pre-treated with QCT (20 mg/kg bw) for seven days, followed by PCZ for seven days; IV co-treated with PCZ and QCT for seven days and V administered QCT alone for seven days. PCZ caused a significant increase in plasma total bilirubin, urea, and creatinine when compared with control (P < 0.05). Similarly, plasma activities of alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyl transferase (γ-GT) were significantly increased in the PCZ-treated group relative to control. Furthermore, PCZ caused a significant decrease in the activities of hepatic superoxide dismutase (SOD), catalase (CAT) and glutathione-S-transferase (GST) as well as levels of ascorbic acid (AA) and glutathione (GSH). This was followed by a significant increase in hepatic malondialdehyde (MDA) content. However, QCT pre-treatment and co-treatment ameliorated the PCZ-induced changes in plasma levels of urea, creatinine, and bilirubin as well as the activities of ALP, AST, ALT, and GGT. QCT also ameliorated hepatic AA and GSH levels and the activities of SOD, CAT, and GST. This all suggests that QCT protected against PCZ-induced oxidative damage in rats.

  7. Nitric Oxide Ameliorates Zinc Oxide Nanoparticles Phytotoxicity in Wheat Seedlings: Implication of the Ascorbate–Glutathione Cycle

    PubMed Central

    Tripathi, Durgesh K.; Mishra, Rohit K.; Singh, Swati; Singh, Samiksha; Vishwakarma, Kanchan; Sharma, Shivesh; Singh, Vijay P.; Singh, Prashant K.; Prasad, Sheo M.; Dubey, Nawal K.; Pandey, Avinash C.; Sahi, Shivendra; Chauhan, Devendra K.

    2017-01-01

    The present study investigates ameliorative effects of nitric oxide (NO) against zinc oxide nanoparticles (ZnONPs) phytotoxicity in wheat seedlings. ZnONPs exposure hampered growth of wheat seedlings, which coincided with reduced photosynthetic efficiency (Fv/Fm and qP), due to increased accumulation of zinc (Zn) in xylem and phloem saps. However, SNP supplementation partially mitigated the ZnONPs-mediated toxicity through the modulation of photosynthetic activity and Zn accumulation in xylem and phloem saps. Further, the results reveal that ZnONPs treatments enhanced levels of hydrogen peroxide and lipid peroxidation (as malondialdehyde; MDA) due to severely inhibited activities of the following ascorbate–glutatione cycle (AsA–GSH) enzymes: ascorbate peroxidase, glutathione reductase, monodehydroascorbate reductase and dehydroascorbate reductase, and its associated metabolites ascorbate and glutathione. In contrast to this, the addition of SNP together with ZnONPs maintained the cellular functioning of the AsA–GSH cycle properly, hence lesser damage was noticed in comparison to ZnONPs treatments alone. The protective effect of SNP against ZnONPs toxicity on fresh weight (growth) can be reversed by 2-(4carboxy-2-phenyl)-4,4,5,5-tetramethyl- imidazoline-1-oxyl-3-oxide, a NO scavenger, and thus suggesting that NO released from SNP ameliorates ZnONPs toxicity. Overall, the results of the present study have shown the role of NO in the reducing of ZnONPs toxicity through the regulation of accumulation of Zn as well as the functioning of the AsA–GSH cycle. PMID:28220127

  8. Nitric Oxide Ameliorates Zinc Oxide Nanoparticles Phytotoxicity in Wheat Seedlings: Implication of the Ascorbate-Glutathione Cycle.

    PubMed

    Tripathi, Durgesh K; Mishra, Rohit K; Singh, Swati; Singh, Samiksha; Vishwakarma, Kanchan; Sharma, Shivesh; Singh, Vijay P; Singh, Prashant K; Prasad, Sheo M; Dubey, Nawal K; Pandey, Avinash C; Sahi, Shivendra; Chauhan, Devendra K

    2017-01-01

    The present study investigates ameliorative effects of nitric oxide (NO) against zinc oxide nanoparticles (ZnONPs) phytotoxicity in wheat seedlings. ZnONPs exposure hampered growth of wheat seedlings, which coincided with reduced photosynthetic efficiency (Fv/Fm and qP), due to increased accumulation of zinc (Zn) in xylem and phloem saps. However, SNP supplementation partially mitigated the ZnONPs-mediated toxicity through the modulation of photosynthetic activity and Zn accumulation in xylem and phloem saps. Further, the results reveal that ZnONPs treatments enhanced levels of hydrogen peroxide and lipid peroxidation (as malondialdehyde; MDA) due to severely inhibited activities of the following ascorbate-glutatione cycle (AsA-GSH) enzymes: ascorbate peroxidase, glutathione reductase, monodehydroascorbate reductase and dehydroascorbate reductase, and its associated metabolites ascorbate and glutathione. In contrast to this, the addition of SNP together with ZnONPs maintained the cellular functioning of the AsA-GSH cycle properly, hence lesser damage was noticed in comparison to ZnONPs treatments alone. The protective effect of SNP against ZnONPs toxicity on fresh weight (growth) can be reversed by 2-(4carboxy-2-phenyl)-4,4,5,5-tetramethyl- imidazoline-1-oxyl-3-oxide, a NO scavenger, and thus suggesting that NO released from SNP ameliorates ZnONPs toxicity. Overall, the results of the present study have shown the role of NO in the reducing of ZnONPs toxicity through the regulation of accumulation of Zn as well as the functioning of the AsA-GSH cycle.

  9. Resveratrol ameliorates cisplatin-induced oxidative injury in New Zealand rabbits.

    PubMed

    Cigremis, Yilmaz; Akgoz, Muslum; Ozen, Hasan; Karaman, Musa; Kart, Asım; Gecer, Murat; Atalan, Gultekin

    2015-08-01

    This study investigated the preventive role of resveratrol in cisplatin-induced nephrotoxicity. The study used groups of New Zealand rabbits that were treated as follows: group C (cisplatin treated), group R (resveratrol treated), group R+C (resveratrol + cisplatin treatment), and group E (control group). Kidney levels of glutathione were significantly lower in group C than in groups E and R, whereas glutathione levels in group R+C were found to be similar to the control values. Malondialdehyde levels in group C were significantly higher than in groups E and R. However, malondialdehyde levels in group R+C were similar to group E. Kidney levels of nitric oxide were significantly higher in the cisplatin group than in the control, whereas nitric oxide levels were at basal values in group R+C. Cisplatin treatment significantly reduced kidney levels of glutathione peroxidase, superoxide dismutase, and catalase activity compared with those of group E, whereas resveratrol treatment significantly increased levels of glutathione peroxidase, superoxide dismutase, and catalase activity in group R+C. However, cisplatin injection did not affect mRNA levels of glutathione peroxidase, superoxide dismutase, or catalase enzymes. Histopathological and immunohistochemical analyses indicated that cisplatin caused kidney damage, which was mostly prevented by resveratrol treatment. In conclusion, resveratrol ameliorates cisplatin-induced oxidative injury in the kidney of rabbit.

  10. Amelioration of alcohol-induced hepatotoxicity and oxidative stress in rats by Acorus calamus.

    PubMed

    Ilaiyaraja, N; Khanum, Farhath

    2011-12-01

    The protective effect of a methanolic extract (ME) of Acorus calamus against alcohol-induced hepatotoxicity and oxidative stress was studied in rats. The in vitro assays using DPPH and ABTS showed a strong antioxidant activity of the extract with the total polyphenolic content of 156 mg/g. Chronic ethanol administration causes an increase in oxidative stress and tissue injury with decreased antioxidant status. In this study, continuous administration of ethanol (7.9 g/kg body weight/day) for a period of 6 weeks resulted in a significant (p < .001) increase in the levels of serum aspartate aminotransferase, serum alanine aminotransferase, alkaline phospahatase, and bilirubin with the decreased level of total antioxidant status. Moreover, the levels of lipid peroxidation markers (malondialdehyde and hydroperoxides) as well as protein carbonyl content were also increased (p < .001), whereas the levels of non-enzymic antioxidants (glutathione, vitamin C, and vitamin E) decreased significantly in the liver tissues of ethanol-administered control rats. Pretreatment of rats with ME at doses of 300 and 600 g/kg body weight before alcohol administration significantly reduced the hepatic marker enzymes, level of lipid peroxidation, and protein oxidation, and increased the enzymatic and non-enzymatic antioxidant levels in liver. These observations were supplemented by histopathological examination of liver sections. Overall, the present study shows that the administration of ME ameliorates the antioxidant status as well as protects against the toxic effects of ethanol in rats, thereby suggesting its use as an effective botanical supplement for hepatoprotection.

  11. Comparison of intestinal warm ischemic injury in PACAP knockout and wild-type mice.

    PubMed

    Ferencz, Andrea; Kiss, Peter; Weber, Gyorgy; Helyes, Zsuzsanna; Shintani, Norihito; Baba, Akemichi; Reglodi, Dora

    2010-11-01

    Pituitary adenylate cyclase-activating polypeptide (PACAP) is present in the gastrointestinal tract and plays a central role in the intestinal physiology, mainly in the secretion and motility. The aim of our study was to compare the ischemic injury in wild-type and PACAP-38 knockout mice following warm mesenteric small bowel ischemia. Warm ischemia groups were designed with occlusion of superior mesenteric artery for 1, 3, and 6 h in wild-type (n = 10 in each group) and PACAP-38 knockout (n = 10 in each group) mice. Small bowel biopsies were collected after laparotomy (control) and at the end of the ischemia periods. To determine oxidative stress parameters, malondialdehyde (MDA), reduced glutathione (GSH), and superoxide dismutase (SOD) were measured. Tissue damage was analyzed by qualitative and quantitative methods on hematoxylin/eosin-stained sections. In PACAP-38 knockout animals, tissue MDA increased significantly after 3 and 6 h ischemia (133.97 ± 6,2; 141.86 ± 5,8) compared to sham-operated (100.92 ± 3,6) and compared to wild-type results (112.8 ± 2,1; 118.4 ± 1.03 μmol/g, p < 0.05). Meanwhile, tissue concentration of GSH and activity of SOD decreased significantly in knockout mice compared to wild-type form (GSH, 795.97 ± 10.4; 665.1 ± 8,8 vs. 893.23 ± μmol/g; SOD, 94.4 ± 1.4; 81.2 ± 3.9 vs. 208.09 ± 3,7 IU/g). Qualitative and quantitative histological results showed destruction of the mucous, submucous layers, and crypts in knockout mice compared to wild-type tissues. These processes correlated with the warm ischemia periods. Our present results propose an important protective effect of endogenous PACAP-38 against intestinal warm ischemia, which provides basis for further investigation to elucidate the mechanism of this protective effect.

  12. The cannabinoid TRPA1 agonist cannabichromene inhibits nitric oxide production in macrophages and ameliorates murine colitis

    PubMed Central

    Romano, B; Borrelli, F; Fasolino, I; Capasso, R; Piscitelli, F; Cascio, MG; Pertwee, RG; Coppola, D; Vassallo, L; Orlando, P; Di Marzo, V; Izzo, AA

    2013-01-01

    Background and Purpose The non-psychotropic cannabinoid cannabichromene is known to activate the transient receptor potential ankyrin-type1 (TRPA1) and to inhibit endocannabinoid inactivation, both of which are involved in inflammatory processes. We examined here the effects of this phytocannabinoid on peritoneal macrophages and its efficacy in an experimental model of colitis. Experimental Approach Murine peritoneal macrophages were activated in vitro by LPS. Nitrite levels were measured using a fluorescent assay; inducible nitric oxide (iNOS), cyclooxygenase-2 (COX-2) and cannabinoid (CB1 and CB2) receptors were analysed by RT-PCR (and/or Western blot analysis); colitis was induced by dinitrobenzene sulphonic acid (DNBS). Endocannabinoid (anandamide and 2-arachidonoylglycerol), palmitoylethanolamide and oleoylethanolamide levels were measured by liquid chromatography-mass spectrometry. Colonic inflammation was assessed by evaluating the myeloperoxidase activity as well as by histology and immunohistochemistry. Key Results LPS caused a significant production of nitrites, associated to up-regulation of anandamide, iNOS, COX-2, CB1 receptors and down-regulation of CB2 receptors mRNA expression. Cannabichromene significantly reduced LPS-stimulated nitrite levels, and its effect was mimicked by cannabinoid receptor and TRPA1 agonists (carvacrol and cinnamaldehyde) and enhanced by CB1 receptor antagonists. LPS-induced anandamide, iNOS, COX-2 and cannabinoid receptor changes were not significantly modified by cannabichromene, which, however, increased oleoylethanolamide levels. In vivo, cannabichromene ameliorated DNBS-induced colonic inflammation, as revealed by histology, immunohistochemistry and myeloperoxidase activity. Conclusion and Implications Cannabichromene exerts anti-inflammatory actions in activated macrophages – with tonic CB1 cannabinoid signalling being negatively coupled to this effect – and ameliorates experimental murine colitis. PMID:23373571

  13. Hydrogen sulfide ameliorates tobacco smoke-induced oxidative stress and emphysema in mice.

    PubMed

    Han, Weihong; Dong, Zheng; Dimitropoulou, Christiana; Su, Yunchao

    2011-10-15

    The mutual interactions between reactive oxygen species, airway inflammation, and alveolar cell death play crucial role in the pathogenesis of chronic obstructive pulmonary disease (COPD). In the present study, we investigated the possibility that hydrogen sulfide (H(2)S) donor sodium hydrosulfide (NaHS) might be a novel option for intervention in COPD. We used a mouse model of tobacco smoke (TS)-induced emphysema. Mice were injected with H(2)S donor NaHS (50 μmol/kg in 0.25 ml phosphate buffer saline, intraperitoneally) or vehicle daily before exposed to TS for 1 h/day, 5 days/week for 12 and 24 weeks. We found that NaHS ameliorated TS-induced increase in mean linear intercepts, the thickness of bronchial walls, and the numbers of total cell counts as well as neutrophils, monocytes, and tumor necrosis factor α in bronchial alveolar lavage. Moreover, NaHS reduced increases in right ventricular systolic pressure, the thickness of pulmonary vascular walls, and the ratio of RV/LV+S in TS-exposed mice. Further, TS exposure for 12 and 24 weeks reduced the protein contents of cystathionine γ-lyase (CGL), cystathionine β-synthetase (CBS), nuclear erythroid-related factor 2 (Nrf2), P(ser473)-Akt, as well as glutathione/oxidized glutathione ratio in the lungs. TS-exposed lungs exhibited large amounts of 8-hydroxyguanine-positive and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells. Treatment with NaHS increased P(ser473)-Akt and attenuated TS-induced reduction of CGL, CBS, and Nrf2 as well as glutathione/oxidized glutathione ratio in the lungs. NaHS also reduced amounts of 8-hydroxyguanine-positive, terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells and active caspase-3 in TS-exposed lungs. Additionally, knocking-down Akt protein abolished the protective effects of NaHS against TS-induced apoptosis and downregulation of Nrf2, CGL, and CBS in pulmonary artery endothelial cells. These results indicate that NaHS protects

  14. Hydrogen Sulfide Ameliorates Tobacco Smoke-Induced Oxidative Stress and Emphysema in Mice

    PubMed Central

    Han, Weihong; Dong, Zheng; Dimitropoulou, Christiana

    2011-01-01

    Abstract Aims The mutual interactions between reactive oxygen species, airway inflammation, and alveolar cell death play crucial role in the pathogenesis of chronic obstructive pulmonary disease (COPD). In the present study, we investigated the possibility that hydrogen sulfide (H2S) donor sodium hydrosulfide (NaHS) might be a novel option for intervention in COPD. Results We used a mouse model of tobacco smoke (TS)-induced emphysema. Mice were injected with H2S donor NaHS (50 μmol/kg in 0.25 ml phosphate buffer saline, intraperitoneally) or vehicle daily before exposed to TS for 1 h/day, 5 days/week for 12 and 24 weeks. We found that NaHS ameliorated TS-induced increase in mean linear intercepts, the thickness of bronchial walls, and the numbers of total cell counts as well as neutrophils, monocytes, and tumor necrosis factor α in bronchial alveolar lavage. Moreover, NaHS reduced increases in right ventricular systolic pressure, the thickness of pulmonary vascular walls, and the ratio of RV/LV+S in TS-exposed mice. Further, TS exposure for 12 and 24 weeks reduced the protein contents of cystathionine γ-lyase (CGL), cystathionine β-synthetase (CBS), nuclear erythroid-related factor 2 (Nrf2), Pser473-Akt, as well as glutathione/oxidized glutathione ratio in the lungs. TS-exposed lungs exhibited large amounts of 8-hydroxyguanine-positive and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells. Treatment with NaHS increased Pser473-Akt and attenuated TS-induced reduction of CGL, CBS, and Nrf2 as well as glutathione/oxidized glutathione ratio in the lungs. NaHS also reduced amounts of 8-hydroxyguanine-positive, terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells and active caspase-3 in TS-exposed lungs. Additionally, knocking-down Akt protein abolished the protective effects of NaHS against TS-induced apoptosis and downregulation of Nrf2, CGL, and CBS in pulmonary artery endothelial cells. Conclusion These

  15. Ameliorative effect of statin therapy on oxidative damage in heart tissue of hypercholesterolemic rabbits.

    PubMed

    Sozer, Volkan

    2015-12-01

    The aim of this study was to investigate the effects of a high-cholesterol diet in the presence and absence of statin on Cu-Zn-superoxide dismutase (Cu,Zn-SOD), malondialdehyde (MDA), protein carbonyl (PCO), and nitric oxide (NO) of blood and heart tissue, the antioxidant activity of serum paraoxonase-1 (PON-1), and on the blood lipid profile of rabbits. The animals were divided into four groups each of which included 10 rabbits. Rabbits in group 1 received a regular rabbit chow diet (normal diet) for 8 weeks; those in group 2 received atorvastatin (0.3 mg atorvastatin per day/kg body weight) for 8 weeks; those in group 3 received high-cholesterol diet for 8 weeks; and those in group 4 received high-cholesterol diet for 4 weeks, a high-cholesterol diet + atorvastatin (0.3 mg atorvastatin per day/kg body weight) for 8 weeks. The parameters were measured by spectrophotometric methods. As expected, the atherogenic diet caused a pronounced increase in lipid profile (not HDL) parameters. Rabbits in group 3 showed higher PCO, MDA, and NO levels in circulating and heart tissue compared to the rabbits in group 1. Atorvastatin has prevented or limited LDL oxidation and has showed constitutively beneficial effects in group 4. Increased LDL-C, PCO, MDA, and NO levels leading to decreasing PON-1 activity thus create a predisposition to atherogenesis in this model. But atorvastatin administration partly ameliorated oxidative damage in heart injury of hypercholesterolemic rabbits. Atorvastatin which functions as a potent antioxidant agent may inhibit this LDL-C oxidation by increasing PON-1 activity in atherogenesis.

  16. Telmisartan ameliorates oxidative stress and subarachnoid haemorrhage-induced cerebral vasospasm.

    PubMed

    Erdi, Fatih; Keskin, Fatih; Esen, Hasan; Kaya, Bulent; Feyzioglu, Bahadir; Kilinc, Ibrahim; Karatas, Yasar; Cuce, Gokhan; Kalkan, Erdal

    2016-03-01

    Growing evidence suggests that oxidative stress is one of the factors contributing to subarachnoid haemorrhage (SAH)-induced cerebral vasospasm. SAH-induced cerebral vasospam alters thioredoxin (Trx) cycle enzymes and thioredoxin-interacting protein (TXNIP) as an important endogenous antioxidant system. In this study, we have explored the effects of telmisartan on the vascular morphological changes, endothelial apoptosis, tissue oxidative stress status and the level of Trx cycle enzymes/ TXNIP in a rabbit SAH model. Forty male New Zealand rabbits were randomly divided into five groups of eight rabbits each: control group, sham group, SAH group, SAH + vehicle group and SAH + telmisartan group. SAH was created by a single cisterna magna blood injection. SAH + telmisartan group received telmisartan treatment (5 mg/kg intraperitoneal, once daily) for 72 h. The brainstem tissue Trx1, Trx2, Trx reductase (TrxR), TrxR1and TXNIP levels were investigated. Total oxidant status (TOS), total antioxidant status (TAS), malondialdehyde (MDA) levels and tumour necrosis factor alpha (TNF alpha) levels were investigated. Basilar artery segments were investigated for cross-sectional area, wall thickness measurements and endothelial apoptosis. Telmisartan treatment restored the lowered level of Trx1, TrxR, TAS and the expression of TrxR1 seen in SAH. Telmisartan treatment also decreased TXNIP expression, TOS, MDA and TNF alpha levels. Morphological changes of cerebral vasospasm were attenuated after treatment. Endothelial apoptosis significantly reduced. Treatment with telmisartan ameliorates oxidative stress and SAH-induced cerebral vasospasm in rabbits. These effects of telmisartan may be associated with downregulation of TXNIP and upregulation of Trx/TrxR.

  17. Coenzyme Q10 ameliorates oxidative stress and prevents mitochondrial alteration in ischemic retinal injury.

    PubMed

    Lee, Dongwook; Kim, Keun-Young; Shim, Myoung Sup; Kim, Sang Yeop; Ellisman, Mark H; Weinreb, Robert N; Ju, Won-Kyu

    2014-04-01

    Coenzyme Q10 (CoQ10) acts by scavenging reactive oxygen species for protecting neuronal cells against oxidative stress in neurodegenerative diseases. We tested whether a diet supplemented with CoQ10 ameliorates oxidative stress and mitochondrial alteration, as well as promotes retinal ganglion cell (RGC) survival in ischemic retina induced by intraocular pressure elevation. A CoQ10 significantly promoted RGC survival at 2 weeks after ischemia. Superoxide dismutase 2 (SOD2) and heme oxygenase-1 (HO-1) expression were significantly increased at 12 h after ischemic injury. In contrast, the CoQ10 significantly prevented the upregulation of SOD2 and HO-1 protein expression in ischemic retina. In addition, the CoQ10 significantly blocked activation of astroglial and microglial cells in ischemic retina. Interestingly, the CoQ10 blocked apoptosis by decreasing caspase-3 protein expression in ischemic retina. Bax and phosphorylated Bad (pBad) protein expression were significantly increased in ischemic retina at 12 h. Interestingly, while CoQ10 significantly decreased Bax protein expression in ischemic retina, CoQ10 showed greater increase of pBad protein expression. Of interest, ischemic injury significantly increased mitochondrial transcription factor A (Tfam) protein expression in the retina at 12 h, however, CoQ10 significantly preserved Tfam protein expression in ischemic retina. Interestingly, there were no differences in mitochondrial DNA content among control- or CoQ10-treated groups. Our findings demonstrate that CoQ10 protects RGCs against oxidative stress by modulating the Bax/Bad-mediated mitochondrial apoptotic pathway as well as prevents mitochondrial alteration by preserving Tfam protein expression in ischemic retina. Our results suggest that CoQ10 may provide neuroprotection against oxidative stress-mediated mitochondrial alterations in ischemic retinal injury.

  18. A structure-function study of PACAP using conformationally restricted analogs: Identification of PAC1 receptor-selective PACAP agonists.

    PubMed

    Ramos-Álvarez, Irene; Mantey, Samuel A; Nakamura, Taichi; Nuche-Berenguer, Bernardo; Moreno, Paola; Moody, Terry W; Maderdrut, Jerome L; Coy, David H; Jensen, Robert T

    2015-04-01

    Pituitary adenylate cyclase-activating polypeptide (PACAP) has widespread physiological/pathophysiological actions and there is increased interest for its use therapeutically, especially in the CNS (neuroprotection). Unfortunately, no selective PACAP-analogs exist for PACAP-preferring PAC1-receptors, primarily because of its high sequence identity to VIP and particularly, because of the inability of structure-function studies to separate the pharmacophore of PAC1-R from VPAC1-R, which has high affinity for PACAP and VIP. The present study attempted to develop PAC1-R-selective agonists primarily by making conformationally restricted PACAP-analogs in positions important for receptor-selectivity/affinity. Forty-six PACAP-related-analogs were synthesized with substitutions in positions 1-4, 14-17, 20-22, 28, 34, 38 and receptor-selectivity determined in PAC1-R,VPAC1-R,VPAC2-R-transfected or native cells from binding or cAMP-generation experiments. Fifteen PACAP-analogs had 6-78-fold higher affinities for PAC1-R than VPAC1-R and 13 were agonists. Although binding-affinities correlated significantly with agonist potency, the degree of receptor-spareness varied markedly for the different PACAP-analogs, resulting in selective potencies for activating the PAC1 receptor over the VPAC1 receptor from 0- to 103-fold. In addition, a number of PACAP-analogs were identified that had high selectivity for PAC1-R over VPAC2-R as well as PACAP-analogs that could prove more useful therapeutically because of substitutions known to extend their half-lives (substitutions at potential sites of proteolysis and attachment of long-chain fatty acids). This study provides for the first time a separation of the pharmacophores for PAC1-R and VPAC1-R, resulting in PACAP-related analogs that are PAC1-R-preferring. Some of these analogs, or their modifications, could prove useful as therapeutic agents for various diseases. Published by Elsevier Inc.

  19. Role of PACAP in Female Fertility and Reproduction at Gonadal Level – Recent Advances

    PubMed Central

    Reglodi, Dora; Tamas, Andrea; Koppan, Miklos; Szogyi, Donat; Welke, Laura

    2012-01-01

    Pituitary adenylate cyclase activating polypeptide (PACAP) is a pleiotropic neuropeptide, first isolated from hypothalamic extracts, but later shown in peripheral organs, such as endocrine glands, gastrointestinal system, cardiovascular system, and reproductive organs. PACAP plays a role in fertility and reproduction. Numerous studies report on the gonadal regulatory effects of PACAP at hypothalamo-hypophyseal levels. However, the local effects of PACAP at gonadal levels are also important. The present review summarizes the effects of PACAP in the ovary. PACAP and its receptors are present in the ovary, and PACAP plays a role in germ cell migration, meiotic division, follicular development, and atresia. The autocrine-paracrine hormonal effects seem to play a regulatory role in ovulation, luteinization, and follicular atrophy. Altogether, PACAP belongs to the ovarian regulatory peptides. PMID:23248616

  20. Ceratonia siliqua pod extract ameliorates Schistosoma mansoni-induced liver fibrosis and oxidative stress.

    PubMed

    Al-Olayan, Ebtesam M; El-Khadragy, Manal F; Alajmi, Reem A; Othman, Mohamed S; Bauomy, Amira A; Ibrahim, Shaimaa R; Abdel Moneim, Ahmed E

    2016-11-08

    Schistosomiasis is a prevalent parasitic disease found predominantly in tropical and sub-tropical areas of the developing world, with the second highest socioeconomic and public health burden despite strenuous control efforts. In the present study, we aimed to investigate the ameliorative effects of Ceratonia siliqua pod extract (CPE) on liver fibrosis and oxidative stress in mice infected with Schistosoma mansoni. The schistosomal hepatopathologic mouse model was established by tail immersion with schistosomal cercaria. The extract was given daily for 10 days beginning 42 days post-infection. Liver samples were obtained from mice sacrificed 9 weeks after infection. Liver histopathological changes were observed with hematoxylin-eosin and Masson trichrome staining. Typical schistosomal hepatopathologic changes were induced in the untreated mice. However, the oral administration of CPE was effective in reducing worm number and the egg load in the liver. This treatment also decreased granuloma size and collagen deposition by inhibiting tissue inhibitor of metalloproteinases-2 (TIMP-2) expression. Schistosomal infection induced oxidative stress by increasing lipid peroxidation (LPO) and nitrite/nitrate (nitric oxide; NO) production along with concomitant decreases in glutathione (GSH) and various antioxidant enzymes, including superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase. However, treatment of mice with CPE at 300 or 600 mg/kg inhibited LPO and NO production, increased GSH content, and restored the activities of the antioxidant enzymes compared with untreated infected mice. Furthermore, treatment with CPE inhibited apoptosis, as indicated by the reduced Bax expression in hepatic tissue. These data indicated that extracts from Ceratonia siliqua pods may play an important role in combating schistosomal hepatopathology and may inhibit granuloma formation and liver fibrosis through down-regulation of TIMP-2 expression.

  1. Erdosteine ameliorates PTZ-induced oxidative stress in mice seizure model.

    PubMed

    Ilhan, Atilla; Aladag, M Arif; Kocer, Abdulkadir; Boluk, Ayhan; Gurel, Ahmet; Armutcu, Ferah

    2005-05-30

    The role of oxygen-derived free radicals has been suggested in genesis of epilepsy and in the post seizure neuronal death. The aim of this study was to investigate whether erdosteine has a preventive effect against epilepsy and postepileptic oxidative stress. The mice (n=27) were divided into three groups: (i) PTZ-induced-epilepsy group (n=9); (ii) PTZ-induced-epilepsy+erdosteine group (n=9); (iii) control group (n=9). The animals were observed for a period of 30 min for latency to first seizure onset, total seizure duration, the number of seizure episodes. Then they were sacrificed and the brains were quickly removed, and frozen for biochemical analysis. Malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD) and xanthine oxidase (XO) activities were carried out in the brain tissue. The latent period between PTZ induction and seizure are longer in the PTZ+erdosteine group than in PTZ-induced-epilepsy group (P<0.05). Biochemical analyses of brain tissue, revealed a significant increase in the MDA, XO and NO levels in the PTZ group according to erdosteine group. SOD level did not change in this group. While MDA and XO levels are significantly lower, SOD level is significantly higher in the PTZ+erdosteine group compared to PTZ and control groups (P<0.01). The present study demonstrated that erdosteine treatment both may increase latent interval between seizures and may decrease oxidative stress, thus may ameliorate neuronal death in brain during seizures. It may be used as an adjunct therapy in epilepsy.

  2. Experimental colitis is ameliorated by inhibition of nitric oxide synthase activity.

    PubMed Central

    Rachmilewitz, D; Karmeli, F; Okon, E; Bursztyn, M

    1995-01-01

    Enhanced nitric oxide (NO) generation by stimulated NO synthase (NOS) activity may, through its oxidative metabolism contribute to tissue injury in experimental colitis. In this study the possible amelioration of experimental colitis by NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NOS activity, was evaluated. Colitis was induced in rats by intracolonic administration of 30 mg trinitrobenzene sulphonic acid (TNB) dissolved in 0.25 ml 50% ethanol or by flushing the colon of capsaicin pretreated rats with 2 ml of 5% acetic acid. In several experiments, L-NAME 0.1 mg/ml was added to the drinking water at the time of colitis induction with TNB or seven days before acetic acid treatment. Rats were killed at various time intervals after induction of colitis. A 10 cm distal colonic segment was isolated, weighed, lesion area measured, and explants organ cultured for 24 hours for determination of NO generation by the Greiss reaction. The rest of the mucosa was scraped for determination of myeloperoxidase and NOS activities and leukotriene generation. In TNB treated rats mean arterial pressure was also determined up to 72 hours after damage induction, with or without cotreatment with nitroprusside. L-NAME significantly decreased the extent of tissue injury in TNB treated rats. Seven days after TNB treatment lesion area was reduced by 55%, colonic weight by 37%, and myeloperoxidase and NOS activity by 59% and 42%, respectively. Acetic acid induced colitis in capsaicin pretreated rats was also significantly decreased by L-NAME. Twenty four hours after acetic acid treatment lesion area was reduced by 61%, colonic weight by 21% and NOS activity by 39%. Mean (SEM) arterial blood pressure in TNB+L-NAME treated rats was 37.6 (8.1) mm Hg higher than in TNB treated rats, an effect that was only partially abolished by nitroprusside. These results show that inhibition of NO synthesis by an L-arginine analogue significantly ameliorates the extent of tissue injury in two

  3. Comprehensive behavioral analysis of pituitary adenylate cyclase-activating polypeptide (PACAP) knockout mice.

    PubMed

    Hattori, Satoko; Takao, Keizo; Tanda, Koichi; Toyama, Keiko; Shintani, Norihito; Baba, Akemichi; Hashimoto, Hitoshi; Miyakawa, Tsuyoshi

    2012-01-01

    Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide acting as a neurotransmitter, neuromodulator, or neurotrophic factor. PACAP is widely expressed throughout the brain and exerts its functions through the PACAP-specific receptor (PAC(1)). Recent studies reveal that genetic variants of the PACAP and PAC(1) genes are associated with mental disorders, and several behavioral abnormalities of PACAP knockout (KO) mice are reported. However, an insufficient number of backcrosses was made using PACAP KO mice on the C57BL/6J background due to their postnatal mortality. To elucidate the effects of PACAP on neuropsychiatric function, the PACAP gene was knocked out in F1 hybrid mice (C57BL/6J × 129SvEv) for appropriate control of the genetic background. The PACAP KO mice were then subjected to a behavioral test battery. PACAP deficiency had no significant effects on neurological screen. As shown previously, the mice exhibited significantly increased locomotor activity in a novel environment and abnormal anxiety-like behavior, while no obvious differences between genotypes were shown in home cage (HC) activity. In contrast to previous reports, the PACAP KO mice showed normal prepulse inhibition (PPI) and slightly decreased depression-like behavior. Previous study demonstrates that the social interaction (SI) in a resident-intruder test was decreased in PACAP KO mice. On the other hand, we showed that PACAP KO mice exhibited increased SI in Crawley's three-chamber social approach test, although PACAP KO had no significant impact on SI in a HC. PACAP KO mice also exhibited mild performance deficit in working memory in an eight-arm radial maze (RM) and the T-maze (TM), while they did not show any significant abnormalities in the left-right discrimination task in the TM. These results suggest that PACAP has an important role in the regulation of locomotor activity, social behavior, anxiety-like behavior and, potentially, working memory.

  4. Comprehensive behavioral analysis of pituitary adenylate cyclase-activating polypeptide (PACAP) knockout mice

    PubMed Central

    Hattori, Satoko; Takao, Keizo; Tanda, Koichi; Toyama, Keiko; Shintani, Norihito; Baba, Akemichi; Hashimoto, Hitoshi; Miyakawa, Tsuyoshi

    2012-01-01

    Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide acting as a neurotransmitter, neuromodulator, or neurotrophic factor. PACAP is widely expressed throughout the brain and exerts its functions through the PACAP-specific receptor (PAC1). Recent studies reveal that genetic variants of the PACAP and PAC1 genes are associated with mental disorders, and several behavioral abnormalities of PACAP knockout (KO) mice are reported. However, an insufficient number of backcrosses was made using PACAP KO mice on the C57BL/6J background due to their postnatal mortality. To elucidate the effects of PACAP on neuropsychiatric function, the PACAP gene was knocked out in F1 hybrid mice (C57BL/6J × 129SvEv) for appropriate control of the genetic background. The PACAP KO mice were then subjected to a behavioral test battery. PACAP deficiency had no significant effects on neurological screen. As shown previously, the mice exhibited significantly increased locomotor activity in a novel environment and abnormal anxiety-like behavior, while no obvious differences between genotypes were shown in home cage (HC) activity. In contrast to previous reports, the PACAP KO mice showed normal prepulse inhibition (PPI) and slightly decreased depression-like behavior. Previous study demonstrates that the social interaction (SI) in a resident-intruder test was decreased in PACAP KO mice. On the other hand, we showed that PACAP KO mice exhibited increased SI in Crawley's three-chamber social approach test, although PACAP KO had no significant impact on SI in a HC. PACAP KO mice also exhibited mild performance deficit in working memory in an eight-arm radial maze (RM) and the T-maze (TM), while they did not show any significant abnormalities in the left-right discrimination task in the TM. These results suggest that PACAP has an important role in the regulation of locomotor activity, social behavior, anxiety-like behavior and, potentially, working memory. PMID:23060763

  5. PACAP causes PAC1/VPAC2 receptor mediated hypertension and sympathoexcitation in normal and hypertensive rats.

    PubMed

    Farnham, M M J; Lung, M S Y; Tallapragada, V J; Pilowsky, P M

    2012-10-01

    Pituitary adenylate cyclase-activating polypeptide (PACAP) is an excitatory neuropeptide that plays an important role in hypertension and stress responses. PACAP acts at three G protein-coupled receptors [PACAP type 1 receptor (PAC(1)) and vasoactive intestinal peptide receptor types 1 and 2 (VPAC(1) and VPAC(2))] and is localized to sites involved in cardiovascular control, most significantly the rostral ventrolateral medulla (RVLM). The RVLM is crucial for the tonic and reflex control of efferent sympathetic activity. Increases in sympathetic activity are observed in most types of hypertension and heart failure. PACAP delivered intrathecally also causes massive sympathoexcitation. We aimed to determine the presence and abundance of the three PACAP receptors in the RVLM, the role, in vivo, of PACAP in the RVLM on tonic and reflex cardiovascular control, and the contribution of PACAP to hypertension in the spontaneously hypertensive rat (SHR). Data were obtained using quantitative PCR and microinjection of PACAP and its antagonist, PACAP(6-38), into the RVLM of anesthetized artificially ventilated normotensive rats or SHRs. All three receptors were present in the RVLM. PACAP microinjection into the RVLM caused sustained sympathoexcitation and tachycardia with a transient hypertension but did not affect homeostatic reflexes. The responses were partially mediated through PAC(1)/VPAC(2) receptors since the effect of PACAP was attenuated (∼50%) by PACAP(6-38). PACAP was not tonically active in the RVLM in this preparation because PACAP(6-38) on its own had no inhibitory effect. PACAP has long-lasting cardiovascular effects, but altered PACAP signaling within the RVLM is not a cause of hypertension in the SHR.

  6. Ameliorative effect of melatonin against gamma-irradiation-induced oxidative stress and tissue injury.

    PubMed

    El-Missiry, M A; Fayed, T A; El-Sawy, M R; El-Sayed, A A

    2007-02-01

    DNA and RNA contents than irradiated rats. The levels of total lipids, cholesterol, TG, HDL, LDL, total proteins, albumin, total globulins, creatinine, and urea, as well as the activities of AST, ALT, and GGT in serum were significantly ameliorated when melatonin was injected before irradiation. In conclusion, the increase in oxidative stress markers and the concomitant change in antioxidant levels indicate the role of oxidative stress in radiation-induced tissue damage. Moreover, melatonin shows a radioprotective impact against ionizing-radiation-induced oxidative stress and organ injury.

  7. PACAP in the BNST Produces Anorexia and Weight Loss in Male and Female Rats

    PubMed Central

    Kocho-Schellenberg, Margaret; Lezak, Kimberly R; Harris, Olivia M; Roelke, Erin; Gick, Niklas; Choi, Inyop; Edwards, Shaquille; Wasserman, Emily; Toufexis, Donna J; Braas, Karen M; May, Victor; Hammack, Sayamwong E

    2014-01-01

    Recent gene association studies have implicated pituitary adenylate cyclase-activating peptide (PACAP) systems in several psychiatric disorders associated with stressor exposure, and we have argued that many of the behavioral consequences of repeated stressor exposure may depend on the expression of PACAP in the bed nucleus of the stria terminalis (BNST). One behavioral consequence of the activation of stress systems can be anorexia and subsequent weight loss, and both the activation of central PACAP systems as well as neuronal activity in the BNST have also been associated with anorexic states in rodents. Hence, we investigated the regulation of food and water intake and weight loss following BNST PACAP infusion. BNST PACAP38 dose-dependently decreased body weight, as well as food and water intake in the first 24 h following infusion. Because different BNST subregions differentially regulate stress responding, we further examined the effects of PACAP38 in either the anterior or posterior BNST. Anterior BNST PACAP38 infusion did not alter weight gain, whereas posterior PACAP38 infusion resulted in weight loss. PACAP38 infused into the lateral ventricles did not alter weight, suggesting that the effects of BNST-infused PACAP were not mediated by leakage into the ventricular system. These data suggest that PACAP receptor activation in posterior BNST subregions can produce anorexia and weight loss, and corroborate growing data implicating central PACAP activation in mediating the consequences of stressor exposure. PMID:24434744

  8. PACAP in the BNST produces anorexia and weight loss in male and female rats.

    PubMed

    Kocho-Schellenberg, Margaret; Lezak, Kimberly R; Harris, Olivia M; Roelke, Erin; Gick, Niklas; Choi, Inyop; Edwards, Shaquille; Wasserman, Emily; Toufexis, Donna J; Braas, Karen M; May, Victor; Hammack, Sayamwong E

    2014-06-01

    Recent gene association studies have implicated pituitary adenylate cyclase-activating peptide (PACAP) systems in several psychiatric disorders associated with stressor exposure, and we have argued that many of the behavioral consequences of repeated stressor exposure may depend on the expression of PACAP in the bed nucleus of the stria terminalis (BNST). One behavioral consequence of the activation of stress systems can be anorexia and subsequent weight loss, and both the activation of central PACAP systems as well as neuronal activity in the BNST have also been associated with anorexic states in rodents. Hence, we investigated the regulation of food and water intake and weight loss following BNST PACAP infusion. BNST PACAP38 dose-dependently decreased body weight, as well as food and water intake in the first 24 h following infusion. Because different BNST subregions differentially regulate stress responding, we further examined the effects of PACAP38 in either the anterior or posterior BNST. Anterior BNST PACAP38 infusion did not alter weight gain, whereas posterior PACAP38 infusion resulted in weight loss. PACAP38 infused into the lateral ventricles did not alter weight, suggesting that the effects of BNST-infused PACAP were not mediated by leakage into the ventricular system. These data suggest that PACAP receptor activation in posterior BNST subregions can produce anorexia and weight loss, and corroborate growing data implicating central PACAP activation in mediating the consequences of stressor exposure.

  9. Whole Body Vibration Improves Insulin Resistance in db/db Mice: Amelioration of Lipid Accumulation and Oxidative Stress.

    PubMed

    Liu, Ying; Zhai, Mingming; Guo, Fan; Shi, Tengrui; Liu, Jiangzheng; Wang, Xin; Zhang, Xiaodi; Jing, Da; Hai, Chunxu

    2016-07-01

    Insulin resistance (IR) is the hallmark of type 2 diabetes mellitus (T2DM), which is one of the most important chronic noncommunicable diseases. Effective and feasible strategies to treat IR are still urgently needed. Previous research studies reported that whole body vibration (WBV) was beneficial for IR in clinical; however, its underlying mechanisms remains unknown. In the present study, db/db mice were treated with WBV administration 60 min/day for 12 weeks and the impaired insulin sensitivity was improved. Besides, liver steatosis was also ameliorated. Further explorations revealed that WBV could reduce the expression of SREBP1c and increase the expression of GSH-Px and consequently suppress oxidative stress. In conclusion, WBV attenuates oxidative stress to ameliorate liver steatosis and thus improves insulin resistance in db/db mice. Therefore, WBV administration is a promising treatment for individuals who suffered from central obesity and IR.

  10. Resveratrol ameliorates hyperglycemia-induced renal tubular oxidative stress damage via modulating the SIRT1/FOXO3a pathway.

    PubMed

    Wang, Xueling; Meng, Linghang; Zhao, Long; Wang, Zengfu; Liu, Haiying; Liu, Gang; Guan, Guangju

    2017-04-01

    Oxidative stress plays an important role in the development and progression of diabetic nephropathy (DN). We aimed to investigate if resveratrol (RSV) could ameliorate hyperglycemia-induced oxidative stress in renal tubules via modulating the SIRT1/FOXO3a pathway. The effects of RSV on diabetes rats were assessed by periodic acid-Schiff, Masson staining, immunohistochemistry, and western blot analyses. Additionally, oxidative indicators (such as catalase, superoxide dismutase, reactive oxygen species, and malondialdehyde), the deacetylase activity of SIRT1 and protein expressions of SIRT1, FOXO3a, and acetylated-FOXO3a were measured. These indicators were similarly evaluated in an in vitro study. Furthermore, the silencing of SIRT1 was used to confirm its role in the resistance to oxidative stress and the relationship between SIRT1 and FOXO3a in vitro. After 16weeks of RSV treatment, the renal function and glomerulosclerosis of rats with DN was dramatically ameliorated. RSV treatment increased SIRT1 deacetylase activity, subsequently decreasing the expression of acetylated-FOXO3a and inhibiting the oxidative stress caused by hyperglycemia both in vivo and in vitro. The silencing of SIRT1 in HK-2 cells aggravated the high glucose-induced oxidative stress and overexpression of acetylated-FOXO3a; RSV treatment failed to protect against these effects. RSV modulates the SIRT1/FOXO3a pathway by increasing SIRT1 deacetylase activity, subsequently ameliorating hyperglycemia-induced renal tubular oxidative stress damage. This mechanism provides the basis for a new approach to developing an effective DN treatment, which is of great clinical significance for reducing the morbidity and mortality associated with DN. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  11. Interaction of Gonadal Steroids and Gonadotropin-Releasing Hormone on Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) and PACAP Receptor Expression in Cultured Rat Anterior Pituitary Cells

    PubMed Central

    Zheng, Weiming; Grafer, Constance M.

    2014-01-01

    Pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptors are expressed in the hypothalamus, the gonadotrope cells of the anterior pituitary gland, and the gonads, forming an autocrine–paracrine system in these tissues. Within the pituitary, PACAP functions either alone or synergistically with gonadotropin-releasing hormone (GnRH) to stimulate gonadotropin gene expression and secretion. Our goal was to define the hormonal regulation of pituitary PACAP and PACAP receptor (PAC1) gene expression by dihydrotestosterone (DHT), estradiol, and progesterone alone or in conjunction with GnRH. Treatment of adult male rat pituitary cell cultures with DHT or progesterone augmented GnRH-mediated increase in PACAP messenger RNA (mRNA) levels, but neither had an effect when present alone. Conversely, estradiol treatment blunted PACAP gene expression but did not alter GnRH effects on PACAP expression. Expression of PACAP receptor mRNA was decreased by GnRH treatment, minimally increased by DHT treatment, but not altered by the addition of estradiol or progesterone. DHT and GnRH together blunted PACAP receptor gene expression. Taken together, these results suggest that the activity of the intrapituitary PACAP-PAC1 system is regulated via the complex interaction of gonadal steroids and hypothalamic GnRH. PMID:23690336

  12. Ascorbate ameliorates Echis coloratus venom-induced oxidative stress in human fibroblasts

    PubMed Central

    Al-Sheikh, Yazeed A.; Ghneim, Hazem K.; Aljaser, Feda S.; Aboul-Soud, Mourad A.M.

    2017-01-01

    Reports related to the effects of Echis coloratus venom (EcV) on the antioxidant capacity of human tissues is very scarce. The present study was undertaken to investigate the activities and gene expression levels of glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST), superoxide dismutase (SOD) and catalase (CAT), as well as the levels of reduced glutathione (GSH), oxidized glutathione (GSSG) and the generation rates of superoxide anions (SOA), hydrogen peroxide (H2O2) and lipid peroxides (LPO) in cultured human fibroblasts incubated with EcV, ascorbate (Asc) and EcV plus Asc at concentrations and incubation periods that maintained cell viability. Results indicated that the activities of all antioxidant enzymes and their corresponding transcripts underwent highly significant decreases and downregulation in EcV-treated cultures (0.5 µg/ml medium for 4 h) compared to venom-free controls (P<0.001). Additionally, there were concurrent equally significant increases in SOA, H2O2 and LPO generation rates in the venom-incubated cultures compared to controls (P<0.001). Results also indicated very significant decreases and parallel equally significant increases in GSH and GSSG levels respectively in the envenomed cultures compared to controls (P<0.001) leading to a drastically lower GSH/GSSG ratio. However, further incubation of the EcV-treated cultures with Asc (400 µM for 12 h) restored the activities and levels of all investigated parameters including the expression levels of the antioxidant genes to control venom-free values. It is concluded that Asc acted to neutralize the increased reactive oxygen species generation, thus ameliorating the EcV-induced oxidative stress and alleviating the downregulation of antioxidant genes. PMID:28672988

  13. Ameliorative effect of vanadium on oxidative stress in stomach tissue of diabetic rats

    PubMed Central

    Yilmaz-Ozden, Tugba; Kurt-Sirin, Ozlem; Tunali, Sevim; Akev, Nuriye; Can, Ayse; Yanardag, Refiye

    2014-01-01

    Between their broad spectrum of action, vanadium compounds are shown to have insulin mimetic/enhancing effects. Increasing evidence in experimental and clinical studies suggests that oxidative stress plays a major role in the pathogenesis of diabetes and on the onset of diabetic complications. Thus, preventive therapy can alleviate the possible side effects of the disease. The aim of the present study was to investigate the effect of vanadyl sulfate supplementation on the antioxidant system in the stomach tissue of diabetic rats. Male Swiss albino rats were randomly divided into 4 groups: control; control+vanadyl sulfate; diabetic; diabetic+vanadyl sulfate. Diabetes was induced by intraperitoneal injection of streptozotocin (STZ; 65 mg/kg body weight). Vanadyl sulfate (100 mg/kg body weight) was given daily by gavage for 60 days. At the last day of the experiment, stomach tissues were taken and homogenized to make a 10% (w/v) homogenate. Catalase (CAT), superoxide dismutase (SOD), glutathione reductase (GR), glutathione peroxidase (GPx), glutathione-S-transferase (GST), myeloperoxidase (MPO), carbonic anhydrase (CA), glucose-6-phosphate dehydrogenase (G6PD) and lactate dehydrogenase (LDH) activities were determined in the stomach tissue. CAT, SOD, GR, GPx, GST, CA, G6PD and LDH activities were increased in diabetic rats when compared to normal rats. Vanadium treatment significantly reduced the elevated activities of GR, GPx, GST compared with the diabetic group whereas the decreases in CAT, SOD, CA, G6PD and LDH activities were insignificant. No significant change was seen for MPO activity between the groups. It was concluded that vanadium could be used for its ameliorative effect against oxidative stress in diabetes. PMID:24856383

  14. Ginkgo biloba extract ameliorates oxidative phosphorylation performance and rescues abeta-induced failure.

    PubMed

    Rhein, Virginie; Giese, Maria; Baysang, Ginette; Meier, Fides; Rao, Stefania; Schulz, Kathrin L; Hamburger, Matthias; Eckert, Anne

    2010-08-24

    Energy deficiency and mitochondrial failure have been recognized as a prominent, early event in Alzheimer's disease (AD). Recently, we demonstrated that chronic exposure to amyloid-beta (Abeta) in human neuroblastoma cells over-expressing human wild-type amyloid precursor protein (APP) resulted in (i) activity changes of complexes III and IV of the oxidative phosphorylation system (OXPHOS) and in (ii) a drop of ATP levels which may finally instigate loss of synapses and neuronal cell death in AD. Therefore, the aim of the present study was to investigate whether standardized Ginkgo biloba extract LI 1370 (GBE) is able to rescue Abeta-induced defects in energy metabolism. We used a high-resolution respiratory protocol to evaluate OXPHOS respiratory capacity under physiological condition in control (stably transfected with the empty vector) and APP cells after treatment with GBE. In addition, oxygen consumption of isolated mitochondria, activities of mitochondrial respiratory enzymes, ATP and reactive oxygen species (ROS) levels as well as mitochondrial membrane mass and mitochondrial DNA content were determined. We observed a general antioxidant effect of GBE leading to an increase of the coupling state of mitochondria as well as energy homeostasis and a reduction of ROS levels in control cells and in APP cells. GBE effect on OXPHOS was even preserved in mitochondria after isolation from treated cells. Moreover, these functional data were paralleled by an up-regulation of mitochondrial DNA. Improvement of the OXPHOS efficiency was stronger in APP cells than in control cells. In APP cells, the GBE-induced amelioration of oxygen consumption most likely arose from the modulation and respective normalization of the Abeta-induced disturbance in the activity of mitochondrial complexes III and IV restoring impaired ATP levels possibly through decreasing Abeta and oxidative stress level. Although the underlying molecular mechanisms of the mode of action of GBE remain to be

  15. Polysaccharides from Cordyceps sinensis mycelium ameliorate exhaustive swimming exercise-induced oxidative stress.

    PubMed

    Yan, Feng; Wang, Beibei; Zhang, Yan

    2014-02-01

    Cordyceps sinensis (Berk.) Sacc. (Clavicipitaceae) is a famous medicinal fungus (mushroom) in Chinese herbal medicine. Polysaccharides from Cordyceps sinensis (CSP) have been identified as active ingredients responsible for its biological activities. Although many pharmacological actions of CSP have received a great deal of attention, research in this area continues. The current study was designed to investigate the effects of CSP on exhaustive exercise-induced oxidative stress. The mice were divided into four groups: control (C), low-dose CSP treated (LC), intermediate-dose CSP treated (IC) and high-dose CSP treated (HC). The treated groups received CSP (100, 200 and 400 mg/kg, ig), while the control group received drinking water for 28 days, followed by being forced to undergo exhaustive swimming exercise, and some biochemical parameters including superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), malondialdehyde (MDA) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) were measured using detection kits according to the manufacturers' instructions. Compared with the C group, exhaustive swimming time was significantly prolonged in the LC, IC and HC groups (p < 0.05); SOD activities in serum, liver and muscle were significantly higher in the IC and HC groups (p < 0.05); GPx activities in serum, liver and muscle were significantly higher in the LC, IC and HC groups (p < 0.05); CAT activities in serum, liver and muscle were significantly higher in the HC groups (p < 0.05); MDA and 8-OHdG levels in serum, liver and muscle were significantly lower in the LC, IC and HC groups (p < 0.05). The results obtained herein indicate that CSP could ameliorate exhaustive exercise-induced oxidative stress.

  16. Gossypetin ameliorates ionizing radiation-induced oxidative stress in mice liver--a molecular approach.

    PubMed

    Khan, Amitava; Manna, Krishnendu; Das, Dipesh Kr; Kesh, Swaraj Bandhu; Sinha, Mahuya; Das, Ujjal; Biswas, Sushobhan; Sengupta, Aaveri; Sikder, Kunal; Datta, Sanjukta; Ghosh, Mahua; Chakrabarty, Anindita; Banerji, Asoke; Dey, Sanjit

    2015-10-01

    Radioprotective action of gossypetin (GTIN) against gamma (γ)-radiation-induced oxidative stress in liver was explored in the present article. Our main aim was to evaluate the protective efficacy of GTIN against radiation-induced alteration of liver in murine system. To evaluate the effect of GTIN, it was orally administered to mice at a dose of 30 mg/kg body weight for three consecutive days prior to γ-radiation at a dose of 5 Gy. Radioprotective efficacy of GTIN were evaluated at physiological, cellular, and molecular level using biochemical analysis, comet assay, flow cytometry, histopathology, immunofluorescence, and immunoblotting techniques. Ionizing radiation was responsible for augmentation of hepatic oxidative stress in terms of lipid peroxidation and depletion of endogenous antioxidant enzymes. Immunoblotting and immunofluorescence studies showed that irradiation enhanced the nuclear translocation of nuclear factor kappa B (NF-κB) level, which leads to hepatic inflammation. To investigate further, we found that radiation induced the activation of stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK)-mediated apoptotic pathway and deactivation of the NF-E2-related factor 2 (Nrf2)-mediated redox signaling pathway, whereas GTIN pretreatment ameliorated these radiation-mediated effects. This is the novel report where GTIN rationally validated the molecular mechanism in terms of the modulation of cellular signaling system' instead of ' This is the novel report where GTIN is rationally validated in molecular terms to establish it as promising radioprotective agents. This might be fruitful especially for nuclear workers and defense personnel assuming the possibility of radiation exposure.

  17. Pituitary adenylate cyclase-activating polypeptide (PACAP) and PACAP-receptor type 1 expression in rat and human placenta.

    PubMed

    Scaldaferri, M L; Modesti, A; Palumbo, C; Ulisse, S; Fabbri, A; Piccione, E; Frajese, G; Moretti, C

    2000-03-01

    Pituitary adenylate cyclase-activating polypeptide (PACAP), the new hypophysiotropic factor member of the vasoactive intestinal peptide (VIP)/secretin/glucagon/GHRH family of neuropeptides, exerts its biological action by interacting with both PACAP-selective type I receptors (PAC1) and type II receptors (VPAC1), which bind both PACAP and VIP. The placenta is a site of production of hypophysiotropic factors that participate in the control of local hormone production, as well as the respective hypothalamic-pituitary neurohormones. In the present study, we show the expression of PACAP gene and irPACAP distribution within rat and human placental tissues, by means of RT-PCR and immunohystochemical experiments. In both rat and human placenta, we evaluated the expression of PAC1 gene by Northern hybridization analysis performed with a 32P-labeled 706 nt complementary DNA probe, derived from the full-length coding region of the rPAC1 complementary DNA. The results of these experiments demonstrate the presence, in both human and rat placenta, of a 7.5-kb transcript similar in size to those detected in the ovary, brain, and hypothalamus. Alternative splicing of two exons occurs in human and rat PAC1 gene generating splice variants with variable tissue-specific expression. To ascertain which of the splice variants were expressed in placental tissue we performed RT-nested PCR using primers flanking the insertion sequence termed hip/hop cassette in rat or SV1/SV2 box in human gene. Electrophoretic analysis of the PCR products showed a different pattern of expression of messenger RNA splicing variants in human and rat placenta. In particular, the rat placenta expresses the short PAC1 receptor (PAC1short), the rPAC1-hip or hop (which are indistinguishable with the primers used), and the rPAC1-hip-hop, whereas the human placenta expresses only the PAC1SV1 (or SV2) variant, structurally homologous to the rat PAC1 hip (or hop). Sequence analysis of the human PCR-amplified PAC1

  18. Role of two genes encoding PACAP in early brain development in zebrafish.

    PubMed

    Wu, Sheng; Adams, Bruce A; Fradinger, Erica A; Sherwood, Nancy M

    2006-07-01

    To study the role of pituitary adenylate cyclase-activating polypeptide (PACAP) in early brain development, we examined PACAP and its receptors for first expression and then separately knocked down the two forms of PACAP in zebrafish where development is rapid and observable. We injected morpholinos (antisense oligonucleotides) into fertilized eggs to block PACAP. Morphological changes in the brain were observed in embryos at 27 h post fertilization (hpf). Using in situ hybridization of early brain marker genes, we found that the most striking effects were an increase in pax2.1 expression in eye stalks associated with absence of either form of PACAP or an increase in eng2 and fgf8 in the midbrain-hindbrain boundary after loss of PACAP2. These marker genes are among the earliest factors in the formation of the midbrain-hindbrain boundary, an early organizing center. We suggest that PACAP is a target gene with feedback inhibition on pax2.1, eng2, or fgf8 in specific brain areas. In the hindbrain, the absence of either form of PACAP had little effect, as shown by expression of ephA4 and meis1.1. During midbrain development, our evidence suggests that PACAP1 can activate mbx. In both the diencephalon and/or forebrain, lack of PACAP1 or PACAP2 led to an increase in fgf8, again suggesting a suppressive effect of PACAP during development on these important genes that help to define cells in the forebrain. The early expression of transcripts for PACAP and its receptors by 0.5-6 hpf make both PACAP1 and PACAP2 candidates for factors that influence brain development.

  19. Pituitary adenylate cyclase activating polypeptide (PACAP), stress, and sex hormones.

    PubMed

    King, S Bradley; Toufexis, Donna J; Hammack, Sayamwong E

    2017-06-14

    Stressor exposure is associated with the onset and severity of many psychopathologies that are more common in women than men. Moreover, the maladaptive expression and function of stress-related hormones have been implicated in these disorders. Evidence suggests that PACAP has a critical role in the stress circuits mediating stress-responding, and PACAP may interact with sex hormones to contribute to sex differences in stress-related disease. In this review, we describe the role of the PACAP/PAC1 system in stress biology, focusing on the role of stress-induced alterations in PACAP expression and signaling in the development of stress-induced behavioral change. Additionally, we present more recent data suggesting potential interactions between stress, PACAP, and circulating estradiol in pathological states, including PTSD. These studies suggest that the level of stress and circulating gonadal hormones may differentially regulate the PACAPergic system in males and females to influence anxiety-like behavior and may be one mechanism underlying the discrepancies in human psychiatric disorders.

  20. Melatonin ameliorates low-grade inflammation and oxidative stress in young Zucker diabetic fatty rats.

    PubMed

    Agil, Ahmad; Reiter, Russel J; Jiménez-Aranda, Aroa; Ibán-Arias, Ruth; Navarro-Alarcón, Miguel; Marchal, Juan Antonio; Adem, Abdu; Fernández-Vázquez, Gumersindo

    2013-05-01

    The aim of this study was to investigate the effects of melatonin on low-grade inflammation and oxidative stress in young male Zucker diabetic fatty (ZDF) rats, an experimental model of metabolic syndrome and type 2 diabetes mellitus (T2DM). ZDF rats (n = 30) and lean littermates (ZL) (n = 30) were used. At 6 wk of age, both lean and fatty animals were subdivided into three groups, each composed of 10 rats: naive (N), vehicle treated (V), and melatonin treated (M) (10 mg/kg/day) for 6 wk. Vehicle and melatonin were added to the drinking water. Pro-inflammatory state was evaluated by plasma levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP). Also, oxidative stress was assessed by plasma lipid peroxidation (LPO), both basal and after Fe(2+)/H2O2 inducement. ZDF rats exhibited higher levels of IL-6 (112.4 ± 1.5 pg/mL), TNF-α (11.0 ± 0.1 pg/mL) and CRP (828 ± 16.0 µg/mL) compared with lean rats (IL-6, 89.9 ± 1.0, P < 0.01; TNF-α, 9.7 ± 0.4, P < 0.01; CRP, 508 ± 21.5, P < 0.001). Melatonin lowered IL-6 (10%, P < 0.05), TNF-α (10%, P < 0.05), and CRP (21%, P < 0.01). Basal and Fe(2+)/H2O2-induced LPO, expressed as malondialdehyde equivalents (µmol/L), were higher in ZDF rats (basal, 3.2 ± 0.1 versus 2.5 ± 0.1 in ZL, P < 0.01; Fe(2+)/H2O2-induced, 8.7 ± 0.2 versus 5.5 ± 0.3 in ZL; P < 0.001). Melatonin improved basal LPO (15%, P < 0.05) in ZDF rats, and Fe(2+)/H2O2- induced LPO in both ZL (15.2%, P < 0.01) and ZDF rats (39%, P < 0.001). These results demonstrated that oral melatonin administration ameliorates the pro-inflammatory state and oxidative stress, which underlie the development of insulin resistance and their consequences, metabolic syndrome, diabetes, and cardiovascular disease.

  1. Characterization of the pharmacology, signal transduction and internalization of the fluorescent PACAP ligand, fluor-PACAP, on NIH/3T3 cells expressing PAC1.

    PubMed

    Germano, P M; Stalter, J; Le, S V; Wu, M; Yamaguchi, D J; Scott, D; Pisegna, J R

    2001-06-01

    Fluor-PACAP, a fluorescent derivative of PACAP-27, has been confirmed to share a high affinity for PAC1 receptors transfected into NIH/3T3 cells and to have comparable pharmacological characteristics to the unconjugated, native form. Through competitive binding with 125I-PACAP-27, the two ligands exhibited similar dose- dependent inhibition. Additional examination of the efficacy of activating adenylyl cyclase revealed that both ligands analogously stimulated the production of cyclic AMP. Furthermore, PAC1 internalization visualized by our Fluor-PACAP, is compareable to that performed with the radioligand, 125I-PACAP-27, with maximal internalization achieved within thirty minutes. Thus, Fluor-PACAP exhibits intracellular signaling abilities homologous to the native ligand.

  2. Brassinosteroid Ameliorates Zinc Oxide Nanoparticles-Induced Oxidative Stress by Improving Antioxidant Potential and Redox Homeostasis in Tomato Seedling

    PubMed Central

    Li, Mengqi; Ahammed, Golam J.; Li, Caixia; Bao, Xiao; Yu, Jingquan; Huang, Chunlei; Yin, Hanqin; Zhou, Jie

    2016-01-01

    In the last few decades use of metal-based nanoparticles (MNPs) has been increased significantly that eventually contaminating agricultural land and limiting crop production worldwide. Moreover, contamination of food chain with MNPs has appeared as a matter of public concern due to risk of potential health hazard. Brassinosteroid has been shown to play a critical role in alleviating heavy metal stress; however, its function in relieving zinc oxide nanoparticles (ZnO NPs)-induced phytotoxicity remains unknown. In this study, we investigated the potential role of 24-epibrassinolide (BR) in mitigating ZnO NPs-induced toxicity in tomato seedlings. Seedling growth, biomass production, and root activity gradually decreased, but Zn accumulation increased with increasing ZnO NPs concentration (10–100 mg/L) in growth media (½ MS). The augmentation of BR (5 nM) in media significantly ameliorated 50 mg/L ZnO NPs-induced growth inhibition. Visualization of hydrogen peroxide (H2O2), and quantification of H2O2 and malondialdehyde (MDA) in tomato roots confirmed that ZnO NPs induced an oxidative stress. However, combined treatment with BR and ZnO NPs remarkably reduced concentration of H2O2 and MDA as compared with ZnO NPs only treatment, indicating that BR supplementation substantially reduced oxidative stress. Furthermore, the activities of key antioxidant enzymes such as superoxide dismutase (SOD), catalase, ascorbate peroxidase and glutathione reductase were increased by combined treatment of BR and ZnO NPs compared with ZnO NPs only treatment. BR also increased reduced glutathione (GSH), but decreased oxidized glutathione (GSSG)] and thus improved cellular redox homeostasis by increasing GSH:GSSG ratio. The changes in relative transcript abundance of corresponding antioxidant genes such as Cu/Zn SOD, CAT1, GSH1, and GR1 were in accordance with the changes in those antioxidants under different treatments. More importantly, combined application of BR and ZnO NPs

  3. PACAP and PAC₁ receptor in the reproductive cycle of male lizard Podarcis sicula.

    PubMed

    Rosati, Luigi; Prisco, Marina; Coraggio, Francesca; Valiante, Salvatore; Scudiero, Rosaria; Laforgia, Vincenza; Andreuccetti, Piero; Agnese, Marisa

    2014-09-01

    Pituitary adenylate cyclase-activating peptide (PACAP) is a neuropeptide involved in multiple functions, including vertebrate reproduction. Recently, we reported the presence of PACAP in the testis of Italian wall lizard Podarcis sicula during reproductive period (May-June). Herein we investigated the PACAP mRNA expression and the localization of PACAP/PACAP receptor system, in the other periods of the Podarcis reproductive cycle, namely in summer stasis, early autumnal resumption, mid-autumnal resumption, winter stasis, and spring resumption. Using biomolecular and immunohistochemical investigations, we demonstrated that PACAP mRNA was widely expressed in all germ and somatic cells; in summer stasis (July-August) and early autumnal resumption (September) in particular, the mRNA was always found in Sertoli cells while was transiently expressed in germ and in Leydig cells. Differently from the mRNA, the protein was always present in germ and somatic cells independently from the reproductive cycle phase. As PACAP, the PAC1 receptor was always present in the testis, except for the summer stasis (July-August) and the early autumnal resumption (September), when PACAP was lacking in germ and somatic cells (Leydig and Sertoli cells). The present results strongly suggest that PACAP/PAC1 receptor system is widely represented during the reproductive cycle of male lizard. The possible involvement of PACAP/PACAP receptor system in the control of spermatogenesis is discussed. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. PACAP38 protects rat cortical neurons against the neurotoxicity evoked by sodium nitroprusside and thrombin

    PubMed Central

    Sanchez, Alma; Rao, Haripriya Vittal; Grammas, Paula

    2009-01-01

    Pituitary adenylate cyclase-activating polypeptide (PACAP) 38 is a multifunctional anti-inflammatory and anti-apoptotic neuropeptide widely distributed in the nervous system. The objective of this study is to determine whether PACAP38 is neuroprotective against sodium nitroprusside (SNP) and thrombin, two mechanistically distinct neurotoxic agents. Treatment of primary cortical neuronal cultures with 1 mM SNP for 4 h causes neuronal cell death that is significantly reduced by 100 nM PACAP38. PACAP38 down-regulates SNP-induced cell cycle protein (cyclin E) expression and up-regulates p57KIP2, a cyclin-dependent kinase inhibitor as well as the anti-apoptotic protein Bcl-2. Similarly, neuronal death induced by 100 nM thrombin or the thrombin receptor activating peptide (TRAP 6) is reduced by PACAP38 treatment. Thrombin-stimulated cell cycle protein (cdk4) expression is decreased by PACAP38 while PACAP38 inhibits thrombin-mediated reduction of p57KIP2. However, the decrease in Bcl-2 evoked by thrombin is not affected by PACAP38. Finally, both SNP and thrombin (or TRAP) increase caspase 3 activity, an effect that is decreased by PACAP38. These data show that PACAP38 supports neuronal survival in vitro suppressing cell cycle progression and enhancing anti-apoptotic proteins. Our results support the possibility that PACAP could be a useful therapeutic agent for reducing neuronal cell death in neurodegenerative diseases. PMID:18682263

  5. Tribulus terrestris ameliorates metronidazole-induced spermatogenic inhibition and testicular oxidative stress in the laboratory mouse

    PubMed Central

    Kumari, Mrinalini; Singh, Poonam

    2015-01-01

    Objective: The present study was undertaken to evaluate the protective effects of the fruit extract of Tribulus terrestris (TT) on the metronidazole (MTZ)-induced alterations in spermatogenesis, sperm count, testicular functions, and oxidative stress. Materials and Methods: Thirty adult Swiss strain mice were divided into six groups. Animals of Groups I and II served as untreated and vehicle-treated controls, while that of Groups III and IV were administered with MTZ (500 mg/kg BW/day) and TT (200 mg/kg BW/day) alone for 28 days, respectively. Low (100 mg/kg BW/day) and high (200 mg/kg BW/day) doses of TT along with MTZ (500 mg/kg BW/day) were administered for 28 days in the mice of Groups V and VI, respectively. Twenty four hours after the last treatment, all the animals were euthanized to study the histological changes in the testis and sperm count in the epididymis. Testicular functional markers, lipid peroxidation (LPO) and the activities of antioxidant enzymes, e.g., superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase, were also assessed in the mice of all the groups. Results: Metronidazole caused marked alterations in the testicular weight, spermatogenesis, activities of antioxidant enzymes, lactate dehydrogenase, alkaline phosphatase, and the level of LPO. The epididymal sperm count also declined significantly in MTZ-treated group. These changes were partially restored following co-administration of 500 mg/kg BW/day of MTZ and 100 mg/kg BW/day of TT. However, in the mice co-administered with 500 mg/kg BW/day of MTZ and 200 mg/kg BW/day of TT, the changes reverted back completely, similar to that of the controls. Conclusion: The fruit extract of TT ameliorates the MTZ-induced alterations in the testis. PMID:26069369

  6. Moringa oleifera from Cambodia Ameliorates Oxidative Stress, Hyperglycemia, and Kidney Dysfunction in Type 2 Diabetic Mice.

    PubMed

    Tang, Yujiao; Choi, Eun-Ju; Han, Weon Cheol; Oh, Mirae; Kim, Jin; Hwang, Ji-Young; Park, Pyo-Jam; Moon, Sang-Ho; Kim, Yon-Suk; Kim, Eun-Kyung

    2017-05-01

    Recent reports have shown the antidiabetic effect of Moringa oleifera from various parts of the world. However, M. oleifera from Cambodia has never determined. Therefore, the aim of this study was to assess the antidiabetic effect of M. oleifera extract from Cambodia. The leaf ethanolic extract contained flavonoids (31.90 mg/mL), polyphenols (53.03 mg/mL), lycopene (0.042 mg/mL), and ß-carotene (0.170 mg/mL), and possessed 2,2-diphenyl-1-picrylhydrazyl, hydrogen peroxide, and hydroxyl radical scavenging activities of 92.40, 99.25, and 83.57 TE/μM at 1 mg/mL, respectively. Db/db mice were orally administered the leaf extract (150 mg/kg/day) for 5 weeks. M. oleifera treatment significantly ameliorated the altered fasting plasma glucose (from 483 to 312 mg/dL), triglyceride (from 42.12 to 23.00 mg/dL), and low-density lipoprotein cholesterol (from 107.21 to 64.25 mg/dL) compared to control group, and increased the insulin levels from 946 ± 92 to 1678 ± 268 pg/mL. The histopathological damage and expression levels of tumor necrosis factor-alpha, interleukin (IL)-1β, IL-6, cyclooxygenase-2, and inducible nitric oxide synthase in renal tissue decreased. These results indicate the potential antidiabetic benefits of M. oleifera ethanolic leaf extract.

  7. Genistein ameliorates cardiac inflammation and oxidative stress in streptozotocin-induced diabetic cardiomyopathy in rats.

    PubMed

    Gupta, Suresh K; Dongare, Shirish; Mathur, Rajani; Mohanty, Ipseeta Ray; Srivastava, Sushma; Mathur, Sandeep; Nag, Tapas C

    2015-10-01

    The present study was undertaken to evaluate the protective effects of genistein against cardiac inflammation and oxidative stress in streptozotocin (STZ) (45 mg/kg body weight)-induced diabetic rats. genistein (300 mg/kg/day) was administered orally for 24 weeks to STZ-induced diabetic rats. The effects of genistein on blood glucose, % glycosylated hemoglobin (HbA1c), C-reactive protein, tumor necrosis factor (TNF- α), transforming growth factor (TGF-β1), and total antioxidant were studied. Ultrastructural and histopathological assessment of injury were also undertaken using transmission electron microscope. STZ-induced diabetes resulted in significant increase in the levels of blood glucose, HbA1c, C-reactive protein, TNF- α and TGF-β1, and a decline in total antioxidant reserve of the myocardium. Administration of genistein to diabetic rats resulted in a decrease in blood glucose (p < 0.001), % HbA1c (p < 0.0001), C-reactive protein (p < 0.001), and expression of TNF- α (p < 0.001) and TGF-β1 (p < 0.0001) proteins. In addition, genistein treatment results in augmentation of total antioxidant (p < 0.01) reserve of the hearts. The above findings were supported by histological as well as immunohistochemical localization of NF-κB (p65) in the heart. Genistein treatment ameliorated the ultrastructural degenerative changes in the cardiac tissues as compared to the diabetic control. The result demonstrates that genistein restored the integrity of the diabetic myocardium by virtue of its anti-inflammatory and antioxidant effects.

  8. Taurine Ameliorates Renal Oxidative Damage and Thyroid Dysfunction in Rats Chronically Exposed to Fluoride.

    PubMed

    Adedara, Isaac A; Ojuade, Temini Jesu D; Olabiyi, Bolanle F; Idris, Umar F; Onibiyo, Esther M; Ajeigbe, Olufunke F; Farombi, Ebenezer O

    2017-02-01

    Excessive exposure to fluoride poses several detrimental effects to human health particularly the kidney which is a major organ involved in its elimination from the body. The influence of taurine on fluoride-induced renal toxicity was investigated in a co-exposure paradigm for 45 days using five groups of eight rats each. Group I rats received normal drinking water alone, group II rats were exposed to sodium fluoride (NaF) in drinking water at 15 mg/L alone, group III received taurine alone at a dose of 200 mg/kg group IV rats were co-administered with NaF and taurine (100 mg/kg), while group V rats were co-administered with NaF and taurine (200 mg/kg). Administration of taurine significantly reversed the fluoride-mediated decrease in absolute weight and organo-somatic index of the kidney in the exposed rats. Taurine significantly prevented fluoride-induced elevation in plasma urea and creatinine levels in the exposed rats. Moreover, taurine restored fluoride-mediated decrease in the circulatory concentrations of triiodothyronine, thyroxine, and the ratio of triiodothyronine to thyroxine. Taurine ameliorated fluoride-mediated decrease in renal antioxidant status by significantly enhancing the antioxidant enzyme activities as well as glutathione level in the exposed rats. Additionally, taurine inhibited fluoride-induced renal oxidative damage by markedly decreasing the hydrogen peroxide and malondialdehyde levels as well as improved the kidney architecture in the treated rats. Collectively, taurine protected against fluoride-induced renal toxicity via enhancement of thyroid gland function, renal antioxidant status, and histology in rats.

  9. Attenuation of Na/K-ATPase Mediated Oxidant Amplification with pNaKtide Ameliorates Experimental Uremic Cardiomyopathy

    PubMed Central

    Liu, Jiang; Tian, Jiang; Chaudhry, Muhammad; Maxwell, Kyle; Yan, Yanling; Wang, Xiaoliang; Shah, Preeya T.; Khawaja, Asad A.; Martin, Rebecca; Robinette, Tylor J.; El-Hamdani, Adee; Dodrill, Michael W.; Sodhi, Komal; Drummond, Christopher A.; Haller, Steven T.; Kennedy, David J.; Abraham, Nader G.; Xie, Zijian; Shapiro, Joseph I.

    2016-01-01

    We have previously reported that the sodium potassium adenosine triphosphatase (Na/K-ATPase) can effect the amplification of reactive oxygen species. In this study, we examined whether attenuation of oxidant stress by antagonism of Na/K-ATPase oxidant amplification might ameliorate experimental uremic cardiomyopathy induced by partial nephrectomy (PNx). PNx induced the development of cardiac morphological and biochemical changes consistent with human uremic cardiomyopathy. Both inhibition of Na/K-ATPase oxidant amplification with pNaKtide and induction of heme oxygenase-1 (HO-1) with cobalt protoporphyrin (CoPP) markedly attenuated the development of phenotypical features of uremic cardiomyopathy. In a reversal study, administration of pNaKtide after the induction of uremic cardiomyopathy reversed many of the phenotypical features. Attenuation of Na/K-ATPase oxidant amplification may be a potential strategy for clinical therapy of this disorder. PMID:27698370

  10. Molecular cloning and mRNA distribution of pituitary adenylate cyclase-activating polypeptide (PACAP)/PACAP-related peptide in the lungfish.

    PubMed

    Lee, L T O; Tam, J K V; Chan, D W; Chow, B K C

    2009-04-01

    In this article, we report the isolation of a full-length cDNA clone encoding pituitary adenylate cyclase-activating polypeptide (PACAP)/PACAP-related peptide (PRP) from lungfish Protopterus dolloi. When comparing the deduced amino acid sequences, the lungfish PACAP was found to be highly conserved with other vertebrates; however, the PRP shares only lower levels of sequence identity with known PRP sequences. Consistently in phylogenetic analysis, the lungfish PRP, similar to sturgeon PRP, fails to cluster with other PRPs. In addition to the full-length clone, another cDNA encoding a short precursor that lacks the first 32 amino acids of the PRP was also isolated. Interestingly, similar isoforms were also identified in several nonmammalian vertebrates, and it was suggested that exon skipping of PRP/PACAP transcripts was a mechanism that regulated the expression ratio of PACAP to PRP in nonmammalian vertebrates. By real-time PCR, both long and short PRP/PACAP transcripts were found almost exclusively in the brain, and the short isoform is the more abundant transcript (3.7 times more), indicating that PACAP is the major product produced in lungfish brain. The expression patterns of lungfish and previously studied frog PRP/PACAP suggest that the PRP/PACAP gene in the tetrapod lineage may first express in the central nervous system; in the process of evolution, the functions of these peptides diversified and were later found in other tissues.

  11. Long-term administration of PACAP receptor antagonist, PACAP(6-27), impairs glucose tolerance and insulin sensitivity in obese diabetic ob/ob mice.

    PubMed

    Green, Brian D; Irwin, Nigel; Cassidy, Roslyn S; Gault, Victor A; Flatt, Peter R

    2006-09-01

    Pituitary adenylate cyclase-activating peptide (PACAP) is a ubiquitous peptide of the glucagon superfamily that is involved in glucose homeostasis and regulation of insulin secretion. This study employed the PACAP receptor antagonist, PACAP(6-27) to evaluate the role of endogenous PACAP in genetic obesity-related diabetes and related metabolic abnormalities using ob/ob mice. Acute in vivo antagonistic potency of PACAP(6-27) was confirmed in ob/ob mice by blockade of the insulin-releasing action but not hyperglycaemia. In longer-term studies, ob/ob mice were given once daily injections of PACAP(6-27) or vehicle for 14 days. Feeding activity, body weight, basal plasma glucose and plasma insulin concentrations were not significantly affected by chronic PACAP(6-27) treatment. However, PACAP(6-27) treatment impaired glucose tolerance, insulin sensitivity and the glycaemic response to feeding. Plasma glucagon and lipids were unchanged. These observations indicate a role of endogenous PACAP for normal glucose homeostasis, but indicate a minor involvement in the regulation of insulin secretion in ob/ob mice.

  12. Administration of Lactobacillus casei and Bifidobacterium bifidum Ameliorated Hyperglycemia, Dyslipidemia, and Oxidative Stress in Diabetic Rats

    PubMed Central

    Sharma, Poonam; Bhardwaj, Priyanka; Singh, Rambir

    2016-01-01

    Background: The present work was planned to evaluate the antihyperglycemic, lipid-lowering, and antioxidant effect of Lactobacillus casei and Bifidobacterium bifidum in streptozotocin (STZ)-induced diabetic rats. Methods: Single daily dose of 1 × 107 cfu/ml of L. casei and B. bifidum alone and in combination of both was given to Wistar rats orally by gavaging for 28 days. Glucose tolerance test, fasting blood glucose (FBG), lipid profile, and glycosylated hemoglobin (HbA1c) were measured from blood. Glycogen from thigh muscles and liver and oxidative stress parameters from pancreas were analyzed. Results: Administration of L. casei and B. bifidum alone and in combination of both to diabetic rats decreased serum FBG (60.47%, 55.89%, and 56.49%, respectively), HbA1c (28.11%, 28.61%, and 28.28%), total cholesterol (171.69%, 136.47%, and 173.58%), triglycerides (9.935%, 8.58%, and 7.91%), low-density lipoproteins (53.27%, 53.35%, and 52.91%) and very low-density lipoproteins (10%, 8.58%, and 11.15%, respectively) and increased high-density lipoproteins (13.73%, 15.47%, and 15.47%), and insulin (19.50%, 25.80%, and 29.47%, respectively). The treatment also resulted in increase in muscle (171.69%, 136.47%, and 173.58%) and liver (25.82%, 6.63%, and 4.02%) glycogen level. The antioxidant indexes in pancreas of diabetic rats returned to normal level with reduction in lipid peroxidation (30.89%, 46.46%, and 65.36%) and elevation in reduced glutathione (104.5%, 161.34%, and 179.04%), superoxide dismutase (38.65%, 44.32%, and 53.35%), catalase (13.08%, 27%, and 31.52%), glutathione peroxidase (55.56%, 72.23%, and 97.23%), glutathione reductase (49.27%, 88.40%, and 110.86%), and glutathione-S-transferase (140%, 220%, and 246.6%, respectively) on treatment with L. casei, B. bifidum, and combination treatment. Conclusions: Administration of L. casei and B. bifidum alone and in combination of both ameliorated hyperglycemia, dyslipidemia, and oxidative stress in STZ

  13. The ameliorative effect of thymol against hydrocortisone-induced hepatic oxidative stress injury in adult male rats.

    PubMed

    Aboelwafa, Hanaa R; Yousef, Hany N

    2015-08-01

    The aim of the present study was to investigate whether hydrocortisone induces oxidative stress in hepatocytes and to evaluate the possible ameliorative effect of thymol against such hepatic injury. Twenty-four adult male rats were divided into control, thymol, hydrocortisone, and hydrocortisone+thymol groups. The 4 groups were treated daily for 15 days. Hydrocortisone significantly induced oxidative stress in the liver tissues, marked by increased serum levels of alanine transaminase (ALT), aspartate transaminase (AST), total oxidative capacity (TOC), and tumor necrosis factor-alpha (TNF-α) accompanied by marked decline of serum levels of total protein, albumin, and total antioxidant capacity (TAC). Also, marked elevation in the levels of the thiobarbituric acid reactive substances (TBARS) and TNF-α, beside significant decrease in the level of glutathione (GSH) in hepatic tissues were recorded. These biochemical alterations were accompanied by histopathological changes marked by destruction of the normal hepatic architecture, in addition to ultrastructural alterations represented by degenerative features covering almost all the cytoplasmic organelles of the hepatocytes. Supplementation of hydrocortisone-treated rats with thymol reversed most of the biochemical, histological, and ultrastructural alterations. The results of our study confirm that thymol has strong ameliorative effect against hydrocortisone-induced oxidative stress injury in hepatic tissues.

  14. Anticonvulsant effect of piperine ameliorates memory impairment, inflammation and oxidative stress in a rat model of pilocarpine-induced epilepsy

    PubMed Central

    Mao, Ke; Lei, Ding; Zhang, Heng; You, Chao

    2017-01-01

    The primary active component of black pepper is piperine, which is purified and used to treat epilepsy, achieving higher efficiency when purified. The present study was conducted to evaluate whether the anticonvulsant effect of piperine ameliorates pilocarpine-induced epilepsy, and to investigate the mechanism underlying these effects. Epilepsy was induced in Sprague Dawley rats using pilocarpine. Pilocarpine-induced epilepsy in the rats was treated with 40 mg/kg piperine for 45 consecutive days. Status epilepticus and a Morris water maze test were used to analyze the anticonvulsant effects of piperine in the epileptic rats. Inflammation and oxidative stress were then measured using commercially-available kits following piperine treatment. Lastly, the activity of caspase-3 and the protein expression levels of B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax) were evaluated using commercially-available kits and western blot analysis, respectively. The results demonstrated that treatment with piperine was able to reduce the status epilepticus and prevented memory impairment following pilocarpine-induced epilepsy in rats. The anticonvulsant effects of piperine decreased inflammation and oxidative stress following pilocarpine-induced epilepsy in rats. The upregulated activity of caspase-3 and expression levels of Bax/Bcl-2 were suppressed following treatment with piperine in the rats with pilocarpine-induced epilepsy. These results suggest that the anticonvulsant effects of piperine ameliorate memory impairment, inflammation and oxidative stress in a rat model of pilocarpine-induced epilepsy. PMID:28352353

  15. Green tea catechins are potent anti-oxidants that ameliorate sodium iodate-induced retinal degeneration in rats

    PubMed Central

    Yang, Yaping; Qin, Yong Jie; Yip, Yolanda W. Y.; Chan, Kwok Ping; Chu, Kai On; Chu, Wai Kit; Ng, Tsz Kin; Pang, Chi Pui; Chan, Sun On

    2016-01-01

    Green tea extracts exhibit anti-oxidative and anti-inflammatory actions in different disease conditions. We hypothesized that green tea extract and its catechin constituents ameliorate sodium iodate-induced retinal degeneration in rats by counteracting oxidative stress. In this study, adult Sprague-Dawley rats were intravenously injected with a single dose of sodium iodate. Green tea extract (GTE; Theaphenon-E) or combinations of its catechin constituents, including (−)-epigallocatechin gallate (EGCG), were administered intra-gastrically before injection. Live imaging analysis using confocal scanning laser ophthalmoscopy and spectral-domain optical coherence tomography showed a progressive increase of degenerating profile across the retinal surface and decrease in thickness of outer nuclear layer (ONL) at Day-14 of post-injection. These lesions were significantly ameliorated by Theaphenon-E and catechin combinations with EGCG. Catechins with exclusion of EGCG did not show obvious protective effect. Histological analyses confirmed that Theaphenon-E and catechins containing EGCG protect the retina by reducing ONL disruption. Retinal protective effects were associated with reduced expression of superoxide dismutase, glutathione peroxidase and caspase-3, and suppression of 8-iso-Prostaglandin F2α generation in the retina. In summary, GTE and its catechin constituents are potent anti-oxidants that offer neuroprotection to the outer retinal degeneration after sodium iodate insult, among which EGCG is the most active constituent. PMID:27383468

  16. Green tea catechins are potent anti-oxidants that ameliorate sodium iodate-induced retinal degeneration in rats.

    PubMed

    Yang, Yaping; Qin, Yong Jie; Yip, Yolanda W Y; Chan, Kwok Ping; Chu, Kai On; Chu, Wai Kit; Ng, Tsz Kin; Pang, Chi Pui; Chan, Sun On

    2016-07-07

    Green tea extracts exhibit anti-oxidative and anti-inflammatory actions in different disease conditions. We hypothesized that green tea extract and its catechin constituents ameliorate sodium iodate-induced retinal degeneration in rats by counteracting oxidative stress. In this study, adult Sprague-Dawley rats were intravenously injected with a single dose of sodium iodate. Green tea extract (GTE; Theaphenon-E) or combinations of its catechin constituents, including (-)-epigallocatechin gallate (EGCG), were administered intra-gastrically before injection. Live imaging analysis using confocal scanning laser ophthalmoscopy and spectral-domain optical coherence tomography showed a progressive increase of degenerating profile across the retinal surface and decrease in thickness of outer nuclear layer (ONL) at Day-14 of post-injection. These lesions were significantly ameliorated by Theaphenon-E and catechin combinations with EGCG. Catechins with exclusion of EGCG did not show obvious protective effect. Histological analyses confirmed that Theaphenon-E and catechins containing EGCG protect the retina by reducing ONL disruption. Retinal protective effects were associated with reduced expression of superoxide dismutase, glutathione peroxidase and caspase-3, and suppression of 8-iso-Prostaglandin F2α generation in the retina. In summary, GTE and its catechin constituents are potent anti-oxidants that offer neuroprotection to the outer retinal degeneration after sodium iodate insult, among which EGCG is the most active constituent.

  17. PACAP modulates the consolidation and extinction of the contextual fear conditioning through NMDA receptors.

    PubMed

    Schmidt, S D; Myskiw, J C; Furini, C R G; Schmidt, B E; Cavalcante, L E; Izquierdo, I

    2015-02-01

    Pituitary adenylate cyclase-activating polypeptide (PACAP) has a broad spectrum of biological functions including neurotransmitter, neurotrophic and neuroprotective. Moreover, it has been suggested that PACAP plays a role in the modulation of learning and memory as well as on the modulation of glutamate signaling. Thus, in the current study we investigated in the CA1 region of hippocampus and in the basolateral amygdala (BLA) the role of PACAP in the consolidation and extinction of contextual fear conditioning (CFC) and the interaction between PACAP and NMDA receptors. Male rats with cannulae implanted in the CA1 region of the hippocampus or in the BLA received immediately after the training or extinction training of the CFC infusions of the Vehicle, PACAP-38 (40 pg/side), PACAP 6-38 (40 pg/side) or PACAP 6-38 plus D-serine (50 μg/side). After 24h, the animals were subjected to a 3-min retention test. The results indicated that in the CA1 region of hippocampus, PACAP participates in the consolidation and extinction of the CFC, and in the BLA, PACAP participates only in the consolidation of the CFC. Additionally, the results suggest that the action of PACAP on the consolidation and extinction of the CFC is mediated by the glutamate NMDA receptors.

  18. Muscarinic and PACAP receptor interactions at pontine level in the rat: significance for REM sleep regulation.

    PubMed

    Ahnaou, A; Laporte, A M; Ballet, S; Escourrou, P; Hamon, M; Adrien, J; Bourgin, P

    2000-12-01

    Cholinergic and PACAPergic systems within the oral pontine reticular nucleus (PnO) play a critical role in REM sleep generation in rats. In this present work, we have investigated whether REM sleep enhancement induced by carbachol (a cholinergic agonist) or PACAP, depends on an interaction between muscarinic and PACAP receptors. This hypothesis was tested by recording sleep-wake cycles in freely moving rats injected into the PnO with PACAP in combination with the muscarinic receptor antagonist atropine, or with carbachol in combination with the PACAP receptor antagonist PACAP6-27. When administered alone, PACAP (3 pmol) or carbachol (110 pmol) induced an enhancement of REM sleep during 8 h (+61%, n = 8; +70%, n = 5), which was totally prevented by infusion of atropine (290 pmol) for PACAP, or of PACAP6-27 (3 pmol) for carbachol. Quantitative autoradiographic studies indicated that (i) PACAP (10-9-10-7 M) induced in the PnO an increase (+35%) of the specific binding of the muscarinic antagonist [3H]quinuclidinyl benzylate, which could be completely prevented by PACAP6-27 (IC50 = 8 x 10-8 M) and (ii) both carbachol and PACAP enhanced [35S]GTP-gamma-S binding in a concentration-dependent manner in the PnO. The maximal increase due to carbachol was significantly higher in the presence (+126%) than in the absence (+102%) of PACAP (0.1 microM). These data showed that interactions between muscarinic and PACAP receptors do exist within the PnO and play a role in the local mechanisms of REM sleep control in the rat.

  19. Altered Gene Expression of RNF34 and PACAP Possibly Involved in Mechanism of Exercise-Induced Analgesia for Neuropathic Pain in Rats

    PubMed Central

    Yamaoka, Shintaro; Oshima, Yusuke; Horiuchi, Hideki; Morino, Tadao; Hino, Masayuki; Miura, Hiromasa; Ogata, Tadanori

    2017-01-01

    Despite the availability of several modalities of treatment, including surgery, pharmacological agents, and nerve blocks, neuropathic pain is often unresponsive and sometimes progresses to intractable chronic pain. Although exercise therapy is a candidate for treatment of neuropathic pain, the mechanism underlying its efficacy has not been elucidated. To clarify the molecular mechanism for pain relief induced by exercise, we measured Rnf34 and Pacap mRNA levels in the spinal cord dorsal horn of SNL rats, a model of neuropathic pain. SNL model rats exhibited stable mechanical hyperalgesia for at least 6 weeks. When the rats were forced to exercise on a treadmill, mechanical and thermal hyperalgesia were significantly ameliorated compared with the non-exercise group. Accordingly, gene expression level of Rnf34 and Pacap were also significantly altered in the time course analysis after surgery. These results suggest that exercise therapy possibly involves pain relief in SNL rats by suppressing Rnf34 and Pacap expression in the spinal cord. PMID:28902127

  20. VIP/PACAP, and their receptors and cancer

    PubMed Central

    Moody, Terry W.; Nuche-Berenguer, Bernardo; Jensen, Robert T.

    2016-01-01

    Purpose of review To summarize the roles of VIP/PACAP and their receptors(VPAC1, VPAC2/PAC1) in human tumors as well as their role in potential novel treatments. Recent findings Considerable progress has been made in understanding of the effects of VIP/PACAP on growth of various tumors as well as in the signaling cascades involved, especially of the role of transactivation of the Epidermal growth factor(EGF) family. The overexpression of VPAC1/2, PAC1 on a number of common neoplasms (breast, lung, prostate, CNS, neuroblastoma) is receiving increased attention both as a means of tumor imaging the location and extent of these tumors, as well as for targeted directed treatment, by coupling cytotoxic agents to VIP/PACAP analogues. Summary VIP/PACAP has prominent growth effects on a number of common neoplasms, which frequently overexpressed the three subtypes of their receptors. The increased understanding of their signaling cascades, effect on tumor growth/differentiation, and the use of the overexpression of these receptors for localization/targeted cytotoxic delivery, are all suggesting possible novel tumor treatments. PMID:26702849

  1. Quercetin ameliorates oxidative stress, inflammation and apoptosis in the heart of streptozotocin-nicotinamide-induced adult male diabetic rats.

    PubMed

    Roslan, Josef; Giribabu, Nelli; Karim, Kamarulzaman; Salleh, Naguib

    2017-02-01

    Quercetin is known to possess beneficial effects in ameliorating diabetic complications, however the mechanisms underlying cardioprotective effect of this compound in diabetes is not fully revealed. In this study, quercetin effect on oxidative stress, inflammation and apoptosis in the heart in diabetes were investigated. Normal and streptozotocin-nicotinamide induced adult male diabetic rats received quercetin (10, 25 and 50mg/kg/bw) orally for 28days were anesthetized and hemodynamic parameters i.e. systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) were measured. Blood was collected for analyses of fasting glucose (FBG), insulin and cardiac injury marker levels (troponin-C, CK-MB and LDH). Following sacrificed, heart was harvested and histopathological changes were observed. Heart was subjected for analyses of oxidative stress marker i.e. lipid peroxidation and activity and expression levels of anti-oxidative enzymes i.e. SOD, CAT and GPx. Levels of inflammation in the heart were determined by measuring nuclear factor (p65-NF-κB), tumor necrosis factor (TNF-α), interleukins (IL)-1β and IL-6 levels by using enzyme-linked immunoassay (ELISA). Distribution and expression levels of TNF-α and Ikk-β (inflammatory markers), caspase-3, caspase-9, Blc-2 and Bax (apoptosis markers) in the heart were identified by immunohistochemistry and Western blotting respectively. Administration of quercetin to diabetic rats caused significant decrease in FBG and cardiac injury marker levels with increased in insulin levels. In diabetic rat heart, lesser histopathological changes were observed with oxidative stress, inflammation and apoptosis levels markedly decreased. Quercetin could potentially be used to ameliorate myocardial damage due to oxidative stress, inflammation and apoptosis in diabetes. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  2. Baicalin ameliorates isoproterenol-induced acute myocardial infarction through iNOS, inflammation and oxidative stress in rat

    PubMed Central

    Chen, Huaguo; Xu, Yongfu; Wang, Jianzhong; Zhao, Wei; Ruan, Huihui

    2015-01-01

    Baicalin belongs to glucuronic acid glycosides and after hydrolysisbaicalein and glucuronic acid come into being. It has such effects as clearing heat and removing toxicity, anti-inflammation, choleresis, bringing high blood pressure down, diuresis, anti-allergic reaction and so on. In this study, we investigated whether baicalin ameliorates isoproterenol-induced acute myocardial infarction and its mechanism. Rat model of acute myocardial infarction was induced by isoproterenol. Casein kinase (CK), the MB isoenzyme of creatine kinase (CK-MB), lactate dehydrogenase (LDH), cardiac troponin T (cTnT) and infarct size measurement were used to measure the protective effect of baicalin on isoproterenol-induced acute myocardial infarction. iNOS protein expression in rat was analyzed using western blot analysis. Tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), malondialdehyde (MDA) and superoxide dismutase (SOD) and caspase-3 activation levels were explored using commercial ELISA kits. In the acute myocardial infarction experiment, baicalin effectively ameliorates the level of CK, CK-MB, LDH and cTnT, reduced infarct size in acute myocardial infarction rat model. Meanwhile, treatment with baicalin effectively decreased the iNOS protein expression, inflammatory factors and oxidative stresses in a rat model of acute myocardial infarction. However, baicalin emerged that anti-apoptosis activity and suppressed the activation of caspase-3 in a rat model of acute myocardial infarction. The data suggest that the protective effect of baicalin ameliorates isoproterenol-induced acute myocardial infarction through iNOS, inflammation and oxidative stress in rat. PMID:26617721

  3. Preventing p38 MAPK-mediated MafA degradation ameliorates β-cell dysfunction under oxidative stress.

    PubMed

    El Khattabi, Ilham; Sharma, Arun

    2013-07-01

    The reduction in the expression of glucose-responsive insulin gene transcription factor MafA accompanies the development of β-cell dysfunction under oxidative stress/diabetic milieu. Humans with type 2 diabetes have reduced MafA expression, and thus preventing this reduction could overcome β-cell dysfunction and diabetes. We previously showed that p38 MAPK, but not glycogen synthase kinase 3 (GSK3), is a major regulator of MafA degradation under oxidative stress. Here, we examined the mechanisms of this degradation and whether preventing MafA degradation under oxidative stress will overcome β-cell dysfunction. We show that under oxidative and nonoxidative conditions p38 MAPK directly binds to MafA and triggers MafA degradation via ubiquitin proteasomal pathway. However, unlike nonoxidative conditions, MafA degradation under oxidative stress depended on p38 MAPK-mediated phosphorylation at threonine (T) 134, and not T57. Furthermore the expression of alanine (A) 134-MafA, but not A57-MafA, reduced the oxidative stress-mediated loss of glucose-stimulated insulin secretion, which was independent of p38 MAPK action on protein kinase D, a regulator of insulin secretion. Interestingly, the expression of proteasomal activator PA28γ that degrades GSK3-phosphorylated (including T57) MafA was reduced under oxidative stress, explaining the dominance of p38 MAPK over the GSK3 pathway in regulating MafA stability under oxidative stress. These results identify two distinct pathways mediating p38 MAPK-dependent MafA degradation under oxidative and nonoxidative conditions and show that inhibiting MafA degradation under oxidative stress ameliorates β-cell dysfunction and could lead to novel therapies for diabetes.

  4. Trichosanthes dioica fruit ameliorates experimentally induced arsenic toxicity in male albino rats through the alleviation of oxidative stress.

    PubMed

    Bhattacharya, Sanjib; Haldar, Pallab Kanti

    2012-08-01

    The present work was focused to evaluate the ameliorative property of aqueous extract of Trichosanthes dioica fruit (AQ T. dioica fruit) against arsenic-induced toxicity in male Wistar albino rats. AQ T. dioica fruit was administered orally to rats at 50 and 100 mg/kg body weight for 20 consecutive days prior to oral administration of sodium arsenite (10 mg/kg) for 10 days. Then the rats were sacrificed for the evaluation of body weights, organ weights, hematological profile, serum biochemical profile, and hepatic and renal antioxidative parameters viz. lipid peroxidation, reduced and oxidized glutathione, glutathione-S-transferase, glutathione peroxidase, glutathione reductase, superoxide dismutase, catalase, and DNA fragmentation. Pretreatment with AQ T. dioica fruit at both doses markedly and significantly normalized body weights, organ weights, hematological profiles, and serum biochemical profile in arsenic-treated animals. Further, AQ T. dioica fruit pretreatment significantly modulated all the aforesaid hepatic and renal biochemical perturbations and reduced DNA fragmentation in arsenic-intoxicated rats. Therefore, from the present findings, it can be concluded that T. dioica fruit possessed remarkable value in amelioration of arsenic-induced hepatic and renal toxicity, mediated by alleviation of arsenic-induced oxidative stress by multiple mechanisms in male albino rats.

  5. Nobiletin, a citrus flavonoid, ameliorates cognitive impairment, oxidative burden, and hyperphosphorylation of tau in senescence-accelerated mouse.

    PubMed

    Nakajima, Akira; Aoyama, Yuki; Nguyen, Thuy-Ty Lan; Shin, Eun-Joo; Kim, Hyoung-Chun; Yamada, Shinnosuke; Nakai, Tsuyoshi; Nagai, Taku; Yokosuka, Akihito; Mimaki, Yoshihiro; Ohizumi, Yasushi; Yamada, Kiyofumi

    2013-08-01

    Senescence-accelerated mouse prone 8 (SAMP8) is a model of aging characterized by the early onset of learning and memory impairment and various pathological features of Alzheimer's disease (AD). Our recent studies have demonstrated that nobiletin, a polymethoxylated flavone from citrus peels, ameliorates learning and memory impairment in olfactory-bulbectomized mice, amyloid precursor protein transgenic mice, and NMDA receptor antagonist-treated mice. Here, we present evidence that this natural compound improves age-related cognitive impairment and reduces oxidative stress and tau phosphorylation in SAMP8 mice. Treatment with nobiletin (10 or 50mg/kg) reversed the impairment of recognition memory and context-dependent fear memory in SAMP8 mice. Treatment with nobiletin also restored the decrease in the GSH/GSSG ratio in the brain of SAMP8 mice. In addition, increases in glutathione peroxidase and manganese-superoxide dismutase activities, as well as a decrease in protein carbonyl level, were observed in the brain of nobiletin-treated SAMP8 mice. Furthermore, nobiletin reduced tau phosphorylation in the hippocampus of SAMP8 mice. Together, the markedly beneficial effects of nobiletin represent a potentially useful treatment for ameliorating the learning and memory deficits, oxidative stress, and hyperphosphorylation of tau in aging as well as age-related neurodegenerative diseases such as AD.

  6. Ganoderma atrum polysaccharide ameliorates anoxia/reoxygenation-mediated oxidative stress and apoptosis in human umbilical vein endothelial cells.

    PubMed

    Zhang, Yan-Song; Li, Wen-Juan; Zhang, Xian-Yi; Yan, Yu-Xin; Nie, Shao-Ping; Gong, De-Ming; Tang, Xiao-Fang; He, Ming; Xie, Ming-Yong

    2017-05-01

    Ganoderma atrum polysaccharide (PSG-1), a main polysaccharide from Ganoderma atrum, possesses potent antioxidant capacity and cardiovascular benefits. The aim of this study was to investigate the role of PSG-1 in oxidative stress and apoptosis in human umbilical vein endothelial cells (HUVECs) under anoxia/reoxygenation (A/R) injury conditions. The results showed that exposure of HUVECs to A/R triggered cell death and apoptosis. Administration of PSG-1 significantly inhibited A/R-induced cell death and apoptosis in HUVECs. PSG-1-reduced A/R injury was mediated via mitochondrial apoptotic pathway, as evidenced by elevation of mitochondrial Bcl-2 protein and mitochondrial membrane potential, and attenuation of Bax translocation, cytochrome c release and caspases activation. Furthermore, PSG-1 enhanced the activities of superoxide dismutase, catalase and glutathione peroxidase and glutathione content, and concomitantly attenuated reactive oxygen species generation, lipid peroxidation and glutathione disulfide content. The antioxidant, N-acetyl-l-cysteine, significantly ameliorated all of these endothelial injuries caused by A/R, suggesting that antioxidant activities might play a key role in PSG-1-induced endothelial protection. Taken together, these findings suggested that PSG-1 could be as a promising adjuvant against endothelial dysfunction through ameliorating oxidative stress and apoptosis. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Does Glucagon-like Peptide-1 Ameliorate Oxidative Stress in Diabetes? Evidence Based on Experimental and Clinical Studies

    PubMed Central

    Petersen, Karen Ekkelund; Rakipovski, Günaj; Raun, Kirsten; Lykkesfeldt, Jens

    2016-01-01

    Glucagon-like peptide-1 (GLP-1) has shown to influence the oxidative stress status in a number of in vitro, in vivo and clinical studies. Well-known effects of GLP-1 including better glycemic control, decreased food intake, increased insulin release and increased insulin sensitivity may indirectly contribute to this phenomenon, but glucose-independent effects on ROS level, production and antioxidant capacity have been suggested to also play a role. The potential ‘antioxidant’ activity of GLP-1 along with other proposed glucose-independent modes of action related to ameliorating redox imbalance remains a controversial topic but could hold a therapeutic potential against micro- and macrovascular diabetic complications. This review discusses the presently available knowledge from experimental and clinical studies on the effects of GLP-1 on oxidative stress in diabetes and diabetes-related complications. PMID:26381142

  8. [Research advance of the protective role of PACAP in the nervous system diseases].

    PubMed

    Mao, Shan-shan; Zhang, Yong-mei

    2011-08-01

    In the central nervous system, pituitary adenylate cyclase-activating polypeptide (PACAP) exerts different actions as neurotransmitter, neuromodulator, neurotrophic and neuroprotective factors via multiple signaling pathways. PACAP plays an important protective role in the nervous system diseases, such as focal cerebral ischemia, traumatic brain injury (TBI), schizophrenia, anxiety disorders Parkinson's disease and Alzheimer's disease. Now, we reviewed the research advances about the protective role of PACAP in the nervous system diseases.

  9. Role for Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) in Cystitis-induced Plasticity of Micturition Reflexes

    PubMed Central

    Braas, Karen M.; May, Victor; Zvara, Peter; Nausch, Bernhard; Kliment, Jan; Dunleavy, J. Dana; Nelson, Mark T.; Vizzard, Margaret A.

    2006-01-01

    PACAP peptides are expressed and regulated in sensory afferents of the micturition pathway. Although these studies have implicated PACAP in bladder control, the physiological significance of these observations has not been firmly established. To clarify these issues, the roles of PACAP and PACAP signaling in micturition and cystitis were examined in receptor characterization and physiological assays. PACAP receptors were identified in various tissues of the micturition pathway including bladder detrusor smooth muscle and urothelium. Bladder smooth muscle expressed heterogeneously PAC1null, PAC1HOP1 and VPAC2 receptors; the urothelium was more restricted in expressing preferentially the PAC1 receptor subtype only. Immunocytochemical studies for PAC1 receptors were consistent with these tissue distributions. Furthermore, the addition of 50 – 100 nM PACAP27 or PACAP38 to isolated bladder strips elicited transient contractions and sustained increases in the amplitude of spontaneous phasic contractions. Treatment of the bladder strips with tetrodotoxin (1 μM) did not alter the spontaneous phasic contractions suggesting direct PACAP effects on bladder smooth muscle. PACAP also increased the amplitude of nerve-evoked contractions. By contrast, VIP had no direct effects on bladder smooth muscle. In a rat cyclophosphamide (CYP)-induced cystitis paradigm, intrathecal or intravesical administration of PAC1 receptor antagonist, PACAP6-38, reduced cystitis-induced bladder overactivity. In sum, these studies support roles for PACAP in micturition and suggest that inflammation-induced plasticity in PACAP expression in peripheral and central micturition pathways contribute to bladder dysfunction with cystitis. PMID:16322346

  10. Curcumin ameliorated diabetic neuropathy partially by inhibition of NADPH oxidase mediating oxidative stress in the spinal cord.

    PubMed

    Zhao, Wei-Cheng; Zhang, Bin; Liao, Mei-Juan; Zhang, Wen-Xuan; He, Wan-You; Wang, Han-Bing; Yang, Cheng-Xiang

    2014-02-07

    Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases are the main enzymes that produce oxidative stress, which plays an important role in painful diabetic neuropathy. Curcumin has been reported to exert an antinociceptive effect in a rat model of diabetic neuropathy by suppressing oxidative stress in the spinal cord. However, it remains unknown whether the mechanism by which curcumin ameliorates diabetic neuropathy can be attributed to spinal NADPH oxidases. This study was designed to determine the effect of curcumin on diabetic neuropathy and to investigate its precise mechanism in relation to NADPH oxidase-mediating oxidative stress in the spinal cord. Diabetic neuropathy was induced in Sprague-Dawley rats by intraperitoneal injection with 1% streptozotocin (STZ; 60 mg/kg). After the onset of diabetic neuropathy, a subset of the diabetic rats received daily intragastric administrations of curcumin (200mg/kg) or intraperitoneal injections of apocynin (2.5mg/kg) for 14 consecutive days, whereas other diabetic rats received equivalent volumes of normal saline (NS). STZ resulted in diabetic neuropathy with hyperglycemia and a lower paw withdrawal threshold (PWT), accompanied by elevations in the expression of the NADPH oxidase subunits p47(phox) and gp91(phox) and in the levels of hydrogen peroxide (H2O2) and malondialdehyde (MDA) and a reduction in superoxide dismutase (SOD) activity (P<0.05) in the spinal cord. Both curcumin and apocynin ameliorated diabetic neuropathy. In conclusion, curcumin attenuated neuropathic pain in diabetic rats, at least partly by inhibiting NADPH oxidase-mediating oxidative stress in the spinal cord. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  11. Investigation of PACAP Fragments and Related Peptides in Chronic Retinal Hypoperfusion

    PubMed Central

    Werling, Dora; Reglodi, Dora; Kiss, Peter; Toth, Gabor; Szabadfi, Krisztina; Tamas, Andrea; Biro, Zsolt; Atlasz, Tamas

    2014-01-01

    Pituitary adenylate cyclase activating polypeptide (PACAP) has neuroprotective effects in different neuronal and retinal injuries. Retinal ischemia can be effectively modelled by permanent bilateral common carotid artery occlusion (BCCAO), which causes chronic hypoperfusion-induced degeneration in the entire rat retina. The retinoprotective effect of PACAP 1-38 and VIP is well-established in ischemic retinopathy. However, little is known about the effects of related peptides and PACAP fragments in ischemic retinopathy. The aim of the present study was to investigate the potential retinoprotective effects of different PACAP fragments (PACAP 4-13, 4-22, 6-10, 6-15, 11-15, and 20-31) and related peptides (secretin, glucagon) in BCCAO-induced ischemic retinopathy. Wistar rats (3-4 months old) were used in the experiment. After performing BCCAO, the right eyes of the animals were treated with PACAP fragments or related peptides intravitreal (100 pM), while the left eyes were injected with saline serving as control eyes. Sham-operated (without BCCAO) rats received the same treatment. Routine histology was performed 2 weeks after the surgery; cells were counted and the thickness of retinal layers was compared. Our results revealed significant neuroprotection by PACAP 1-38 but did not reveal retinoprotective effect of the PACAP fragments or related peptides. These results suggest that PACAP 1-38 has the greatest efficacy in ischemic retinopathy. PMID:24900914

  12. The ameliorative effects of sesamol against seizures, cognitive impairment and oxidative stress in the experimental model of epilepsy

    PubMed Central

    Hassanzadeh, Parichehr; Arbabi, Elham; Rostami, Fatemeh

    2014-01-01

    Objective(s): A growing interest has recently been attracted towards the identification of plant-based medications including those with protective effects against cognitive impairment. Sesamol has shown promising antioxidant and neuroprotective effects, therefore, we aimed to evaluate its therapeutic potential in epilepsy which is commonly associated with oxidative stress and cognitive impairment. Materials and Methods: Male Wistar rats received pentylenetetrazole (PTZ) (30 mg/kg, IP) once every other day until the development of kindling, i.e., the occurrence of stage 5 of seizures for three consecutive trials. After the completion of kindling procedure, behavioural tests including elevated plus maze and passive avoidance were performed in order to assess learning and memory. Oxidative stress was assessed by estimation of lipid peroxidation and reduced glutathione. The effects of pretreatment with sesamol (10, 20, and 30 mg/kg, IP) against PTZ-induced seizures, cognitive impairment and oxidative stress were investigated. Results: 32.45 ± 1.86 days after treatment with PTZ, kindling was developed that was associated with myoclonic jerks and generalized tonic-clonic seizures. Moreover, PTZ kindling induced a remarkable cognitive impairment and oxidative stress. Sesamol (30 mg/kg) significantly delayed the development of kindling and prevented seizure-induced cognitive impairment and oxidative stress. Conclusion: Sesamol exerts ameliorative effects in the experimental model of epilepsy. This phytochemical may be considered as a beneficial adjuvant for antiepileptic drugs. PMID:24711892

  13. Diallyl trisulfide ameliorates arsenic-induced hepatotoxicity by abrogation of oxidative stress, inflammation, and apoptosis in rats.

    PubMed

    Sumedha, N C; Miltonprabu, S

    2015-05-01

    The present study investigates the possible ameliorative effects of diallyl trisulfide (DATS) against arsenic (As)-induced hepatotoxicity and oxidative stress in rats. The four experimental groups evaluated include: (1) vehicle control; (2) As (5 mg/kg/day); (3) DATS (80 mg/kg/day) + As; and (4) DATS. Induction of As in rats caused severe hepatotoxicity as evidenced by an elevation of serum aspartate aminotransferase and alanine aminotransferase activities and increased total bilirubin concentration, indicating hepatic function abnormalities. Histopathological examination revealed various structural changes in the liver, characterized by hepatocyte degeneration/necrosis, congestion, sinusoidal dilatation, vacuolation, and inflammatory cell infiltration. The significant decrease in reduced glutathione content, catalase, superoxide dismutase, glutathione peroxidase, and glutathione reductase activities and the significant increase in lipid peroxidation (thiobarbituric acid reactive substance) and protein oxidation (protein carbonyl) contents indicated that As-induced hepatotoxicity was mediated through oxidative stress. As intoxication also elevated the levels of Cas-3 and nitric oxide and increased the expression of nuclear factor-κB p65 in the liver. In contrast, DATS pretreatment significantly improved As-induced serum biochemical, immunohistochemical, and histopathological alterations reflecting hepatic dysfunction. These results may contribute to a better understanding of the hepatoprotective role of DATS, emphasizing the influence of this garlic trisulfide in the diet for human health, possibly preventing the hepatic injury associated with As intoxication, presumably due to its ability to inhibit lipid peroxidation, protein oxidation, and restoration of antioxidant status.

  14. Hydroxytyrosol ameliorates oxidative stress and mitochondrial dysfunction in doxorubicin-induced cardiotoxicity in rats with breast cancer.

    PubMed

    Granados-Principal, Sergio; El-Azem, Nuri; Pamplona, Reinald; Ramirez-Tortosa, Cesar; Pulido-Moran, Mario; Vera-Ramirez, Laura; Quiles, Jose L; Sanchez-Rovira, Pedro; Naudí, Alba; Portero-Otin, Manuel; Perez-Lopez, Patricia; Ramirez-Tortosa, Mcarmen

    2014-07-01

    Oxidative stress is involved in several processes including cancer, aging and cardiovascular disease, and has been shown to potentiate the therapeutic effect of drugs such as doxorubicin. Doxorubicin causes significant cardiotoxicity characterized by marked increases in oxidative stress and mitochondrial dysfunction. Herein, we investigate whether doxorubicin-associated chronic cardiac toxicity can be ameliorated with the antioxidant hydroxytyrosol in rats with breast cancer. Thirty-six rats bearing breast tumors induced chemically were divided into 4 groups: control, hydroxytyrosol (0.5mg/kg, 5days/week), doxorubicin (1mg/kg/week), and doxorubicin plus hydroxytyrosol. Cardiac disturbances at the cellular and mitochondrial level, mitochondrial electron transport chain complexes I-IV and apoptosis-inducing factor, and oxidative stress markers have been analyzed. Hydroxytyrosol improved the cardiac disturbances enhanced by doxorubicin by significantly reducing the percentage of altered mitochondria and oxidative damage. These results suggest that hydroxytyrosol improve the mitochondrial electron transport chain. This study demonstrates that hydroxytyrosol protect rat heart damage provoked by doxorubicin decreasing oxidative damage and mitochondrial alterations.

  15. Klotho ameliorates oxidized low density lipoprotein (ox-LDL)-induced oxidative stress via regulating LOX-1 and PI3K/Akt/eNOS pathways.

    PubMed

    Yao, Yansheng; Wang, Yanbing; Zhang, Yibo; Liu, Chang

    2017-04-13

    Atherosclerosis is a common cardiovascular disease that causes myocardial infarction, heart failure, and stroke. Increased oxidized low density lipoprotein (ox-LDL) in the sub-endothelium is the characteristic origin of atherogenesis. Klotho, an anti-aging protein, has been reported to protect against atherosclerosis and ameliorate endothelial dysfunction in vivo. The aim of this study is to investigatethe anti-oxidative activity of Klothoin ox-LDL-treated human umbilical vein endothelial cells (HUVECs). After pre-treatment with 200 pMKlotho for 1 h, HUVECs were stimulated with 50 μg/ml ox-LDL for 24 h. Reactive oxygen species (ROS) and superoxide dismutase (SOD) levels were analyzed in the cells. Nitric oxide (NO) concertation was measured in the medium supernatant. Related proteins or genes were detected with Western blot or real time PCR, respectively, in the cell lysates. Initially, oxidative damage in HUVECs was established by adding 50 μg/mL ox-LDL, which resulted in decreased cellular viability, SOD/Cu/Zn-SOD and endothelial NO synthase (eNOS) expression and NO production, as well as increased malondialdehyde (MDA) levels, ROS production, inducible NO synthase (iNOS), phosphatidyl inositol-3 kinase (PI3K), protein kinase B (Akt), gp91 phox, and lectin-like ox-LDL receptor (LOX-1) expression in HUVECs. Pre-incubation with recombinant Klotho (200 pM) significantly prevented all of these alterations. These results suggest that Klotho can attenuate ox-LDL-induced oxidative stress in HUVECs through upregulating oxidative scavengers (SOD and NO) viaactivating the PI3K/Akt/eNOS pathway and depressing LOX-1expression. These results suggest that Klotho has a potential therapeutic effect on attenuating endothelial dysfunction and ameliorating atherosclerosis.

  16. Heat-Processed Scutellariae Radix Protects Hepatic Inflammation Through the Amelioration of Oxidative Stress in Lipopolysaccharide-Induced Mice.

    PubMed

    Park, Chan Hum; Shin, Mi-Rae; An, Byung Kwan; Joh, Hyun Woo; Lee, Jang Cheon; Roh, Seong-Soo; Yokozawa, Takako

    2017-08-22

    The present study evaluated the effects of heat-processed Scutellariae Radix (Scutellaria baicalensis) on lipopolysaccharide (LPS)-induced liver injury in mice. Scutellariae Radix heat-processed at 160[Formula: see text]C or 180[Formula: see text]C was orally administered at a dose of 100 mg/kg body weight for three days before the intraperitoneal injection of LPS, and the effects were compared with those of vehicle-treated LPS administered to control mice. The administration of Scutellariae Radix decreased the elevated serum monocyte chemotactic protein-1 (MCP-1), interleukin-6 (IL-6), reactive oxygen species (ROS), nitrite/nitrate, peroxynitrite, and hepatic functional parameters, and reduced the increased ROS in the liver. The augmented expressions of hepatic oxidative stress and inflammation-related proteins, phospho-p38, phosphorylated extracellular signal-regulated kinase, phosphorylated c-Jun N-terminal kinase, nuclear factor-[Formula: see text] B p65, activator protein-1, cyclooxygenase-2, inducible nitric oxide synthase, MCP-1, intercellular adhesion molecule-1, tumor necrosis factor-[Formula: see text], and IL-6, were downregulated by the heat-processed Scutellariae Radix. Hematoxylin-eosin staining showed that the increased hepatocellular damage in the liver of LPS-treated mice improved with the administration of heat-processed Scutellariae Radix. Overall, the ameliorative effects of Scutellariae Radix were superior to those when heat-processed at 180[Formula: see text]C. Our results indicate that heat-processed Scutellariae Radix acts as an anti-inflammatory agent by ameliorating oxidative stress in the liver of mice with LPS-induced liver injury.

  17. Propionate Ameliorates Dextran Sodium Sulfate-Induced Colitis by Improving Intestinal Barrier Function and Reducing Inflammation and Oxidative Stress

    PubMed Central

    Tong, Ling-chang; Wang, Yue; Wang, Zhi-bin; Liu, Wei-ye; Sun, Sheng; Li, Ling; Su, Ding-feng; Zhang, Li-chao

    2016-01-01

    Propionate is a short chain fatty acid that is abundant as butyrate in the gut and blood. However, propionate has not been studied as extensively as butyrate in the treatment of colitis. The present study was to investigate the effects of sodium propionate on intestinal barrier function, inflammation and oxidative stress in dextran sulfate sodium (DSS)-induced colitis mice. Animals in DSS group received drinking water from 1 to 6 days and DSS [3% (w/v) dissolved in double distilled water] instead of drinking water from 7 to 14 days. Animals in DSS+propionate (DSS+Prop) group were given 1% sodium propionate for 14 consecutive days and supplemented with 3% DSS solution on day 7–14. Intestinal barrier function, proinflammatory factors, oxidative stress, and signal transducer and activator of transcription 3 (STAT3) signaling pathway in the colon were determined. It was found that sodium propionate ameliorated body weight loss, colon-length shortening and colonic damage in colitis mice. Sodium propionate significantly inhibited the increase of FITC-dextran in serum and the decrease of zonula occludens-1 (ZO-1), occludin, and E-cadherin expression in the colonic tissue. It also inhibited the expression of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) mRNA and phosphorylation of STAT3 in colitis mice markedly, reduced the myeloperoxidase (MPO) level, and increased the superoxide dismutase and catalase level in colon and serum compared with DSS group. Sodium propionate inhibited macrophages with CD68 marker infiltration into the colonic mucosa of colitis mice. These results suggest that oral administration of sodium propionate could ameliorate DSS-induced colitis mainly by improving intestinal barrier function and reducing inflammation and oxidative stress via the STAT3 signaling pathway. PMID:27574508

  18. Indomethacin ameliorates trimethyltin-induced neuronal damage in vivo by attenuating oxidative stress in the dentate gyrus of mice.

    PubMed

    Huong, Nguyen Quynh; Nakamura, Yukary; Kuramoto, Nobuyuki; Yoneyama, Masanori; Nagashima, Reiko; Shiba, Tatsuo; Yamaguchi, Taro; Hasebe, Shigeru; Ogita, Kiyokazu

    2011-01-01

    The organotin trimethyltin (TMT) is well known to cause neuronal degeneration in the hippocampal dentate gyrus of mice. The first purpose of the present study was to examine whether the cyclooxygenase (COX) inhibitor indomethacin could ameliorate neuronal degeneration in the dentate gyrus of mice following TMT treatment in vivo. The systemic injection into mice of TMT at 2.8 mg/kg produced activation of endogenous caspase-3 and calpain, enhanced the gene expression of COX-1 and COX-2, activated microglial cells, and caused the formation of the lipid peroxidation product 4-hydroxynonenal in the hippocampus. Given at 12-h post-TMT treatment, the systemic injection of indomethacin (5 or 10 mg/kg, subcutaneously) significantly decreased the TMT-induced damage to neurons having active caspase-3 and single-stranded DNA in the dentate granule cell layer of the hippocampus. The results of the α-Fodrin degradation test revealed that the post-treatment with indomethacin was effective in attenuating TMT-induced activation of endogenous caspases and calpain in the hippocampus. In TMT-treated animals, interestingly, the post-treatment with indomethacin produced not only activation of microglial cells in the dentate gyrus but also the formation of 4-hydroxynonenal in the dentate granule cell layer. Taken together, our data suggest that COX inhibition by indomethacin ameliorated TMT-induced neuronal degeneration in the dentate gyrus by attenuating intensive oxidative stress.

  19. Fish oil ameliorates trimethylamine N-oxide-exacerbated glucose intolerance in high-fat diet-fed mice.

    PubMed

    Gao, Xiang; Xu, Jie; Jiang, Chengzi; Zhang, Yi; Xue, Yong; Li, Zhaojie; Wang, Jingfeng; Xue, Changhu; Wang, Yuming

    2015-04-01

    Trimethylamine N-oxide (TMAO), a component commonly present in seafood, has been found to have a harmful impact on glucose tolerance in high-fat diet (HFD)-fed mice. However, seafood also contains fish oil (FO), which has been shown to have beneficial effects on metabolism. Here, we investigated the effect of FO on TMAO-induced impaired glucose tolerance in HFD-fed mice. Male C57BL/6 mice were randomly assigned to the high fat (HF), TMAO, and fish oil groups. The HF group was fed a diet containing 25% fat, the TMAO group was fed the HFD plus 0.2% TMAO, and the FO group was fed the HFD plus 0.2% TMAO and 2% fish oil for 12 weeks. After 10 weeks of feeding, oral glucose tolerance tests were performed. Dietary FO improved the fasting glucose level, the fasting insulin level, HOMA-IR value, QUICKI score and ameliorated TMAO-induced exacerbated impaired glucose tolerance in HFD-fed mice. These effects were associated with the expression of genes related to the insulin signalling pathway, glycogen synthesis, gluconeogenesis, and glucose transport in peripheral tissues. Dietary fish oil also decreased TMAO-aggravated adipose tissue inflammation. Our results suggested that dietary FO ameliorated TMAO-induced impaired glucose tolerance, insulin signal transduction in peripheral tissue, and adipose tissue inflammation in HFD-fed mice.

  20. Beetroot (Beta vulgaris L.) Extract Ameliorates Gentamicin-Induced Nephrotoxicity Associated Oxidative Stress, Inflammation, and Apoptosis in Rodent Model

    PubMed Central

    El Gamal, Ali A.; AlSaid, Mansour S.; Raish, Mohammad; Al-Sohaibani, Mohammed; Al-Massarani, Shaza M.; Ahmad, Ajaz; Hefnawy, Mohamed; Al-Yahya, Mohammed; Basoudan, Omer A.; Rafatullah, Syed

    2014-01-01

    The present investigation was designed to investigate the protective effect of (Beta vulgaris L.) beat root ethanolic extract (BVEE) on gentamicin-induced nephrotoxicity and to elucidate the potential mechanism. Serum specific kidney function parameters (urea, uric acid, total protein, creatinine, and histopathology of kidney tissue) were evaluated to access gentamicin-induced nephrotoxicity. The oxidative/nitrosative stress (Lipid peroxidation, MDA, NP-SH, Catalase, and nitric oxide levels) was assessed. The inflammatory response (TNF-α, IL-6, MPO, NF-κB (p65), and NF-κB (p65) DNA binding) and apoptotic marker (Caspase-3, Bax, and Bcl-2) were also evaluated. BVEE (250 and 500 mg/kg) treatment along with gentamicin restored/increased the renal endogenous antioxidant status. Gentamicin-induced increased renal inflammatory cytokines (TNF-α and IL-6), nuclear protein expression of NF-κB (p65), NF-κB-DNA binding activity, myeloperoxidase (MPO) activity, and nitric oxide level were significantly down regulated upon BVEE treatment. In addition, BVEE treatment significantly reduced the amount of cleaved caspase 3 and Bax, protein expression and increased the Bcl-2 protein expression. BVEE treatment also ameliorated the extent of histologic injury and reduced inflammatory infiltration in renal tubules. These findings suggest that BVEE treatment attenuates renal dysfunction and structural damage through the reduction of oxidative stress, inflammation, and apoptosis in the kidney. PMID:25400335

  1. Ameliorative Effects of Acacia Honey against Sodium Arsenite-Induced Oxidative Stress in Some Viscera of Male Wistar Albino Rats

    PubMed Central

    Aliyu, Muhammad; Ibrahim, Sani; Inuwa, Hajiya M.; Sallau, Abdullahi B.; Abbas, Olagunju; Aimola, Idowu A.; Habila, Nathan; Uche, Ndidi S.

    2013-01-01

    Cancer is a leading cause of death worldwide and its development is frequently associated with oxidative stress-induced by carcinogens such as arsenicals. Most foods are basically health-promoting or disease-preventing and a typical example of such type is honey. This study was undertaken to investigate the ameliorative effects of Acacia honey on sodium arsenite-induced oxidative stress in the heart, lung and kidney tissues of male Wistar rats. Male Wistar albino rats divided into four groups of five rats each were administered distilled water, Acacia honey (20%), sodium arsenite (5 mg/kg body weight), Acacia honey, and sodium arsenite daily for one week. They were sacrificed anesthetically using 60 mg/kg sodium pentothal. The tissues were used for the assessment of glutathione peroxidase, catalase, and superoxide dismutase activities, protein content and lipid peroxidation. Sodium arsenite significantly (P < 0.05) suppressed the glutathione peroxidase, catalase, superoxide dismutase activities with simultaneous induction of lipid peroxidation. Administration of Acacia honey significantly increased (P < 0.05) glutathione peroxidase, catalase, and superoxide dismutase activities with concomitant suppression of lipid peroxidation as evident by the decrease in malondialdehyde level. From the results obtained, Acacia honey mitigates sodium arsenite induced-oxidative stress in male Wistar albino rats, which suggest that it may attenuate oxidative stress implicated in chemical carcinogenesis. PMID:24368942

  2. Beetroot (Beta vulgaris L.) extract ameliorates gentamicin-induced nephrotoxicity associated oxidative stress, inflammation, and apoptosis in rodent model.

    PubMed

    El Gamal, Ali A; AlSaid, Mansour S; Raish, Mohammad; Al-Sohaibani, Mohammed; Al-Massarani, Shaza M; Ahmad, Ajaz; Hefnawy, Mohamed; Al-Yahya, Mohammed; Basoudan, Omer A; Rafatullah, Syed

    2014-01-01

    The present investigation was designed to investigate the protective effect of (Beta vulgaris L.) beat root ethanolic extract (BVEE) on gentamicin-induced nephrotoxicity and to elucidate the potential mechanism. Serum specific kidney function parameters (urea, uric acid, total protein, creatinine, and histopathology of kidney tissue) were evaluated to access gentamicin-induced nephrotoxicity. The oxidative/nitrosative stress (Lipid peroxidation, MDA, NP-SH, Catalase, and nitric oxide levels) was assessed. The inflammatory response (TNF-α, IL-6, MPO, NF-κB (p65), and NF-κB (p65) DNA binding) and apoptotic marker (Caspase-3, Bax, and Bcl-2) were also evaluated. BVEE (250 and 500 mg/kg) treatment along with gentamicin restored/increased the renal endogenous antioxidant status. Gentamicin-induced increased renal inflammatory cytokines (TNF-α and IL-6), nuclear protein expression of NF-κB (p65), NF-κB-DNA binding activity, myeloperoxidase (MPO) activity, and nitric oxide level were significantly down regulated upon BVEE treatment. In addition, BVEE treatment significantly reduced the amount of cleaved caspase 3 and Bax, protein expression and increased the Bcl-2 protein expression. BVEE treatment also ameliorated the extent of histologic injury and reduced inflammatory infiltration in renal tubules. These findings suggest that BVEE treatment attenuates renal dysfunction and structural damage through the reduction of oxidative stress, inflammation, and apoptosis in the kidney.

  3. Tocotrienol-Rich Fraction Ameliorates Antioxidant Defense Mechanisms and Improves Replicative Senescence-Associated Oxidative Stress in Human Myoblasts

    PubMed Central

    Wan Ngah, Wan Zurinah; Abdul Karim, Norwahidah

    2017-01-01

    During aging, oxidative stress affects the normal function of satellite cells, with consequent regeneration defects that lead to sarcopenia. This study aimed to evaluate tocotrienol-rich fraction (TRF) modulation in reestablishing the oxidative status of myoblasts during replicative senescence and to compare the effects of TRF with other antioxidants (α-tocopherol (ATF) and N-acetyl-cysteine (NAC)). Primary human myoblasts were cultured to young, presenescent, and senescent phases. The cells were treated with antioxidants for 24 h, followed by the assessment of free radical generation, lipid peroxidation, antioxidant enzyme mRNA expression and activities, and the ratio of reduced to oxidized glutathione. Our data showed that replicative senescence increased reactive oxygen species (ROS) generation and lipid peroxidation in myoblasts. Treatment with TRF significantly diminished ROS production and decreased lipid peroxidation in senescent myoblasts. Moreover, the gene expression of superoxide dismutase (SOD2), catalase (CAT), and glutathione peroxidase (GPX1) was modulated by TRF treatment, with increased activity of superoxide dismutase and catalase and reduced glutathione peroxidase in senescent myoblasts. In comparison to ATF and NAC, TRF was more efficient in heightening the antioxidant capacity and reducing free radical insults. These results suggested that TRF is able to ameliorate antioxidant defense mechanisms and improves replicative senescence-associated oxidative stress in myoblasts. PMID:28243354

  4. Newcastle disease virus (NDV) induces protein oxidation and nitration in brain and liver of chicken: Ameliorative effect of vitamin E.

    PubMed

    Venkata Subbaiah, Kadiam C; Valluru, Lokanatha; Rajendra, Wudayagiri; Ramamurthy, Chiteti; Thirunavukkarusu, Chinnasamy; Subramanyam, Rajagopal

    2015-07-01

    The present study was aimed at investigating the therapeutic efficacy of vitamin E on oxidative injury in brain and liver of Newcastle disease virus (NDV) challenged chickens. We have analyzed the xanthine oxidase (XOD) activity; uric acid (UA) levels and superoxide radical generation by using electron spin resonance spectroscopy. Further, protein oxidation, nitration and apoptosis were evaluated in the brain and liver of the control, NDV-infected and NDV+Vit. E treated groups. A significant elevation was observed in XOD activity and UA levels in brain (p<0.001) and liver (p<0.05) of NDV infected birds when compared to controls. Further, significant increase in the production of superoxides, enhanced intracellular protein carbonyls and nitrates were observed in the brain and liver of NDV-infected birds over healthy subjects. Apoptosis studies also suggested that a larger number of TUNEL positive cells were observed in brain and a moderately in liver of NDV-infected chickens. However, all these perturbations were significantly ameliorated in NDV+Vit. E treated chickens as compared to NDV-infected birds. Taken together, our results suggested that NDV-induced neuronal and hepatic damage at least in part mediates oxidative stress and on the other hand, supplementation of vitamin E mitigates NDV-induced oxidative damage thereby protects brain and liver of chickens. These findings could provide new insights into the understanding of NDV pathogenesis and therapeutic effects of dietary antioxidants.

  5. Mulberry leaf phenolics ameliorate hyperglycemia-induced oxidative stress and stabilize mitochondrial membrane potential in HepG2 cells.

    PubMed

    Zou, Yu-Xiao; Shen, Wei-Zhi; Liao, Sen-Tai; Liu, Fan; Zheng, Shan-Qing; Blumberg, Jeffrey B; Chen, C-Y Oliver

    2014-12-01

    To investigate the effect of phenolics in mulberry leaves (mulberry leaf phenolics; MLP) on hyperglycemia-induced oxidative stress and mitochondrial membrane potential (ΔΨm) in HepG2 cells; we treated HepG2 with glucose [5.5 (N-Glc) or 50 mmol/L (Hi-Glc)] with or without MLP at 10 or 100 µmol/L gallic acid equivalents and assessed level of reactive oxidant species (ROS), ΔΨm, malondialdehyde (MDA) and nuclear factor-kappaB (NF-κB) activation. Hi-Glc-induced oxidative damage was demonstrated by a series of increase in superoxides (560%, 0.5 h), MDA (400%, 24 h), NF-κB activation (474%, 4 h) and a wild fluctuation of ΔΨm relative to the control cells (p ≤ 0.05). MLP treatments ameliorate Hi-Glc-induced negative effects by a 40% reduction in ROS production, 34-44% reduction in MDA production, over 35% inhibition of NF-κB activation, as well as exert protective effect on HepG2 cells from change in ΔΨm. Our data show that MLP in vitro can protect hepatoctyes from hyperglycemia-induced oxidative damages.

  6. The role of PACAP in gonadotropic hormone secretion at hypothalamic and pituitary levels.

    PubMed

    Köves, Katalin; Kántor, Orsolya; Molnár, Judith; Heinzlmann, Andrea; Szabó, Enikö; Szabó, Flóra; Nemeskéri, Agnes; Horváth, Judit; Arimura, Akira

    2003-04-01

    The presence of pituitary adenylate cyclase-activating polypeptide (PACAP) and its mRNAin the three levels of the hypothalamo-hypophyseal-ovarian axis was previously demonstrated using immunohistochemistry, in situ hybridization, and reverse transcriptase polymerase chain reaction (RT-PCR). In the hypothalamus, PACAP is present in neuroendocrine effector cells and in the median eminence. In the anterior pituitary and ovary, PACAP is transiently present during the proestrous stage of the estrous cycle. In the pituitary, PACAP was observed in gonadotropes. In the ovary, PACAP was demonstrated in the granulosa cells of the preovulatory ovarian follicles. The effect of PACAP on luteinizing hormone (LH) secretion was demonstrated in in vivo and in vitro models. In our work we have studied the role of PACAP in gonadotropic hormone secretion at hypothalamic and pituitary levels. At the hypothalamic level, PACAP, administered intracerebroventricularly to female rats before the critical period of the proestrus stage, can inhibit LH release and ovulation. Its inhibiting effect is mediated through corticotropin-releasing factor (CRF) and endogenous opioids. PACAP administered to neonatal female rats delayed the onset of puberty by influencing the luteinizing hormone-releasing hormone (LHRH) neuronal system. In the pituitary gland, the release of PACAP depended on the stage of the estrous cycle and on the time of day the animals were sacrificed. On the day of proestrus, the number of PACAP-releasing cells showed a diurnal change with two peaks (in the morning and in the evening). The peak was much higher in the evening at the end of the LH surge than in the morning.

  7. Nitric oxide ameliorates the damaging effects of oxidative stress induced by iron deficiency in cyanobacterium Anabaena 7120.

    PubMed

    Kaushik, Manish Singh; Srivastava, Meenakshi; Srivastava, Alka; Singh, Anumeha; Mishra, Arun Kumar

    2016-11-01

    In cyanobacterium Anabaena 7120, iron deficiency leads to oxidative stress with unavoidable consequences. Nitric oxide reduces pigment damage and supported the growth of Anabaena 7120 in iron-deficient conditions. Elevation in nitric oxide accumulation and reduced superoxide radical production justified the role of nitric oxide in alleviating oxidative stress in iron deficiency. Increased activities of antioxidative enzymes and higher levels of ROS scavengers (ascorbate, glutathione and thiol) in iron deficiency were also observed in the presence of nitric oxide. Nitric oxide also supported the membrane integrity of Anabaena cells and reduces protein and DNA damage caused by oxidative stress induced by iron deficiency. Results suggested that nitric oxide alleviates the damaging effects of oxidative stress induced by iron deficiency in cyanobacterium Anabaena 7120.

  8. Ozone oxidative postconditioning ameliorates joint damage and decreases pro-inflammatory cytokine levels and oxidative stress in PG/PS-induced arthritis in rats.

    PubMed

    Vaillant, Jaqueline Dranguet; Fraga, Angela; Díaz, María Teresa; Mallok, A; Viebahn-Hänsler, Renate; Fahmy, Ziad; Barberá, Ariana; Delgado, Liván; Menéndez, Silvia; Fernández, Olga Sonia León

    2013-08-15

    Rheumatoid Arthritis (RA) is the most prevalent chronic condition present in ~1% of the adult population. Many pro-inflammatory mediators are increased in RA, including Reactive Oxygen Species such as nitric oxide NO, pro-inflammatory cytokines as tumor necrosis factor alpha (TNF-α), interleukin-1beta (IL-1β) and other molecules. Ozone oxidative postconditioning has regulatory effects on some pathological targets associated with RA. Thus, the aim of this study was to investigate the efficacy of ozone therapy in PG/PS-induced arthritis in rats in point of joints inflammation and morphology. Moreover, cytokines, nitric oxide and oxidative stress levels in spleen homogenates were evaluated. Ozone treatment ameliorated joint damage, reduced TNF-α concentrations as well as TNF-α and IL-1β mRNA levels. Besides, cellular redox balance, nitric oxide and fructolysine levels were reestablished after ozone oxidative postconditioning. It was concluded that pleiotropic ozone's effects clarify its therapeutic efficacy in RA. Decreasing inflammation and joint injury, reduction of pro-inflammatory cytokines, TNF-α and IL-1β transcripts and re-establishment of cellular redox balance after ozone treatment were demonstrated.

  9. Olmesartan ameliorates urinary dysfunction in the spontaneously hypertensive rat via recovering bladder blood flow and decreasing oxidative stress.

    PubMed

    Shimizu, Shogo; Saito, Motoaki; Oiwa, Harunori; Ohmasa, Fumiya; Tsounapi, Panagiota; Oikawa, Ryo; Dimitriadis, Fotios; Martin, Darryl T; Satoh, Itaru; Kinoshita, Yukako; Tomita, Shuhei

    2014-03-01

    As hypertension (HT) is one of the risk factors for lower urinary tract symptoms, we investigated the effect of an angiotensin II type I receptor blocker, olmesartan, on bladder dysfunction in the spontaneously hypertensive rat (SHR). Twelve-week-old male SHRs were administered perorally with olmesartan (0, 1, or 3 mg/kg/day) or nifedipine (30 mg/kg/day) for 6 weeks. Wistar rats were used as normotensive controls. The effects of olmesartan or nifedipine on blood pressure (BP), bladder blood flow (BBF), urodynamic parameters, tissue levels of malondialdehyde (MDA), nuclear factor erythroid 2-related factor 2 (Nrf2), and nerve growth factor (NGF) were measured in the bladder. Localization of 4-hydroxy-2-nonenal (4-HNE), Nrf2, and NGF in the bladder was shown by immunohistochemistry. The SHRs showed significant increase in BP, micturition frequency, and expression of MDA, 4-HNE, Nrf2, and NGF when compared to the control Wistar rats. Conversely, there was a decrease in BBF and single voided volume in SHRs when compared to Wistar rats. Treatment with olmesartan and nifedipine significantly improved BP. However, only olmesartan significantly ameliorated urodynamic parameters and oxidative damage compared to the non-treated SHR. The immunoreactivities of 4-HNE, Nrf2, and NGF in SHR urothelium and blood vessels were increased compared to the control. Treatment with a high dose of olmesartan decreased the expressions of 4-HNE, Nrf2, and NGF in the bladder. Our data suggest that BP, BBF, and oxidative stress may be responsible for the functional changes in HT-related bladder dysfunction. Olmesartan significantly ameliorated this bladder dysfunction. © 2013 Wiley Periodicals, Inc.

  10. Satureja bachtiarica ameliorate beta-amyloid induced memory impairment, oxidative stress and cholinergic deficit in animal model of Alzheimer's disease.

    PubMed

    Soodi, Maliheh; Saeidnia, Soodabeh; Sharifzadeh, Mohammad; Hajimehdipoor, Homa; Dashti, Abolfazl; Sepand, Mohammad Reza; Moradi, Shahla

    2016-04-01

    Extracellular deposition of Beta-amyloid peptide (Aβ) is the main finding in the pathophysiology of Alzheimer's disease (AD), which damages cholinergic neurons through oxidative stress and reduces the cholinergic neurotransmission. Satureja bachtiarica is a medicinal plant from the Lamiaceae family which was widely used in Iranian traditional medicine. The aim of the present study was to investigate possible protective effects of S. bachtiarica methanolic extract on Aβ induced spatial memory impairment in Morris Water Maze (MWM), oxidative stress and cholinergic neuron degeneration. Pre- aggregated Aβ was injected into the hippocampus of each rat bilaterally (10 μg/rat) and MWM task was performed 14 days later to evaluate learning and memory function. Methanolic extract of S.bachtiarica (10, 50 and 100 mg/Kg) was injected intraperitoneally for 19 consecutive days, after Aβ injection. After the probe test the brain tissue were collected and lipid peroxidation, Acetylcholinesterase (AChE) activity and Cholin Acetyl Transferees (ChAT) immunorectivity were measured in the hippocampus. Intrahipocampal injection of Aβ impaired learning and memory in MWM in training days and probe trail. Methanolic extract of S. bachtiarica (50 and 100 mg/Kg) could attenuate Aβ-induced memory deficit. ChAT immunostaining revealed that cholinergic neurons were loss in Aβ- injected group and S. bachtiarica (100 mg/Kg) could ameliorate Aβ- induced ChAT reduction in the hippocampus. Also S. bachtiarica could ameliorate Aβ-induced lipid peroxidation and AChE activity increase in the hippocampus. In conclusion our study represent that S.bachtiarica methanolic extract can improve Aβ-induced memory impairment and cholinergic loss then we recommended this extract as a candidate for further investigation in treatment of AD.

  11. Amelioration of Hyperglycaemia, Oxidative Stress and Dyslipidaemia in Alloxan-Induced Diabetic Wistar Rats Treated with Probiotic and Vitamin C

    PubMed Central

    Aluwong, Tagang; Ayo, Joseph O.; Kpukple, Alkali; Oladipo, Olusola Olalekan

    2016-01-01

    Clinical and experimental evidence suggests that hyperglycaemia is responsible for the oxidative stress in diabetes mellitus. The study was designed to investigate the comparative effects of probiotic and vitamin C (Vit-C) treatments on hyperglycaemia, oxidative stress and dyslipidaemia in alloxan-induced diabetic rats. Type 1 diabetes (T1DM) was induced in male Wistar rats by a single intraperitoneal (i.p.) injection of alloxan (150 mg/kg). Six groups of the animals received the following treatment regimens for four weeks: (1) Normal saline, per os; (2) alloxan (150 mg/kg, i.p.); (3) alloxan (150 mg/kg) + insulin (4 U/kg, subcutaneously); (4) alloxan (150 mg/kg) + probiotic (4.125 × 106 CFU/100 mL per os); (5) alloxan (150 mg/kg) + Vit-C (100 mg/kg, i.m.); (6) alloxan (150 mg/kg) + probiotic (4.125 × 106 CFU/100 mL per os) + Vit-C (100 mg/kg, intramuscularly). Probiotic + Vit-C decreased (p < 0.05) blood glucose concentration in diabetic treated group, when compared with the untreated diabetic group. Probiotic + Vit-C reduced malondialdehyde concentration, in the serum, brain and kidneys, respectively, but increased the activity of antioxidant enzymes. Probiotic and Vit-C may be more effective than Vit-C alone, in ameliorating hyperglycaemia, oxidative stress and dyslipidaemia in alloxan-induced diabetic rats. PMID:27164129

  12. Comparison of vitamin E, L-carnitine and melatonin in ameliorating carbon tetrachloride and diabetes induced hepatic oxidative stress.

    PubMed

    Shaker, M E; Houssen, M E; Abo-Hashem, E M; Ibrahim, T M

    2009-09-01

    This study aimed to investigate whether treatments with vitamin E, L-carnitine and melatonin can protect against CCl(4) and diabetes-induced hepatic oxidative stress. Hepatic oxidative stress was performed in rats through 50% v/v carbon tetrachloride (CCl(4)) (1 ml/kg/3 days, i.p.), and through diabetes mellitus induced by streptozotocin (STZ) (40 mg/kg, i.p.). Vitamin E (100 mg/kg/day, i.p), L-carnitine (300 mg/kg/day, i.p.) and melatonin (10 mg/kg/day, i.p.) were injected for a period of 6 weeks. Thereafter, changes in serum glucose level, liver function tests, hepatic malondialdehyde (MDA) content, hepatic reduced glutathione (GSH) content, hepatic superoxide dismutase (SOD) activity, and serum total antioxidant capacity (TAC) level were evaluated. In CCl(4)-induced liver fibrosis, the efficacy order was melatonin > L-carnitine > vitamin E, while in STZ-induced diabetes, the efficacy order was vitamin E > or = melatonin > L-carnitine. In conclusion, these data indicate that low dose of melatonin is more effective than high doses of vitamin E and L-carnitine in reducing hepatic oxidative stress induced by CCl(4) and diabetes. Moreover, the potent effect of vitamin E in ameliorating diabetes can be linked not only to the antioxidant actions, but also to the superior effect in reducing diabetes-induced hyperglycaemia. Meanwhile, potency of L-carnitine was nearly the same in CCl(4) and diabetes-induced liver damage.

  13. Green Synthesis of Oxovanadium(IV)/chitosan Nanocomposites and Its Ameliorative Effect on Hyperglycemia, Insulin Resistance, and Oxidative Stress.

    PubMed

    Liu, Yanjun; Jie, Xu; Guo, Yongli; Zhang, Xin; Wang, Jingfeng; Xue, Changhu

    2016-02-01

    In this paper, the preparation, characterization, and ameliorative effect on high-fat high-sucrose diet-induced hyperglycemia, insulin resistance, oxidative stress in mice of novel oxovanadium(IV)/chitosan (OV/CS) nanocomposites were investigated. The nanobiocomposite was produced by chemical reduction by chitosan and L-ascorbic acid using microwave heating, under environment-friendly conditions, using aqueous solutions, and notably, by using both mediators as reducing and stabilizing agents. In addition, OV/CS nanocomposites were characterized by transmission electron microscopy, energy dispersive spectroscopy, particle size, and zeta potential measurements. In vivo experiments were designed to examine whether the OV/CS nanocomposites would provide additional benefits on oxidative stress, hyperglycemia, and insulin resistance in mice with type 2 diabetes. The results rendered insulin resistant by treating with OV/CS nanocomposites alleviate insulin resistance and improve oxidative stress. Such nanocomposite seem to be a valuable therapy to achieve and/or maintain glycemic control and therapeutic agents in the treatment arsenal for insulin resistance and type 2 diabetes.

  14. Amelioration of Hyperglycaemia, Oxidative Stress and Dyslipidaemia in Alloxan-Induced Diabetic Wistar Rats Treated with Probiotic and Vitamin C.

    PubMed

    Aluwong, Tagang; Ayo, Joseph O; Kpukple, Alkali; Oladipo, Olusola Olalekan

    2016-05-05

    Clinical and experimental evidence suggests that hyperglycaemia is responsible for the oxidative stress in diabetes mellitus. The study was designed to investigate the comparative effects of probiotic and vitamin C (Vit-C) treatments on hyperglycaemia, oxidative stress and dyslipidaemia in alloxan-induced diabetic rats. Type 1 diabetes (T1DM) was induced in male Wistar rats by a single intraperitoneal (i.p.) injection of alloxan (150 mg/kg). Six groups of the animals received the following treatment regimens for four weeks: (1) Normal saline, per os; (2) alloxan (150 mg/kg, i.p.); (3) alloxan (150 mg/kg) + insulin (4 U/kg, subcutaneously); (4) alloxan (150 mg/kg) + probiotic (4.125 × 10⁶ CFU/100 mL per os); (5) alloxan (150 mg/kg) + Vit-C (100 mg/kg, i.m.); (6) alloxan (150 mg/kg) + probiotic (4.125 × 10⁶ CFU/100 mL per os) + Vit-C (100 mg/kg, intramuscularly). Probiotic + Vit-C decreased (p < 0.05) blood glucose concentration in diabetic treated group, when compared with the untreated diabetic group. Probiotic + Vit-C reduced malondialdehyde concentration, in the serum, brain and kidneys, respectively, but increased the activity of antioxidant enzymes. Probiotic and Vit-C may be more effective than Vit-C alone, in ameliorating hyperglycaemia, oxidative stress and dyslipidaemia in alloxan-induced diabetic rats.

  15. Growth hormone ameliorates adipose dysfunction during oxidative stress and inflammation and improves glucose tolerance in obese mice.

    PubMed

    Fukushima, M; Okamoto, Y; Katsumata, H; Ishikawa, M; Ishii, S; Okamoto, M; Minami, S

    2014-08-01

    Patients with adult growth hormone deficiency exhibit visceral fat accumulation, which gives rise to a cluster of metabolic disorders such as impaired glucose tolerance and dyslipidemia. Plasma growth hormone levels are lower in obese patients with metabolic syndrome than in healthy subjects. Here we examined the hypothesis that exogenous growth hormone administration regulates function of adipose tissue to improve glucose tolerance in diet-induced obese mice. Twelve-week-old obese male C57BL/6 J mice received bovine growth hormone daily for 6 weeks. In epididymal fat, growth hormone treatment antagonized diet-induced changes in the gene expression of adiponectin, leptin, and monocyte chemoattractant protein-1, and significantly increased the gene expression of interleukin-10 and CD206. Growth hormone also suppressed the accumulation of oxidative stress marker, thiobarbituric acid-reactive substances, in the epididymal fat and enhanced the gene expression of anti-oxidant enzymes. Moreover, growth hormone significantly restored glucose tolerance in obese mice. In cultured 3T3-L1 adipocytes, growth hormone prevented the decline in adiponectin gene expression in the presence of hydrogen peroxide. These results suggest that growth hormone administration ameliorates glucose intolerance in obese mice presumably by decreasing adipose mass, oxidative stress, and chronic inflammation in the visceral fat. © Georg Thieme Verlag KG Stuttgart · New York.

  16. Camel's milk ameliorates TNBS-induced colitis in rats via downregulation of inflammatory cytokines and oxidative stress.

    PubMed

    Arab, Hany H; Salama, Samir A; Eid, Ahmed H; Omar, Hany A; Arafa, El-Shaimaa A; Maghrabi, Ibrahim A

    2014-07-01

    Current treatment strategies for inflammatory bowel diseases (IBD) are associated with several adverse effects, and thus, the search for effective agents with minimal side effects merits attention. Camel's milk (CM) is endowed with antioxidant/anti-inflammatory features and has been reported to protect against diabetes and hepatic injury, however, its effects on IBD have not been previously explored. In the current study, we aimed to investigate the potential alleviating effects of CM against TNBS-induced colitis in rats. CM (10 ml/kg b.i.d. by oral gavage) effectively suppressed the severity of colon injury as evidenced by amelioration of macroscopic damage, colon weight/length ratio, histopathological alterations, leukocyte influx and myeloperoxidase activity. Administration of CM mitigated the colonic levels of TNF-α and IL-10 cytokines. The attenuation of CM to colon injury was also associated with suppression of oxidative stress via reduction of lipid peroxides and nitric oxide along with boosting the antioxidant defenses through restoration of colon glutathione and total anti-oxidant capacity. In addition, caspases-3 activity, an apoptotic marker, was inhibited. Together, our study highlights evidences for the promising alleviating effects of CM in colitis. Thus, CM may be an interesting complementary approach for the management of IBD.

  17. PACAP27 regulates ciliary function in primary cultures of rat brain ependymal cells.

    PubMed

    Mönkkönen, K S; Mnkkönen, K S; Hirst, R A; Laitinen, J T; O'Callaghan, C

    2008-01-01

    Ependymal cells line the brain ventricles and separate the CSF from the underlying neuronal tissue. The function of ependymal cilia is largely unclear however they are reported to be involved in the regulation of CSF homeostasis and host defence against pathogens. Here we present data that implicates a role of pituitary adenylate cyclase-activating polypeptide (PACAP) in the inhibition of ependymal ciliary function, and also that the PACAP effects are not entirely dependent on adenylyl cyclase activation. Primary ependymal cultures were treated with increasing doses of PACAP27 or adenylyl cyclase toxin (ACT), and ciliary beating was recorded using high-speed digital video imaging. Ciliary beat frequency (CBF) and amplitude were determined from the videos. Ependymal CBF and ciliary amplitude were attenuated by PACAP27 in a concentration- and time-dependent manner. The peptide antagonist PACAP6-27 blocked PACAP27-induced decreases in amplitude and CBF. Treatment with ACT caused a decrease in amplitude but had no effect on CBF, this suggests that the inhibition of CBF and amplitude seen with PACAP27 may not be completely explained by G(s)-AC-cAMP pathway. We present here the first observational study to show that activation of PAC1 receptors with PACAP27 has an important role to play in the regulation of ependymal ciliary function.

  18. Regulation of bed nucleus of the stria terminalis PACAP expression by stress and corticosterone.

    PubMed

    Lezak, Kimberly R; Roman, Carolyn W; Braas, Karen M; Schutz, Kristin C; Falls, William A; Schulkin, Jay; May, Victor; Hammack, Sayamwong E

    2014-11-01

    Single-nucleotide polymorphisms (SNPs) in the genes for pituitary adenylyl cyclase-activating peptide (PACAP) and the PAC1 receptor have been associated with stress-related psychiatric disorders. Although, from recent work, we have argued that stress-induced PACAP expression in the bed nucleus of the stria terminalis (BNST) may mediate stress-related psychopathology, it is unclear whether stress-induced increases in BNST PACAP expression require acute or repeated stressor exposure and whether increased BNST PACAP expression is related to stress-induced increases in circulating glucocorticoids. In the current work, we have used real-time quantitative polymerase chain reaction (qPCR) to assess transcript expression in brain punches from rats after stressor exposure paradigms or corticosterone injection. BNST PACAP and PAC1 receptor transcript expression was increased only after 7 days of repeated stressor exposure; no changes in transcript levels were observed 2 or 24 hours after a single-restraint session. Moreover, repeated corticosterone treatment for 7 days was not sufficient to reliably increase BNST PACAP transcript levels, suggesting that stress-induced elevations in corticosterone may not be the primary drivers of BNST PACAP expression. These results may help clarify the mechanisms and temporal processes that underlie BNST PACAP induction for intervention in stress-related anxiety disorders.

  19. Anti-inflammatory and anti-oxidant activities of olmesartan medoxomil ameliorate experimental colitis in rats

    SciTech Connect

    Nagib, Marwa M.; Tadros, Mariane G.; ELSayed, Moushira I.; Khalifa, Amani E.

    2013-08-15

    Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) driven through altered immune responses with production of proinflammatory cytokines. Many therapies are used, but side effects and loss of response limit long-term effectiveness. New therapeutic strategies are thus needed for patients who don't respond to current treatments. Recently, there is suggested involvement of the proinflammatory hormone angiotensin II in inflammatory bowel disease. The aim of this study was to investigate the possible role of olmesartan medoxomil (OLM-M), an angiotensin II receptor blocker in ameliorating ulcerative colitis. Colitis was induced in male Wistar rats by administration of 5% dextran sodium sulphate (DSS) in drinking water for 5 days. OLM-M (1, 3 and 10 mg/kg) was administered orally during 21 days prior to the induction of colitis, and for 5 days after. Sulfasalazine (500 mg/kg) was used as reference drug. All animals were tested for changes in colon length, disease activity index (DAI) and microscopic damage. Colon tissue concentration/activity of tumor necrosis alpha (TNF-α), myeloperoxidase (MPO), prostaglandin E2 (PGE2), reduced glutathione (GSH) and malondialdehyde (MDA) were assessed. Results showed that the OLM-M dose-dependently ameliorated the colonic histopathological and biochemical injuries, an effect that is comparable or even better than that of the standard sulfasalazine. These results suggest that olmesartan medoxomil may be effective in the treatment of UC through its anti-inflammatory and antioxidant effects. - Highlights: • Olmesartan medoximil reduced dextran sodium sulphate- induced colitis. • Mechanism involved anti-inflammatory and antioxidant effects dose- dependently. • It suppressed malondialdehyde and restored reduced glutathione levels. • It reduced inflammatory markers levels and histological changes.

  20. The role of genetics on migraine induction triggered by CGRP and PACAP38.

    PubMed

    Guo, Song

    2017-03-01

    Migraine has a strong genetic component and is characterized by multiphasic events including an initial premonitory phase with premonitory symptoms (PS). Calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating peptide-38 (PACAP38) are endogenous neuropeptides that can trigger migraine attacks and have in recent years gained considerable interest in the migraine field. Yet, the exact pathophysiological mechanisms underlying CGRP- and PACAP38-induced attacks are not fully clarified. Human provocation models have shown that these peptides induce attacks in only two- thirds of migraine patients. Whether this diverse migraine response after CGRP or PACAP38 may be explained by genetic factors is unknown. The present thesis includes four studies that explore different factors that may be associated with the CGRP- and PACAP38-induced migraine response. In study I and II we investigated the role of familial predisposition (family load) and number of risk conferring gene variants on migraine attacks induced by CGRP or PA-CAP38. In study III, we investigated biochemical changes of CGRP, vasoactive intestinal peptide (VIP), S100B and TNF-alpha in the blood after PACAP38. Finally in study IV, we studied whether CGRP or PACAP38 may induce PS. Study I and II demonstrated that PACAP38 and CGRP induce migraine attacks in 63% and 72% of the patients, respectively. Moreover, we showed that patients with high family load or a high number of migraine associated gene variants did not report more migraine attacks after CGRP or PACAP38 than those with no familial predisposition or few gene variants. Study III showed that PACAP38 infusion caused changes in plasma concentrations for VIP and S100B, but not CGRP and TNF-alpha, suggesting activation of parasympathetic nerve endings. Study IV showed absence of PS after CGRP and lack of statistical difference in PS between patients who reported and not reported attacks after PACAP38 suggesting peripheral mechanisms of

  1. PACAP Interactions in the Mouse Brain: Implications for Behavioral and Other Disorders

    SciTech Connect

    Acquaah-Mensah, George; Taylor, Ronald C.; Bhave, Sanjiv V.

    2012-01-10

    As an activator of adenylate cyclase, the neuropeptide Pituitary Adenylate Cyclase Activating Peptide (PACAP) impacts levels of cyclic AMP, a key second messenger available in brain cells. PACAP is involved in certain adult behaviors. To elucidate PACAP interactions, a compendium of microarrays representing mRNA expression in the adult mouse whole brain was pooled from the Phenogen database for analysis. A regulatory network was computed based on mutual information between gene pairs using gene expression data across the compendium. Clusters among genes directly linked to PACAP, and probable interactions between corresponding proteins were computed. Database 'experts' affirmed some of the inferred relationships. The findings suggest ADCY7 is probably the adenylate cyclase isoform most relevant to PACAP's action. They also support intervening roles for kinases including GSK3B, PI 3-kinase, SGK3 and AMPK. Other high-confidence interactions are hypothesized for future testing. This new information has implications for certain behavioral and other disorders.

  2. Structural and Morphometric Comparison of Lower Incisors in PACAP-Deficient and Wild-Type Mice.

    PubMed

    Sandor, B; Fintor, K; Reglodi, D; Fulop, D B; Helyes, Z; Szanto, I; Nagy, P; Hashimoto, H; Tamas, A

    2016-06-01

    Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide with widespread distribution. PACAP plays an important role in the development of the nervous system, it has a trophic and protective effect, and it is also implicated in the regulation of various physiological functions. Teeth are originated from the mesenchyme of the neural crest and the ectoderm of the first branchial arch, suggesting similarities with the development of the nervous system. Earlier PACAP-immunoreactive fibers have been found in the odontoblastic and subodontoblastic layers of the dental pulp. Our previous examinations have shown that PACAP deficiency causes alterations in the morphology and structure of the developing molars of 7-day-old mice. In our present study, morphometric and structural comparison was performed on the incisors of 1-year-old wild-type and PACAP-deficient mice. Hard tissue density measurements and morphometric comparison were carried out on the mandibles and the lower incisors with micro-CT. For structural examination, Raman microscopy was applied on frontal thin sections of the mandible. With micro-CT morphometrical measurements, the size of the incisors and the relative volume of the pulp to dentin were significantly smaller in the PACAP-deficient group compared to the wild-type animals. The density of calcium hydroxyapatite in the dentin was reduced in the PACAP-deficient mice. No structural differences could be observed in the enamel with Raman microscopy. Significant differences were found in the dentin of PACAP-deficient mice with Raman microscopy, where increased carbonate/phosphate ratio indicates higher intracrystalline disordering. The evaluation of amide III bands in the dentin revealed higher structural diversity in wild-type mice. Based upon our present and previous results, it is obvious that PACAP plays an important role in tooth development with the regulation of morphogenesis, dentin, and enamel mineralization. Further studies are

  3. VIP/PACAP receptor mediation of cutaneous active vasodilation during heat stress in humans.

    PubMed

    Kellogg, Dean L; Zhao, Joan L; Wu, Yubo; Johnson, John M

    2010-07-01

    Vasoactive intestinal peptide (VIP) is implicated in cutaneous active vasodilation in humans. VIP and the closely related pituitary adenylate cyclase activating peptide (PACAP) act through several receptor types: VIP through VPAC1 and VPAC2 receptors and PACAP through VPAC1, VPAC2, and PAC1 receptors. We examined participation of VPAC2 and/or PAC1 receptors in cutaneous vasodilation during heat stress by testing the effects of their specific blockade with PACAP6-38. PACAP6-38 dissolved in Ringer's was administered by intradermal microdialysis at one forearm site while a control site received Ringer's solution. Skin blood flow was monitored by laser-Doppler flowmetry (LDF). Blood pressure was monitored noninvasively and cutaneous vascular conductance (CVC) calculated. A 5- to 10-min baseline period was followed by approximately 70 min of PACAP6-38 (100 microM) perfusion at one site in normothermia and a 3-min period of body cooling. Whole body heating was then performed to engage cutaneous active vasodilation and was maintained until CVC had plateaued at an elevated level at all sites for 5-10 min. Finally, 58 mM sodium nitroprusside was perfused through both microdialysis sites to effect maximal vasodilation. No CVC differences were found between control and PACAP6-38-treated sites during normothermia (19 +/- 3%max untreated vs. 20 +/- 3%max, PACAP6-38 treated; P > 0.05 between sites) or cold stress (11 +/- 2%max untreated vs. 10 +/- 2%max, PACAP6-38 treated, P > 0.05 between sites). PACAP6-38 attenuated the increase in CVC during whole body heating when compared with untreated sites (59 +/- 3%max untreated vs. 46 +/- 3%max, PACAP6-38 treated, P < 0.05). We conclude that VPAC2 and/or PAC1 receptor activation is involved in cutaneous active vasodilation in humans.

  4. A structure-function study of PACAP using conformationally-restricted analogs: identification of PAC1 receptor-selective PACAP agonists

    PubMed Central

    Ramos-Álvarez, Irene; Mantey, Samuel A.; Nakamura, Taichi; Nuche-Berenguer, Bernardo; Moreno, Paola; Moody, Terry W.; Maderdrut, Jerome L.; Coy, David H.; Jensen, Robert T.

    2015-01-01

    Pituitary adenylate-cyclase-activating polypeptide (PACAP) has widespread physiological/pathophysiological actions and there is increased interest for its use therapeutically, especially in the CNS (neuroprotection). Unfortunately, no selective PACAP-analogs exist for PACAP-preferring PAC1-receptors, primarily because of its high sequence identity to VIP and particularly, because of the inability of structure-function studies to separate the pharmacophore of PAC1-R from VPAC1-R, which has high affinity for PACAP and VIP. The present study attempted to develop PAC1-R-selective agonists primarily by making conformationally-restricted PACAP -analogs in positions important for receptor-selectivity/affinity. Forty-six PACAP-related-analogs were synthesized with substitutions in positions 1–4, 14–17, 20–22 ,28,34,38 and receptor-selectivity determined in PAC1-R,VPAC1-R,VPAC2-R-transfected or native cells from binding or cAMP-generation experiments. Fifteen PACAP-analogs had 6–78-fold higher affinities for PAC1-R than VPAC1-R and 13 were agonists. Although binding-affinities correlated significantly with agonist potency, the degree of receptor-spareness varied markedly for the different PACAP-analogs, resulting in selective potencies for activating the PAC1 receptor over the VPAC1 receptor from 0- to-103-fold. In addition, a number of PACAP-analogs were identified that had high selectivity for PAC1-R over VPAC2-R as well as PACAP-analogs that could prove more useful therapeutically because of substitutions known to extend their half-lives (substitutions at potential sites of proteolysis and attachment of long-chain fatty acids). This study provides for the first time a separation of the pharmacophores for PAC1-R and VPAC1-R, resulting in PACAP-related analogs that are PAC1-R-preferring. Some of these analogs, or their modifications, could prove useful as therapeutic agents for various diseases. PMID:25698233

  5. Purification and primary structure of pituitary adenylate cyclase activating polypeptide (PACAP) from the brain of an elasmobranch, stingray, Dasyatis akajei.

    PubMed

    Matsuda, K; Yoshida, T; Nagano, Y; Kashimoto, K; Yatohgo, T; Shimomura, H; Shioda, S; Arimura, A; Uchiyama, M

    1998-01-01

    Pituitary adenylate cyclase activating polypeptide (PACAP) was isolated from ovine hypothalami and found to exist as two amidated forms with 38 (PACAP 38) and 27 (PACAP 27) residues. The amino acid sequences of PACAPs isolated from the vertebrates, such as a bird, a frog and teleost fish, appear to be well conserved. In the present study, we attempted to isolate PACAP from the brain of an elasmobranch fish, Dasyatis akajei (stingray), which belongs to the Chondrichthyes (cartilaginous fish), by extraction of the acetone-dried powder with acetic acid, followed by successive high-performance liquid chromatography (HPLC) on a gel-filtration, a cation-exchange and two reverse-phase columns. Purification was monitored by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis (PAGE) and Western blotting analysis using an anti-PACAP 27 serum. The PACAP thus obtained consisted of 44 residues. The amino acid sequence of the comparable portion of its N-terminal 38 residues showed 92%, 89%, 89%, and 82% identity with those of mammalian, chicken, frog and teleost PACAPs with 38 residues, respectively. The extra six C-terminal residues of the stingray resembled those of tetrapod and teleost PACAP precursors which were deduced from the respective cDNAs. These results indicate that PACAP, which has an amino acid sequence showing high similarity with those of tetrapod and teleost PACAPs, is present in the elasmobranch brain.

  6. CYP2J2 Overexpression Ameliorates Hyperlipidemia via Increased Fatty Acid Oxidation Mediated by the AMPK Pathway

    PubMed Central

    Zhang, Shasha; Chen, Guangzhi; Li, Ning; Dai, Meiyan; Chen, Chen; Wang, Peihua; Tang, Huiru; Hoopes, Samantha L.; Zeldin, Darryl C.; Wang, Dao Wen; Xu, Xizhen

    2015-01-01

    Objective The study aims to investigate the effect of Cytochrome P450 2J2 (CYP2J2) overexpression on hyperlipidemia in mice and further to explore their effect on fatty acid oxidation in vivo and in vitro. Methods The effects and mechanisms of endothelial-specific CYP2J2 transgene (Tie2-CYP2J2-Tr) on lipid and fatty acids metabolism were investigated in high fat diet (HFD)-treated mice. HepG2, LO2 cells and HUVECs were exposed to 0.4 mM free fatty acid (FFA) for 24h and used as a model to investigate the roles of CYP2J2 overexpression and epoxyeicosatrienoic acids (EETs) on fatty acid β oxidation in vitro. Results Tie2-CYP2J2-Tr mice had significantly lower plasma and liver triglycerides, lower liver cholesterol and fatty acids, and the reduction in HFD-induced lipid accumulation. CYP2J2 overexpression resulted in activation of the hepatic and endothelial AMPKα, increased ACC phosphorylation, increased expression of CPT-1 and PPARα, which were all reduced by HFD treatment. In FFA-treated HepG2, LO2 and HUVECs, both CYP2J2 overexpression and EETs significantly decreased lipid accumulation and increased fatty acid oxidation via activating the AMPK and PPARα pathway. Conclusions Endothelial specific CYP2J2 overexpression alleviates HFD–induced hyperlipidemia in vivo. CYP2J2 ameliorates FFA-induced dyslipidemia via increased fatty acid oxidation mediated by the AMPK and PPARα pathway. PMID:26053032

  7. Resveratrol ameliorates cardiac oxidative stress in diabetes through deacetylation of NFkB-p65 and histone 3.

    PubMed

    Bagul, Pankaj K; Deepthi, Nancy; Sultana, Razia; Banerjee, Sanjay K

    2015-11-01

    Resveratrol, a phytoalexin, has recently gained attention for protective effects against metabolic and cardiac diseases. The beneficial effects of resveratrol have been linked to sirtuin-1 (SIRT-1) activation. However, little is known about the effect of resveratrol in cardiac complications associated with diabetes. Here, we have demonstrated that resveratrol ameliorates cardiac hypertrophy, electrocardiographic abnormalities and oxidative stress in the fructose-fed diabetic rat heart. Mechanistic studies revealed that fructose feeding to Sprague-Dawley rats over a period of 8 weeks leads to cardiac hypertrophy and increased oxidative stress through increased activity of NADPH oxidase (NOX) and reactive oxygen species production. We found increased activity of nuclear factor kappa B (NFkB) p-65 along with decreased SIRT-1 activity in the diabetic heart. Resveratrol activates SIRT-1, which deacetylates NFkB-p65 at lysine 310 and histone 3 (H3) at lysine 9 position. SIRT1 activation leads to decreased binding of NFkB-p65 to DNA and attenuated cardiac hypertrophy and oxidative stress through reduced transcription of NADPH oxidase subunits. In vitro analysis also revealed that SIRT-1 activation by resveratrol is associated with decreased NFkB-p65 activity and NOX transcription. Similarly, knockdown or inhibition of SIRT1 in H9C2 cells increased acetylation of NFkB-p65 K310 and H3K9. Overall, our data demonstrated that SIRT-1 activation by resveratrol leads to deacetylation of both NFkB-p65 and H3, thereby attenuating cardiac oxidative stress and complications in diabetes. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Tephrosia purpurea ameliorates N-diethylnitrosamine and potassium bromate-mediated renal oxidative stress and toxicity in Wistar rats.

    PubMed

    Khan, N; Sharma, S; Alam, A; Saleem, M; Sultana, S

    2001-06-01

    In an earlier communication, we have shown that Tephrosia purpurea ameliorates benzoyl peroxide-induced oxidative stress in murine skin (Saleem et al. 1999). The present study was designed to investigate a chemopreventive efficacy of T purpurea against N-diethylnitrosamine-initiated and potassium bromate-mediated oxidative stress and toxicity in rat kidney. A single intraperitoneal dose of N-diethylnitrosamine (200 mg/kg body weight) one hr prior to the dose of KBrO3 (125 mg/kg body weight) increases microsomal lipid peroxidation and the activity of xanthine oxidase and decreases the activities of renal antioxidant enzymes viz., catalase, glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase, phase II metabolizing enzymes such as glutathione-S-transferase and quinone reductase and causes depletion in the level of renal glutathione content. A sharp increase in blood urea nitrogen and serum creatinine has also been observed. Prophylactic treatment of rats with T. purpurea at doses of 5 mg/kg body weight and 10 mg/kg body weight prevented N-diethylnitrosamine-initiated and KBrO3 promoted renal oxidative stress and toxicity. The susceptibility of renal microsomal membrane for iron ascorbate-induced lipid peroxidation and xanthine oxidase activities were significantly reduced (P<0.01). The depleted levels of glutathione, the inhibited activities of antioxidant enzymes, phase II metabolizing enzymes and the enhanced levels of serum creatinine and blood urea nitrogen were recovered to a significant level (P<0.01). All the antioxidant enzymes were recovered dose-dependently. Our data indicate that T purpurea besides a skin antioxidant can be a potent chemopreventive agent against renal oxidative stress and carcinogenesis induced by N-diethylnitrosamine and KBrO3.

  9. Amelioration of doxorubicin-induced myocardial oxidative stress and immunosuppression by grape seed proanthocyanidins in tumour-bearing mice.

    PubMed

    Zhang, Xiao-Yu; Li, Wen-Guang; Wu, Yong-Jie; Gao, Ming-Tang

    2005-08-01

    We have investigated the protective effects of grape seed proanthocyanidins on doxorubicin-induced toxicity in tumour-bearing mice. The intraperitoneal administration of doxorubicin (2 mg kg(-1) every other day, cumulative dosage for 18 mg kg(-1)) significantly inhibited the growth of sarcoma 180, and induced myocardial oxidative stress with decreased superoxide dismutase and glutathione peroxidase activity while increasing malondialdehyde formation in the heart or serum. Doxorubicin-induced myocardial oxidative stress also reduced lactate dehydrogenase and creatine kinase activity in the heart and elevated their levels in the serum. Doxorubicin also affected immune functions of tumour-bearing mice with significantly decreased interleukin-2 (IL-2) and interferon-gamma (INF-gamma) production, and slightly decreased natural killer (NK) cell cytotoxicity, lymphocyte proliferation and CD4+/CD8+ ratio. It markedly increased the percentages of cytotoxic T cells (CD3+CD8+), helper T cells (CD3+CD4+), IL-2R+CD4+, and IL-2R+ cells as compared with untreated tumour-bearing mice. The intragastric administration of proanthocyanidin (200 mg kg(-1) daily) significantly inhibited tumour growth, and increased NK cell cytotoxicity, lymphocyte proliferation, CD4+/CD8+ ratio, IL-2 and INF-gamma production. Moreover, proanthocyanidin strongly enhanced the anti-tumour effect of doxorubicin and the above immune responses, and completely eliminated myocardial oxidative stress induced by doxorubicin. In conclusion, intragastric administration of proanthocyanidin could enhance the anti-tumour activity of doxorubicin and ameliorate doxorubicin-induced myocardial oxidative stress and immunosuppression in tumour-bearing mice.

  10. Lutein protects dopaminergic neurons against MPTP-induced apoptotic death and motor dysfunction by ameliorating mitochondrial disruption and oxidative stress.

    PubMed

    Nataraj, Jagatheesan; Manivasagam, Thamilarasan; Thenmozhi, Arokiasamy Justin; Essa, Musthafa Mohammed

    2016-07-01

    Mitochondrial dysfunction and oxidative stress-mediated apoptosis plays an important role in various neurodegenerative diseases including Huntington's disease, Parkinson's disease (PD) and Alzheimer's disease (AD). 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), the most widely used neurotoxin mimics the symptoms of PD by inhibiting mitochondrial complex I that stimulates excessive intracellular reactive oxygen species (ROS) and finally leads to mitochondrial-dependent apoptosis. Lutein, a carotenoid of xanthophyll family, is found abundantly in leafy green vegetables such as spinach, kale and in egg yolk, animal fat and human eye retinal macula. Increasing evidence indicates that lutein has offers benefits against neuronal damages during diabetic retinopathy, ischemia and AD by virtue of its mitochondrial protective, antioxidant and anti-apoptotic properties. Male C57BL/6 mice (23-26 g) were randomized and grouped in to Control, MPTP, and Lutein treated groups. Lutein significantly reversed the loss of nigral dopaminergic neurons by increasing the striatal dopamine level in mice. Moreover, lutein-ameliorated MPTP induced mitochondrial dysfunction, oxidative stress and motor abnormalities. In addition, lutein repressed the MPTP-induced neuronal damage/apoptosis by inhibiting the activation of pro-apoptotic markers (Bax, caspases-3, 8 and 9) and enhancing anti-apoptotic marker (Bcl-2) expressions. Our current results revealed that lutein possessed protection on dopaminergic neurons by enhancing antioxidant defense and diminishing mitochondrial dysfunction and apoptotic death, suggesting the potential benefits of lutein for PD treatment.

  11. Ameliorative effect of riboflavin on hyperglycemia, oxidative stress and DNA damage in type-2 diabetic mice: Mechanistic and therapeutic strategies.

    PubMed

    Alam, Md Maroof; Iqbal, Sarah; Naseem, Imrana

    2015-10-15

    Increasing evidence in both experimental and clinical studies suggests that oxidative stress play a major role in the pathogenesis of type-2 diabetes mellitus (T2DM). Abnormally high levels of free radicals and the simultaneous decline of antioxidant defence mechanisms can lead to damage of cellular organelles and enzymes. Riboflavin constitutes an essential nutrient for humans and is also an important food additive for animals. It is a precursor of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) which serves as a coenzyme for several enzymes. The aim of this study was to observe the effects of illuminated and non-illuminated riboflavin in a diabetic mice model. The protocol included treatment of diabetic mice with illuminated RF and a control set without light. To our surprise, group receiving RF without light gave better results in a dose dependent manner. Significant amelioration of oxidative stress was observed with an increased glucose uptake in skeletal muscles and white adipose tissue. Histological studies showed recovery in the liver and kidney tissue injury. Cellular DNA damage was also recovered. Therefore, it is suggested that supplementation with dietary riboflavin might help in the reduction of diabetic complications. A possible mechanism of action is also proposed. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Ameliorative effects of Bacopa monniera on lead-induced oxidative stress in different regions of rat brain.

    PubMed

    Velaga, Manoj Kumar; Basuri, Charan Kumar; Robinson Taylor, Kendra S; Yallapragada, Prabhakara Rao; Rajanna, Sharada; Rajanna, Bettaiya

    2014-07-01

    Bacopa monniera is a rejuvenating herb for brain cells enhancing learning and cognitive ability. In the present investigation, the ameliorative effects of Bacopa monniera were examined against lead-induced oxidative stress in different regions of rat brain. Male rats were divided into five groups: control (1000 ppm sodium acetate) and exposed (1000 ppm lead acetate) for 4 weeks; DMSA (Meso-2,3-Dimercaptosuccinic acid)-treated (90 mg/kg body weight/day); Bacopa monniera-treated (BM) (10 mg/kg body weight/day) and a combination of BM + DMSA for seven consecutive days after 4 weeks of lead exposure. After treatment, the whole brain was isolated by sacrificing rats and four regions were separated namely cerebellum, hippocampus, frontal cortex and brain stem. Results indicated a significant (p < 0.05) increase in reactive oxygen species (ROS), lipid peroxidation products (LPP) and total protein carbonyl content (TPCC) in association with tissue metal content in all the four regions of brain for exposed group compared with their respective controls. However, the lead-induced ROS, LPP, TPCC and tissue metal content were lowered on treatment with Bacopa monniera, almost reaching the control group values in all the above brain regions compared to DMSA and a combination therapy. Results suggest that Bacopa monniera can mitigate the lead induced-oxidative stress tissue specifically by pharmacologic interventions which encompass both chelation as well as antioxidant functions.

  13. Activity-dependent neuroprotective protein (ADNP)-derived peptide (NAP) ameliorates hypobaric hypoxia induced oxidative stress in rat brain.

    PubMed

    Sharma, Narendra K; Sethy, Niroj K; Meena, Ram Niwas; Ilavazhagan, Govindsamy; Das, Mainak; Bhargava, Kalpana

    2011-06-01

    Hypobaric hypoxia is a socio-economic problem affecting cognitive, memory and behavior functions. Severe oxidative stress caused by hypobaric hypoxia adversely affects brain areas like cortex, hippocampus, basal ganglia, and cerebellum. In the present study, we have investigated the antioxidant and memory protection efficacy of the synthetic NAP peptide (NAPVSIPQ) during long-term chronic hypobaric hypoxia (7, 14, 21 and 28 days, 25,000ft) in rats. Intranasal supplementation of NAP peptide (2μg/Kg body weight) improved antioxidant status of brain evaluated by biochemical assays for free radical estimation, lipid peroxidation, GSH and GSSG level. Analysis of expression levels of SOD revealed that NAP significantly activated antioxidant genes as compared to hypoxia exposed rats. We have also observed a significant increased expression of Nrf2, the master regulator of antioxidant defense system and its downstream targets such as HO-1, GST and SOD1 by NAP supplementation, suggesting activation of Nrf2-mediated antioxidant defense response. In corroboration, our results also demonstrate that NAP supplementation improved the memory function assessed with radial arm maze. These cumulative results suggest the therapeutic potential of NAP peptide for ameliorating hypobaric hypoxia-induced oxidative stress.

  14. Carvacrol ameliorates thioacetamide-induced hepatotoxicity by abrogation of oxidative stress, inflammation, and apoptosis in liver of Wistar rats.

    PubMed

    Nafees, S; Ahmad, S T; Arjumand, W; Rashid, S; Ali, N; Sultana, S

    2013-12-01

    The present study was designed to investigate the protective effects of carvacrol against thioacetamide (TAA)-induced oxidative stress, inflammation and apoptosis in liver of Wistar rats. In this study, rats were subjected to concomitant prophylactic oral pretreatment of carvacrol (25 and 50 mg kg(-1) body weight (b.w.)) against the hepatotoxicity induced by intraperitoneal administration of TAA (300 mg kg(-1) b.w.). Efficacy of carvacrol against the hepatotoxicity was evaluated in terms of biochemical estimation of antioxidant enzyme activities, histopathological changes, and expressions of inflammation and apoptosis. Carvacrol pretreatment prevented deteriorative effects induced by TAA through a protective mechanism in a dose-dependent manner that involved reduction of oxidative stress, inflammation and apoptosis. We found that the protective effect of carvacrol pretreatment is mediated by its inhibitory effect on nuclear factor kappa B activation, Bax and Bcl-2 expression, as well as by restoration of histopathological changes against TAA administration. We may suggest that carvacrol efficiently ameliorates liver injury caused by TAA.

  15. Boron inhibits the proliferating cell nuclear antigen index, molybdenum containing proteins and ameliorates oxidative stress in hepatocellular carcinoma.

    PubMed

    Zafar, Hina; Ali, Shakir

    2013-01-15

    Hepatocellular carcinoma (HCC) is a common malignancy and the main cause of mortality in patients with chronic liver diseases. This study reports the inhibitory effect of boron on HCC induced in rats by administering thioacetamide (TAA) (0.03%) in drinking water for 400days. Boron (4mg/kg body weight) was administered orally after induction of carcinoma. Treatment was continued for 122days, and cell proliferation, histology and biochemistry of treated and control group of rats were studied. Proliferating cell nuclear antigen (PCNA), and [(3)H]-thymidine incorporation, which increased in rats exposed to carcinogen, significantly decreased after boron treatment. PCNA index decreased from 80 in HCC rats to 32 after boron treatment. In the control group, it was 20. Boron caused a dose-dependent decrease in carcinogen-induced [(3)H]-thymidine uptake by the rat hepatocyte. It could partially reverse the activity of selected biochemical indicators of hepatic damage, oxidative stress, selenium and serum retinol, which are depleted in liver cancer, and improved overall health of animal. The study implicates the elevated levels of mammalian molybdenum Fe-S containing flavin hydroxylases, which increase the free radical production and oxidative stress, consequently causing increased hepatic cell proliferation in HCC, and reports boron to ameliorate these changes in liver cancer. Copyright © 2012 Elsevier Inc. All rights reserved.

  16. Astaxanthin Attenuates Early Acute Kidney Injury Following Severe Burns in Rats by Ameliorating Oxidative Stress and Mitochondrial-Related Apoptosis

    PubMed Central

    Guo, Song-Xue; Zhou, Han-Lei; Huang, Chun-Lan; You, Chuan-Gang; Fang, Quan; Wu, Pan; Wang, Xin-Gang; Han, Chun-Mao

    2015-01-01

    Early acute kidney injury (AKI) is a devastating complication in critical burn patients, and it is associated with severe morbidity and mortality. The mechanism of AKI is multifactorial. Astaxanthin (ATX) is a natural compound that is widely distributed in marine organisms; it is a strong antioxidant and exhibits other biological effects that have been well studied in various traumatic injuries and diseases. Hence, we attempted to explore the potential protection of ATX against early post burn AKI and its possible mechanisms of action. The classic severe burn rat model was utilized for the histological and biochemical assessments of the therapeutic value and mechanisms of action of ATX. Upon ATX treatment, renal tubular injury and the levels of serum creatinine and neutrophil gelatinase-associated lipocalin were improved. Furthermore, relief of oxidative stress and tubular apoptosis in rat kidneys post burn was also observed. Additionally, ATX administration increased Akt and Bad phosphorylation and further down-regulated the expression of other downstream pro-apoptotic proteins (cytochrome c and caspase-3/9); these effects were reversed by the PI3K inhibitor LY294002. Moreover, the protective effect of ATX presents a dose-dependent enhancement. The data above suggested that ATX protects against early AKI following severe burns in rats, which was attributed to its ability to ameliorate oxidative stress and inhibit apoptosis by modulating the mitochondrial-apoptotic pathway, regarded as the Akt/Bad/Caspases signalling cascade. PMID:25871290

  17. Oxidative damage is ameliorated by curcumin treatment in brain and sciatic nerve of diabetic rats.

    PubMed

    Acar, Abdullah; Akil, Esref; Alp, Harun; Evliyaoglu, Osman; Kibrisli, Erkan; Inal, Ali; Unan, Fatma; Tasdemir, Nebahat

    2012-07-01

    To date, there have not been enough studies about the effects of curcumin against oxidative stress on sciatic nerves caused by streptozotocin (STZ) in diabetic rats. Therefore, this study was undertaken to determine whether curcumin, by virtue of its antioxidant properties, could affect the oxidant/antioxidant balance in the sciatic nerve and brain tissues of streptozotocin (STZ)-induced diabetic rats. A total of 28 rats were randomly divided into four groups of seven rats each: normal controls, only curcumin treated, diabetic controls, and diabetics treated with curcumin. Biomarkers-malondialdehyde (MDA), total oxidant status (TOS), total antioxidant status (TAS), oxidative stress index (OSI), and NO levels-for oxidative stress in the brain and sciatic nerve tissues of the rats were measured. We found a significant increase in MDA, NO, TOS, and OSI, along with a reduction in TAS levels in the brains and sciatic nerves of the STZ-induced diabetic rats (for both parameters p < 0.05). The MDA, TOS, OSI, and NO levels in these tissues were significantly reduced in the curcumin-treated diabetic group compared to the untreated diabetic group. In conclusion, the results of this study suggested that curcumin exhibits neuroprotective effects against oxidative damage in the brain and sciatic tissues of diabetic rats.

  18. Alkaline ameliorants increase nitrous oxide emission from acidified black soil in Northeastern China.

    PubMed

    Han, Zuoqiang; Zhang, Xilin; Qiao, Yanjiao; Wang, Lianfeng

    2011-06-01

    Lime and plant ash are common management used to achieve optimum pH for plant growth and improve soil properties in agricultural soils. Laboratory incubation was conducted to assess N20 emissions as influenced by different soil amendments (lime and plant ash) in a slightly acidic arable soil (pH 5.34). The experimental treatments consisted of CK, lime and plant ash fertilized with NH4(+)-N or N03(-)-N as nitrogen resource. The results show that lime and plant ash dramatically increases the soil pH and N20 emission. For N03(-)-N fertilization, the cumulative N20 emissions from CK, lime and ash are 421, 1669 and 921 μg N20-N/kg, respectively. For NH4(+)-N fertilization, the cumulative N20 emissions from CK, lime and ash are 361, 576 and 559 μg N20-N/kg, respectively. N03(-)-N addition leads to more N20 emission than that of NH4(+)-N addition, and lime increases more N20 emission than that of plant ash. After incubation, N03(-)-N content decreased largely. The findings suggested that alkaline ameliorants increase N20 emissions due to enhancement of soil denitrification. Copyright © 2011 The Research Centre for Eco-Environmental Sciences, Chinese Academy of Sciences. Published by Elsevier B.V. All rights reserved.

  19. Sodium Thiosulfate Ameliorates Oxidative Stress and Preserves Renal Function in Hyperoxaluric Rats

    PubMed Central

    Bijarnia, Rakesh K.; Bachtler, Matthias; Chandak, Prakash G.; van Goor, Harry; Pasch, Andreas

    2015-01-01

    Background Hyperoxaluria causes crystal deposition in the kidney, which leads to oxidative stress and to injury and damage of the renal epithelium. Sodium thiosulfate (STS, Na2S2O3) is an anti-oxidant, which has been used in human medicine for decades. The effect of STS on hyperoxaluria-induced renal damage is not known. Methods Hyperoxaluria and renal injury were induced in healthy male Wistar rats by chronic exposure to ethylene glycol (EG, 0.75%) in the drinking water for 4 weeks. The treatment effects of STS, NaCl or Na2SO4 were compared. Furthermore, the effects of STS on oxalate-induced oxidative stress were investigated in vitro in renal LLC-PK1 cells. Results Chronic EG exposure led to hyperoxaluria, oxidative stress, calcium oxalate crystalluria and crystal deposition in the kidneys. Whereas all tested compounds significantly reduced crystal load, only STS-treatment maintained tissue superoxide dismutase activity and urine 8-isoprostaglandin levels in vivo and preserved renal function. In in vitro studies, STS showed the ability to scavenge oxalate-induced ROS accumulation dose dependently, reduced cell-released hydrogen peroxide and preserved superoxide dismutase activity. As a mechanism explaining this finding, STS was able to directly inactivate hydrogen peroxide in cell-free experiments. Conclusions STS is an antioxidant, which preserves renal function in a chronic EG rat model. Its therapeutic use in oxidative-stress induced renal-failure should be considered. PMID:25928142

  20. MSM ameliorates HIV-1 Tat induced neuronal oxidative stress via rebalance of the glutathione cycle

    PubMed Central

    Kim, Seol-hee; Smith, Adam J; Tan, Jun; Shytle, R Douglas; Giunta, Brian

    2015-01-01

    HIV-1 Tat protein is a key neuropathological element in HIV associated neurogcognitive disorders (HAND); a type of cognitive syndrome thought to be at least partially mediated by increased levels of brain reactive oxygen species (ROS) and nitric oxide (NO). Methylsulfonylmethane (MSM) is a sulfur-containing compound known to reduce oxidative stress. This study was conducted to determine whether administration of MSM attenuates HIV-1 Tat induced oxidative stress in mouse neuronal cells. MSM treatment significantly decreased neuronal cell NO and ROS secretion. Further, MSM significantly reversed HIV-1 Tat mediated reductions in reduced glutathione (GSH) as well as HIV-1 Tat mediated increases in oxidized glutathione (GSSG). In addition, Tat reduced nuclear translocation of nuclear factor-erythroid 2 p45-related factor 2 (Nrf2), a key nuclear promoter of antioxidant activity, while MSM increased its translocation to the nucleus in the presence of Tat. These results suggest that HIV-1 Tat reduces the resiliency of neuron cells to oxidative stress which can be reversed by MSM. Given the clinical safety of MSM, future preclinical in vivo studies will be required to further confirm these results in effort to validate MSM as a neuroprotectant in patients at risk of, or who are already diagnosed with, HAND. PMID:25893035

  1. Preconditioning L6 Muscle Cells with Naringin Ameliorates Oxidative Stress and Increases Glucose Uptake

    PubMed Central

    Dhanya, R.; Arun, K. B.; Nisha, V. M.; Syama, H. P.; Nisha, P.; Santhosh Kumar, T. R.; Jayamurthy, P.

    2015-01-01

    Enhanced oxidative stress contributes to pathological changes in diabetes and its complications. Thus, strategies to reduce oxidative stress may alleviate these pathogenic processes. Herein, we have investigated Naringin mediated regulation of glutathione (GSH) & intracellular free radical levels and modulation of glucose uptake under oxidative stress in L6 cell lines. The results from the study demonstrated a marked decrease in glutathione with a subsequent increase in free radical levels, which was reversed by the pretreatment of Naringin. We also observed that the increased malondialdehyde level, the marker of lipid peroxidation on induction of oxidative stress was retrieved on Naringin pretreatment. Addition of Naringin (100 μM) showed approximately 40% reduction in protein glycation in vitro. Furthermore, we observed a twofold increase in uptake of fluorescent labeled glucose namely 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-Deoxyglucose (2 - NBDG) on Naringin treatment in differentiated L6 myoblast. The increased uptake of 2-NBDG by L6 myotubes may be attributed due to the enhanced translocation of GLUT4. Our results demonstrate that Naringin activate GSH synthesis through a novel antioxidant defense mechanism against excessive Reactive Oxygen Species (ROS) production, contributing to the prevention of oxidative damage in addition to its effect on glycemic control. PMID:26147673

  2. Berberine ameliorate oxidative stress and astrogliosis in the hippocampus of STZ-induced diabetic rats.

    PubMed

    Moghaddam, Hamid Kalalian; Baluchnejadmojarad, Tourandokht; Roghani, Mehrdad; Khaksari, Mehdi; Norouzi, Pirasteh; Ahooie, Malihea; Mahboobi, Fatemeh

    2014-04-01

    Diabetes mellitus increases the risk of central nervous system (CNS) disorders such as stroke, seizures, dementia, and cognitive impairment. Berberine, a natural isoquinoline alkaloid, is reported to exhibit beneficial effect in various neurodegenerative and neuropsychiatric disorders. Moreover, astrocytes are proving critical for normal CNS function, and alterations in their activity and impaired oxidative stress could contribute to diabetes-related cognitive dysfunction. Metabolic and oxidative insults often cause rapid changes in glial cells. Key indicators of this response are increased synthesis of glial fibrillary acidic protein (GFAP) as an astrocytic marker. Therefore, we examined the effects of berberine on glial reactivity of hippocampus in streptozotocin (STZ)-induced diabetic rats, using GFAP immunohistochemistry. Lipid peroxidation, superoxide dismutase (SOD) activity, and nitrite levels were assessed as the parameters of oxidative stress. Eight weeks after diabetes induction, we observed increased numbers of GFAP(+) astrocytes immunostaining associated with increased lipid peroxidation, decreased superoxide dismutase activity, and elevated nitrite levels in the hippocampus of STZ-diabetic rats. In contrast, chronic treatment with berberine (50 and 100 mg/kg p.o. once daily) lowered hyperglycemia, reduced oxidative stress, and prevented the upregulation of GFAP in the brain of diabetic rats. In conclusion, the present study demonstrated that the treatment with berberine resulted in an obvious reduction of oxidative stress and GFAP-immunoreactive astrocytes in the hippocampus of STZ-induced diabetic rats.

  3. Preconditioning L6 Muscle Cells with Naringin Ameliorates Oxidative Stress and Increases Glucose Uptake.

    PubMed

    Dhanya, R; Arun, K B; Nisha, V M; Syama, H P; Nisha, P; Santhosh Kumar, T R; Jayamurthy, P

    2015-01-01

    Enhanced oxidative stress contributes to pathological changes in diabetes and its complications. Thus, strategies to reduce oxidative stress may alleviate these pathogenic processes. Herein, we have investigated Naringin mediated regulation of glutathione (GSH) & intracellular free radical levels and modulation of glucose uptake under oxidative stress in L6 cell lines. The results from the study demonstrated a marked decrease in glutathione with a subsequent increase in free radical levels, which was reversed by the pretreatment of Naringin. We also observed that the increased malondialdehyde level, the marker of lipid peroxidation on induction of oxidative stress was retrieved on Naringin pretreatment. Addition of Naringin (100 μM) showed approximately 40% reduction in protein glycation in vitro. Furthermore, we observed a twofold increase in uptake of fluorescent labeled glucose namely 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-Deoxyglucose (2-NBDG) on Naringin treatment in differentiated L6 myoblast. The increased uptake of 2-NBDG by L6 myotubes may be attributed due to the enhanced translocation of GLUT4. Our results demonstrate that Naringin activate GSH synthesis through a novel antioxidant defense mechanism against excessive Reactive Oxygen Species (ROS) production, contributing to the prevention of oxidative damage in addition to its effect on glycemic control.

  4. The Role of Calcium in Ameliorating the Oxidative Stress of Fluoride in Rats.

    PubMed

    Mohamed, N E

    2016-03-01

    The present study was carried out to investigate the effects of fluoride toxicity on some biochemical, hormonal, and histological parameters of female rats and the protective role of calcium against such effects. Adult female albino rats were divided into five groups; control group received distilled water for 60 days, calcium group received calcium carbonate with dose of 50 mg/kg three times per week for 60 days, fluoride group received sodium fluoride with dose of 20 mg/kg three times per week for 60 days, calcium + fluoride group received calcium carbonate (50 mg/kg) then after 2 h received sodium fluoride (20 mg/kg) three times per week for 60 days, and fluoride + calcium group received sodium fluoride (20 mg/kg) three times per week for 30 days then received calcium carbonate (50 mg/kg) three times per week for another 30 days. The results showed that the levels of thiobarbituric acid reactive substances, urea, creatinine, alkaline phosphatase, triiodothyronine, thyroxine, parathormone, phosphorous, magnesium, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and gamma glutamyl transferase were significantly increased in rats treated with fluoride while serum estradiol, calcium, and organ glutathione were significantly decreased. The histological examination of the femur bone revealed that fluoride treatment induced thinning of bone trabeculae with wilding of marrow space, demineralization, and loss of trabeculae interconnections. Also, the histological examination of hepatic and renal tissues of fluoride-treated rats showed some damages in these tissues while administration of calcium carbonate for 30 or 60 days during fluoride treatment minimized such damages. It could be concluded that administration of calcium to female rats can ameliorate the hazardous effects of fluoride observed in the biochemical, hormonal, and histological parameters.

  5. Ameliorating effect of piperine on behavioral abnormalities and oxidative markers in sodium valproate induced autism in BALB/C mice.

    PubMed

    Pragnya, B; Kameshwari, J S L; Veeresh, B

    2014-08-15

    Post natal exposure to VPA (valproic acid) in mice induces behavioral deficits, abnormal sensitivity to sensory stimuli and self-injurious behavior, observed in autism. Piperine has been reported to have protective effect on brain. The present study aimed at evaluating effect of piperine on VPA induced neurobehavioral and biochemical alterations in BALB/c mice. Young BALB/c mice 13 days old were procured from five different litters and segregated into five groups (n=6; 3 male, 3 female) i.e., Group I served as control group, received physiological saline on PND (Post natal day) 14 & Tween 80 p.o. from PND13-40. Group II served as normal treated group and received piperine (20mg/kg p.o.) from PND 13-40 and saline s.c. on PND 14. Group III served as valproate treated group received VPA (400mg/kg s.c.) on PND 14 and Tween 80 p.o. from PND 13-40. Group IV & V served as disease treated group received VPA (400mg/kg s.c.) on PND 14 & piperine (5 & 20mg/kg p.o.) from PND 13-40 respectively. BALB/c mice pups were subjected to behavioral testing to assess motor skill development, nociceptive response, locomotion, anxiety, and cognition on various postnatal days up to PND 40. At the end of behavioral evaluation, mice were sacrificed; brain was isolated for biochemical estimations (serotonin, glutathione, MDA and nitric oxide) and histopathological examination. Our study revealed that treatment with piperine significantly improved behavioral alterations, lowered oxidative stress markers, and restored histoarchitecture of cerebellum. This ameliorating effect of piperine is attributed to its anti-oxidant activity, cognition enhancing and neuroprotective activity. Copyright © 2014 Elsevier B.V. All rights reserved.

  6. Dioclea violacea lectin ameliorates oxidative stress and renal dysfunction in an experimental model of acute kidney injury

    PubMed Central

    Freitas, Flavia PS; Porto, Marcella L; Tranhago, Camilla P; Piontkowski, Rogerio; Miguel, Emilio C; Miguel, Thaiz BAR; Martins, Jorge L; Nascimento, Kyria S; Balarini, Camille M; Cavada, Benildo S; Meyrelles, Silvana S; Vasquez, Elisardo C; Gava, Agata L

    2015-01-01

    Acute kidney injury (AKI) is characterized by rapid and potentially reversible decline in renal function; however, the current management for AKI is nonspecific and associated with limited supportive care. Considering the need for more novel therapeutic approaches, we believe that lectins from Dioclea violacea (Dvl), based on their anti-inflammatory properties, could be beneficial for the treatment of AKI induced by renal ischemia/reperfusion (IR). Dvl (1 mg/kg, i.v.) or vehicle (100 µL) was administered to Wistar rats prior to the induction of bilateral renal ischemia (45 min). Following 24 hours of reperfusion, inulin and para-aminohippurate (PAH) clearances were performed to determine glomerular filtration rate (GFR), renal plasma flow (RPF), renal blood flow (RBF) and renal vascular resistance (RVR). Renal inflammation was assessed using myeloperoxidase (MPO) activity. Kidney sections were stained with hematoxylin-eosin to evaluate morphological changes. Intracellular superoxide anions, hydrogen peroxide, peroxynitrite, nitric oxide and apoptosis were analyzed using flow cytometry. IR resulted in diminished GFR, RPF, RBF, and increased RVR; however, these changes were ameliorated in rats receiving Dvl. AKI-induced histomorphological changes, such as tubular dilation, tubular necrosis and proteinaceous casts, were attenuated by Dvl administration. Treatment with Dvl resulted in diminished renal MPO activity, oxidative stress and apoptosis in rats submitted to IR. Our data reveal that Dvl has a protective effect in the kidney, improving renal function after IR injury, probably by reducing neutrophil recruitment and oxidative stress. These results indicate that Dvl can be considered a new therapeutic approach for AKI-induced kidney injury. PMID:26885258

  7. Amelioration of anti-tuberculosis drug induced oxidative stress in kidneys by Spirulina fusiformis in a rat model.

    PubMed

    Martin, Sherry Joseph; Sabina, Evan Prince

    2016-08-01

    Nephrotoxicity is a rare complication caused by anti-tuberculosis therapy-induced oxidative stress. The Cyanobacterium Spirulina fusiformis Voronikhin belonging to Oscillatoriaceae family is used traditionally as a source of antioxidants against oxidative stress. We aimed to investigate the efficacy of S. fusiformis in modifying isoniazid (INH) and rifampicin (RIF)-induced changes in Wistar rat kidneys. Animals were divided into six groups: normal control rats; toxic control (INH & RIF-50 mg/kg b.w./d each; p.o.); INH & RIF + S. fusiformis (400 mg/kg b.w./d); INH & RIF + S. fusiformis (800 mg/kg b.w./d); S. fusiformis (800 mg/kg b.w./d) alone-treated rats; INH & RIF + silymarin (25 mg/kg b.w./d). Study duration was 28 d after which blood and kidneys were analyzed. We also studied the binding and interactions of the transcription factors Liver X Receptor (LXR) and Farnesoid X Receptor (FXR) with INH, RIF, and representative active compounds of S. fusiformis by in silico methods. INH & RIF treatment caused significant (p< 0.05) decrease in antioxidant levels and significant (p< 0.05) increase in the levels of creatinine, urea, and uric acid showing impaired kidney function. Spirulina fusiformis ameliorated these effects in a dose dependent manner. Histological examination of kidneys supported these findings. Results of the in silico analyses showed that selected active components of S. fusiformis interact with LXR and FXR and could be a possible mechanism of action. S. fusiformis rendered protection against anti-tuberculosis drugs-induced oxidative stress in kidney tissues of rats.

  8. D-004 ameliorates phenylephrine-induced urodynamic changes and increased prostate and bladder oxidative stress in rats

    PubMed Central

    Oyarzábal, Ambar; Pérez, Yohani; Mas, Rosa; Ravelo, Yazmin; Jiménez, Sonia

    2015-01-01

    Background Lower urinary tract symptoms (LUTS) in patients with benign prostatic hyperplasia (BPH) mainly depend on alpha1-adrenoreceptors (α1-ADR) stimulation, but a link with oxidative stress (OS) is also involved. D-004, a lipid extract of Roystonea regia fruits, antagonizes ADR-induced responses and produces antioxidant effects. The objective of this study was to investigate whether D-004 produce antioxidant effects in rats with phenylephrine (PHE)-induced urodynamic changes. Methods Rats were randomized into eight groups (ten rats/group): a negative vehicle control and seven groups injected with PHE: a positive control, three treated with D-004 (200, 400 and 800 mg/kg) and three others with tamsulosin (0.4 mg/kg), grape seed extract (GSE) (250 mg/kg) and vitamin E (VE) (250 mg/kg), respectively. Results Effects on urinary total volume (UTV), volume voided per micturition (VM), malondialdehyde (MDA) and carbonyl groups (CG) concentrations in prostate and bladder homogenates were study outcomes. While VM and UTV lowered significantly in the positive control as compared to the negative control group, the opposite occurred with prostate and bladder MDA and CG values. D-004 (200-800 mg/kg) increased significantly both VM and UTV, lowered significantly MDA in prostate and bladder homogenates, and reduced GC levels only in the prostate. Tamsulosin increased significantly VM and UTV, but unchanged oxidative variables. GSE and VE unchanged the UTV, whereas VE, not GSE, modestly but significantly attenuated the PHE-induced decrease of VM. Conclusions Single oral administration of D-004 (200-800 mg/kg) was the only treatment that ameliorated the urodynamic changes and reduced increased oxidative variables in the prostate of rats with PHE-induced prostate hyperplasia. PMID:26816837

  9. Coenzyme Q(10) supplementation ameliorates inflammatory signaling and oxidative stress associated with strenuous exercise.

    PubMed

    Díaz-Castro, Javier; Guisado, Rafael; Kajarabille, Naroa; García, Carmen; Guisado, Isabel M; de Teresa, Carlos; Ochoa, Julio J

    2012-10-01

    Exhausting exercise induces muscle damage associated with high production of free radicals and pro-inflammatory mediators. The objective of this study was to determine for the first time and simultaneously whether oral coenzyme Q(10) (CoQ(10)) supplementation can prevent over-expression of inflammatory mediators and oxidative stress associated with strenuous exercise. The participants were classified in two groups: CoQ(10) group (CG) and placebo group (PG). The physical test consisted in a constant run (50 km) that combined several degrees of high effort (mountain run and ultra-endurance), in permanent climbing. Exercise was associated with an increase in TNF-α, IL-6, 8-hydroxy-2'-deoxyguanosine (8-OHdG), and isoprostane levels, revealing the degree of inflammation and oxidative stress induced. Oral supplementation of CoQ(10) during exercise was efficient reducing oxidative stress (decreased membrane hydroperoxides, 8-OHdG and isoprostanes generation, increased catalase, and total antioxidant status), which would lead to the maintenance of the cell integrity. Data obtained also indicate that CoQ(10) prevents over-expression of TNF-α after exercise, together with an increase in sTNF-RII that limits the pro-inflammatory actions of TNF. Moreover, CoQ(10) supplementation reduced creatinine production. CoQ(10) supplementation before strenuous exercise decreases the oxidative stress and modulates the inflammatory signaling, reducing the subsequent muscle damage.

  10. Amelioration of scopolamine induced cognitive dysfunction and oxidative stress by Inonotus obliquus - a medicinal mushroom.

    PubMed

    Giridharan, Vijayasree Vayalanellore; Thandavarayan, Rajarajan Amirthalingam; Konishi, Tetsuya

    2011-06-01

    The present study was aimed to investigate the cognitive enhancing and anti-oxidant activities of Inonotus obliquus (Chaga) against scopolamine-induced experimental amnesia. Methanolic extract of Chaga (MEC) at 50 and 100 mg kg (-1)doses were administered orally for 7 days to amnesic mice. Learning and memory was assessed by passive avoidance task (PAT) and Morris water maze (MWM) test. Tacrine (THA, 10 mg kg (-1), orally (p.o)) used as a reference drug. To elucidate the mechanism of the cognitive enhancing activity of MEC, the activities of acetylcholinesterase (AChE), anti-oxidant enzymes, the levels of acetylcholine (ACh) and nitrite of mice brain homogenates were evaluated. MEC treatment for 7 days significantly improved the learning and memory as measured by PAT and MWM paradigms. Further, MEC significantly reduced the oxidative-nitritive stress, as evidenced by a decrease in malondialdehyde and nitrite levels and restored the glutathione and superoxide dismutase levels in a dose dependent manner. In addition, MEC treatment significantly decreased the AChE activity in both the salt and detergent-soluble fraction of brain homogenates. Further, treatment with MEC restored the levels of ACh as did THA. Thus, the significant cognitive enhancement observed in mice after MEC administration is closely related to higher brain anti-oxidant properties and inhibition of AChE activity. These findings stress the critical impact of Chaga, a medicinal mushroom, on the higher brain functions like learning and memory.

  11. Myelophil ameliorates brain oxidative stress in mice subjected to restraint stress.

    PubMed

    Lee, Jin-Seok; Kim, Hyung-Geug; Han, Jong-Min; Lee, Jong-Suk; Son, Seung-Wan; Ahn, Yo-Chan; Son, Chang-Gue

    2012-12-03

    We evaluated the pharmacological effects of Myelophil, a 30% ethanol extract of a mix of Astragali Radix and Salviae Radix, on oxidative stress-induced brain damage in mice caused by restraint stress. C57BL/6 male mice (eight weeks old) underwent daily oral administration of distilled water, Myelophil (25, 50, or 100mg/kg), or ascorbic acid (100mg/kg) 1h before induction of restraint stress, which involved 3h of immobilization per day for 21days. Nitric oxide levels, lipid peroxidation, activities of antioxidant enzymes (superoxide dismutase, catalase, and glutathione redox system enzymes), and concentrations of adrenaline, corticosterone, and interferon-γ, were measured in brain tissues and/or sera. Restraint stress-induced increases in nitric oxide levels (serum and brain tissues) and lipid peroxidation (brain tissues) were significantly attenuated by Myelophil treatment. Restraint stress moderately lowered total antioxidant capacity, catalase activity, glutathione content, and the activities of glutathione reductase, glutathione peroxidase, and glutathione S-transferase; all these responses were reversed by Myelophil. Myelophil significantly attenuated the elevated serum concentrations of adrenaline and corticosterone and restored serum and brain interferon-γ levels. Moreover, Myelophil normalized expression of the genes encoding monoamine oxidase A, catechol-O-methyltransferase, and phenylethanolamine N-methyltransferase, which was up-regulated by restraint stress in brain tissues. These results suggest that Myelophil has pharmacological properties protects brain tissues against stress-associated oxidative stress damage, perhaps in part through regulation of stress hormones.

  12. Astaxanthin ameliorates aluminum chloride-induced spatial memory impairment and neuronal oxidative stress in mice.

    PubMed

    Al-Amin, Md Mamun; Reza, Hasan Mahmud; Saadi, Hasan Mahmud; Mahmud, Waich; Ibrahim, Abdirahman Adam; Alam, Musrura Mefta; Kabir, Nadia; Saifullah, A R M; Tropa, Sarjana Tarannum; Quddus, A H M Ruhul

    2016-04-15

    Aluminum chloride induces neurodegenerative disease in animal model. Evidence suggests that aluminum intake results in the activation of glial cells and generation of reactive oxygen species. By contrast, astaxanthin is an antioxidant having potential neuroprotective activity. In this study, we investigate the effect of astaxanthin on aluminum chloride-exposed behavioral brain function and neuronal oxidative stress (OS). Male Swiss albino mice (4 months old) were divided into 4 groups: (i) control (distilled water), (ii) aluminum chloride, (iii) astaxanthin+aluminum chloride, and (iv) astaxanthin. Two behavioral tests; radial arm maze and open field test were conducted, and OS markers were assayed from the brain and liver tissues following 42 days of treatment. Aluminum exposed group showed a significant reduction in spatial memory performance and anxiety-like behavior. Moreover, aluminum group exhibited a marked deterioration of oxidative markers; lipid peroxidation (MDA), nitric oxide (NO), glutathione (GSH) and advanced oxidation of protein products (AOPP) in the brain. To the contrary, co-administration of astaxanthin and aluminum has shown improved spatial memory, locomotor activity, and OS. These results indicate that astaxanthin improves aluminum-induced impaired memory performances presumably by the reduction of OS in the distinct brain regions. We suggest a future study to determine the underlying mechanism of astaxanthin in improving aluminum-exposed behavioral deficits. Copyright © 2016 Elsevier B.V. All rights reserved.

  13. Boldine Ameliorates Vascular Oxidative Stress and Endothelial Dysfunction: Therapeutic Implication for Hypertension and Diabetes

    PubMed Central

    Lau, Yeh Siiang; Ling, Wei Chih; Murugan, Dharmani

    2015-01-01

    Abstract: Epidemiological and clinical studies have demonstrated that a growing list of natural products, as components of the daily diet or phytomedical preparations, are a rich source of antioxidants. Boldine [(S)-2,9-dihydroxy-1,10-dimethoxy-aporphine], an aporphine alkaloid, is a potent antioxidant found in the leaves and bark of the Chilean boldo tree. Boldine has been extensively reported as a potent “natural” antioxidant and possesses several health-promoting properties like anti-inflammatory, antitumor promoting, antidiabetic, and cytoprotective. Boldine exhibited significant endothelial protective effect in animal models of hypertension and diabetes mellitus. In isolated thoracic aorta of spontaneously hypertensive rats, streptozotocin-induced diabetic rats, and db/db mice, repeated treatment of boldine significantly improved the attenuated acetylcholine-induced endothelium-dependent relaxations. The endothelial protective role of boldine correlated with increased nitric oxide levels and reduction of vascular reactive oxygen species via inhibition of the nicotinamide adenine dinucleotide phosphate oxidase subunits, p47phox and nicotinamide adenine dinucleotide phosphate oxidase 2, and angiotensin II–induced bone morphogenetic protein-4 oxidative stress cascade with downregulation of angiotensin II type 1 receptor and bone morphogenetic protein-4 expression. Taken together, it seems that boldine may exert protective effects on the endothelium via several mechanisms, including protecting nitric oxide from degradation by reactive oxygen species as in oxidative stress–related diseases. The present review supports a complimentary therapeutic role of the phytochemical, boldine, against endothelial dysfunctions associated with hypertension and diabetes mellitus by interfering with the oxidative stress–mediated signaling pathway. PMID:25469805

  14. Sildenafil ameliorates oxidative stress and DNA damage in the stenotic kidneys in mice with renovascular hypertension

    PubMed Central

    2014-01-01

    Background Oxidative stress and DNA damage have been implicated in the pathogenesis of renovascular hypertension induced by renal artery stenosis in the two-kidney, one-clip (2K1C) Goldblatt model. Considering our previous report indicating that the chronic blockade of phosphodiesterase 5 with sildenafil (Viagra®) has marked beneficial effects on oxidative stress and DNA damage, we tested the hypothesis that sildenafil could also protect the stenotic kidneys of 2K1C hypertensive mice against oxidative stress and genotoxicity. Methods The experiments were performed with C57BL6 mice subjected to renovascular hypertension by left renal artery clipping. Two weeks after clipping, the mice were treated with sildenafil (40 mg/kg/day for 2 weeks, 2K1C-sildenafil group) or the vehicle (2K1C). These mice were compared with control mice not subjected to renal artery clipping (Sham). After hemodynamic measurements, the stenotic kidneys were assessed using flow cytometry to evaluate cell viability and the comet assay to evaluate DNA damage. Measurements of intracellular superoxide anions and hydrogen peroxide levels as well as nitric oxide bioavailability were also obtained. Results Sildenafil treatment significantly reduced mean arterial pressure (15%), heart rate (8%), intrarenal angiotensin II (50%) and renal atrophy (36%). In addition, it caused a remarkable decrease of reactive oxygen species production. On the other hand, sildenafil increased nitric oxide levels relative to those in the nontreated 2K1C mice. Sildenafil treatment also significantly reduced the high level of kidney DNA damage that is a characteristic of renovascular hypertensive mice. Conclusions Our data reveal that sildenafil has a protective effect on the stenotic kidneys of 2K1C mice, suggesting a new use of phosphodiesterase 5 inhibitors for protection against the DNA damage observed in the hypoperfused kidneys of individuals with renovascular hypertension. Further translational research is

  15. Central PACAP mediates the sympathetic effects of leptin in a tissue-specific manner.

    PubMed

    Tanida, M; Hayata, A; Shintani, N; Yamamoto, N; Kurata, Y; Shibamoto, T; Morgan, D A; Rahmouni, K; Hashimoto, H

    2013-05-15

    We previously demonstrated that the peptidergic neurotransmitter pituitary adenylate cyclase-activating polypeptide (PACAP) affects the autonomic system and contributes to the control of metabolic and cardiovascular functions. Previous studies have demonstrated the importance of centrally-mediated sympathetic effects of leptin for obesity-related hypertension. Here we tested whether PACAP signaling in the brain is implicated in leptin-induced sympathetic excitation and appetite suppression. In anesthetized mice, intracerebroventricular (ICV) pre-treatment with PACAP6-38, an antagonist of the PACAP receptors (PAC1-R and VPAC2), inhibited the increase in white adipose tissue sympathetic nerve activity (WAT-SNA) produced by ICV leptin (2μg). In contrast, leptin-induced stimulation of renal sympathetic nerve activity (RSNA) was not affected by ICV pre-treatment with PACAP6-38. Moreover, in PACAP-deficient (Adcyap1-/-) mice, ICV leptin-induced WAT-SNA increase was impaired, whereas RSNA response was preserved. The reductions in food intake and body weight evoked by ICV leptin were attenuated in Adcyap1-/- mice. Our data suggest that hypothalamic PACAP signaling plays a key role in the control by leptin of feeding behavior and lipocatabolic sympathetic outflow, but spares the renal sympathetic traffic.

  16. [Structure, localization and physiologic role of pituitary adenylate cyclase activating polypeptide (PACAP)].

    PubMed

    Vincze, E; Köves, K

    2001-03-11

    PACAP was isolated on the basis of its ability to stimulate adenylate cyclase in primary anterior pituitary cell culture from ovine hypothalami by Miyata et al. in 1989. This peptide is structurally related to the secretin family and shows a 67% sequence homology with vasoactive intestinal polypeptide (VIP). The amino acid sequence of PACAP has been highly preserved during the evolution that may be connected with its important physiological role. Similar to other "brain-gut peptides" PACAP is localized not only in the central but in the peripheral nervous system and in non-neural tissues as well. In addition to its hypophysiotropic effects in the hypothalamo-hypophysial system PACAP exerts its effects on water-salt balance, cardiovascular functions, gastrointestinal motility and secretion and also on the regulation of reproductive functions. PACAP has a role in certain neuro-immuno-endocrine processes, in the differentiation of the nervous system, and it has neuroprotective effects in the case of ischaemia and various toxic agents. Locally PACAP takes its effects as an auto- and paracrine hormone, a neurotransmitter or a neuromodulator in different organs. Besides VIP, PACAP plays an important role in the function of the photo-neuro-endocrine system.

  17. Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Is Involved in Adult Mouse Hippocampal Neurogenesis After Stroke.

    PubMed

    Matsumoto, Minako; Nakamachi, Tomoya; Watanabe, Jun; Sugiyama, Koichi; Ohtaki, Hirokazu; Murai, Norimitsu; Sasaki, Shun; Xu, Zhifang; Hashimoto, Hitoshi; Seki, Tamotsu; Miyazaki, Akira; Shioda, Seiji

    2016-06-01

    In the subgranular zone (SGZ) of the hippocampus, neurogenesis persists throughout life and is upregulated following ischemia. Accumulating evidence suggests that enhanced neurogenesis stimulated by ischemic injury contributes to recovery after stroke. However, the mechanisms underlying the upregulation of neurogenesis are unclear. We have demonstrated that a neuropeptide, pituitary adenylate cyclase-activating polypeptide (PACAP), exerts a wide range of effects on neural stem cells (NSCs) during neural development. Here, we examined the effects of endogenous and exogenous PACAP in adult NSCs of the SGZ. Immunostaining showed expression of the PACAP receptor PAC1R in nestin-positive NSCs of adult naive mice. PACAP injection into the lateral ventricle increased bromodeoxyuridine (BrdU)-positive proliferative cells in the SGZ. These data suggest that PACAP promoted the proliferation of NSCs. In global ischemia model mice, the number of BrdU-positive cells was increased in wild-type mice but not in PACAP heterozygous knockout mice. The BrdU-positive cells that increased in number after ischemia were immunopositive for SOX2, a marker of NSCs, and differentiated into NeuN-positive mature neurons at 4 weeks after ischemia. These findings suggest that PACAP contributes to the proliferation of NSCs and may be associated with recovery after brain injury.

  18. PAC₁ receptors mediate positive chronotropic responses to PACAP-27 and VIP in isolated mouse atria.

    PubMed

    Hoover, Donald B; Girard, Beatrice M; Hoover, Jeffrey L; Parsons, Rodney L

    2013-08-05

    PACAP and VIP have prominent effects on cardiac function in several species, but little is known about their influence on the murine heart. Accordingly, we evaluated the expression of PACAP/VIP receptors in mouse heart and the response of isolated atria to peptide agonists. Quantitative PCR demonstrated that PAC₁, VPAC₁, and VPAC₂ receptor mRNAs are present throughout the mouse heart. Expression of all three receptor transcripts was low, PAC₁ being the lowest. No regional differences in expression were detected for individual receptor mRNAs after normalization to L32. Pharmacological effects of PACAP-27, VIP, and the selective PAC₁ agonist maxadilan were evaluated in isolated, spontaneously beating atria from C57BL/6 mice of either sex. Incremental additions of PACAP-27 at 1 min intervals caused a concentration-dependent tachycardia with a logEC₅₀=-9.08 ± 0.15 M (n=7) and a maximum of 96.3 ± 5.9% above baseline heart rate. VIP and maxadilan also caused tachycardia but their potencies were about two orders of magnitude less. Increasing the dosing interval to 5 min caused a leftward shift of the concentration-response curve to maxadilan but no changes in the curves for PACAP-27 or VIP. Under this condition, neither the potency nor the efficacy of maxadilan differed from those of PACAP-27. Neither PACAP-27 nor maxadilan caused tachyphylaxis, and maximal responses to maxadilan were maintained for at least 2 h. We conclude that all three VIP/PACAP family receptors are expressed by mouse cardiac tissue, but only PAC₁ receptors mediate positive chronotropic responses to PACAP-27 and VIP.

  19. Agnathan VIP, PACAP and Their Receptors: Ancestral Origins of Today's Highly Diversified Forms

    PubMed Central

    Ng, Stephanie Y. L.; Chow, Billy K. C.; Kasamatsu, Jun; Kasahara, Masanori; Lee, Leo T. O.

    2012-01-01

    VIP and PACAP are pleiotropic peptides belonging to the secretin superfamily of brain-gut peptides and interact specifically with three receptors (VPAC1, PAC1 and VPAC2) from the class II B G protein-coupled receptor family. There is immense interest regarding their molecular evolution which is often described closely alongside gene and/or genome duplications. Despite the wide array of information available in various vertebrates and one invertebrate the tunicate, their evolutionary origins remain unresolved. Through searches of genome databases and molecular cloning techniques, the first lamprey VIP/PACAP ligands and VPAC receptors are identified from the Japanese lamprey. In addition, two VPAC receptors (VPACa/b) are identified from inshore hagfish and ligands predicted for sea lamprey. Phylogenetic analyses group these molecules into their respective PHI/VIP, PRP/PACAP and VPAC receptor families and show they resemble ancestral forms. Japanese lamprey VIP/PACAP peptides synthesized were tested with the hagfish VPAC receptors. hfVPACa transduces signal via both adenylyl cylase and phospholipase C pathways, whilst hfVPACb was only able to transduce through the calcium pathway. In contrast to the widespread distribution of VIP/PACAP ligands and receptors in many species, the agnathan PACAP and VPAC receptors were found almost exclusively in the brain. In situ hybridisation further showed their abundance throughout the brain. The range of VIP/PACAP ligands and receptors found are highly useful, providing a glimpse into the evolutionary events both at the structural and functional levels. Though representative of ancestral forms, the VIP/PACAP ligands in particular have retained high sequence conservation indicating the importance of their functions even early in vertebrate evolution. During these nascent stages, only two VPAC receptors are likely responsible for eliciting functions before evolving later into specific subtypes post-Agnatha. We also propose VIP and

  20. PACAP is essential for the adaptive thermogenic response of brown adipose tissue to cold exposure.

    PubMed

    Diané, Abdoulaye; Nikolic, Nikolina; Rudecki, Alexander P; King, Shannon M; Bowie, Drew J; Gray, Sarah L

    2014-09-01

    Pituitary adenylate cyclase-activating polypeptide (PACAP) is a widely distributed neuropeptide that acts as a neurotransmitter, neuromodulator, neurotropic factor, neuroprotectant, secretagogue, and neurohormone. Owing to its pleiotropic biological actions, knockout of Pacap (Adcyap1) has been shown to induce several abnormalities in mice such as impaired thermoregulation. However, the underlying physiological and molecular mechanisms remain unclear. A previous report has shown that cold-exposed Pacap null mice cannot supply appropriate levels of norepinephrine (NE) to brown adipocytes. Therefore, we hypothesized that exogenous NE would rescue the impaired thermogenic response of Pacap null mice during cold exposure. We compared the adaptive thermogenic capacity of Pacap(-/-) to Pacap(+/+) mice in response to NE when housed at room temperature (24 °C) and after a 3.5-week cold exposure (4 °C). Biochemical parameters, expression of thermogenic genes, and morphological properties of brown adipose tissue (BAT) and white adipose tissue (WAT) were also characterized. Results showed that there was a significant effect of temperature, but no effect of genotype, on the resting metabolic rate in conscious, unrestrained mice. However, the normal cold-induced increase in the basal metabolic rate and NE-induced increase in thermogenesis were severely blunted in cold-exposed Pacap(-/-) mice. These changes were associated with altered substrate utilization, reduced β3-adrenergic receptor (β3-Ar (Adrb3)) and hormone-sensitive lipase (Hsl (Lipe)) gene expression, and increased fibroblast growth factor 2 (Fgf2) gene expression in BAT. Interestingly, Pacap(-/-) mice had depleted WAT depots, associated with upregulated uncoupling protein 1 expression in inguinal WATs. These results suggest that the impairment of adaptive thermogenesis in Pacap null mice cannot be rescued by exogenous NE perhaps in part due to decreased β3-Ar-mediated BAT activation.

  1. Resveratrol Attenuates Copper and Zinc Homeostasis and Ameliorates Oxidative Stress in Type 2 Diabetic Rats.

    PubMed

    Asadi, Soheila; Moradi, Mohammad Nabi; Khyripour, Nejat; Goodarzi, Mohammad Taghi; Mahmoodi, Marzieh

    2017-05-01

    Diabetes is a common metabolic disorder characterized by elevated blood glucose level. Trace element homeostasis causes disturbances in diabetes due to hyperglycemia. Superoxide dismutase (SOD), an antioxidant enzyme, contains zinc and copper ions as its cofactors. Defects in SOD level and activity have been observed in diabetes. Resveratrol (RSV) has displayed hypoglycemic effects and is proven to improve oxidative stress. The aim of the present study was to examine the possible effects of RSV on blood glucose level, serum copper and zinc levels, SOD, and a number of other oxidative markers in type 2 diabetic rats. Diabetes was induced in male Wistar rats with administration of streptozotocin and nicotine amide. The studied groups containing six animals per group were as follows: group 1 normal control group; group 2 diabetic control group; groups 3, 4, and 5 diabetic rats that received 1, 5, and 10 mg/kg body weight of RSV, respectively for 30 days. Serum glucose, copper, zinc, SOD activity, total oxidant status (TOS) as well as thiol groups were all measured. Blood glucose in RSV treated groups significantly decreased. Similarly, copper significantly decreased in diabetic groups treated with RSV. Treatment with 10 mg/kg RSV resulted in significantly increased serum zinc. Furthermore, Cu/Zn ratio was observed to decrease in treated groups compared with untreated diabetic control group. RSV treated groups revealed an increased level of SOD activity as well as improved oxidative status. In summary, the results showed that RSV has potential hypoglycemic effect, attenuates trace element homeostasis, and consequently increases SOD activity level.

  2. Amelioration of the haloperidol-induced memory impairment and brain oxidative stress by cinnarizine

    PubMed Central

    Abdel-Salam, Omar M.E.; El-Sayed El-Shamarka, Marwa; Salem, Neveen A.; El-Mosallamy, Aliaa E.M.K.; Sleem, Amany A.

    2012-01-01

    Haloperidol is a classic antipsychotic drug known for its propensity to cause extrapyramidal symptoms and impaired memory, owing to blockade of striatal dopamine D2 receptors. Cinnarizine is a calcium channel blocker with D2 receptor blocking properties which is widely used in treatment of vertiginous disorders. The present study aimed to see whether cinnarizine would worsen the effect of haloperidol on memory function and on oxidative stress in mice brain. Cinnarizine (5, 10 or 20 mg/kg), haloperidol, or haloperidol combined with cinnarizine was administered daily via the subcutaneous route and mice were examined on weekly basis for their ability to locate a submerged plate in the water maze test. Mice were euthanized 30 days after starting drug injection. Malondialdehyde (MDA), reduced glutathione (GSH) and nitric oxide (nitrite/nitrate) were determined in brain. Haloperidol substantially impaired water maze performance. The mean time taken to find the escape platform (latency) was significantly delayed by haloperidol (2 mg/kg, i.p.) on weeks 1-8 of the test, compared with saline control group. In contrast, those treated with haloperidol and cinnarizine showed significantly shorter latencies, which indicated that learning had occurred immediately. Haloperidol resulted in increased MDA in cortex, striatum, cerebellum and midbrain. GSH decreased in cortex, striatum and cerebellum and nitric oxide increased in cortex. Meanwhile, treatment with cinnarizine (20 mg/kg) and haloperidol resulted in significant decrease in MDA cortex, striatum, cerebellum and midbrain and an increase in GSH in cortex and striatum, compared with haloperidol group. These data suggest that cinnarizine improves the haloperidol induced brain oxidative stress and impairment of learning and memory in the water maze test in mice. PMID:27540345

  3. Curcumin Ameliorates Kidney Function and Oxidative Stress in Experimental Chronic Kidney Disease.

    PubMed

    Ali, Badreldin H; Al-Salam, Suhail; Al Suleimani, Yousuf; Al Kalbani, Jamila; Al Bahlani, Shadia; Ashique, Mohammed; Manoj, Priyadarsini; Al Dhahli, Buthaina; Al Abri, Nadia; Naser, Heba T; Yasin, Javed; Nemmar, Abderrahim; Al Za'abi, Mohammed; Hartmann, Christina; Schupp, Nicole

    2017-05-31

    Chronic kidney disease (CKD) is known to involve inflammation, oxidative stress and apoptosis. Here, we investigated the impact of curcumin (diferuloyl methane, a phenolic turmeric pigment), which has strong antioxidant, anti-inflammatory and anti-apoptotic activities on kidney structure and function in rats with adenine-induced CKD. Rats were treated for 5 weeks with adenine to induce CKD-like renal damage and combined with three doses of curcumin. Markers of kidney function and oxidative stress were quantified in plasma, urine, renal homogenates and on kidney tissue. Curcumin was found to significantly abate adenine-induced toxic effects such as reduced creatinine clearance, elevated neutrophil gelatinase-associated lipocalin levels and raised urinary N-acetyl-β-D-glucosaminidase activities. Curcumin markedly reduced renal morphological damage and histopathological markers of inflammation, fibrosis and apoptosis. Curcumin further reduced adenine-induced hypertension, urinary albumin, the inflammatory cytokines IL-1β, IL-6 and TNF-α, cystatin C and adiponectin. It restored plasma sclerostin concentrations and lowered oxidative stress in renal homogenates. In animals treated with the two higher curcumin concentrations, alone or in combination with adenine, an increased expression of the antioxidative transcription factor Nrf2 was found as well as up-regulation of the activity of its direct target glutathione reductase, and of an indirect target, the glutathione level. In conclusion, curcumin exhibits salutary effects against adenine-induced CKD in rats by reducing inflammation and oxidative stress via up-regulation of the transcription factor Nrf2. © 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

  4. Diosgenin ameliorates development of neuropathic pain in diabetic rats: Involvement of oxidative stress and inflammation.

    PubMed

    Kiasalari, Zahra; Rahmani, Tayebeh; Mahmoudi, Narges; Baluchnejadmojarad, Tourandokht; Roghani, Mehrdad

    2017-02-01

    Neuropathic pain is one of the prevalent complications of diabetes mellitus (DM). Oxidative stress and inflammation are the principal determinants for its development. Pharmacological interventions targeted at alleviating or suppressing these pathways are clinically promising. Diosgenin is a natural steroidal saponin with anti-diabetic and multiple protective properties. This study was designed to study the efficacy of chronic diosgenin administration on alleviation of hyperalgesia in streptozotocin (STZ)-diabetic rats. Rats were allocated to control, diosgenin-treated control, diabetic, and diosgenin-treated-diabetic groups. Diosgenin was daily administered at a dose of 40mg/kg for 5 weeks. Nociceptive behavior was assessed using paw pressure, hot tail immersion, and formalin tests. In addition, some oxidative stress and inflammation markers were measured. Diosgenin treatment of diabetic group increased mechanical and thermal nociceptive thresholds and lowered pain score at late phase of the formalin test, but not at its early phase. Biochemical analysis of serum samples and sciatic nerve and dorsal root ganglion (DRG) lysates showed restoration or improvement of nuclear factor-B (NF-κB), malondialdehyde (MDA) level, activity of superoxide dismutase (SOD), catalase, tumor necrosis factor α (TNFα), and interleukin 1β (IL-1β) upon diosgenin treatment of diabetic rats. The obtained results exhibited antinociceptive potential of diosgenin in diabetic rats through lowering oxidative stress and inflammation and improving antioxidant defense system. This suggests possible therapeutic potential of diosgenin for alleviation and management of diabetic neuropathic pain.

  5. Origanum majorana Attenuates Nephrotoxicity of Cisplatin Anticancer Drug through Ameliorating Oxidative Stress

    PubMed Central

    Soliman, Amel M.; Desouky, Shreen; Marzouk, Mohamed; Sayed, Amany A.

    2016-01-01

    Despite the fact that cisplatin is an important anticancer drug, its clinical utilization is limited by nephrotoxicity during long term medication. Combined cisplatin chemotherapy with plant extracts can diminish toxicity and enhance the antitumor efficacy of the drug. This study evaluated the effect of Originum majorana ethanolic extract (OMEE) on cisplatin-induced nephrotoxicity. Eighteen male rats were divided into three groups as follows: a control group, a group treated with cisplatin (3 mg/kg body weight), and a group that received both cisplatin and OMEE (500 mg/kg body weight) for 14 days. Cisplatin induced a significant increase in creatinine, urea, uric acid, blood urea nitrogen, malondialdehyde, and nitric oxide levels. However, glutathione, superoxide dismutase, and catalase levels were significantly diminished. Conversely, OMEE significantly modulated the renal and oxidative markers negatively impacted by cisplatin. OMEE significantly reduced the effects of cisplatin-induced changes in renal and oxidative markers, possibly through its free radical scavenging activity. Thus, OMEE may be combined with cisplatin to alleviate nephrotoxicity in cancer chemotherapy. PMID:27164131

  6. Origanum majorana Attenuates Nephrotoxicity of Cisplatin Anticancer Drug through Ameliorating Oxidative Stress.

    PubMed

    Soliman, Amel M; Desouky, Shreen; Marzouk, Mohamed; Sayed, Amany A

    2016-05-05

    Despite the fact that cisplatin is an important anticancer drug, its clinical utilization is limited by nephrotoxicity during long term medication. Combined cisplatin chemotherapy with plant extracts can diminish toxicity and enhance the antitumor efficacy of the drug. This study evaluated the effect of Originum majorana ethanolic extract (OMEE) on cisplatin-induced nephrotoxicity. Eighteen male rats were divided into three groups as follows: a control group, a group treated with cisplatin (3 mg/kg body weight), and a group that received both cisplatin and OMEE (500 mg/kg body weight) for 14 days. Cisplatin induced a significant increase in creatinine, urea, uric acid, blood urea nitrogen, malondialdehyde, and nitric oxide levels. However, glutathione, superoxide dismutase, and catalase levels were significantly diminished. Conversely, OMEE significantly modulated the renal and oxidative markers negatively impacted by cisplatin. OMEE significantly reduced the effects of cisplatin-induced changes in renal and oxidative markers, possibly through its free radical scavenging activity. Thus, OMEE may be combined with cisplatin to alleviate nephrotoxicity in cancer chemotherapy.

  7. Pioglitazone Enhances Cytosolic Lipolysis, β-oxidation and Autophagy to Ameliorate Hepatic Steatosis.

    PubMed

    Hsiao, Pi-Jung; Chiou, Hsin-Ying Clair; Jiang, He-Jiun; Lee, Mei-Yueh; Hsieh, Tusty-Jiuan; Kuo, Kung-Kai

    2017-08-22

    Non-alcoholic fatty liver disease closely contributes to the development of obesity and insulin resistance. Even though pioglitazone has been reported to effectively lessen hepatic steatosis in human studies, its molecular mechanism remains unclear. This study is designed to investigate the regulation of cytosolic lipolysis, β-oxidation and autophagy by pioglitazone in a mice model of high fat diet (HFD) and cell model incubated with palmitic acid. Our results revealed hepatic steatosis was apparently induced by HFD and it was significantly reversed by pioglitazone. The serum insulin and hepatic triglyceride content was significantly decreased by co-administered pioglitazone with HFD. Hepatic expression of cytosolic-lipolysis related proteins (ATGL, HSL), β-oxidation (CPT-1A) and autophagy-related proteins (ATG7, LC3, LAL) was significantly enhanced by pioglitazone. Knockdown PPARα/PPARγ in AML12 cells significantly and proportionally reduced the expressions of ATGL, CPT-1A and LC3II, which was induced by pioglitazone. Furthermore, facilitation of the autophagic flux by pioglitazone was obviously blocked by lysosomal inhibitor, leupeptin, to demonstrate accumulation of the LC3II and intracellular lipid in AML12 cells. Our results demonstrated that pioglitazone attenuating the hepatic steatosis may be mediated by enhancing cytosolic lipolysis, β-oxidation and autophagy in a PPARα and PPARγ dependent manner.

  8. Green tea catechins ameliorate adipose insulin resistance by improving oxidative stress.

    PubMed

    Yan, Jingqi; Zhao, Yan; Suo, Siqingaowa; Liu, Yang; Zhao, Baolu

    2012-05-01

    Epidemiological data have suggested that drinking green tea is negatively associated with diabetes, and adipose oxidative stress may have a central role in causing insulin resistance, according to recent findings. The aim of this work is to elucidate a new mechanism for green tea's anti-insulin resistance effect. We used obese KK-ay mice, high-fat diet-induced obese rats, and induced insulin resistant 3T3-L1 adipocytes as models. Insulin sensitivity and adipose reactive oxidative species (ROS) levels were detected in animals and adipocytes. The oxidative stress assay and glucose uptake ability assay were performed, and the effects of EGCG on insulin signals were detected. Green tea catechins (GTCs) significantly decreased glucose levels and increased glucose tolerance in animals. GTCs reduced ROS content in both models of animal and adipocytes. EGCG attenuated dexamethasone and TNF-α promoted ROS generation and increased glucose uptake ability. EGCG also decreased JNK phosphorylation and promoted GLUT-4 translocation. EGCG and GTCs could improve adipose insulin resistance, and exact this effect on their ROS scavenging functions. Copyright © 2012 Elsevier Inc. All rights reserved.

  9. Tamarix gallica ameliorates thioacetamide-induced hepatic oxidative stress and hyperproliferative response in Wistar rats.

    PubMed

    Sehrawat, Anuradha; Sultana, Sarwat

    2006-04-01

    Tamarix gallica, a hepatic stimulant and tonic, was examined for its ability to inhibit thioacetamide (TAA)-induced hepatic oxidative stress, toxicity and early tumor promotion response in male Wistar rats. TAA (6.6 mmol/kg body wt. i.p) enhanced lipid peroxidation, hydrogen peroxide content, glutathione S-transferase and xanthine oxidase with reduction in the activities of hepatic antioxidant enzymes viz., glutathione peroxidase, superoxide dismutase and caused depletion in the level of hepatic glutathione content. A marked increase in liver damage markers was also observed. TAA treatment also enhanced tumor promotion markers, ornithine decarboxylase (ODC) activity and [3H] thymidine incorporation into hepatic DNA. Pretreatment of rats orally with Tamarix gallica extract (25 and 50 mg/kg body weight) prevented TAA-promoted oxidative stress and toxicity. Prophylaxis with Tamarix gallica significantly reduced the susceptibility of the hepatic microsomal membrane for iron-ascorbate induced lipid peroxidation, H2O2 content, glutathione S-transferase and xanthine oxidase activities. There was also reversal of the elevated levels of liver marker parameters and tumor promotion markers. Our data suggests that Tamarix gallica is a potent chemopreventive agent and may suppress TAA-mediated hepatic oxidative stress, toxicity, and tumor promotion response in rats.

  10. Changes in PACAP immunoreactivity in human milk and presence of PAC1 receptor in mammary gland during lactation.

    PubMed

    Csanaky, Katalin; Banki, Eszter; Szabadfi, Krisztina; Reglodi, Dora; Tarcai, Ibolya; Czegledi, Levente; Helyes, Zsuzsanna; Ertl, Tibor; Gyarmati, Judit; Szanto, Zalan; Zapf, Istvan; Sipos, Erika; Shioda, Seiji; Tamas, Andrea

    2012-11-01

    Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide with widespread occurrence in the nervous system and peripheral organs, including the mammary gland. Previously, we have shown that PACAP38 is present in the human milk at higher levels than in respective blood samples. However, it is not known how PACAP levels and the expression of PAC1 receptor change during lactation. Therefore, the aim of our study was to investigate PACAP38-like immunoreactivity (PACAP38-LI) in human colostrums and transitional and mature milk during lactation and to compare the expression of PAC1 receptors in lactating and non-lactating mammary glands. We found that PACAP38-LI was significantly higher in human colostrum samples than in the transitional and mature milk. PACAP38-LI did not show any significant changes within the first 10-month period of lactation, but a significant increase was observed thereafter, up to the examined 17th month. Weak expression of PAC1 receptors was detected in non-lactating sheep and human mammary glands, but a significant increase was observed in the lactating sheep samples. In summary, the present study is the first to show changes of PACAP levels in human milk during lactation. The presence of PACAP in the milk suggests a potential role in the development of newborn, while the increased expressions of PAC1 receptors on lactating breast may indicate a PACAP38/PAC1 interaction in the mammary gland during lactation.

  11. Myricetin protects against diet-induced obesity and ameliorates oxidative stress in C57BL/6 mice.

    PubMed

    Su, Hong-Ming; Feng, Li-Na; Zheng, Xiao-Dong; Chen, Wei

    2016-06-01

    Myricetin is a naturally occurring antioxidant commonly found in various plants. However, little information is available with respect to its direct anti-obesity effects. This study was undertaken to investigate the effect of myricetin on high-fat diet (HFD)-induced obesity in C57BL/6 mice. Administration of myricetin dramatically reduced the body weight of diet-induced obese mice compared with solely HFD-induced mice. Several parameters related to obesity including serum glucose, triglyceride, and cholesterol were significantly decreased in myricetin-treated mice. Moreover, obesity-associated oxidative stress (glutathione peroxidase (GPX) activity, total antioxidant capacity (T-AOC), and malondialdehyde (MDA)) and inflammation (tumor necrosis factor-α (TNF-α)) were ameliorated in myricetin-treated mice. Further investigation revealed that the protective effect of myricetin against HFD-induced obesity in mice appeared to be partially mediated through the down-regulation of mRNA expression of adipogenic transcription factors peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα), and lipogenic transcription factor sterol regulatory element-binding protein 1c (SREBP-1c). Consumption of myricetin may help to prevent obesity and obesity-related metabolic complications.

  12. Myricetin protects against diet-induced obesity and ameliorates oxidative stress in C57BL/6 mice*

    PubMed Central

    Su, Hong-ming; Feng, Li-na; Zheng, Xiao-dong; Chen, Wei

    2016-01-01

    Background: Myricetin is a naturally occurring antioxidant commonly found in various plants. However, little information is available with respect to its direct anti-obesity effects. Objective: This study was undertaken to investigate the effect of myricetin on high-fat diet (HFD)-induced obesity in C57BL/6 mice. Results: Administration of myricetin dramatically reduced the body weight of diet-induced obese mice compared with solely HFD-induced mice. Several parameters related to obesity including serum glucose, triglyceride, and cholesterol were significantly decreased in myricetin-treated mice. Moreover, obesity-associated oxidative stress (glutathione peroxidase (GPX) activity, total antioxidant capacity (T-AOC), and malondialdehyde (MDA)) and inflammation (tumor necrosis factor-α (TNF-α)) were ameliorated in myricetin-treated mice. Further investigation revealed that the protective effect of myricetin against HFD-induced obesity in mice appeared to be partially mediated through the down-regulation of mRNA expression of adipogenic transcription factors peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα), and lipogenic transcription factor sterol regulatory element-binding protein 1c (SREBP-1c). Conclusions: Consumption of myricetin may help to prevent obesity and obesity-related metabolic complications. PMID:27256677

  13. Pentoxifylline ameliorates non-alcoholic fatty liver disease in hyperglycaemic and dyslipidaemic mice by upregulating fatty acid β-oxidation

    PubMed Central

    Ye, Jia-Hung; Chao, Jung; Chang, Ming-Ling; Peng, Wen-Huang; Cheng, Hao-Yuan; Liao, Jiunn-Wang; Pao, Li-Heng

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD), which includes simple steatosis, steatohepatitis, fibrosis, and cirrhosis, is characterised by abnormal fat accumulation in the liver in the absence of excessive alcohol intake. In patients with type 2 diabetes (T2D), concurrent NAFLD might increase the risk of chronic kidney disease and the mortality rate. Although several studies have examined the effectiveness of pentoxifylline (PTX) in NAFLD treatment, no results are available to verify the effectiveness of PTX in treating T2D associated with NAFLD. In this study, we developed a combined high-fat diet-induced obesity and low-dose streptozocin-induced hyperglycaemia mouse model to mimic the concurrent NAFLD and T2D pathological condition. By combining physiological assessments, pathological examinations, metabolomics studies on blood, urine, and liver, and measurements of gene and protein expression, we elucidated the effectiveness and the underlying mechanism of action of PTX in the hyperglycaemic and dyslipidaemic mice. Our results revealed that PTX ameliorated NAFLD in the hyperglycaemic and dyslipidaemic mice by upregulating fatty acid β-oxidation. Furthermore, the glycolysis pathway and branched-chain amino acid-related pathways in these mice were restored by PTX. PMID:27612024

  14. Lignans from Schisandra chinensis ameliorate cognition deficits and attenuate brain oxidative damage induced by D-galactose in rats.

    PubMed

    Yan, Tingxu; Shang, Lei; Wang, Mengshi; Zhang, Chenning; Zhao, Xu; Bi, Kaishun; Jia, Ying

    2016-06-01

    The aim of this study was to explore the neuroprotective effects of active compounds from Schisandra chinensis (Trucz.) Baill. (Magnoliaceae) against the D-galactose (D-gal)-induced neurotoxicity in rat. The Wistar rats were subcutaneously injected with D-gal (150 mg/(kg day)) for six weeks and orally administered with water extract or 95 % ethanol extract (partitioned with petroleum ether (PE), chloroform (CF), ethyl acetate (EA) and n-Butanol (NB), respectively) of the fruits of Schisandra chinensis simultaneously. The alteration of cognitive functions was assessed by using Morris water maze and Step-down type passive avoidance test. The results demonstrated that PE fraction was the most effective fraction to ameliorate cognitive deficits. Further biochemical examination indicated that PE could attenuate the activities decreasing of superoxide dismutase (SOD), catalase (CAT), the total antioxidant (T-AOC) induced by D-gal, and maintain the normal levels of glutathione (GSH), malondialdehyde (MDA) and nitric oxide (NO) in the serum, prefrontal cortex, striatum and hippocampus of the brain of related rat, selectively. Meanwhile, the compounds of PE fraction were also identified as mainly lignans, thus, these results suggest that lignans from the PE fraction of Schisandra chinensis represented a potential source of medicine for the treatment of the aging-associated neurodegenerative diseases.

  15. Expression of PACAP and PAC1 Receptor in Normal Human Thyroid Gland and in Thyroid Papillary Carcinoma.

    PubMed

    Bardosi, Sebastian; Bardosi, Attila; Nagy, Zsuzsanna; Reglodi, Dora

    2016-10-01

    Pituitary adenylate cyclase activating polypeptide (PACAP) belongs to the vasoactive intestinal peptide-secretin-glucagon peptide family, isolated first from ovine hypothalamus. The diverse physiological effects of PACAP are known mainly from animal experiments, including several actions in endocrine glands. Alteration of PACAP expression has been shown in several tumors, but changes in expression of PACAP and its specific PAC1 receptor in human thyroid gland pathologies have not yet been investigated. Therefore, the aim of the present study was to investigate expression of PACAP and its PAC1 receptor in human thyroid papillary carcinoma, the most common endocrine malignant tumor. PACAP and PAC1 receptor expressions were investigated from thyroid gland samples of patients with papillary carcinomas. The staining intensity of follicular epithelial cells and thyroid colloid of tumor tissue was compared to that of tumor-free tissue in the same thyroid glands in a semi-quantitative way. Our results reveal that both PACAP(-like) and PAC1 receptor(-like) immunoreactivities are altered in papillary carcinoma. Stronger PACAP immunoreactivity was observed in active follicles. Colloidal PACAP immunostaining was either lacking or very weak, and more tumorous cells displayed strong apical immunoreactivity. Regarding PAC1 receptor, cells of the normal thyroid tissue showed strong granular expression, which was lacking in the tumor cells. The cytoplasm of tumor cells displayed weak, minimal staining, while in a few tumor cells we observed strong PAC1 receptor expression. This pattern was similar to that observed in the PACAP expression, but fewer in number. In summary, we showed alteration of PACAP and PAC1 receptor expression in human thyroid papillary carcinoma, indicating that PACAP regulation is disturbed in tumorous tissue of the thyroid gland. The exact role of PACAP in thyroid tumor growth should be further explored.

  16. PKA, novel PKC isoforms, and ERK is mediating PACAP auto-regulation via PAC1R in human neuroblastoma NB-1 cells.

    PubMed

    Georg, Birgitte; Falktoft, Birgitte; Fahrenkrug, Jan

    2016-12-01

    The neuropeptide PACAP is expressed throughout the central and peripheral nervous system where it modulates diverse physiological functions including neuropeptide gene expression. We here report that in human neuroblastoma NB-1 cells PACAP transiently induces its own expression. Maximal PACAP mRNA expression was found after stimulation with PACAP for 3h. PACAP auto-regulation was found to be mediated by activation of PACAP specific PAC1Rs as PACAP had >100-fold higher efficacy than VIP, and the PAC1R selective agonist Maxadilan potently induced PACAP gene expression. Experiments with pharmacological kinase inhibitors revealed that both PKA and novel but not conventional PKC isozymes were involved in the PACAP auto-regulation. Inhibition of MAPK/ERK kinase (MEK) also impeded the induction, and we found that PKA, novel PKC and ERK acted in parallel and were thus not part of the same pathways. The expression of the transcription factor EGR1 previously ascribed as target of PACAP signalling was found to be transiently induced by PACAP and pharmacological inhibition of either PKC or MEK1/2 abolished PACAP mediated EGR1 induction. In contrast, inhibition of PKA mediated increased PACAP mediated EGR1 induction. Experiments using siRNA against EGR1 to lower the expression did however not affect the PACAP auto-regulation indicating that this immediate early gene product is not part of PACAP auto-regulation in NB-1 cells. We here reveal that in NB-1 neuroblastoma cells, PACAP induces its own expression by activation of PAC1R, and that the signalling is different from the PAC1R signalling mediating induction of VIP in the same cells. PACAP auto-regulation depends on parallel activation of PKA, novel PKC isoforms, and ERK, while EGR1 does not seem to be part of the PACAP auto-regulation. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Fasting ameliorates metabolism, immunity, and oxidative stress in carbon tetrachloride-intoxicated rats.

    PubMed

    Sadek, Km; Saleh, Ea

    2014-12-01

    Fasting has been recently discovered to improve overall health, but its beneficial effects in the presence of hepatic insufficiency have not been proven. The influence of fasting on the metabolism, immunological aspects, and oxidative stress of 40 male carbon tetrachloride (CCl4)-intoxicated Wistar rats was investigated in the present study. The rats were divided into four groups, including a placebo group, CCl4-intoxicated rats, which were injected subcutaneously with 1.0 ml/kg of CCl4 solution, a fasting group, which was fasted 12 h/day for 30 days, and a fourth group, which was injected with CCl4 and fasted. The metabolism, immunity, and oxidative stress improved in CCl4-intoxicated rats fasted for 12 h/day for 30 days, as evidenced in significant increase (p < 0.05) in total protein, globulin, immunoglobulin M (IgM) and IgG levels, and total antioxidant capacity. In contrast, significant decrease (p < 0.05) in blood glucose, total cholesterol, low-density lipoprotein-cholesterol, alanine aminotransferase, C-reactive protein, and malondialdehyde levels were observed. Compared with CCl4-intoxicated rats, significant differences in the albumin, triacylglycerol, high-density lipoprotein-cholesterol, very low-density lipoprotein-cholesterol, cardiovascular risk factor, calcium and magnesium levels were not detected. The results of the present study showed that fasting improved metabolism, immunity, and oxidative stress in CCl4-intoxicated rats. Thus, fasting during Ramadan is safe for patients with hepatic disorders, as the prophet Mohammed (S) said "Keep the fast, keep your health". © The Author(s) 2014.

  18. Boron ameliorates fulminant hepatic failure by counteracting the changes associated with the oxidative stress.

    PubMed

    Pawa, Sonica; Ali, Shakir

    2006-03-25

    Boron has well-defined biological effects and may be of therapeutic benefit. In the current paper, the effect of boron in the form of borax was tested in experimental animal model of fulminant hepatic failure (FHF). The syndrome was induced in female Wistar rats by three consecutive daily intraperitoneal injections of thioacetamide (400 mg/kg). In the treatment groups, rats received borax (4.0 mg/kg) orally for three consecutive days followed by thioacetamide. The group administered with thioacetamide plus vehicle, and the borax alone treated rats served as controls. In all groups, rats were terminated 4 h after administering the last dose of thioacetamide, and the tissue/serum was used to measure hepatic levels of thiobarbituric acid reactive substances, reduced glutathione, and various enzymes associated with oxidative stress including peroxide metabolizing enzymes and xanthine oxidase. In thioacetamide treated group, many fold increase in the activity level of serum marker enzymes suggesting FHF was observed that could be brought down significantly in rats receiving boron. Modulation and a correlation in the activity level of oxidant generating enzyme and lipid peroxidation as well as hepatic glutathione level was also observed in rats receiving thioacetamide. In the group receiving boron followed by thioacetamide, these changes could be minimized moderately. The activity level of the peroxide metabolizing enzymes and the tripeptide glutathione, which decreased following thioacetamide treatment were moderately elevated in the group receiving boron followed by thioacetamide. The data clearly shows that borax partly normalizes the liver and offsets the deleterious effects observed in FHF by modulating the oxidative stress parameters.

  19. Melatonin Supplementation Ameliorates Energy Charge and Oxidative Stress Induced by Acute Exercise in Rat Heart Tissue.

    PubMed

    Cimen, Behzat; Uz, Ali; Cetin, Ihsan; Cimen, Leyla; Cetin, Aysun

    2017-09-01

    Regular physical exercises may help people to be more resistant to everyday problems; however, how acute and intense exercises affect the heart tissues functioning with maximum capacity and how melatonin changes the effect of acute and intense exercises are still not obvious. We aimed to comprehend whether melatonin intravenous injection supports the oxidative/antioxidative conditions and energy charge in heart tissues of rats exposed to acute swimming exercise. Thirty Wistar-albino male rats were categorized into 3 groups with equal number of subjects. Control group performed no application, and acute intensive swimming exercise group were subjected to acute intensive swimming exercise for 30 minutes, and melatonin group were applied 25 mg/kg single dose melatonin administration prior to 30 minutes acute intensive swimming exercise. The levels of malondialdehyde (MDA), and superoxide dismutase, catalase and glutathione peroxidase activities were measured by spectrophotometric method; and the levels of 3-nitrotyrosine (3-NT) and energy charge were determined by a high performance liquid chromatography. Tissue MDA and 3-NT levels of the acute intensive exercise group were found to be higher than the control group. It was also found that the melatonin administration increased the energy charge and antioxidant activities, while decreased tissue MDA and 3-NT levels in heart tissues. Our results provide evidence for melatonin that can exert potent protective effects on oxidative stress and energy charge for heart tissues in acute swimming exercise. These findings suggest that the direct beneficial effects of melatonin could be potentially applied on prevention of oxidative stress and energy deficit.

  20. Ameliorative effect of Opuntia ficus indica juice on ethanol-induced oxidative stress in rat erythrocytes.

    PubMed

    Alimi, Hichem; Hfaeidh, Najla; Bouoni, Zouhour; Sakly, Mohsen; Rhouma, Khémais Ben

    2013-05-01

    The aim of the present study was to investigate the efficacy of Opuntia ficus indica f. inermis fruit juice (OFIj) on reversing oxidative damages induced by chronic ethanol intake in rat erythrocytes. OFIj was firstly analyzed with HPLC for phenolic and flavonoids content. Secondly, 40 adult male Wistar rats were equally divided into five groups and treated for 90 days as follows: control (C), ethanol-only 3 g/kg body weight (b.w) (E), low dose of OFIj 2 ml/100 g b.w+ethanol (Ldj+E), high dose of OFIj 4 ml/100 g b.w+ethanol (Hdj+E), and only a high dose of OFIj 4 ml/100g b.w (Hdj). HPLC analysis indicated high concentrations of phenolic acids and flavonoids in OFIj. Ethanol treatment markedly decreased the activities of erythrocyte superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), and the level of reduced glutathione (GSH). Changes in the erythrocyte's antioxidant ability were accompanied by enhanced oxidative modification of lipids (increase of malondialdeyde level) and proteins (increase in carbonyl groups). Interestingly, pre-administration of either 2 ml/100 g b.w or 4 ml/100 g b.w of OFIj to ethanol-intoxicated rats significantly reversed decreases in enzymatic as well as non enzymatic antioxidants parameters in erythrocytes. Also, the administration of OFIj significantly protected lipids and proteins against ethanol-induced oxidative modifications in rat erythrocytes. The beneficial effect of OFIj can result from the inhibition of ethanol-induced free radicals chain reactions in rat erythrocytes or from the enhancement of the endogenous antioxidants activities. Copyright © 2011 Elsevier GmbH. All rights reserved.

  1. Isotetrandrine ameliorates tert-butyl hydroperoxide-induced oxidative stress through upregulation of heme oxygenase-1 expression

    PubMed Central

    Wang, Lidong; Ci, Xinxin; Lv, Hongming; Wang, Xiaosong

    2016-01-01

    1R, 1′S-isotetrandrine, a naturally occurring plant alkaloid found in Mahonia of Berberidaceae, possesses anti-inflammatory, antibacterial, and antiviral properties, but the antioxidative activity and mechanism action remain unclear. In this study, we demonstrated the antioxidative effect and mechanism of 1R, 1'S-isotetrandrine against tert-butyl hydroperoxide-induced oxidative damage in HepG2 cells. We found that 1R, 1′S-isotetrandrine suppressed cytotoxicity, reactive oxygen species generation, and glutathione depletion. Additionally, our study confirmed that 1R, 1′S-isotetrandrine significantly increased the antioxidant enzyme heme oxygenase-1 expression and nuclear translocation of factor-erythroid 2 p45-related factor 2 (Nrf2). Specifically, the nuclear translocation of Nrf2 induced by 1R, 1′S-isotetrandrine was associated with Nrf2 negative regulatory protein Keap1 inactivation and phosphorylation of both extracellular signal-regulated protein kinase and c-Jun NH2-terminal kinase. Preincubation with thiol-reducing agents reduced 1R, 1′S-isotetrandrine-induced heme oxygenase-1 expression, and treatment with either extracellular signal-regulated protein kinase or c-Jun NH2-terminal kinase inhibitors attenuated the levels of 1R, 1′S-isotetrandrine-induced Nrf2 activation and heme oxygenase-1 expression. Furthermore, the cytoprotective effect of 1R, 1′S-isotetrandrine was abolished by heme oxygenase-1, extracellular signal-regulated protein kinase, and c-Jun NH2-terminal kinase inhibitors. These results indicated that the 1R, 1′S-isotetrandrine ameliorated tert-butyl hydroperoxide-induced oxidative damage through upregulation of heme oxygenase-1 expression by the dissociation of Nrf2 from Nrf2-Keap1 complex via extracellular signal-regulated protein kinase and c-Jun NH2-terminal kinase activation and Keap1 inactivation. PMID:27190261

  2. Ameliorative effects of pyrazinoic acid against oxidative and metabolic stress manifested in rats with dimethylhydrazine induced colonic carcinoma.

    PubMed

    Sahdev, Anil K; Raj, Vinit; Singh, Ashok K; Rai, Amit; Keshari, Amit K; De, Arnab; Samanta, Amalesh; Kumar, Umesh; Rawat, Atul; Kumar, Dinesh; Nath, Sneha; Prakash, Anand; Saha, Sudipta

    2017-03-30

    Pyrazinoic acid (PA) is structurally similar to nicotinic acid which acts on G-protein-coupled receptor (GPR109A). GPR109A expresses in colonic and intestinal epithelial sites, and involves in DNA methylation and cellular apoptosis. Therefore, it may be assumed that PA has similar action like nicotinic acid and may be effective against colorectal carcinoma (CRC). CRC was produced via subcutaneous injection of dimethylhydrazine (DMH) at 40 mg/kg body weight once in a week for four weeks. After that, PA was administered orally at two doses of 10 and 25 mg/kg daily for 15 days to observe the antiproliferative effect. Various physiological, oxidative stress, molecular parameters, histopathology, RT-PCR and NMR based metabolomics were performed to evaluate the antiproliferative potential of PA. Our results collectively suggested that PA reduced body weight, tumor volume and incidence no. to normal. It restored various oxidative stress parameters and normalized IL-2, IL-6, and COX-2 as compared to carcinogen control. In molecular level, over expressed IL-6 and COX-2 genes became normal after PA administration. Again, normal tissue architecture was prominent after PA administration. Score plots of PLS-DA models exhibited that PA treated groups were significantly different from CRC group. We found that CRC rat sera have increased levels of acetate, glutamine, o-acetyl-glycoprotein, succinate, citrulline, choline, o-acetyl choline, tryptophan, glycerol, creatinine, lactate, citrate and decreased levels of 3-hydroxy butyrate, dimethyl amine, glucose, maltose, myoinositol. Further the PA therapy has ameliorated the CRC-induced metabolic alterations, signifying its antiproliferative properties. In conclusion, our study provided the evidence that PA demonstrated good antiproliferative effect on DMH induced CRC and thus demonstrated the potential of PA as a useful drug for future anticancer therapy.

  3. Melatonin ameliorates oxidative stress, inflammation, proteinuria, and progression of renal damage in rats with renal mass reduction.

    PubMed

    Quiroz, Yasmir; Ferrebuz, Atilio; Romero, Freddy; Vaziri, Nosratola D; Rodriguez-Iturbe, Bernardo

    2008-02-01

    The progressive deterioration of renal function and structure resulting from renal mass reduction are mediated by a variety of mechanisms, including oxidative stress and inflammation. Melatonin, the major product of the pineal gland, has potent_antioxidant and anti-inflammatory properties, and its production is impaired in chronic renal failure. We therefore investigated if melatonin treatment would modify the course of chronic renal failure in the remnant kidney model. We studied rats followed 12 wk after renal ablation untreated (Nx group, n = 7) and treated with melatonin administered in the drinking water (10 mg/100 ml) (Nx + MEL group, n = 8). Sham-operated rats (n = 10) were used as controls. Melatonin administration increased 13-15 times the endogenous hormone levels. Rats in the Nx + MEL group had reduced oxidative stress (malondialdehyde levels in plasma and in the remnant kidney as well as nitrotyrosine renal abundance) and renal inflammation (p65 nuclear factor-kappaB-positive renal interstitial cells and infiltration of lymphocytes and macrophages). Collagen, alpha-smooth muscle actin, and transforming growth factor-beta renal abundance were all increased in the remnant kidney of the untreated rats and were reduced significantly by melatonin treatment. Deterioration of renal function (plasma creatinine and proteinuria) and structure (glomerulosclerosis and tubulointerstitial damage) resulting from renal ablation were ameliorated significantly with melatonin treatment. In conclusion, melatonin administration improves the course of chronic renal failure in rats with renal mass reduction. Further studies are necessary to define the potential usefulness of this treatment in other animal models and in patients with chronic renal disease.

  4. The Coadministration of Unoxidized and Oxidized Desi Ghee Ameliorates the Toxic Effects of Thermally Oxidized Ghee in Rabbits

    PubMed Central

    Uddin, Islam

    2017-01-01

    Desi Ghee was thermally oxidized at 160°C for 9 h and characterized for peroxide value (PV), free fatty acid (FFA), thiobarbituric acid reactive substances (TBARS), radical scavenging activity (RSA), and fatty acid and cholesterol composition using GC-MS. Oxidized (OG) and normal ghee (NG) were fed to rabbits in different doses. Blood was collected for hematology and biochemical analyses after 7 and 14 days. The oxidation of desi ghee increased the PV, FFA, and TBARS values and showed a decline in the RSA values. GC-MS revealed that desi ghee was rich in saturated fatty acids (55.9 g/100 g) and significant amounts of oleic acid (26.2 g/100 g). The OG significantly decreased the body weight, which was normalized by the coadministration of NG. Serum lipid profile showed a dose dependent increase in total cholesterol, triglycerides, and low density lipoproteins (LDL) and decrease in RBCs count, hematocrit, glucose, and hemoglobin concentration with OG feeding. These parameters were normalized by coadministration of NG. Liver histopathology of OG fed groups showed bile duct dilation and necrotic changes, while normal architecture showed in NG groups, compared to control. These results indicate that NG has no significant effect on rabbits comparing with OG and that it was beneficial when coadministered with oxidized ghee. PMID:28299204

  5. Pyrroloquinoline quinone-secreting probiotic Escherichia coli Nissle 1917 ameliorates ethanol-induced oxidative damage and hyperlipidemia in rats.

    PubMed

    Singh, Ashish K; Pandey, Sumeet K; Naresh Kumar, Gattupalli

    2014-07-01

    Chronic ethanol (EtOH) consumption is associated with oxidative tissue damage, decrease in antioxidant enzyme activities, and increase in hepatic and plasma lipids. This study investigates the effect of modified probiotic Escherichia coli Nissle 1917 (EcN) secreting pyrroloquinoline quinone (PQQ) against EtOH-induced metabolic disorder in rats. Male Charles Foster rats were gavaged with EtOH (5 g/kg body weight [acute study] and 3 g/kg body weight per day for 10 weeks [chronic study]). Pretreatment of PQQ, vitamin C, and PQQ-secreting EcN prevented acute EtOH-induced oxidative damage in rats reflected by reduced lipid peroxidation in blood and liver and increased hepatic reduced glutathione. However, PQQ given externally was found to be most effective against acute EtOH toxicity. In the chronic study, rats treated with PQQ-secreting EcN showed remarkable reduction in oxidative tissue damage (liver, colon, blood, and kidney) with significant increase in antioxidant enzyme activities as compared to only EtOH-treated rats. Additionally, these rats had significantly lowered hepatic and plasma lipid levels with concomitant reduction in mRNA expression of fatty acid synthase (0.5-fold) and increase in mRNA expression of acyl coenzyme A oxidase (2.4-fold) in hepatic tissue. Antioxidant and hyperlipidemic effects of PQQ-secreting EcN are correlated with increased colonic short chain fatty acids (SCFAs; i.e., acetate, propionate, and butyrate) levels, and PQQ concentration in fecal samples (2-fold) and liver (4-fold). Extracted PQQ and vitamin C were given once a week, but they did not exhibit any ameliorative effect against chronic EtOH toxicity. Accumulated PQQ in tissues prevents hepatic and systemic oxidative damage. PQQ along with SCFAs reduced hyperlipidemia, which can be correlated with changes in mRNA expression of hepatic lipid metabolizing genes. Our study suggests that endogenous generation of PQQ by EcN could be an effective strategy in preventing alcoholic

  6. Myocardial ischemia results in tetrahydrobiopterin (BH4) oxidation with impaired endothelial function ameliorated by BH4

    PubMed Central

    Dumitrescu, Cristian; Biondi, Roberto; Xia, Yong; Cardounel, Arturo J.; Druhan, Lawrence J.; Ambrosio, Giuseppe; Zweier, Jay L.

    2007-01-01

    Coronary vasodilation is impaired in the postischemic heart with a loss of endothelial nitric oxide synthase (eNOS) activity, but the mechanisms underlying ischemia-induced eNOS dysfunction are not understood. For nitric oxide (NO) synthesis, eNOS requires the redox-sensitive cofactor tetrahydrobiopterin (BH4); however, the role of BH4 in ischemia-induced endothelial dysfunction remains unknown. Therefore, isolated rat hearts were subjected to varying durations of ischemia, and the alterations in NOS-dependent vasodilation were measured and correlated with assays of eNOS activity and cardiac BH4 concentrations. Ischemia time-dependently decreased cardiac BH4 content with 85, 95, or 97% irreversible degradation after 30, 45, or 60 min of ischemia, respectively. Paralleling the decreases in BH4, reductions of eNOS activity were seen of 58, 86, or 92%, and NOS-derived superoxide production was greatly increased. Addition of 10 μM BH4 enhanced eNOS activity in nonischemic hearts and partially restored activity after ischemia. It also suppressed NOS-derived superoxide production. Impaired coronary flow during postischemic reperfusion was improved by BH4 infusion. Thus, BH4 depletion contributes to postischemic eNOS dysfunction, and BH4 treatment is effective in partial restoration of endothelium-dependent coronary flow. Supplementation of BH4 may therefore be an important therapeutic approach to reverse endothelial dysfunction in postischemic tissues. PMID:17848522

  7. Ameliorative effect of aspalathin from rooibos (Aspalathus linearis) on acute oxidative stress in Caenorhabditis elegans.

    PubMed

    Chen, Wei; Sudji, Ikhwan Resmala; Wang, Erjia; Joubert, Elizabeth; van Wyk, Ben-Erik; Wink, Michael

    2013-02-15

    Rooibos leaves and fine stems (Aspalathus linearis; Fabaceae) are increasingly enjoyed as herbal tea, largely in fermented (oxidised) red-brown form, but also in unfermented (unoxidised) green form. Rooibos is rich in antioxidant polyphenols, with the dihydrochalcone, aspalathin, as a major active ingredient. We used Caenorhabditis elegans as model organism to investigate the effect of rooibos extracts against oxidative stress in vivo. In a high glucose environment, C. elegans treated with rooibos extract exhibited an extended lifespan. Furthermore, green rooibos was a more potent antioxidant than red rooibos, probably due to its substantially higher aspalathin content. In addition, rooibos decreased acute oxidative damage caused by the superoxide anion radical generator, juglone, with aspalathin playing a major role in improving the survival rate of C. elegans. Quantitative real-time PCR results demonstrated that aspalathin targets stress and ageing related genes, reducing the endogenous intracellular level of ROS. These findings suggest that rooibos increases stress resistance and promotes longevity under stress, probably mediated via a regulation of the DAF-16/FOXO insulin-like signalling pathway, supporting some of the health claims put forward for rooibos tea.

  8. Amelioration of Isoproterenol-Induced Oxidative Damage in Rat Myocardium by Withania somnifera Leaf Extract

    PubMed Central

    Khalil, Md. Ibrahim; Ahmmed, Istiyak; Ahmed, Romana; Tanvir, E. M.; Afroz, Rizwana; Paul, Sudip; Gan, Siew Hua; Alam, Nadia

    2015-01-01

    We investigated the protective role of Withania somnifera leaf extract (WSLEt) on isoproterenol- (ISO-) induced myocardial infarction (MI) in rats. Subcutaneous injection of ISO (85 mg/kg body weight (b.w.)) administered to rats for two consecutive days caused a significant increase in cardiac troponin I (cTnI) levels and serum lipid profiles, as well as the activities of some marker enzymes. In addition to these diagnostic markers, there were increased levels of lipid peroxidation (LPO) and decreased activities of enzymatic antioxidants (superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GRx), and glutathione-S-transferase (GST)) in the myocardium. However, oral pretreatment (100 mg/kg b.w.) with WSLEt for 4 weeks elicited a significant cardioprotective activity by lowering the levels of cTnI, lipid profiles, and marker enzymes. The levels of LPO products were also significantly decreased. Elevated activities of antioxidant enzymes were also observed in rats pretreated with WSLEt. As further confirmed histopathologically, our findings strongly suggest that the cardioprotective effect of WSLEt on myocardium experiencing ISO-induced oxidative damage may be due to an augmentation of the endogenous antioxidant system and an inhibition of LPO in the myocardial membrane. We conclude that WSLEt confers some protection against oxidative damage in ISO-induced MI in rats. PMID:26539517

  9. High amylose resistant starch diet ameliorates oxidative stress, inflammation, and progression of chronic kidney disease.

    PubMed

    Vaziri, Nosratola D; Liu, Shu-Man; Lau, Wei Ling; Khazaeli, Mahyar; Nazertehrani, Sohrab; Farzaneh, Seyed H; Kieffer, Dorothy A; Adams, Sean H; Martin, Roy J

    2014-01-01

    Inflammation is a major mediator of CKD progression and is partly driven by altered gut microbiome and intestinal barrier disruption, events which are caused by: urea influx in the intestine resulting in dominance of urease-possessing bacteria; disruption of epithelial barrier by urea-derived ammonia leading to endotoxemia and bacterial translocation; and restriction of potassium-rich fruits and vegetables which are common sources of fermentable fiber. Restriction of these foods leads to depletion of bacteria that convert indigestible carbohydrates to short chain fatty acids which are important nutrients for colonocytes and regulatory T lymphocytes. We hypothesized that a high resistant starch diet attenuates CKD progression. Male Sprague Dawley rats were fed a chow containing 0.7% adenine for 2 weeks to induce CKD. Rats were then fed diets supplemented with amylopectin (low-fiber control) or high fermentable fiber (amylose maize resistant starch, HAM-RS2) for 3 weeks. CKD rats consuming low fiber diet exhibited reduced creatinine clearance, interstitial fibrosis, inflammation, tubular damage, activation of NFkB, upregulation of pro-inflammatory, pro-oxidant, and pro-fibrotic molecules; impaired Nrf2 activity, down-regulation of antioxidant enzymes, and disruption of colonic epithelial tight junction. The high resistant starch diet significantly attenuated these abnormalities. Thus high resistant starch diet retards CKD progression and attenuates oxidative stress and inflammation in rats. Future studies are needed to explore the impact of HAM-RS2 in CKD patients.

  10. Benzothiazole Amphiphiles Ameliorate Amyloid β-Related Cell Toxicity and Oxidative Stress.

    PubMed

    Cifelli, Jessica L; Chung, Tim S; Liu, Haiyan; Prangkio, Panchika; Mayer, Michael; Yang, Jerry

    2016-06-15

    Oxidative stress from the increase of reactive oxygen species in cells is a common part of the normal aging process and is accelerated in patients with Alzheimer's disease (AD). Herein, we report the evaluation of three benzothiazole amphiphiles (BAMs) that exhibit improved biocompatibility without loss of biological activity against amyloid-β induced cell damage compared to a previously reported hexa(ethylene glycol) derivative of benzothiazole aniline (BTA-EG6). The reduced toxicity of these BAM agents compared to BTA-EG6 corresponded with their reduced propensity to induce membrane lysis. In addition, all of the new BAMs were capable of protecting differentiated SH-SY5Y neuroblastoma cells from toxicity and concomitant oxidative stress induced by AD-related aggregated Aβ (1-42) peptides. Binding and microscopy studies support that these BAM agents target Aβ and inhibit the interactions of catalase with Aβ in cells, which, in turn, can account for an observed inhibition of Aβ-induced increases in hydrogen peroxide in cells treated with these compounds. These results support that this family of benzothiazole amphiphiles may have therapeutic potential for treating cellular damage associated with AD and other Aβ-related neurologic diseases.

  11. A Beverage Containing Fermented Black Soybean Ameliorates Ferric Nitrilotriacetate-Induced Renal Oxidative Damage in Rats

    PubMed Central

    Okazaki, Yasumasa; Iqbal, Mohammad; Kawakami, Norito; Yamamoto, Yorihiro; Toyokuni, Shinya; Okada, Shigeru

    2010-01-01

    It is beneficial to seek scientific basis for the effects of functional foods. Natural pigments derived from plants are widely known as possible antioxidants. Black soybean contains a larger amount of anthocyanins than regular soybean. Here we studied the antioxidative effect of a beverage obtained via citric acid fermentation of black soybean (BBS), using a rat model of renal oxidative injury induced by a renal carcinogen, ferric nitrilotriacetate. BBS (10 ml/kg) was orally administered 30 min before ferric nitrilotriacetate treatment. Renal lipid peroxidation was significantly suppressed in the BBS-pretreated animals concomitant with decrease in 4-hydroxy-2-nonenal-modified proteins and 8-hydroxy-2'-deoxyguanosine. Maintenance of renal activities of antioxidative enzymes including catalase, glutathione peroxidase, glutathione reductase, glutathione S-transferase, glucose-6-phosphate dehydrogenase and quinone reductase was significantly better in the BBS-pretreated rats. Elevation of serum creatinine and urea nitrogen was significantly suppressed in the BBS-pretreated rats. These data suggest that dietary intake of BBS is useful for the prevention of renal tubular oxidative damage mediate by iron, and warrant further investigation. PMID:21103028

  12. Partial IGF-1 deficiency induces brain oxidative damage and edema, which are ameliorated by replacement therapy.

    PubMed

    Puche, Juan E; Muñoz, Úrsula; García-Magariño, Mariano; Sádaba, María C; Castilla-Cortázar, Inma

    2016-01-01

    Insulin-like growth factor 1 (IGF-1) induces multiple cytoprotective effects on every tissue, including the brain. Since the mechanisms by which IGF-1 produces neuroprotection are not fully understood, the aim of this work was to delve into the underlying mechanisms. IGF-1 deficient mice (Hz) were compared with wild type (WT) and Hz mice treated with low doses of IGF-1 (2 µg/100 g body weight/day) for 10 days (Hz + IGF). Gene expression, quantitative PCR, histology, and magnetic resonance imaging were performed in the three groups. IGF-1 deficiency induced increased oxidative damage determined by markers of lipid peroxidation and hypoxia, as well as gene expression of heat shock proteins, antioxidant enzymes, and molecules involved in inflammation, apoptosis, and mitochondrial protection. These changes correlated with edema and learning impairment in Hz mice. IGF-1 therapy improved all these alterations. In conclusion, IGF-1 deficiency is responsible for increased brain oxidative damage, edema, and impaired learning and memory capabilities which are rescued by IGF-1 replacement therapy. © 2016 International Union of Biochemistry and Molecular Biology.

  13. Chlorogenic acid ameliorates endotoxin-induced liver injury by promoting mitochondrial oxidative phosphorylation

    SciTech Connect

    Zhou, Yan; Ruan, Zheng; Zhou, Lili; Shu, Xugang; Sun, Xiaohong; Mi, Shumei; Yang, Yuhui; Yin, Yulong

    2016-01-22

    Acute or chronic hepatic injury is a common pathology worldwide. Mitochondrial dysfunction and the depletion of adenosine triphosphate (ATP) play important roles in liver injury. Chlorogenic acids (CGA) are some of the most abundant phenolic acids in human diet. This study was designed to test the hypothesis that CGA may protect against chronic lipopolysaccharide (LPS)-induced liver injury by modulating mitochondrial energy generation. CGA decreased the activities of serum alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase. The contents of ATP and adenosine monophosphate (AMP), as well as the ratio of AMP/ATP, were increased after CGA supplementation. The activities of enzymes that are involved in glycolysis were reduced, while those of enzymes involved in oxidative phosphorylation were increased. Moreover, phosphorylated AMP-activated protein kinase (AMPK), and mRNA levels of AMPK-α, peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α), nuclear respiratory factor 1, and mitochondrial DNA transcription factor A were increased after CGA supplementation. Collectively, these findings suggest that the hepatoprotective effect of CGA might be associated with enhanced ATP production, the stimulation of mitochondrial oxidative phosphorylation and the inhibition of glycolysis. - Highlights: • Dietary supplementation with chlorogenic acid (CGA) improved endotoxin-induced liver injury. • Chlorogenic acid enhances ATP increase and shifts energy metabolism, which is correlated with up-regulation AMPK and PGC-1α. • The possible mechanism of CGA on mitochondrial biogenesis was correlated with up-regulation AMPK and PGC-1α.

  14. Melatonin administration ameliorates cadmium-induced oxidative stress and morphological changes in the liver of rat.

    PubMed

    El-Sokkary, Gamal H; Nafady, Allam A; Shabash, Elhammaly H

    2010-03-01

    The oxidative status and the morphological changes of liver of rats exposed to cadmium (5 mg Cd/kg body weight subcutaneously) for 22 days and the protective role of melatonin (10mg/kg b.w.) against the toxicity of cadmium was studied. The concentration of malondialdehyde (MDA), as an indicator of lipid peroxidation, activity of the antioxidant enzyme superoxide dismutase (SOD) as well as the concentration of glutathione (GSH) was measured in the liver. The morphological changes were investigated using both light and electron microscopes. The exposure to Cd led to an increase of MDA levels and a decrease of both the activity of SOD and GSH concentration in the liver. In contrast, melatonin administration restored the previous changes to nearly the normal levels. Morphologically, Cd led to different histopathological changes such as loss of normal architecture of the parenchymatous tissue, cytoplasmic vacuolization, cellular degeneration and necrosis, congested blood vessels, destructed cristae mitochondria, fat globules, severe glycogen depletion, lipofuscin pigments, and collagenous fibers formation. Again, melatonin administration counteracts all changes and the tissue appears more or less normal. The rate of recovery was faster when melatonin was administered for treatment after the exposure to cadmium than if the animals left without any treatment. The results suggest that melatonin may be useful as an antioxidant in combating free radical-induced oxidative stress and tissue injury that is a result of cadmium toxicity. (c) 2009 Elsevier Inc. All rights reserved.

  15. Exposure to Zinc Oxide Nanoparticles Induces Neurotoxicity and Proinflammatory Response: Amelioration by Hesperidin.

    PubMed

    Ansar, Sabah; Abudawood, Manal; Hamed, Sherifa Shaker; Aleem, Mukhtar M

    2017-02-01

    Zinc oxide nanoparticles (ZnONPs) are widely used in food packaging and may enter the body directly if exposed. Hereby, in this study, the oral administration was selected as the route of exposure for rats to nanoparticles and the effect of hesperidin (HSP, 100 mg/kg bwt) was evaluated on ZnONP (600 mg/kg bwt)-induced neurotoxicity in rats. ZnONPs were characterized using transmission electron microscopy. Neurotoxicity was observed as seen by elevation in serum inflammatory markers including tumor necrosis factor alpha (TNF-α), interleukin 1 (IL-1β), interleukin-6 (IL-6), C-reactive protein (CRP), and activities of catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione (GSH) content in rat brains. Pretreatment of rats with HSP in ZnONP-treated group elevated activities of antioxidant enzymes. HSP also caused decrease in TNF-α, IL-1β, IL-6, and CRP levels which was higher in the ZnONP-treated group. The results suggest that HSP augments antioxidant defense with anti-inflammatory response against ZnONP-induced neurotoxicity. The increased antioxidant enzymes enhance the antioxidant potential to reduce oxidative stress.

  16. Resveratrol ameliorates the oxidative damage induced by arsenic trioxide in the feline lung.

    PubMed

    Cheng, Yanyan; Xue, Jiangdong; Yao, Chunyu; Gao, Li; Ma, Dexing; Liu, Yan; Zhang, Zhigang

    2013-01-01

    The objective of this study was to evaluate the possible protection of resveratrol against lung injury induced by arsenic trioxide (As2O3). Twenty-four healthy Chinese Dragon Li cats of either sex were randomly divided into four groups: control (1 ml/kg physiological saline), As2O3 (1 mg/kg), resveratrol (3 mg/kg) and resveratrol (3 mg/kg) + As2O3 (1 mg/kg). The resveratrol + As2O3- treated group was given resveratrol 1 hr before As2O3 (1 mg/kg) administration. We found that pretreatment with resveratrol in a clinically comparable dose regimen can reversed the changes in morphological and biochemical parameters induced by As2O3 in the lung. Resveratrol treatment also upregulated the activities of antioxidant enzymes and attenuated As2O3-induced increases in reactive oxygen species, 8-hydroxydeoxyguanosine and malondialdehyde production in the lung. In addition, resveratrol attenuated the As2O3-induced reduction in the ratio of reduced glutathione to oxidized glutathione, the content of total glutathione and lung arsenic burden. These findings indicated that resveratrol can provide significant protection against As2O3-induced oxidative damage.

  17. The Leaf of Diospyros kaki Thumb Ameliorates Renal Oxidative Damage in Mice with Type 2 Diabetes

    PubMed Central

    Choi, Myung-Sook; Jeong, Mi Ji; Park, Yong Bok; Kim, Sang Ryong; Jung, Un Ju

    2016-01-01

    Diabetic kidney disease is the most common and severe chronic complication of diabetes. The leaf of Diospyros kaki Thumb (persimmon) has been commonly used for herbal tea and medicinal purposes to treat a variety of conditions, including hypertension and atherosclerosis. However, the effect of persimmon leaf on kidney failure has not been investigated. This study aimed to examine the role of persimmon leaf in protecting the diabetes-associated kidney damage in a mouse model of type 2 diabetes. Mice were fed either a normal chow diet with or without powered persimmon leaf (5%, w/w) for 5 weeks. In addition to kidney morphology and blood markers of kidney function, we assessed levels of oxidative stress markers as well as antioxidant enzymes activities and mRNA expression in the kidney. Supplementation of the diet with powered persimmon leaf not only decreased the concentration of blood urea nitrogen in the plasma but also improved glomerular hypertrophy. Furthermore, the persimmon leaf significantly decreased the levels of hydrogen peroxide and lipid peroxide in the kidney. The activities of superoxide dismutase, catalase, and glutathione peroxidase and the mRNA expression of their respective genes were also increased in the kidney of persimmon leaf-supplemented db/db mice. Taken together, these results suggest that supplementation with the persimmon leaf may have protective effects against type 2 diabetes-induced kidney dysfunction and oxidative stress. PMID:28078262

  18. The Leaf of Diospyros kaki Thumb Ameliorates Renal Oxidative Damage in Mice with Type 2 Diabetes.

    PubMed

    Choi, Myung-Sook; Jeong, Mi Ji; Park, Yong Bok; Kim, Sang Ryong; Jung, Un Ju

    2016-12-01

    Diabetic kidney disease is the most common and severe chronic complication of diabetes. The leaf of Diospyros kaki Thumb (persimmon) has been commonly used for herbal tea and medicinal purposes to treat a variety of conditions, including hypertension and atherosclerosis. However, the effect of persimmon leaf on kidney failure has not been investigated. This study aimed to examine the role of persimmon leaf in protecting the diabetes-associated kidney damage in a mouse model of type 2 diabetes. Mice were fed either a normal chow diet with or without powered persimmon leaf (5%, w/w) for 5 weeks. In addition to kidney morphology and blood markers of kidney function, we assessed levels of oxidative stress markers as well as antioxidant enzymes activities and mRNA expression in the kidney. Supplementation of the diet with powered persimmon leaf not only decreased the concentration of blood urea nitrogen in the plasma but also improved glomerular hypertrophy. Furthermore, the persimmon leaf significantly decreased the levels of hydrogen peroxide and lipid peroxide in the kidney. The activities of superoxide dismutase, catalase, and glutathione peroxidase and the mRNA expression of their respective genes were also increased in the kidney of persimmon leaf-supplemented db/db mice. Taken together, these results suggest that supplementation with the persimmon leaf may have protective effects against type 2 diabetes-induced kidney dysfunction and oxidative stress.

  19. Resveratrol ameliorates oxidative stress and organ dysfunction in Schistosoma mansoni infected mice.

    PubMed

    Soliman, R H; Ismail, O A; Badr, M S; Nasr, S M

    2017-03-01

    Schistosoma mansoni causes a major chronic debilitating disease in more than 230 million people around the world. The pathognomonic granuloma is a major cause of the oxidative stress encountered as a consequence of infection not only in the liver, but also in other important organs as spleen, lung, brain and kidney. Resveratrol administration at a dose of 20 mg/kg once daily for two weeks to mice infected with Schistosoma mansoni resulted in improvement in serum cholesterol and triglyceride levels. Enzymatic antioxidant profile showed significant modulations in Superoxide dismutase, catalase activities and reduced glutathione levels. Specific biomarkers for homeostasis of brain and lung i.e. Tau and RAGE respectively, showed significant improvement after resveratrol administration.

  20. Ukrain (NSC 631570) ameliorates intestinal ischemia-reperfusion-induced acute lung injury by reducing oxidative stress

    PubMed Central

    Kocak, Cengiz; Kocak, Fatma Emel; Akcilar, Raziye; Akcilar, Aydin; Savran, Bircan; Zeren, Sezgin; Bayhan, Zulfu; Bayat, Zeynep

    2016-01-01

    Intestinal ischemia-reperfusion (I/R) causes severe destruction in remote organs. Lung damage is a frequently seen complication after intestinal I/R. Ukrain (NSC 631570) is a synthetic thiophosphate derivative of alkaloids from the extract of the celandine (Chelidonium majus L.) plant. We investigated the effect of Ukrain in animals with lung injury induced by intestinal I/R. Adult male Spraque-Dawley rats were randomly divided into four groups: control, Ukrain, I/R, I/R with Ukrain. Before intestinal I/R was induced, Ukrain was administered intraperitoneally at a dose of 7.0 mg/body weight. After 1 h ischemia and 2 h reperfusion period, lung tissues were excised. Tissue levels of total oxidative status (TOS), total antioxidant status (TAS) were measured and oxidative stress indices (OSI) were calculated. Lung tissues were also examined histopathologically. TOS and OSI levels markedly increased and TAS levels decreased in the I/R group compared to the control group (P < 0.05). TOS and OSI levels markedly decreased and TAS levels increased in the I/R with Ukrain group compared with the group subjected to IR only (P < 0.05). Severe hemorrhage, alveolar septal thickening, and leukocyte infiltration were observed in the I/R group. In the I/R with Ukrain group, morphologic changes occurring as a result of lung damage attenuated and histopathological scores reduced compared to the I/R group (P < 0.05). Our results suggest that Ukrain pretreatment could reduce lung injury induced by intestinal I/R induced via anti-inflammatory and antioxidant effects. PMID:26773189

  1. Calcium, zinc and vitamin E ameliorate cadmium-induced renal oxidative damage in albino Wistar rats.

    PubMed

    Adi, Pradeepkiran Jangampalli; Burra, Siva Prasad; Vataparti, Amardev Rajesh; Matcha, Bhaskar

    2016-01-01

    This study was aimed to examine the protective effects of supplementation with calcium + zinc (Ca + Zn) or vitamin E (Vit-E) on Cd-induced renal oxidative damage. Young albino Wistar rats (180 ± 10 g) (n = 6) control rats, Cd, Cd + Ca + Zn, and Cd + Vit-E experimental groups and the experimental period was 30 days. Rats were exposed to Cd (20 mg/kg body weight) alone treated as Cd treated group and the absence or presence of Ca + Zn (2 mg/kg each) or Vit-E (20 mg/kg body weight) supplementation treated as two separate groups. The activities of the stress marker enzymes superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and lipid peroxidase (LPx) were determined in renal mitochondrial fractions of experimental rats. We observed quantitative changes in SOD isoenzymatic patterns by non-denaturing PAGE analysis, and quantified band densities. These results showed that Cd exposure leads to decreases in SOD, CAT, GR, and GPx activities and a concomitant increase in LPx and GST activities. Ca + Zn and Vit-E administration with Cd significantly reversed Cd-induced perturbations in oxidative stress marker enzymes. However, Vit-E showed more inhibitory activity against Cd than did Ca + Zn, and it protected against Cd-induced nephrotoxicity.

  2. Telmisartan ameliorates experimental autoimmune myocarditis associated with inhibition of inflammation and oxidative stress.

    PubMed

    Sukumaran, Vijayakumar; Watanabe, Kenichi; Veeraveedu, Punniyakoti T; Ma, Meilei; Gurusamy, Narasimman; Rajavel, Varatharajan; Suzuki, Kenji; Yamaguchi, Ken'ichi; Kodama, Makoto; Aizawa, Yoshifusa

    2011-02-10

    Excess cytokine produced by inflammatory stimuli contributes to the progression of myocardial damage in myocarditis. Angiotensin-II has been shown to play a pivotal role in the pathophysiology of various organs, especially the cardiovascular system. Some angiotensin II type 1 receptor antagonists are reported to inhibit proinflammatory cytokine production in vitro and in vivo. We investigated whether telmisartan, an angiotensin II type 1 receptor antagonist protects against experimental autoimmune myocarditis by suppression of inflammatory cytokines and oxidative stress. Experimental autoimmune myocarditis was induced in Lewis rats by immunization with porcine cardiac myosin. The rats were divided into two groups and treated with either telmisartan (10mg/kg/day) or vehicle for 21days. Age-matched normal rats without immunization were also included in this study. Myocardial functional parameters were significantly improved by treatment with telmisartan compared with vehicle-treated rats. Increased myocardial mRNA expressions of inflammatory cytokines [interleukin (IL-6), IL-1β, tumor necrosis factor-α and interferon-γ] were also suppressed by telmisartan treatment compared with vehicle-treated rats. Myocardial protein expressions of NADPH oxidase subunits p47phox, Nox-4, and gp91phox, myocardial levels of 8-hydroxydeoxyguanosine and 4-hydroxy-2-nonenal, and myocardial apoptosis were also significantly decreased by telmisartan treatment compared with vehicle-treated rats. Further, telmisartan significantly decreased endoplasmic reticulum stress markers in experimental autoimmune myocarditis rats. These findings suggest that telmisartan protects against experimental autoimmune myocarditis in rats, at least in part by suppressing inflammatory cytokines and oxidative stress; however, further investigations are needed before clinical use. 2010 Elsevier B.V. All rights reserved.

  3. Andrographis paniculata ameliorates carbon tetrachloride (CCl(4))-dependent hepatic damage and toxicity: diminution of oxidative stress.

    PubMed

    Koh, Pei Hoon; Mokhtar, Ruzaidi Azli Mohd; Iqbal, Mohammad

    2011-01-01

    Andrographis paniculata (hempedu bumi) is a plant that possesses many medicinal values in treating several diseases and for health care maintenance. However, its hepatoprotective activity and mechanism of action have not been fully investigated. Therefore, this study aimed to evaluate the hepatoprotective effects of A. paniculata and its mechanism of action in rats. Carbon tetrachloride (CCl(4)) challenge of rats at a dose of 1.2 ml/kg body weight-induced oxidative stress in the liver. This was evidenced by augmentation in lipid peroxidation, which was accompanied by a decrease in the activities of antioxidant enzymes and depletion in the level of reduced glutathione (P < 0.05). Parrallel to these changes, CCl(4) challenge too, enhanced hepatic damage as evidenced by sharp increase in serum transaminases (e.g. alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase) (P < 0.05). Additionally, the impairment of liver function corresponded to histolopathological changes. However, most of these changes were reversed in a dose-dependent fashion by pre-treatment of animals with A. paniculata (P < 0.05). The ability of A. paniculata to scavenge the 2,2-Diphenyl-2-picrylhydrazyl radical was determined through its EC(50) value. The EC(50) value of A. paniculata was 583.60 ± 4.25 µg/ml. In addition, A. paniculata was found to contain 65.37 ± 1.20 mg/g total phenolics expressed as gallic acid equivalent. From these studies, it is concluded that A. paniculata could be used as a hepatoprotective agent and possesses the potential to treat or prevent degenerative diseases where oxidative stress is implicated.

  4. PAC1 and PACAP expression, signaling, and effect on the growth of HCT8, human colonic tumor cells.

    PubMed

    Le, Sang V; Yamaguchi, Dean J; McArdle, Craig A; Tachiki, Ken; Pisegna, Joseph R; Germano, Patrizia

    2002-11-15

    The pituitary adenylate cyclase-activating polypeptide (PACAP) type 1 receptor (PAC1) is a heptahelical, G protein-coupled receptor that has been shown to be expressed by non-squamous lung cancer and breast cancer cell lines, and to be coupled to the growth of these tumors. We have previously shown that PACAP and its receptor, PAC1, are expressed in rat colonic tissue. In this study, we used polyclonal antibodies directed against the COOH terminal of PAC1, as well as fluorescently labeled PACAP, Fluor-PACAP, to demonstrate the expression of PAC1 on HCT8 human colonic tumor cells, using FACS analysis and confocal laser scanning microscopy. Similarly, anti-PACAP polyclonal antibodies were used to confirm the expression of PACAP hormone by this cell line. We then investigated the signal transduction properties of PAC1 in these tumor cells. PACAP-38 elevated intracellular cAMP levels in a dose-dependent manner, with a half-maximal (EC(50)) stimulation of approximately 3 nM. In addition, PACAP-38 stimulation caused an increase in cytosolic Ca(2+) concentration [Ca(2+)](i), which was partially inhibited by the PACAP antagonist, PACAP-(6-38). Finally, we studied the potential role of PACAP upon the growth of these tumor cells. We found that PACAP-38, but not VIP, increased the number of viable HCT8 cells, as measured by MTT activity. We also demonstrated that HCT8 cells expressed the Fas receptor (Fas-R/CD95), which was subsequently down-regulated upon activation with PACAP-38, further suggesting a possible role for PACAP in the growth and survival of these tumor cells. These data indicate that HCT8 human colon tumor cells express PAC1 and produce PACAP hormone. Furthermore, PAC1 activation is coupled to adenylate cyclase, increase cytosolic [Ca(2+)](i), and cellular proliferation. Therefore, PACAP is capable of increasing the number of viable cells and regulating Fas-R expression in a human colonic cancer cell line, suggesting that PACAP might play a role in the

  5. Defatted Soy Flour Supplementation of Wheat Bread ameliorates Blood Chemistry and Oxidative Stress in Wistar rats.

    PubMed

    Ebuehi, O A T; Okafor, H K

    2015-01-01

    Bread is a convenience food made from wheat flour, which is derived from wheat and whose technology of which dates back to the ancient Egyptians. It is therefore of economic advantage if wheat importation to Nigeria can be reduced by substitution with other suitable materials. This led to the whole idea of composite flour, which is a mixture of wheat with other materials to form suitable flour for baking'purposes. The study is to ascertain the effect of supplementation of bread with defatted soy flour on blood chemistry and oxidative stress in Wistar rats. Wheat flour mixed with high quality defatted Soy flour at several ratios: 90:10, 80:20, 70:30, and 60:40. The 90:10, 80:20, 70:30, and 60:40 flour mixtures were used to prepare 10%, 20%, 30%, and 40% Soya bread, respectively. The control bread (100%) was prepared with 100% wheat flour. Bread produced with these blends compared with regular 100% wheat bread and was tested for chemical and. organoleptic characteristics. Sixteen rats were randomly given codes and allocated to 2 different groups via tables with random numbers to feed on the 100% wheat blend and soy supplemented bread (90% wheat flour/10% soy flour) for 28 days. The weights and feedintake of the rats were computed on dailybasis. Blood was taken for biochemical assays and liver was used for antioxidant assay, that is activities of catalase, super oxider dismutase (SOD) and reduced glutathine level. The activities of serum SOD and catalase were significantly increase (p<0.05) in rats fed the composite bread as compared to the control, (wheat bread) and a significant decrease (p<0.05) in lipid peroxidation marker (malondialdehyde level) relative to control group. The activities of the liver enzymes (alanine amino transferase, aspartase amino transferase and alkaline phosphatase) and markers (low density lipoprotein, cholesterol and triacyl glycerol levels) showed significant decrease (p<0.05) in rats fed supplemented soy flour bread as compared to the

  6. Water Spinach, Ipomoea aquatica (Convolvulaceae), Ameliorates Lead Toxicity by Inhibiting Oxidative Stress and Apoptosis

    PubMed Central

    Dewanjee, Saikat; Dua, Tarun K.; Khanra, Ritu; Das, Shilpa; Barma, Sujata; Joardar, Swarnalata; Bhattacharjee, Niloy; Zia-Ul-Haq, M.; Jaafar, Hawa Z. E.

    2015-01-01

    Background Ipomoea aquatica (Convolvulaceae), an aquatic edible plant, is traditionally used against heavy metal toxicity in India. The current study intended to explore the protective role of edible (aqueous) extract of I. aquatica (AEIA) against experimentally induced Pb-intoxication. Methods The cytoprotective role of AEIA was measured on mouse hepatocytes by cell viability assay followed by Hoechst staining and flow cytometric assay. The effect on ROS production, lipid peroxidation, protein carbonylation, intracellular redox status were measured after incubating the hepatocytes with Pb-acetate (6.8 μM) along with AEIA (400 μg/ml). The effects on the expressions of apoptotic signal proteins were estimated by western blotting. The protective role of AEIA was measured by in vivo assay in mice. Haematological, serum biochemical, tissue redox status, Pb bioaccumulation and histological parameters were evaluated to estimate the protective role of AEIA (100 mg/kg) against Pb-acetate (5 mg/kg) intoxication. Results Pb-acetate treated hepatocytes showed a gradual reduction of cell viability dose-dependently with an IC50 value of 6.8 μM. Pb-acetate treated hepatocytes exhibited significantly enhanced levels (p < 0.01) of ROS production, lipid peroxidation, protein carbonylation with concomitant depletion (p < 0.01) of antioxidant enzymes and GSH. However, AEIA treatment could significantly restore the aforementioned parameters in murine hepatocytes near to normalcy. Besides, AEIA significantly reversed (p < 0.05–0.01) the alterations of transcription levels of apoptotic proteins viz. Bcl 2, Bad, Cyt C, Apaf-1, cleaved caspases [caspase 3, caspase 8 and caspase 9], Fas and Bid. In in vivo bioassay, Pb-acetate treatment caused significantly high intracellular Pb burden and oxidative pressure in the kidney, liver, heart, brain and testes in mice. In addition, the haematological and serum biochemical factors were changed significantly in Pb-acetate-treated animals. AEIA

  7. Water Spinach, Ipomoea aquatic (Convolvulaceae), Ameliorates Lead Toxicity by Inhibiting Oxidative Stress and Apoptosis.

    PubMed

    Dewanjee, Saikat; Dua, Tarun K; Khanra, Ritu; Das, Shilpa; Barma, Sujata; Joardar, Swarnalata; Bhattacharjee, Niloy; Zia-Ul-Haq, M; Jaafar, Hawa Z E

    2015-01-01

    Ipomoea aquatica (Convolvulaceae), an aquatic edible plant, is traditionally used against heavy metal toxicity in India. The current study intended to explore the protective role of edible (aqueous) extract of I. aquatica (AEIA) against experimentally induced Pb-intoxication. The cytoprotective role of AEIA was measured on mouse hepatocytes by cell viability assay followed by Hoechst staining and flow cytometric assay. The effect on ROS production, lipid peroxidation, protein carbonylation, intracellular redox status were measured after incubating the hepatocytes with Pb-acetate (6.8 μM) along with AEIA (400 μg/ml). The effects on the expressions of apoptotic signal proteins were estimated by western blotting. The protective role of AEIA was measured by in vivo assay in mice. Haematological, serum biochemical, tissue redox status, Pb bioaccumulation and histological parameters were evaluated to estimate the protective role of AEIA (100 mg/kg) against Pb-acetate (5 mg/kg) intoxication. Pb-acetate treated hepatocytes showed a gradual reduction of cell viability dose-dependently with an IC50 value of 6.8 μM. Pb-acetate treated hepatocytes exhibited significantly enhanced levels (p < 0.01) of ROS production, lipid peroxidation, protein carbonylation with concomitant depletion (p < 0.01) of antioxidant enzymes and GSH. However, AEIA treatment could significantly restore the aforementioned parameters in murine hepatocytes near to normalcy. Besides, AEIA significantly reversed (p < 0.05-0.01) the alterations of transcription levels of apoptotic proteins viz. Bcl 2, Bad, Cyt C, Apaf-1, cleaved caspases [caspase 3, caspase 8 and caspase 9], Fas and Bid. In in vivo bioassay, Pb-acetate treatment caused significantly high intracellular Pb burden and oxidative pressure in the kidney, liver, heart, brain and testes in mice. In addition, the haematological and serum biochemical factors were changed significantly in Pb-acetate-treated animals. AEIA treatment restored

  8. Synergistic antioxidant action of vitamin E and rutin SNEDDS in ameliorating oxidative stress in a Parkinson’s disease model

    NASA Astrophysics Data System (ADS)

    Sharma, Shrestha; Narang, Jasjeet K.; Ali, Javed; Baboota, Sanjula

    2016-09-01

    in ameliorating oxidative stress in neurodegenerative disorders like Parkinson’s disease.

  9. Neuronal nitric oxide synthase-dependent amelioration of diastolic dysfunction in rats with chronic renocardiac syndrome.

    PubMed

    Bongartz, Lennart G; Soni, Siddarth; Cramer, Maarten-Jan; Steendijk, Paul; Gaillard, Carlo A J M; Verhaar, Marianne C; Doevendans, Pieter A; van Veen, Toon A; Joles, Jaap A; Braam, Branko

    2015-02-01

    We have recently described the chronic renocardiac syndrome (CRCS) in rats with renal failure, cardiac dysfunction and low nitric oxide (NO) availability by combining subtotal nephrectomy and transient low-dose NO synthase (NOS) inhibition. Cardiac gene expression of the neuronal isoform of NOS (nNOS) was induced. Hence, we studied the role of nNOS, in vivo cardiac function and β-adrenergic response in our CRCS model by micromanometer/conductance catheter. Left ventricular (LV) hemodynamics were studied during administration of dobutamine (dobu), the highly specific irreversible inhibitor of nNOS L-VNIO [L-N5-(1-Imino-3-butenyl)-ornithine], or both at steady state and during preload reduction. Rats with CRCS showed LV systolic dysfunction at baseline, together with prolonged diastolic relaxation and rightward shift of the end-systolic pressure-volume relationships. After L-VNIO infusion, diastolic relaxation of CRCS rats further prolonged. The time constant of active relaxation (tau) increased by 25 ± 6% from baseline (p < 0.05), and the maximal rate of pressure decrease was 36 ± 7% slower (p < 0.001). These variables did not change in controls. In our CRCS model, nNOS did not seem to affect systolic dysfunction. In summary, in this model of CRCS, blockade of nNOS further worsens diastolic dysfunction and L-VNIO does not influence inherent contractility and the response to dobu stress.

  10. Advent and recent advances in research on the role of pituitary adenylate cyclase-activating polypeptide (PACAP) in the regulation of gonadotropic hormone secretion of female rats.

    PubMed

    Köves, Katalin; Kántor, Orsolya; Lakatos, András; Szabó, Enikő; Kirilly, Eszter; Heinzlmann, Andrea; Szabó, Flóra

    2014-11-01

    PACAP (ADCYAP1) was isolated from ovine hypothalami. PACAP activates three distinct receptor types: G-protein coupled PAC1, VPAC1, and VPAC2 with seven transmembrane domains. Eight splice variants of PAC1 receptor are described. A part of the hypothalamic PACAP is released into the hypophyseal portal circulation. Both hypothalamic and pituitary PACAP are involved in the dynamic control of gonadotropic hormone secretion. In female rats, PACAP in the paraventricular nucleus is upregulated in the morning and pituitary PACAP is upregulated in the late evening of the proestrus stage of the reproductive cycle. PACAP mRNA peak in the hypothalamic PVN precedes the LHRH release into the portal circulation. It is supposed that PACAP peak is evoked by the elevated estrogen on proestrous morning. At the beginning of the so-called critical period of the same day, PACAP level starts to decline allowing LHRH release into the portal circulation, resulting in the LH surge that evokes ovulation. Just before the critical period, icv-administered exogenous PACAP blocks the LH surge and ovulation. The blocking effect of PACAP is mediated through CRF and endogenous opioids. The effect of the pituitary-born PACAP depends on the intracellular cross-talk between PACAP and LHRH.

  11. CRF mediates the anxiogenic and anti-rewarding, but not the anorectic effects of PACAP.

    PubMed

    Dore, Riccardo; Iemolo, Attilio; Smith, Karen L; Wang, Xiaofan; Cottone, Pietro; Sabino, Valentina

    2013-10-01

    Anxiety disorders represent the most common mental disturbances in the world, and they are characterized by an abnormal response to stress. Pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptor PAC1 have been proposed to have a key role in mediating the responses to stress as well as the regulation of food intake and body weight. Corticotropin-releasing factor (CRF), the major stress peptide in the brain, has been hypothesized to be involved in PACAP effects, but the reports are conflicting so far. The present study was aimed at further characterizing the behavioral effects of PACAP in rats and at determining the role of central CRF receptors. We found that intracerebroventricular PACAP treatment induced anxiety-like behavior in the elevated plus maze test and elevated intracranial self-stimulation thresholds; both of these effects were fully blocked by concurrent treatment with the CRF receptor antagonist D-Phe-CRF(12-41). Interestingly, the CRF antagonist had no effect on PACAP-induced increased plasma corticosterone, reduction of food intake, and body weight loss. Finally, we found that PACAP increased CRF levels in the paraventricular nucleus of the hypothalamus and, importantly, in the central nucleus of the amygdala, as measured by solid phase radioimmunoassay and quantitative real-time PCR. Our results strengthen the notion that PACAP is a strong mediator of the behavioral response to stress and prove for the first time that this neuropeptide has anti-rewarding (ie, pro-depressant) effects. In addition, we identified the mechanism by which PACAP exerts its anxiogenic and pro-depressant effects, via the recruitment of the central CRF system and independently from HPA axis activation.

  12. Ameliorative effect of diallyl trisulphide on arsenic-induced oxidative stress in rat erythrocytes and DNA damage in lymphocytes.

    PubMed

    Prabu, Selvaraj Milton; Sumedha, Naorem Chanu

    2014-05-01

    Arsenic (As) is a naturally occurring semimetallic element that is classified as a toxicant and a human carcinogen. Diallyl trisulphide (DATS), an organosulphur compound, is an antioxidative substance that is extracted from garlic (Allium sativum). Erythrocytes are very expedient models to understand the susceptibility of membrane to oxidative damage induced by different xenobiotic compounds. Arsenic has been reported to induce oxidative stress to erythrocytes due to lipid peroxidation and alteration in defence mechanism as erythrocytes are the first target that arsenic compounds attack in the body after systemic absorption. In the light of this fact, the purpose of this study is to characterise the ameliorative effect of DATS on arsenic-induced oxidative stress in rat erythrocytes. Experimental rats were randomly divided into four groups and treated orally for 28 days: control, As [5 mg/kg body weight (BW)] treated, As+DATS (80 mg/kg BW) treated, DATS (80 mg/kg BW) treated and As+vitamin C (100 mg/kg BW) treated. Oxidative stress in erythrocytes was recorded by estimating plasma marker enzymes, plasma and erythrocyte membrane oxidative stress markers, erythrocyte membrane antioxidant enzymes and non-antioxidant enzymes, etc. Oral administration of arsenic at 5 mg/kg BW per day elevated the levels of plasma marker enzymes, namely, aspartate transaminase (AST), alanine transaminase (ALT), acid phosphatase (ACP), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), and γ-glutamyl transferase (γGT) (U/L) with significantly increased lipid peroxidation markers such as thiobarbituric acid reactive substances (TBARS), malondialdehyde (MDA), lipid hydroperoxides (LH), conjugated dienes (CD), and protein carbonyl (PC) contents were also elevated in As-treated rat plasma and erythrocytes. The levels of non-enzymatic antioxidants (reduced glutathione, vitamins C and E) and enzymatic antioxidants such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase

  13. Ellagic acid ameliorates isoproterenol induced oxidative stress: Evidence from electrocardiological, biochemical and histological study.

    PubMed

    Kannan, M Mari; Quine, S Darlin

    2011-05-20

    The present study was designed to evaluate the cardioprotective effects of ellagic acid against isoproterenol induced myocardial infarction in rats by studying electrocardiography, blood pressure, cardiac markers, lipid peroxidation, antioxidant defense system and histological changes. Male Wistar rats were treated orally with ellagic acid (7.5 and 15mg/kg) daily for a period of 10 days. After 10 days of pretreatment, isoproterenol (100mg/kg) was injected subcutaneously to rats at an interval of 24h for 2 days to induce myocardial infarction. Isoproterenol administered rats showed significant changes in the electrocardiogram pattern, arterial pressure, and heart rate. Isoproterenol-induced rats also showed significant (P<0.05) increase in the levels of serum troponin-I, creatine kinase, lactate dehydrogenase, C-reactive protein, plasma homocysteine, heart tissue thiobarbituric acid reactive substances and lipid hydro peroxides. The activities/levels of antioxidant system were decreased in isoproterenol-induced rats. The histopathological findings of the myocardial tissue evidenced myocardial damage in isoproterenol induced rats. The oral pretreatment of ellagic acid restored the pathological electrocardiographic patterns, regulated the arterial blood pressures and heart rate in the isoproterenol induced myocardial infarcted rats. The ellagic acid pretreatment significantly reduced the levels of biochemical markers, lipid peroxidation and significantly increased the activities/levels of the antioxidant system in the isoproterenol induced rats. An inhibited myocardial necrosis was evidenced by the histopathological findings in ellagic acid pretreated isoproterenol induced rats. Our study shows that oral pretreatment of ellagic acid prevents isoproterenol induced oxidative stress in myocardial infarction.

  14. The Ayurvedic drug, Ksheerabala, ameliorates quinolinic acid-induced oxidative stress in rat brain.

    PubMed

    Swathy, S S; Indira, M

    2010-01-01

    One of the mechanisms of neurotoxicity is the induction of oxidative stress. There is hardly any cure for neurotoxicity in modern medicine, whereas many drugs in Ayurveda possess neuroprotective effects; however, there is no scientific validation for these drugs. Ksheerabala is an ayurvedic drug which is used to treat central nervous system disorders, arthritis, and insomnia. The aim of our study was to evaluate the effect of Ksheerabala on quinolinic acid-induced toxicity in rat brain. The optimal dose of Ksheerabala was found from a dose escalation study, wherein it was found that Ksheerabala showed maximum protection against quinolinic acid-induced neurotoxicity at a dose of 15 microL/100 g body weight/day, which was selected for further experiments. Four groups of female albino rats were maintained for 21 days as follows: 1. Control group, 2. Quinolinic acid (55 microg/100 g body weight), 3. Ksheerabala (15 microL/100 g body weight), 4. Ksheerabala (15 microL/100 g body weight) + Quinolinic acid (55 microg/100 g body weight). At the end of the experimental period, levels of lipid peroxidation products, protein carbonyls, and activities of scavenging enzymes were analyzed. The results revealed that quinolinic acid intake caused enhanced lipid and protein peroxidation as evidenced by increased levels of peroxidation products such as malondialdehyde, hydroperoxide, conjugated dienes, and protein carbonyls. On the other hand, the activities of scavenging enzymes such as catalase, superoxide dismutase (SOD), glutathione peroxidase, and glutathione reductase as well as the concentration of glutathione were reduced. On coadminstration of Ksheerabala along with quinolinic acid, the levels of all the biochemical parameters were restored to near-normal levels, indicating the protective effect of the drug. These results were reinforced by histopathological studies.

  15. Ameliorative effect of butylated hydroxyanisole against ferric nitrilotriacetate-induced hepatotoxicity and oxidative stress in rats.

    PubMed

    Ansar, S; Iqbal, M

    2015-11-01

    Ferric nitrilotriacetate (Fe-NTA) is a known renal carcinogen and has been shown to adversely induce oxidative stress and tissue toxicity after both acute and chronic exposure. Present studies were designed to study the hepatoprotective and antioxidant potential of butylated hydroxyanisole (BHA), a phenolic antioxidant used in foods on ferric nitrilotriacetate (Fe-NTA) induced hepatotoxicity in rats. Male albino rats of Wistar strain (4-6 weeks old) weighing 125-150 g were used in this study. Animals were given a single dose of Fe-NTA (9 mg/kg body weight, intraperitoneal) after a week's treatment with BHA. BHA was administered orally once daily for 7 days at doses of 1 and 2 mg/animal/day. The hepatoprotective activity was assessed using various biochemical parameters as serum transaminases (alanine transaminase (ALT), aspartate transaminase (AST)) and lactate dehydrogenase (LDH). Fe-NTA treatment increased ALT, AST, and LDH levels significantly when compared to the corresponding saline-treated group (p < 0.001). Fe-NTA also depleted the levels of glutathione and the activities of antioxidant enzymes namely glutathione reductase and glutathione-S-tranferase (p < 0.05). Pretreatment with BHA significantly decreased ALT, AST and LDH levels in a dose-dependent manner (p < 0.05). BHA also increased antioxidant enzymes level and decreased lipid peroxidation and hydrogen peroxide generation to 1.3-1.5-fold as compared to Fe-NTA-treated group. The results show the strong hepatoprotective activity of BHA which could be due to its potent antioxidant effects.

  16. Dietary nitrate ameliorates pulmonary hypertension: cytoprotective role for endothelial nitric oxide synthase and xanthine oxidoreductase

    PubMed Central

    Baliga, Reshma S; Milsom, Alexandra B; Ghosh, Suborno M; Trinder, Sarah L; MacAllister, Raymond J; Ahluwalia, Amrita; Hobbs, Adrian J

    2012-01-01

    Background Pulmonary hypertension (PH) is a multi-factorial disease characterized by increased pulmonary vascular resistance and right ventricular failure; morbidity and mortality remain unacceptably high. Loss of nitric oxide (NO) bioactivity is thought to contribute to the pathogenesis of PH and agents that augment pulmonary NO signaling are clinically effective in the disease. Inorganic nitrate (NO3−) and nitrite (NO2−) elicit a reduction in systemic blood pressure in healthy individuals; this effect is underpinned by endogenous and sequential reduction to NO. Herein, we determined whether dietary nitrate and nitrite might be preferentially reduced to NO by the hypoxia associated with PH, and thereby offer a convenient, inexpensive method of supplementing NO functionality to reduce disease severity. Methods & Results Dietary nitrate reduced the right ventricular pressure and hypertrophy, and pulmonary vascular re-modeling, in wild-type mice exposed to 3 weeks hypoxia; this beneficial activity was mirrored largely by dietary nitrite. The cytoprotective effects of dietary nitrate were associated with increased plasma & lung concentrations of nitrite and cGMP. The beneficial effects of dietary nitrate and nitrite were reduced in mice lacking endothelial NO synthase (eNOS) or treated with the xanthine oxidoreductase (XOR) inhibitor allopurinol. Conclusions These data demonstrate that dietary nitrate, and to a lesser extent dietary nitrite, elicit pulmonary dilatation, prevent pulmonary vascular remodeling, and reduce the RVH characteristic of PH. This favorable pharmacodynamic profile is dependent on eNOS and XOR -catalyzed reduction of nitrite to NO. Exploitation of this mechanism (i.e. dietary nitrate/nitrite supplementation) represents a viable, orally-active therapy for PH. PMID:22572914

  17. Antitumor efficacy and amelioration of oxidative stress by Trichosanthes dioica root against Ehrlich ascites carcinoma in mice.

    PubMed

    Bhattacharya, Sanjib; Prasanna, Angelene; Majumdar, Piyali; Kumar, R B Suresh; Haldar, Pallab K

    2011-09-01

    Trichosanthes dioica Roxb. (Cucurbitaceae) is a dioecious climber, traditionally used in India for several medicinal purposes. The present study assessed the hydroalcoholic extract of T. dioica root (TDA) for antitumor effect and antioxidant influence against Ehrlich ascites carcinoma (EAC) in Swiss albino mice. Twenty four hours after intraperitoneal inoculation of tumor (EAC) cells in mice, TDA was administered at 5 and 10 mg/kg body weight daily for 9 consecutive days. On the 10th day, half of the mice were sacrificed for estimation of tumor proliferation, hematological, and liver antioxidant parameters viz. lipid peroxidation, reduced glutathione (GSH), glutathione S-transferase (GST), superoxide dismutase (SOD) and catalase (CAT); and the rest were kept alive for assessment of increase in life span. The antitumor effect of TDA was assessed by evaluating tumor weight, tumor volume, packed cell volume, viable and non-viable tumor cell counts, median survival time and percentage increase in life span of EAC bearing mice. TDA exhibited dose dependent and significant (p < 0.001) decrease in tumor weight, tumor volume, packed cell volume and viable cell count and extended the life span of EAC bearing hosts. Hematological profiles were significantly (p < 0.001) restored near to normal in TDA treated mice as compared to EAC control. TDA treatment significantly (p < 0.001) modulated the aforesaid liver antioxidant parameters as compared to EAC control. The present study demonstrated that TDA possessed promising antitumor efficacy in mice, plausibly mediated by amelioration of oxidative stress by multiple mechanisms.

  18. Adverse Effects of Hemorrhagic Shock Resuscitation with Stored Blood are Ameliorated by Inhaled Nitric Oxide in Lambs

    PubMed Central

    Baron, David M.; Beloiartsev, Arkadi; Nakagawa, Akito; Martyn, Trejeeve; Stowell, Christopher P.; Malhotra, Rajeev; Mayeur, Claire; Bloch, Kenneth D.; Zapol, Warren M.

    2013-01-01

    Objectives Transfusion of stored red blood cells (RBCs) is associated with increased morbidity and mortality in trauma patients. Plasma hemoglobin scavenges nitric oxide (NO), which can cause vasoconstriction, induce inflammation and activate platelets. We hypothesized that transfusion of RBCs stored for prolonged periods would induce adverse effects (pulmonary vasoconstriction, tissue injury, inflammation, and platelet activation) in lambs subjected to severe hemorrhagic shock, and that concurrent inhalation of NO would prevent these adverse effects. Design Animal study. Setting Research laboratory at the Massachusetts General Hospital, Boston, MA. Subjects Seventeen awake Polypay-breed lambs. Interventions Lambs were subjected to 2 h of hemorrhagic shock by acutely withdrawing 50% of their blood volume. Lambs were resuscitated with autologous RBCs stored for 2 h or less (fresh) or 39±2 (mean±SD) days (stored). Stored RBCs were administered with or without breathing NO (80 ppm) during resuscitation and for 21 h thereafter. Measurements and Main Results We measured hemodynamic and oxygenation parameters, markers of tissue injury and inflammation, plasma hemoglobin concentrations, and platelet activation. Peak pulmonary arterial pressure was higher after resuscitation with stored than with fresh RBCs (24±4 vs. 14±2 mmHg, p<0.001) and correlated with peak plasma hemoglobin concentrations (R2=0.56, p=0.003). At 21 h after resuscitation, pulmonary myeloperoxidase activity was higher in lambs resuscitated with stored than with fresh RBCs (11±2 vs. 4±1 U/g, p=0.007). Furthermore, transfusion of stored RBCs increased plasma markers of tissue injury and sensitized platelets to adenosine diphosphate activation. Breathing NO prevented the pulmonary hypertension, and attenuated the pulmonary myeloperoxidase activity, as well as tissue injury and sensitization of platelets to adenosine diphosphate. Conclusions Our data suggest that resuscitation of lambs from hemorrhagic

  19. Lactucopicrin ameliorates oxidative stress mediated by scopolamine-induced neurotoxicity through activation of the NRF2 pathway.

    PubMed

    Venkatesan, Ramu; Subedi, Lalita; Yeo, Eui-Ju; Kim, Sun Yeou

    2016-10-01

    Cholinergic activity plays a vital role in cognitive function, and is reduced in individuals with neurodegenerative diseases. Scopolamine, a muscarinic cholinergic antagonist, has been employed in many studies to understand, identify, and characterize therapeutic targets for Alzheimer's disease (AD). Scopolamine-induced dementia is associated with impairments in memory and cognitive function, as seen in patients with AD. The current study aimed to investigate the molecular mechanisms underlying scopolamine-induced cholinergic neuronal dysfunction and the neuroprotective effect of lactucopicrin, an inhibitor of acetylcholine esterase (AChE). We investigated apoptotic cell death, caspase activation, generation of reactive oxygen species (ROS), mitochondrial dysfunction, and the expression levels of anti- and pro-apoptotic proteins in scopolamine-treated C6 cells. We also analyzed the expression levels of antioxidant enzymes and nuclear factor (erythroid-derived 2)-like 2 (NRF2) in C6 cells and neurite outgrowth in N2a neuroblastoma cells. Our results revealed that 1 h scopolamine pre-treatment induced cytotoxicity by increasing apoptotic cell death via oxidative stress-mediated caspase 3 activation and mitochondrial dysfunction. Scopolamine also downregulated the expression the antioxidant enzymes superoxide dismutase, glutathione peroxidase, and catalase, and the transcription factor NRF2. Lactucopicrin treatment protected C6 cells from scopolamine-induced toxicity by reversing the effects of scopolamine on those markers of toxicity. In addition, scopolamine attenuated the secretion of neurotrophic nerve growth factor (NGF) in C6 cells and neurite outgrowth in N2a cells. As expected, lactucopicrin treatment enhanced NGF secretion and neurite outgrowth. Our study is the first to show that lactucopicrin, a potential neuroprotective agent, ameliorates scopolamine-induced cholinergic dysfunction via NRF2 activation and subsequent expression of antioxidant enzymes.

  20. Chlorpyrifos-induced changes in oxidant/antioxidant status and haematological parameters of Cyprinus carpio carpio: ameliorative effect of lycopene.

    PubMed

    Ural, Mevlüt Şener

    2013-02-01

    The present study was carried out to investigate the potential ameliorative effects of lycopene against chlorpyrifos (CPF) toxicity in carp. The fish were divided into 7 different experimental groups and received the following treatments: Group 1, control; Group 2, orally administered corn oil; Group 3, oral lycopene (10 mg kg(-1) body weight); Group 4, exposure to 0.040 mg L(-1) CPF; Group 5, exposure to 0.040 mg L(-1) CPF plus oral administration of 10 mg kg(-1) lycopene; Group 6, exposure to 0.080 mg L(-1) CPF; and Group 7, exposure to 0.040 mg L(-1) CPF plus oral administration of 10 mg kg(-1) lycopene. Treatment was continued for 14 d and samples of the blood and tissue (liver, kidney, and gill) were collected at the end of the experiment and analysed for their oxidant-antioxidant status, including the malondialdehyde (MDA) levels, and the superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activity. The samples were also measured for changes in the haematological parameters, such as the red blood cell (RBC) and white blood cell (WBC) counts, the haemoglobin concentration (Hb), the haematocrit (Ht) level, and the erythrocyte indices: the mean corpuscular volume (MCV), the mean corpuscular haemoglobin (MCH) and the mean corpuscular haemoglobin concentration (MCHC). The findings of this study demonstrated that CPF had a negative effect on the haematological parameters and the antioxidant enzyme activities of the fish; this toxic effect was neutralised by the administration of lycopene. The present results suggest that lycopene (10 mg kg(-1)) can be effective in the protection of CPF-induced toxicity in fish. Copyright © 2012 Elsevier Ltd. All rights reserved.

  1. Selenium ameliorates arsenic induced oxidative stress through modulation of antioxidant enzymes and thiols in rice (Oryza sativa L.).

    PubMed

    Kumar, Amit; Singh, Rana Pratap; Singh, Pradyumna Kumar; Awasthi, Surabhi; Chakrabarty, Debasis; Trivedi, Prabodh Kumar; Tripathi, Rudra Deo

    2014-09-01

    Arsenic (As) contamination of rice is a major problem for South-East Asia. In the present study, the effect of selenium (Se) on rice (Oryza sativa L.) plants exposed to As was studied in hydroponic culture. Arsenic accumulation, plant growth, thiolic ligands and antioxidative enzyme activities were assayed after single (As and Se) and simultaneous supplementations (As + Se). The results indicated that the presence of Se (25 µM) decreased As accumulation by threefold in roots and twofold in shoots as compared to single As (25 µM) exposed plants. Arsenic induced oxidative stress in roots and shoots was significantly ameliorated by Se supplementation. The observed positive response was found associated with the increased activities of ascorbate peroxidase (APX; EC 1.11.1.11), catalase (CAT; EC 1.11.1.6) and glutathione peroxidase (GPx; EC 1.11.1.9) and induced levels of non-protein thiols (NPTs), glutathione (GSH) and phytochelatins (PCs) in As + Se exposed plants as compared to single As treatment. Selenium supplementation modulated the thiol metabolism enzymes viz., γ-glutamylcysteine synthetase (γ-ECS; EC 6.3.2.2), glutathione-S-transferase (GST; EC 2.5.1.18) and phytochelatin synthase (PCS; EC 2.3.2.15). Gene expression analysis of several metalloid responsive genes (LOX, SOD and MATE) showed upregulation during As stress, however, significant downregulation during As + Se exposure as compared to single As treatment. Gene expressions of enzymes of antioxidant and GSH and PC biosynthetic systems, such as APX, CAT, GPx, γ-ECS and PCS were found to be significantly positively correlated with their enzyme activities. The findings suggested that Se supplementation could be an effective strategy to reduce As accumulation and toxicity in rice plants.

  2. Silibinin ameliorates arsenic induced nephrotoxicity by abrogation of oxidative stress, inflammation and apoptosis in rats.

    PubMed

    Prabu, S Milton; Muthumani, M

    2012-12-01

    Arsenic (As) is an environmental and industrial pollutant that affects various organs in human and experimental animals. Silibinin is a naturally occurring plant bioflavonoid found in the milk thistle of Silybum marianum, which has been reported to have a wide range of pharmacological properties. A body of evidence has accumulated implicating the free radical generation with subsequent oxidative stress in the biochemical and molecular mechanisms of As toxicity. Since kidney is the critical target organ of chronic As toxicity, we carried out this study to investigate the effects of silibinin on As-induced toxicity in the kidney of rats. In experimental rats, oral administration of sodium arsenite [NaAsO(2), 5 mg/(kg day)] for 4 weeks significantly induced renal damage which was evident from the increased levels of serum urea, uric acid, creatinine with a significant (p < 0.05) decrease in creatinine clearance. As also significantly decreased the levels of urea, uric acid and creatinine in urine. A markedly increased levels of lipid peroxidation markers (thiobarbituric acid reactive substances and lipid hydroperoxides) and protein carbonyl contents with significant (p < 0.05) decrease in non-enzymatic antioxidants (total sulfhydryl groups, reduced glutathione, vitamin C and vitamin E) and enzymatic antioxidants (superoxide dismutase, catalase, glutathione peroxidase and glutathione S-transferase), Glutathione metabolizing enzymes (glutathione reductase and glutathione-6-phosphate dehydrogenase) and membrane bound ATPases were also observed in As treated rats. Co-administration of silibinin (75 mg/kg day) along with As resulted in a reversal of As-induced biochemical changes in kidney accompanied by a significant decrease in lipid peroxidation and an increase in the level of renal antioxidant defense system. The histopathological and immunohistochemical studies in the kidney of rats also shows that silibinin (75 mg/kg day) markedly reduced the toxicity of As and

  3. Ameliorative effect of Sida cordifolia in rotenone induced oxidative stress model of Parkinson's disease.

    PubMed

    Khurana, Navneet; Gajbhiye, Asmita

    2013-12-01

    Present study focused on the evaluation of aqueous extract of Sida cordifolia (AESC), and its different fractions; hexane (HFSC), chloroform (CFSC) and aqueous (AFSC), against rotenone induced biochemical, neurochemical, histopathological and behavioral alterations in a rat model of Parkinson's disease (PD). An estimation of the level of thiobarbituric acid reactive substances (TBARS), glutathione (GSH) and catalase (CAT) along with superoxide anion generation (SAG) in different brain regions (cortex, midbrain and cerebellum) was carried out to assess biochemical changes. Behavioral evaluation tests (catalepsy, rearing behavior and posture instability) and neurochemical estimations (norepinephrine, dopamine and serotonin level) along with histopathological evaluations of different brain regions were also performed. The varying doses (50, 100, 250mg/kg; p.o.) of different test treatments (AESC, HFSC, CFSC and AFSC) were co-administered along with rotenone (2mg/kg; s.c.), for a period of 35 days to rats of various groups and compared with rotenone per se (negative control) and l-deprenyl (positive control; 10mg/kg; p.o.) treated groups for the above mentioned parameters. The increase in catalepsy and posture instability along with decrease in rearing behavior observed due to rotenone treatment was significantly attenuated by co-treatment with varying doses of AESC and AFSC. Results of the histopathological studies of different brain regions of rats showed eosinophilic lesions in the mid brain region due to rotenone treatment. The eosinophilic lesions were significantly attenuated in co-treated groups of AESC-100mg/kg and AFSC-100mg/kg. Rotenone induced oxidative damage, revealed by increased level of TBARS, SAG and decreased level of GSH and CAT in mid brain region of rats, was attenuated by the co-treatment of AESC and AFSC. The rotenone induced decrease of dopamine level in the midbrain region of rats was also attenuated by co-treatment of AESC-100mg/kg and AFSC

  4. Exogenous nitric oxide improves salt tolerance during establishment of Jatropha curcas seedlings by ameliorating oxidative damage and toxic ion accumulation.

    PubMed

    Gadelha, Cibelle Gomes; Miranda, Rafael de Souza; Alencar, Nara Lídia M; Costa, José Hélio; Prisco, José Tarquinio; Gomes-Filho, Enéas

    2017-05-01

    Jatropha curcas is an oilseed species that is considered an excellent alternative energy source for fossil-based fuels for growing in arid and semiarid regions, where salinity is becoming a stringent problem to crop production. Our working hypothesis was that nitric oxide (NO) priming enhances salt tolerance of J. curcas during early seedling development. Under NaCl stress, seedlings arising from NO-treated seeds showed lower accumulation of Na(+) and Cl(-) than those salinized seedlings only, which was consistent with a better growth for all analyzed time points. Also, although salinity promoted a significant increase in hydrogen peroxide (H2O2) content and membrane damage, the harmful effects were less aggressive in NO-primed seedlings. The lower oxidative damage in NO-primed stressed seedlings was attributed to operation of a powerful antioxidant system, including greater glutathione (GSH) and ascorbate (AsA) contents as well as catalase (CAT) and glutathione reductase (GR) enzyme activities in both endosperm and embryo axis. Priming with NO also was found to rapidly up-regulate the JcCAT1, JcCAT2, JcGR1 and JcGR2 gene expression in embryo axis, suggesting that NO-induced salt responses include functional and transcriptional regulations. Thus, NO almost completely abolished the deleterious salinity effects on reserve mobilization and seedling growth. In conclusion, NO priming improves salt tolerance of J. curcas during seedling establishment by inducing an effective antioxidant system and limiting toxic ion and reactive oxygen species (ROS) accumulation. Copyright © 2017 Elsevier GmbH. All rights reserved.

  5. Increased constitutive nitric oxide production by whole body periodic acceleration ameliorates alterations in cardiomyocytes associated with utrophin/dystrophin deficiency.

    PubMed

    Lopez, Jose R; Kolster, Juan; Zhang, Rui; Adams, Jose

    2017-07-01

    Duchenne Muscular Dystrophy (DMD) cardiomyopathy is a progressive lethal disease caused by the lack of the dystrophin protein in the heart. The most widely used animal model of DMD is the dystrophin-deficient mdx mouse; however, these mice exhibit a mild dystrophic phenotype with heart failure only late in life. In contrast, mice deficient for both dystrophin and utrophin (mdx/utrn(-/-), or dKO) can be used to model severe DMD cardiomyopathy where pathophysiological indicators of heart failure are detectable by 8-10weeks of age. Nitric oxide (NO) is an important signaling molecule involved in vital functions of regulating rhythm, contractility, and microcirculation of the heart, and constitutive NO production affects the function of proteins involved in excitation-contraction coupling. In this study, we explored the efficacy of enhancing NO production as a therapeutic strategy for treating DMD cardiomyopathy using the dKO mouse model of DMD. Specifically, NO production was induced via whole body periodic acceleration (pGz), a novel non-pharmacologic intervention which enhances NO synthase (NOS) activity through sinusoidal motion of the body in a headward-footward direction, introducing pulsatile shear stress to the vascular endothelium and cardiomyocyte plasma membrane. Male dKO mice were randomized at 8weeks of age to receive daily pGz (480cpm, Gz±3.0m/s(2), 1h/d) for 4weeks or no treatment, and a separate age-matched group of WT animals (pGz-treated and untreated) served as non-diseased controls. At the conclusion of the protocol, cardiomyocytes from untreated dKO animals had, respectively, 4.3-fold and 3.5-fold higher diastolic resting concentration of Ca(2+) ([Ca(2+)]d) and Na(+) ([Na(+)]d) compared to WT, while pGz treatment significantly reduced these levels. For dKO cardiomyocytes, pGz treatment also improved the depressed contractile function, decreased oxidative stress, blunted the elevation in calpain activity, and mitigated the abnormal increase in [Ca

  6. Baicalin ameliorates isoproterenol-induced acute myocardial infarction through iNOS, inflammation, oxidative stress and P38MAPK pathway in rat

    PubMed Central

    Sun, Shen-Jie; Wu, Xiao-Peng; Song, Heng-Liang; Li, Gui-Qi

    2015-01-01

    Baicalin is one of the active ingredients in the skullcap, with a variety of pharmacological effects, such as blood pressure reduction, sedation, liver-protection, gallbladder-protection, anti-bacteria, anti-inflammation, etc. The aim of this study was to investigate the potential cardioprotective effects of baicalin ameliorates isoproterenol-induced acute myocardial infarction (AMI) through inducible nitric oxide synthase (iNOS), inflammation, oxidative stress and P38MAPK passageway in rat. Rat model of AMI was induced by isoproterenol (100 mg/kg) and then treated baicalin (various does of baicalin: 1 mg/kg, 10 mg/kg and 100 mg/kg, respectively) for 24 h. Infarct size, the heart weight to body weight ratio and creatine kinase (CK), the MB isoenzyme of creatine kinase (CK-MB), lactate dehydrogenase (LDH) and cardiac troponin T (cTnT) of rats with AMI induced by isoproterenol were used to evaluate curative effect of baicalin on AMI. Meanwhile, iNOS and phosphorylation-p38 MAPK (p-p38) protein expressions, inflammatory factor and oxidative stress were inspected using western blot and commercial kits, respectively. In the present study, pre-treatment with baicalin (10 or 100 mg/kg) significantly ameliorated infarct size, the heart weight to body weight ratio and CK, CK-MB, LDH and cTnT levels in rats with AMI induced by isoproterenol. iNOS protein expression, the serum TNF-α, IL-6, MDA and SOD levels and p-38 protein expressions were significantly suppressed by treatment with baicalin (10 or 100 mg/kg). These results suggest that acute treatment with baicalin ameliorates AMI, iNOS, inflammation, oxidative stress and P38MAPK pathway in rat with AMI induced by isoproterenol. PMID:26885181

  7. Baicalin ameliorates isoproterenol-induced acute myocardial infarction through iNOS, inflammation, oxidative stress and P38MAPK pathway in rat.

    PubMed

    Sun, Shen-Jie; Wu, Xiao-Peng; Song, Heng-Liang; Li, Gui-Qi

    2015-01-01

    Baicalin is one of the active ingredients in the skullcap, with a variety of pharmacological effects, such as blood pressure reduction, sedation, liver-protection, gallbladder-protection, anti-bacteria, anti-inflammation, etc. The aim of this study was to investigate the potential cardioprotective effects of baicalin ameliorates isoproterenol-induced acute myocardial infarction (AMI) through inducible nitric oxide synthase (iNOS), inflammation, oxidative stress and P38MAPK passageway in rat. Rat model of AMI was induced by isoproterenol (100 mg/kg) and then treated baicalin (various does of baicalin: 1 mg/kg, 10 mg/kg and 100 mg/kg, respectively) for 24 h. Infarct size, the heart weight to body weight ratio and creatine kinase (CK), the MB isoenzyme of creatine kinase (CK-MB), lactate dehydrogenase (LDH) and cardiac troponin T (cTnT) of rats with AMI induced by isoproterenol were used to evaluate curative effect of baicalin on AMI. Meanwhile, iNOS and phosphorylation-p38 MAPK (p-p38) protein expressions, inflammatory factor and oxidative stress were inspected using western blot and commercial kits, respectively. In the present study, pre-treatment with baicalin (10 or 100 mg/kg) significantly ameliorated infarct size, the heart weight to body weight ratio and CK, CK-MB, LDH and cTnT levels in rats with AMI induced by isoproterenol. iNOS protein expression, the serum TNF-α, IL-6, MDA and SOD levels and p-38 protein expressions were significantly suppressed by treatment with baicalin (10 or 100 mg/kg). These results suggest that acute treatment with baicalin ameliorates AMI, iNOS, inflammation, oxidative stress and P38MAPK pathway in rat with AMI induced by isoproterenol.

  8. PACAP intraperitoneal treatment suppresses appetite and food intake via PAC1 receptor in mice by inhibiting ghrelin and increasing GLP-1 and leptin.

    PubMed

    Vu, John P; Goyal, Deepinder; Luong, Leon; Oh, Suwan; Sandhu, Ravneet; Norris, Joshua; Parsons, William; Pisegna, Joseph R; Germano, Patrizia M

    2015-11-15

    Pituitary adenylate cyclase-activating peptide (PACAP) is expressed within the gastroenteric system, where it has profound physiological effects. PACAP was shown to regulate food intake and thermogenesis centrally; however, PACAP peripheral regulation of appetite and feeding behavior is unknown. Therefore, we studied PACAP's effect on appetite and food intake control by analyzing feeding behavior and metabolic hormones in PAC1-deficient (PAC1-/-) and age-matched wild-type (WT) mice intraperitoneally injected with PACAP1-38 or PACAP1-27 before the dark phase of feeding. Food intake and feeding behavior were analyzed using the BioDAQ system. Active ghrelin, glucagon-like peptide-1 (GLP-1), leptin, peptide YY, pancreatic polypeptide, and insulin were measured following PACAP1-38 administration in fasted WT mice. PACAP1-38/PACAP1-27 injected into WT mice significantly decreased in a dose-dependent manner cumulative food intake and reduced bout and meal feeding parameters. Conversely, PACAP1-38 injected into PAC1-/- mice failed to significantly change food intake. Importantly, PACAP1-38 reduced plasma levels of active ghrelin compared with vehicle in WT mice. In PAC1-/- mice, fasting levels of active ghrelin, GLP-1, insulin, and leptin and postprandial levels of active ghrelin and insulin were significantly altered compared with levels in WT mice. Therefore, PAC1 is a novel regulator of appetite/satiety. PACAP1-38/PACAP1-27 significantly reduced appetite and food intake through PAC1. In PAC1-/- mice, the regulation of anorexigenic/orexigenic hormones was abolished, whereas active ghrelin remained elevated even postprandially. PACAP significantly reduced active ghrelin in fasting conditions. These results establish a role for PACAP via PAC1 in the peripheral regulation of appetite/satiety and suggest future studies to explore a therapeutic use of PACAP or PAC1 agonists for obesity treatment.

  9. Induction of Serpinb1a by PACAP or NGF is required for PC12 cells survival after serum withdrawal

    PubMed Central

    Seaborn, Tommy; Ravni, Aurélia; Au, Ruby; Chow, Bill K.C.; Fournier, Alain; Wurtz, Olivier; Vaudry, Hubert; Eiden, Lee E.; Vaudry, David

    2014-01-01

    PC12 cells are used to study the signaling mechanisms underlying the neurotrophic and neuroprotective activities of pituitary adenylate cyclase-activating polypeptide (PACAP) and nerve growth factor (NGF). Previous microarray experiments indicated that serpinb1a was the most induced gene after 6 h of treatment with PACAP or NGF. The present study confirmed that serpinb1a is strongly activated by PACAP and NGF in a time-dependent manner with a maximum induction (~50-fold over control) observed after 6 h of treatment. Co-incubation with PACAP and NGF resulted in a synergistic up-regulation of serpinb1a expression (200-fold over control), suggesting that PACAP and NGF act through complementary mechanisms. Consistently, PACAP-induced serpinb1a expression was not blocked by TrkA receptor inhibition. Nevertheless, the stimulation of serpinb1a expression by PACAP and NGF was significantly reduced in the presence of ERK, calcineurin, PKA, p38 and PI3K inhibitors, indicating that the two trophic factors share some common pathways in the regulation of serpinb1a. Finally, functional investigations conducted with siRNA revealed that serpinb1a is not involved in the effects of PACAP and NGF on PC12 cell neuritogenesis, proliferation or body volume but mediates their ability to block caspase-3/7 activity and to promote PC12 cell survival. PMID:24899316

  10. Behavioral effects of local microinfusion of pituitary adenylate cyclase activating polypeptide (PACAP) into the paraventricular nucleus of the hypothalamus (PVN).

    PubMed

    Norrholm, Seth D; Das, Mahasweta; Légrádi, Gábor

    2005-05-15

    Pituitary adenylate cyclase activating polypeptide (PACAP) has been implicated in the regulation of several autonomic and neuroendocrine functions. In the hypothalamic paraventricular nucleus (PVN), for example, PACAP-immunoreactive fibers densely innervate corticotropin-releasing hormone (CRH)-containing neurons in the medial parvocellular region, suggesting that PACAP acts to mediate stress responses. Therefore, we examined the behavioral effects of an intra-PVN PACAP injection (25 pmol) in combination with a mild stressor. PACAP or artificial cerebrospinal fluid (aCSF) was microinjected into the PVN (0.25 l) and then animals were restrained or placed in their home cage for 5 min. Exploratory activity (total distance traveled) and scored behaviors (face washing, body grooming, wet dog shakes, and rearing) were observed in a familiar open field for 10 min. In animals receiving aCSF, there were no behavioral differences between restrained and unrestrained groups. For the entire 10-min observation period, animals receiving PACAP, whether restrained or not, displayed elevated face washing and body grooming with decreased locomotor activity and rearing. Among PACAP-injected animals, restrained animals displayed increased body grooming compared to unrestrained animals during the first 2 min in the open field suggesting a summation of the effects of peptide injection and stressor. The observed elevation in grooming is consistent with previous studies reporting similar increases following electrical-, NMDA-, CRH-, or stressor-induced activation of the PVN. Thus, at the level of the PVN, PACAP may act as an excitatory neuropeptide and augment behavioral responses to stressors.

  11. PACAP receptor pharmacology and agonist bias: analysis in primary neurons and glia from the trigeminal ganglia and transfected cells

    PubMed Central

    Walker, C S; Sundrum, T; Hay, D L

    2014-01-01

    Background and Purpose A major challenge in the development of new medicines targeting GPCRs is the ability to quantify drug action in physiologically relevant models. Primary cell models that closely resemble the clinically relevant in vivo site of drug action are important translational tools in drug development. However, pharmacological studies in these models are generally very limited due to the methodology used. Experimental Approach We used a neuropeptide system to demonstrate the applicability of using highly sensitive signalling assays in primary cells. We quantified the action of pituitary adenylate cyclase-activating peptide (PACAP)-38, PACAP-27 and vasoactive intestinal polypeptide in primary cultures of neurons and glia derived from rat trigeminal ganglia (TG), comparing our observations to transfected cells. Key Results PACAP-responsive receptors in rat trigeminal neurons, glia and transfected PAC1n receptors were pharmacologically distinct. PACAP-38, but not PACAP-27, activated ERK in glia, while both forms stimulated cellular cAMP production. PACAP(6–38) also displayed cell-type-dependent, agonist-specific, antagonism. Conclusions and Implications The complexity of PACAP pharmacology in the TG may help to direct, more effectively, the development of disease treatments targeting the PACAP receptor. We suggest that these methodologies are broadly applicable to other primary cell types of human or animal origin, and that our approach may allow more thorough characterization of ligand properties in physiologically relevant cell types. PMID:24303997

  12. PACAP regulation of secretion and proliferation of pure populations of gastric ECL cells.

    PubMed

    Oh, David S; Lieu, Sandy N; Yamaguchi, Dean J; Tachiki, Ken; Lambrecht, Nils; Ohning, Gordon V; Sachs, George; Germano, Patrizia M; Pisegna, Joseph R

    2005-01-01

    The gastric enterochromaffin-like (ECL) cell plays a major role in the regulation of gastric acid secretion. We have previously described that Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) is present on myenteric neurons in the rat and colocalizes with its high-affinity receptor, PAC1, expressed on the surface of gastric ECL cells. The study of ECL cell physiology has been hampered by the inability to isolate and purify ECL cells to homogeneity. Density gradient elutriation alone yields only 65-70% purity of ECL cells. In the present study, we used fluorescence-activated cell sorting (FACS) with a novel fluorescent ligand, Fluor-PACAP-38, for isolating pure ECL cells. FACS was used to isolate ECL cells based on their relatively small size, low density, and ability to bind the fluorescent ligand Fluor-PACAP-38. The sorted cells were unambiguously identified as ECL cells by immunohistochemical analysis using anti-PACAP type-I (PAC1), anti-histidine decarboxylase (HDC), and anti-somatostatin antibodies. Further confocal microscopy demonstrated that Fluor-PACAP-38, a ligand with a higher affinity for PAC1, bound to extracellular receptors of these FACS-purified cells. FACS yielded an average of 2 million ECL cells/4 rat stomachs, and >99% of the sorted cells were positive for PAC1 receptor and HDC expression. The absence of immunohistochemical staining for somatostatin indicated lack of contamination by gastric D cells, which are similar in size and shape to the ECL cells. Internalization of PACAP receptors and a rapid Ca2+ response in purified ECL cells were observed upon PACAP activation, suggesting that these cells are viable and biologically active. These ECL cells demonstrated a dose-dependent stimulation of proliferation in response to PACAP, with a maximum of 30% proliferation at a concentration of 10-7 M. Microarray studies were perfor med to confirm the expression of genes specific for ECL cells. These results demonstrate that rat gastric ECL

  13. PACAP38/PAC1 Signaling Induces Bone Marrow-Derived Cells Homing to Ischemic Brain

    PubMed Central

    Lin, Chen-Huan; Chiu, Lian; Lee, Hsu-Tung; Chiang, Chun-Wei; Liu, Shih-Ping; Hsu, Yung-Hsiang; Lin, Shinn-Zong; Hsu, Chung Y; Hsieh, Chia-Hung; Shyu, Woei-Cherng

    2015-01-01

    Understanding stem cell homing, which is governed by environmental signals from the surrounding niche, is important for developing effective stem cell-based repair strategies. The molecular mechanism by which the brain under ischemic stress recruits bone marrow-derived cells (BMDCs) to the vascular niche remains poorly characterized. Here we report that hypoxia-inducible factor-1α (HIF-1α) activation upregulates pituitary adenylate cyclase-activating peptide 38 (PACAP38), which in turn activates PACAP type 1 receptor (PAC1) under hypoxia in vitro and cerebral ischemia in vivo. BMDCs homing to endothelial cells in the ischemic brain are mediated by HIF-1α activation of the PACAP38-PAC1 signaling cascade followed by upregulation of cellular prion protein and α6-integrin to enhance the ability of BMDCs to bind laminin in the vascular niche. Exogenous PACAP38 confers a similar effect in facilitating BMDCs homing into the ischemic brain, resulting in reduction of ischemic brain injury. These findings suggest a novel HIF-1α-activated PACAP38-PAC1 signaling process in initiating BMDCs homing into the ischemic brain for reducing brain injury and enhancing functional recovery after ischemic stroke. Stem Cells 2015;33:1153–1172 PMID:25523790

  14. Ameliorating effect of chicory (Chichorium intybus L.) fruit extract against 4-tert-octylphenol induced liver injury and oxidative stress in male rats.

    PubMed

    Saggu, Shalini; Sakeran, Mohamed I; Zidan, Nahla; Tousson, Ehab; Mohan, Anand; Rehman, Hasibur

    2014-10-01

    The current study was carried out to elucidate the modulating effect of chicory (Cichorium intybus L.) fruit extract (CFR) against 4-tert-OP induced oxidative stress and hepatotoxicity in male rats. Rats were divided into four groups and treated for 8 weeks as follow: group 1: normal control-treated (saline); group 2: chicory fruit extract-treated (100 mg/kg); group 3: 4-tert-OP treated; group 4: 4-tert-OP plus chicory fruit extract. The obtained results revealed that rats which received 4-tert-OP showed a significant increase in liver TBARS and bilirubin, aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP) and gamma-glutamyl transpeptidase (GGTP) activities. While a significant decrease in the levels of GSH, SOD, catalase recorded. On the other hand, CFR extract succeeded to modulate these observed abnormalities resulting from 4-tert-OP as indicated by the reduction of TBARS and the pronounced improvement of the investigated biochemical and antioxidant parameters. Histopathological evidence, together with observed PCNA and DNA fragmentation, supported the detrimental effect of 4-tert-OP and the ameliorating effect of CFR extract on liver toxicity. So, it could be concluded that chicory has a promising role and it worth to be considered as a natural substance for ameliorating the oxidative stress and hepatic injury induced by 4-tert-OP compound.

  15. PACAP controls adrenomedullary catecholamine secretion and expression of catecholamine biosynthetic enzymes at high splanchnic nerve firing rates characteristic of stress transduction in male mice.

    PubMed

    Stroth, N; Kuri, B A; Mustafa, T; Chan, S-A; Smith, C B; Eiden, L E

    2013-01-01

    The neuropeptide PACAP (pituitary adenylate cyclase-activating polypeptide) is a cotransmitter of acetylcholine at the adrenomedullary synapse, where autonomic regulation of hormone secretion occurs. We have previously reported that survival of prolonged metabolic stress in mice requires PACAP-dependent biosynthesis and secretion of adrenomedullary catecholamines (CAs). In the present experiments, we show that CA secretion evoked by direct high-frequency stimulation of the splanchnic nerve is abolished in native adrenal slices from male PACAP-deficient mice. Further, we demonstrate that PACAP is both necessary and sufficient for CA secretion ex vivo during stimulation protocols designed to mimic stress. In vivo, up-regulation of transcripts encoding adrenomedullary CA-synthesizing enzymes (tyrosine hydroxylase, phenylethanolamine N-methyltransferase) in response to both psychogenic and metabolic stressors (restraint and hypoglycemia) is PACAP-dependent. Stressor-induced alteration of the adrenomedullary secretory cocktail also appears to require PACAP, because up-regulation of galanin mRNA is abrogated in male PACAP-deficient mice. We further show that hypoglycemia-induced corticosterone secretion is not PACAP-dependent, ruling out the possibility that glucocorticoids are the main mediators of the aforementioned effects. Instead, experiments with bovine chromaffin cells suggest that PACAP acts directly at the level of the adrenal medulla. By integrating prolonged CA secretion, expression of biosynthetic enzymes and production of modulatory neuropeptides such as galanin, PACAP is crucial for adrenomedullary function. Importantly, our results show that PACAP is the dominant adrenomedullary neurotransmitter during conditions of enhanced secretory demand.

  16. Pyrroloquinoline quinone (PQQ) has potential to ameliorate streptozotocin-induced diabetes mellitus and oxidative stress in mice: A histopathological and biochemical study.

    PubMed

    Kumar, Narendra; Kar, Anand

    2015-10-05

    Enhanced oxidative stress and hyperglycemia are associated with diabetes mellitus (DM). As pyrroloquinoline quinone (PQQ) is known to protect cells from oxidative stress, the present study was undertaken to reveal the hitherto unknown effects of PQQ in DM and associated problems in different tissues. Forty two mice were randomly divided into six groups. Group I receiving only citrate buffer served as the normal control, while group II animals were injected with citrate buffer and PQQ at 20 mg/kg for 15 days and served as test drug control. Animals of groups III-VI were rendered diabetic by single dose of streptozotocin (STZ, 150 mg/kg body weight), following which PQQ at a dose of 5, 10 and 20 mg/kg, was injected to the animals of group IV, V and VI respectively for 15 days. At the end, alterations in serum indices such as glucose, different lipids, insulin, amylase, urea, uric acid, serum glutamate pyruvate transaminase and serum glutamate oxaloacetate transaminase; tissue antioxidants and histopathological alterations in liver, kidney and pancreas were evaluated. STZ-treated animals developed oxidative stress as indicated by a significant increase in tissue lipid peroxidation (LPO) and lipid hydroperoxide, serum glucose, total cholesterol, triglyceride and urea, with a parallel decrease in the levels of serum insulin and tissue antioxidants. When diabetic animals received different doses of PQQ, these adverse effects were ameliorated. However, 20 mg/kg of PQQ appeared to be most effective. Findings revealed for the first time that PQQ has the potential to mitigate STZ-induced DM and oxidative damage in different organs of mice, suggesting that it may ameliorate diabetes mellitus and associated problems.

  17. Markers of oxidative stress and aging in Duchene muscular dystrophy patients and the possible ameliorating effect of He:Ne laser

    PubMed Central

    Abdel Salam, E; Abdel-Meguid, I; Korraa, S

    2007-01-01

    Summary Replicative aging and oxidative stress are two plausible theories explaining the etiology of muscular dystrophy. The first theory indicates that replicative aging of myogenic cells (satellite cells), owing to enhanced myofiber turnover, is a plausible explanation of the progression of Duchenne muscular dystrophy (DMD). The oxidative stress theory indicates that failure of muscle regeneration to keep up with the ongoing apoptosis and necrosis following oxidative stress, that normally associates muscular exercise, leads to muscle atrophy in DMD. To test for these two theories, markers of replicative aging and oxidative stress were assessed in the blood of 30 DMD patients vs. 20 normal healthy age matching controls. Markers of replicative aging showed significantly lower telomerase activity, significantly increased expression of receptors for advanced glycation end products (RAGEs) mRNA and Bax mRNA (an apoptotic gene) in DMD compared to controls. There was a significant increase in markers of oxidative stress among DMD patients compared to controls, measured in terms of increased apoptotic percentage in circulating mononuclear cells, increased lipid peroxidation measured in terms of plasma malondialdehyde (MDA) and increased protein carbonyls. Levels of plasma nitric oxide (NO), which neutralizes oxygen radicals, and expression of inducible nitric oxide synthase (iNOS) mRNA in neutrophils was significantly lower among DMD compared to controls. Biostimulation of WBC by helium neon (He:Ne) laser irradiation induced a significant increase in the expression of iNOS mRNA and plasma NO levels, but still at a lower level compared to controls. He:Ne laser irradiation induced a marked decrease in markers of oxidative stress among DMD patients compared to their level before irradiation, measured in terms of decreased plasma protein carbonyls, decreased plasma MDA, and decreased apoptosis percentage. Conclusion: This study points to that oxidative stress is the prime

  18. S-allyl cysteine ameliorates the quality of sperm and provides protection from age-related sperm dysfunction and oxidative stress in rats

    PubMed Central

    Takemura, Shigekazu; Ichikawa, Hiroshi; Naito, Yuji; Takagi, Tomohisa; Yoshikawa, Toshikazu; Minamiyama, Yukiko

    2014-01-01

    Reactive oxygen species play a central role in the pathophysiology of the age-related decrease in male fertility. It has been reported that the total protein of DJ-1 was decreased in a proteomic analysis of seminal plasma from asthenozoospermia patients and a DJ-1 protein acts as a sensor of cellular redox homeostasis. Therefore, we evaluated the age-related changes in the ratio of the oxidized/reduced forms of the DJ-1 protein in the epididymis. In addition, the protective effects of S-allyl cysteine (SAC), a potent antioxidant, were evaluated against sperm dysfunction. Male rats aged 15–75 weeks were used to assess age-associated sperm function and oxidative stress. Sperm count increased until 25 weeks, but then decreased at 50 and 75 weeks. The rate of sperm movement at 75 weeks was decreased to approximately 60% of the rate observed at 25 weeks. Expression of DJ-1 decreased, but oxidized-DJ-1 increased with age. In addition, 4-hydroxy-2-nonenal modified proteins in the epididymis increased until 50 weeks of age. The total number and DNA synthetic potential of the sperm increased until 25 weeks, and then decreased. In rats 75 weeks of age, SAC (0.45% diet) attenuated the decrease in the number, motility, and DNA synthesis of sperm and inhibited the oxidized proteins. These results suggest that SAC ameliorates the quality of sperm subjected to age-associated oxidative stress. PMID:25411519

  19. Direct renin inhibitor ameliorates insulin resistance by improving insulin signaling and oxidative stress in the skeletal muscle from post-infarct heart failure in mice.

    PubMed

    Fukushima, Arata; Kinugawa, Shintaro; Takada, Shingo; Matsumoto, Junichi; Furihata, Takaaki; Mizushima, Wataru; Tsuda, Masaya; Yokota, Takashi; Matsushima, Shouji; Okita, Koichi; Tsutsui, Hiroyuki

    2016-05-15

    Insulin resistance can occur as a consequence of heart failure (HF). Activation of the renin-angiotensin system (RAS) may play a crucial role in this phenomenon. We thus investigated the effect of a direct renin inhibitor, aliskiren, on insulin resistance in HF after myocardial infarction (MI). MI and sham operation were performed in male C57BL/6J mice. The mice were divided into 4 groups and treated with sham-operation (Sham, n=10), sham-operation and aliskiren (Sham+Aliskiren; 10mg/kg/day, n=10), MI (n=11), or MI and aliskiren (MI+Aliskiren, n=11). After 4 weeks, MI mice showed left ventricular dilation and dysfunction, which were not affected by aliskiren. The percent decrease of blood glucose after insulin load was significantly smaller in MI than in Sham (14±5% vs. 36±2%), and was ameliorated in MI+Aliskiren (34±5%) mice. Insulin-stimulated serine-phosphorylation of Akt and glucose transporter 4 translocation were decreased in the skeletal muscle of MI compared to Sham by 57% and 69%, and both changes were ameliorated in the MI+Aliskiren group (91% and 94%). Aliskiren administration in MI mice significantly inhibited plasma renin activity and angiotensin II (Ang II) levels. Moreover, (pro)renin receptor expression and local Ang II production were upregulated in skeletal muscle from MI and were attenuated in MI+Aliskiren mice, in tandem with a decrease in superoxide production and NAD(P)H oxidase activities. In conclusion, aliskiren ameliorated insulin resistance in HF by improving insulin signaling in the skeletal muscle, at least partly by inhibiting systemic and (pro)renin receptor-mediated local RAS activation, and subsequent NAD(P)H oxidase-induced oxidative stress.

  20. The Antidiabetic Effect of Garlic Oil is Associated with Ameliorated Oxidative Stress but Not Ameliorated Level of Pro-inflammatory Cytokines in Skeletal Muscle of Streptozotocin-induced Diabetic Rats.

    PubMed

    Liu, Cheng-Tzu; Hsu, Tien-Wei; Chen, Ke-Ming; Tan, Ya-Ping; Lii, Chong-Kuei; Sheen, Lee-Yan

    2012-04-01

    Oxidative stress and inflammatory condition has been broadly accepted being associated with the progression of diabetes. On the other hand, garlic ( dà suàn, bulb of Allium sativum) has been shown to possess both antioxidant and anti-inflammatory action in several clinical conditions. Our previous study demonstrated that treatment with garlic oil improves oral glucose tolerance and insulin tolerance and improves the insulin-stimulated utilization of glucose to synthesize glycogen in skeletal muscle in streptozotocin (STZ)-induced diabetes, in vivo and ex vivo, respectively. The aim of the present study is to investigate the antioxidant and anti-inflammatory effects of garlic oil (GO) in the skeletal muscle of diabetic rats. Rats with STZ-induced diabetes received GO (10, 50, or 100 mg/kg body weight) or corn oil by gavage every other day for 3 weeks. Control rats received corn oil only. GO dose-dependently improved insulin sensitivity, as assessed by the insulin tolerance test, and oral glucose tolerance. GO significantly elevated total glutathione and glutathione peroxidase activity and lowered the nitrate/nitrite content in skeletal muscle at 50 and 100 mg/kg and significantly elevated glutathione reductase activity and lowered lipid peroxidation at 100 mg/kg. By contrast, GO did not reverse diabetes-induced elevation of IL-1β and TNF-α in skeletal muscle at any tested dose. On the other hand, GO elevated the expression of GLUT4 in skeletal muscle along with glycogen content as observed with PAS staining. In conclusion, the antidiabetic effect of garlic oil is associated with ameliorated oxidative stress in skeletal muscle.

  1. The Antidiabetic Effect of Garlic Oil is Associated with Ameliorated Oxidative Stress but Not Ameliorated Level of Pro-inflammatory Cytokines in Skeletal Muscle of Streptozotocin-induced Diabetic Rats

    PubMed Central

    Liu, Cheng-Tzu; Hsu, Tien-Wei; Chen, Ke-Ming; Tan, Ya-Ping; Lii, Chong-Kuei; Sheen, Lee-Yan

    2012-01-01

    Oxidative stress and inflammatory condition has been broadly accepted being associated with the progression of diabetes. On the other hand, garlic (大蒜 dà suàn, bulb of Allium sativum) has been shown to possess both antioxidant and anti-inflammatory action in several clinical conditions. Our previous study demonstrated that treatment with garlic oil improves oral glucose tolerance and insulin tolerance and improves the insulin-stimulated utilization of glucose to synthesize glycogen in skeletal muscle in streptozotocin (STZ)-induced diabetes, in vivo and ex vivo, respectively. The aim of the present study is to investigate the antioxidant and anti-inflammatory effects of garlic oil (GO) in the skeletal muscle of diabetic rats. Rats with STZ-induced diabetes received GO (10, 50, or 100 mg/kg body weight) or corn oil by gavage every other day for 3 weeks. Control rats received corn oil only. GO dose-dependently improved insulin sensitivity, as assessed by the insulin tolerance test, and oral glucose tolerance. GO significantly elevated total glutathione and glutathione peroxidase activity and lowered the nitrate/nitrite content in skeletal muscle at 50 and 100 mg/kg and significantly elevated glutathione reductase activity and lowered lipid peroxidation at 100 mg/kg. By contrast, GO did not reverse diabetes-induced elevation of IL-1β and TNF-α in skeletal muscle at any tested dose. On the other hand, GO elevated the expression of GLUT4 in skeletal muscle along with glycogen content as observed with PAS staining. In conclusion, the antidiabetic effect of garlic oil is associated with ameliorated oxidative stress in skeletal muscle. PMID:24716126

  2. PACAP-deficient mice show attenuated corticosterone secretion and fail to develop depressive behavior during chronic social defeat stress.

    PubMed

    Lehmann, Michael L; Mustafa, Tomris; Eiden, Adrian M; Herkenham, Miles; Eiden, Lee E

    2013-05-01

    The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) regulates activation of the hypothalamic-pituitary-adrenal (HPA) axis and the adrenal gland in response to various stressors. We previously found that in response to acute psychological stress (restraint), elevated corticotrophin-releasing hormone (CRH) mRNA levels in the hypothalamic paraventricular nucleus (PVN) as well as elevated plasma corticosterone (CORT) were profoundly attenuated in PACAP-deficient mice. To determine whether HPA axis responses and stress-induced depressive-like behaviors in a chronic stress paradigm are affected by PACAP deficiency, we subjected mice to 14 days of social defeat stress. Defeat-exposed PACAP-/- mice showed a marked attenuation of stress-induced increases in serum CORT levels, cellular PVN ΔFosB immunostaining, and depressive-like behaviors (social interaction and forced swim tests) compared to wild-type control mice. The PACAP-/- mice showed reduced PVN FosB-positive cell numbers, but relatively elevated cell counts in several forebrain areas including the medial prefrontal cortex, after social stress. PACAP appears to be specific for mediating HPA activation only in psychological stress because marked elevations in plasma CORT after a systemic stressor (lipopolysaccharide administration) occurred regardless of genotype. We conclude that chronically elevated CORT is a key component of depressive effects of social defeat, and that attenuation of the CORT response at the level of the PVN, as well as extrahypothalamic forebrain regions, in PACAP-deficient mice protects from development of depressive behavior.

  3. Delivery of a protein transduction domain-mediated Prdx6 protein ameliorates oxidative stress-induced injury in human and mouse neuronal cells

    PubMed Central

    Singh, Shatrunjai P.; Chhunchha, Bhavana; Fatma, Nigar; Kubo, Eri; Singh, Sanjay P.

    2015-01-01

    Oxidative stress or reduced expression of naturally occurring antioxidants during aging has been identified as a major culprit in neuronal cell/tissue degeneration. Peroxiredoxin (Prdx) 6, a protective protein with GSH peroxidase and acidic calcium-independent phospholipase A2 activities, acts as a rheostat in regulating cellular physiology by clearing reactive oxygen species (ROS) and thereby optimizing gene regulation. We found that under stress, the neuronal cells displayed reduced expression of Prdx6 protein and mRNA with increased levels of ROS, and the cells subsequently underwent apoptosis. Using Prdx6 fused to TAT transduction domain, we showed evidence that Prdx6 was internalized in human brain cortical neuronal cells, HCN-2, and mouse hippocampal cells, HT22. The cells transduced with Prdx6 conferred resistance against the oxidative stress inducers paraquat, H2O2, and glutamate. Furthermore, Prdx6 delivery ameliorated damage to neuronal cells by optimizing ROS levels and overstimulation of NF-κB. Intriguingly, transduction of Prdx6 increased the expression of endogenous Prdx6, suggesting that protection against oxidative stress was mediated by both extrinsic and intrinsic Prdx6. The results demonstrate that Prdx6 expression is critical to protecting oxidative stress-evoked neuronal cell death. We propose that local or systemic application of Prdx6 can be an effective means of delaying/postponing neuronal degeneration. PMID:26447207

  4. Ameliorative effects of Rosmarinus officinalis leaf extract and Vitamin C on cadmium-induced oxidative stress in Nile tilapia Oreochromis niloticus.

    PubMed

    Al-Anazi, Marim Saleh; Virk, Promy; Elobeid, Mai; Siddiqui, Muzammil Iqbal

    2015-11-01

    The present studywas undertaken to assess the bioaccumulation potential of cadmium in liver, kidney, gills and muscles of freshwater fish, Nile tilapia Oreochromis niloticus and the changes in oxidative stress indices in liver and kidney with or without simultaneous treatment with waterborne vitamin C and rosemary leaf extract. Adult tilapia were divided into seven groups. Six groups were exposed to sublethal concentrations of Cd, three groups to 5 ppm, while other three to 10 ppm. Two groups from each of the Cd exposed groups were treated with Vitamin C (5ppm) and rosemary leaf extract (2.5 ppm) for a period of 21 days. Cadmium concentration in liver, kidneys and gills was significantly higher in the cadmium exposed groups being invariably high in the groups exposed to 10 ppm CdCl2.H2O.Treatment with Vitamin C and rosemary leaf extract significantly reduced cadmium concentration in comparison to non-treated Cd exposed groups. Treatment with Vitamin C and rosemary leaf extract significantly reduced oxidative stress in Cd exposed fish as evidenced from lower concentration of lipid peroxides and reduced activity of catalase and higher activity of superoxide dismutase in liver and kidney as compared to control fish. Reduction in Cd induced oxidative stress and bioaccumulation was comparable between the two antioxidant treatments, Vitamin C and rosemary leaf extract. The key findings suggest that both the antioxidants used showed ameliorative potential to reduce tissue accumulation of Cd and associated oxidative stress in fresh water fish, Nile tilapia.

  5. Selenium-containing polysaccharides from Ziyang green tea ameliorate high-fructose diet induced insulin resistance and hepatic oxidative stress in mice.

    PubMed

    Ren, Daoyuan; Hu, Yuanyuan; Luo, Yiyang; Yang, Xingbin

    2015-10-01

    The present study was designed to evaluate the effects of selenium-containing tea polysaccharides (Se-GTP) from a new variety of selenium-enriched Ziyang green tea against high fructose (HF)-induced insulin resistance and hepatic oxidative stress in mice. Healthy male Kunming mice were fed 20% high fructose water and administered 200, 400 and 800 mg per kg bw Se-GTP for 8 weeks. Mice fed HF in drinking water displayed significant insulin resistance, hepatic steatosis and oxidative stress observed by hyperglycemia and hyperinsulinemia, as well as increases in hepatic non-esterified fatty acid (NEFA) and malonaldehyde (MDA). The administration of Se-GTP at 400 and 800 mg per kg bw significantly improved insulin sensitivity, and reduced liver steatosis and oxidative stress damage, and brought back the antioxidants and hepatic lipids towards near-normal values. In the oral glucose tolerance test, the administration of Se-GTP at 400 and 800 mg per kg bw had reduced plasma glucose concentrations after 30 min of glucose loading in HF-fed mice, suggesting that Se-GTP improved glucose intolerance. Histopathological examination indicated that the impaired pancreatic/hepatic tissues were effectively restored in HF-fed mice following the Se-GTP treatment. This is the first report showing that Se-GTP can ameliorate the high fructose-induced insulin resistance and hepatic oxidative injury.

  6. Passage through the Ocular Barriers and Beneficial Effects in Retinal Ischemia of Topical Application of PACAP1-38 in Rodents

    PubMed Central

    Werling, Dora; Banks, William A.; Salameh, Therese S.; Kvarik, Timea; Kovacs, Laszlo Akos; Vaczy, Alexandra; Szabo, Edina; Mayer, Flora; Varga, Rita; Tamas, Andrea; Toth, Gabor; Biro, Zsolt; Atlasz, Tamas; Reglodi, Dora

    2017-01-01

    The neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP) has two active forms, PACAP1-27 and PACAP1-38. Among the well-established actions are PACAP’s neurotrophic and neuroprotective effects, which have also been proven in models of different retinopathies. The route of delivery is usually intravitreal in studies proving PACAP’s retinoprotective effects. Recently, we have shown that PACAP1-27 delivered as eye drops in benzalkonium-chloride was able to cross the ocular barriers and exert retinoprotection in ischemia. Since PACAP1-38 is the dominant form of the naturally occurring PACAP, our aim was to investigate whether the longer form is also able to cross the barriers and exert protective effects in permanent bilateral common carotid artery occlusion (BCCAO), a model of retinal hypoperfusion. Our results show that radioactive PACAP1-38 eye drops could effectively pass through the ocular barriers to reach the retina. Routine histological analysis and immunohistochemical evaluation of the Müller glial cells revealed that PACAP1-38 exerted retinoprotective effects. PACAP1-38 attenuated the damage caused by hypoperfusion, apparent in almost all retinal layers, and it decreased the glial cell overactivation. Overall, our results confirm that PACAP1-38 given in the form of eye drops is a novel protective therapeutic approach to treat retinal diseases. PMID:28335564

  7. Methanolic bark extract of Acacia catechu ameliorates benzo(a)pyrene induced lung toxicity by abrogation of oxidative stress, inflammation, and apoptosis in mice.

    PubMed

    Shahid, Ayaz; Ali, Rashid; Ali, Nemat; Kazim Hasan, Syed; Barnwal, Preeti; Mohammad Afzal, Shekh; Vafa, Abul; Sultana, Sarwat

    2016-12-29

    Benzo(a)pyrene [B(a)P] is a well-known carcinogen present in the environment. In this study, we evaluated the protective potential of methanolic bark extract of Acacia catechu Willd. (MEBA) against the lung toxicity induced by B(a)P in Swiss albino mice. To determine the protective efficacy of MEBA, it was orally administered to the mice at two doses (200 and 400 mg/kg body weight) once daily for 7 days. Mice were also exposed (orally) to B(a)P at a dose of 125 mg/kg body weight on 7th day. Administration of B(a)P increased the activities of toxicity markers such as LDH, LPO, and XO with a subsequent decrease in the activities of tissue anti-oxidant armory (CAT, SOD, GST, GPx, GR, QR, and GSH). It also caused activation of the apoptotic and inflammatory pathway by upregulation of TNF-α, NF-kB, COX-2, p53, bax, caspase-3, and downregulating Bcl-2. Pretreatment with MEBA at two different doses (200 and 400 mg/kg body weight) significantly ameliorates B(a)P-induced increased toxicity markers and activities of detoxifying enzymes along with the levels of glutathione content. It also significantly attenuated expression of apoptotic and inflammatory markers in the lungs. Histological results further confirmed the protective role of MEBA against B(a)P-induced lung toxicity. The results indicate that MEBA may be beneficial in ameliorating the B(a)P-induced oxidative stress, inflammation, and apoptosis in the lungs of mice.

  8. Methanolic seed extract of Vitis vinifera ameliorates oxidative stress, inflammation and ATPase dysfunction in infarcted and non-infarcted heart of streptozotocin-nicotinamide induced male diabetic rats.

    PubMed

    Giribabu, Nelli; Roslan, Josef; Rekha, Somesula Swapna; Salleh, Naguib

    2016-11-01

    We hypothesized that consumption of Vitis vinifera seed by diabetics could help to ameliorate myocardial damage. Therefore, in this study, we investigated effects of V. vinifera seed methanolic extract (VVSME) on parameters related to myocardial damage in diabetes with or without myocardial infarction (MI). Streptozotocin-nicotinamide induced diabetic rats received oral VVSME for 28days. MI was induced by intraperitoneal injection of isoproterenol on last two days. Prior to sacrifice, blood was collected and fasting blood glucose (FBG), glycated hemoglobin (HbA1c), lipid profile and insulin levels were measured. Levels of serum cardiac injury marker (troponin-I and CK-MB) were determined and histopathological changes in the heart were observed following harvesting. Levels of oxidative stress (LPO, SOD, CAT, GPx and RAGE), inflammation (NF-κB, TNF-α, IL-1β and IL-6) and cardiac ATPases (Na(+)/K(+)-ATPase and Ca(2+)-ATPase) were determined in heart homogenates. LC-MS was used to identify constituents in the extracts. Consumption of VVSME by diabetic rats with or without MI improved the metabolic profiles while decreased the cardiac injury marker levels with lesser myocardial damage observed. Additionally, VVSME consumption reduced the levels of LPO, RAGE, TNF-α, Iκκβ, NF-κβ, IL-1β and IL-6 while increased the levels of SOD, CAT, GPx, Na(+)/K(+)-ATPase and Ca(2+)-ATPase in the infarcted and non-infarcted heart of diabetic rats (p<0.05). LC-MS analysis revealed 17 major compounds in VVSME which might be responsible for the observed effects. Consumption of VVSME by diabetics helps to ameliorate damage to the infarcted and non-infarcted myocardium by decreasing oxidative stress, inflammation and cardiac ATPases dysfunctions. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  9. Comparison between PACAP- and enriched environment-induced retinal protection in MSG-treated newborn rats.

    PubMed

    Kiss, Peter; Atlasz, Tamas; Szabadfi, Krisztina; Horvath, Gabor; Griecs, Monika; Farkas, Jozsef; Matkovits, Attila; Toth, Gabor; Lubics, Andrea; Tamas, Andrea; Gabriel, Robert; Reglodi, Dora

    2011-01-10

    Pituitary adenylate cyclase activating polypeptide (PACAP) and its receptors occur throughout the nervous system, including the retina. PACAP exerts diverse actions in the eye: it influences ocular blood flow, contraction of the ciliary muscle, and has retinoprotective effects. This effect has been proven in different models of retinal degeneration. We have previously shown that PACAP protects against monosodium-glutamate (MSG)-induced damage in neonatal rats. The beneficial effects of enriched environment, another neuroprotective strategy, have long been known. Environmental enrichment has been shown to decrease different neuronal injuries. It also influences the development of the visual system. We have recently demonstrated that significant neuroprotection can be achieved in MSG-induced retinal degeneration in animals kept in an enriched environment. Combination of neuroprotective strategies often results in increased protection. Therefore, the aim of the present study was to compare the two neuroprotective strategies alone and in combination therapy. We found that both PACAP and environmental enrichment led to a similar degree of retinal protection, but the two treatments together did not lead to increased protection: their effects were not additive.

  10. PACAP system evolution and its role in melanophore function in teleost fish skin.

    PubMed

    Cardoso, João C R; Félix, Rute C; Martins, Rute S T; Trindade, Marlene; Fonseca, Vera G; Fuentes, Juan; Power, Deborah M

    2015-08-15

    Pituitary adenylate cyclase-activating polypeptide (PACAP) administered to tilapia melanophores ex-vivo causes significant pigment aggregation and this is a newly identified function for this peptide in fish. The G-protein coupled receptors (GPCRs), adcyap1r1a (encoding Pac1a) and vipr2a (encoding Vpac2a), are the only receptors in melanophores with appreciable levels of expression and are significantly (p < 0.05) down-regulated in the absence of light. Vpac2a is activated exclusively by peptide histidine isoleucine (PHI), which suggests that Pac1a mediates the melanin aggregating effect of PACAP on melanophores. Paradoxically activation of Pac1a with PACAP caused a rise in cAMP, which in fish melanophores is associated with melanin dispersion. We hypothesise that the duplicate adcyap1ra and vipr2a genes in teleosts have acquired a specific role in skin and that the melanin aggregating effect of PACAP results from the interaction of Pac1a with Ramp that attenuates cAMP-dependent PKA activity and favours the Ca(2+)/Calmodulin dependent pathway. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  11. Acylated and desacyl ghrelin are associated with hepatic lipogenesis, β-oxidation and autophagy: role in NAFLD amelioration after sleeve gastrectomy in obese rats.

    PubMed

    Ezquerro, Silvia; Méndez-Giménez, Leire; Becerril, Sara; Moncada, Rafael; Valentí, Víctor; Catalán, Victoria; Gómez-Ambrosi, Javier; Frühbeck, Gema; Rodríguez, Amaia

    2016-12-23

    Bariatric surgery improves non-alcoholic fatty liver disease (NAFLD). Our aim was to investigate the potential role of ghrelin isoforms in the resolution of hepatic steatosis after sleeve gastrectomy, a restrictive bariatric surgery procedure, in diet-induced obese rats. Male Wistar rats (n = 161) were subjected to surgical (sham operation and sleeve gastrectomy) or dietary interventions [fed ad libitum a normal (ND) or a high-fat (HFD) diet or pair-fed]. Obese rats developed hepatosteatosis and showed decreased circulating desacyl ghrelin without changes in acylated ghrelin. Sleeve gastrectomy induced a dramatic decrease of desacyl ghrelin, but increased the acylated/desacyl ghrelin ratio. Moreover, sleeve gastrectomy reduced hepatic triglyceride content and lipogenic enzymes Mogat2 and Dgat1, increased mitochondrial DNA amount and induced AMPK-activated mitochondrial FFA β-oxidation and autophagy to a higher extent than caloric restriction. In primary rat hepatocytes, the incubation with both acylated and desacyl ghrelin (10, 100 and 1,000 pmol/L) significantly increased TG content, triggered AMPK-activated mitochondrial FFA β-oxidation and autophagy. Our data suggest that the decrease in the most abundant isoform, desacyl ghrelin, after sleeve gastrectomy contributes to the reduction of lipogenesis, whereas the increased relative acylated ghrelin levels activate factors involved in mitochondrial FFA β-oxidation and autophagy in obese rats, thereby ameliorating NAFLD.

  12. Aqueous Extract from Hibiscus sabdariffa Linnaeus Ameliorate Diabetic Nephropathy via Regulating Oxidative Status and Akt/Bad/14-3-3γ in an Experimental Animal Model

    PubMed Central

    Wang, Shou-Chieh; Lee, Shiow-Fen; Wang, Chau-Jong; Lee, Chao-Hsin; Lee, Wen-Chin; Lee, Huei-Jane

    2011-01-01

    Several studies point out that oxidative stress maybe a major culprit in diabetic nephropathy. Aqueous extract of Hibiscus sabdariffa L. (HSE) has been demonstrated as having beneficial effects on anti-oxidation and lipid-lowering in experimental studies. This study aimed at investigating the effects of Hibiscus sabdariffa L. on diabetic nephropathy in streptozotocin induced type 1 diabetic rats. Our results show that HSE is capable of reducing lipid peroxidation, increasing catalase and glutathione activities significantly in diabetic kidney, and decreasing the plasma levels of triglyceride, low-density lipoprotein (LDL) and increasing high-density lipoprotein (HDL) value. In histological examination, HSE improves hyperglycemia-caused osmotic diuresis in renal proximal convoluted tubules (defined as hydropic change) in diabetic rats. The study also reveals that up-regulation of Akt/Bad/14-3-3γ and NF-κB-mediated transcription might be involved. In conclusion, our results show that HSE possesses the potential effects to ameliorate diabetic nephropathy via improving oxidative status and regulating Akt/Bad/14-3-3γ signaling. PMID:19965962

  13. Acylated and desacyl ghrelin are associated with hepatic lipogenesis, β-oxidation and autophagy: role in NAFLD amelioration after sleeve gastrectomy in obese rats

    PubMed Central

    Ezquerro, Silvia; Méndez-Giménez, Leire; Becerril, Sara; Moncada, Rafael; Valentí, Víctor; Catalán, Victoria; Gómez-Ambrosi, Javier; Frühbeck, Gema; Rodríguez, Amaia

    2016-01-01

    Bariatric surgery improves non-alcoholic fatty liver disease (NAFLD). Our aim was to investigate the potential role of ghrelin isoforms in the resolution of hepatic steatosis after sleeve gastrectomy, a restrictive bariatric surgery procedure, in diet-induced obese rats. Male Wistar rats (n = 161) were subjected to surgical (sham operation and sleeve gastrectomy) or dietary interventions [fed ad libitum a normal (ND) or a high-fat (HFD) diet or pair-fed]. Obese rats developed hepatosteatosis and showed decreased circulating desacyl ghrelin without changes in acylated ghrelin. Sleeve gastrectomy induced a dramatic decrease of desacyl ghrelin, but increased the acylated/desacyl ghrelin ratio. Moreover, sleeve gastrectomy reduced hepatic triglyceride content and lipogenic enzymes Mogat2 and Dgat1, increased mitochondrial DNA amount and induced AMPK-activated mitochondrial FFA β-oxidation and autophagy to a higher extent than caloric restriction. In primary rat hepatocytes, the incubation with both acylated and desacyl ghrelin (10, 100 and 1,000 pmol/L) significantly increased TG content, triggered AMPK-activated mitochondrial FFA β-oxidation and autophagy. Our data suggest that the decrease in the most abundant isoform, desacyl ghrelin, after sleeve gastrectomy contributes to the reduction of lipogenesis, whereas the increased relative acylated ghrelin levels activate factors involved in mitochondrial FFA β-oxidation and autophagy in obese rats, thereby ameliorating NAFLD. PMID:28008992

  14. Multimodal Neuroprotection Induced by PACAP38 in Oxygen–Glucose Deprivation and Middle Cerebral Artery Occlusion Stroke Models

    PubMed Central

    Cohen, Gadi; Arien-Zakay, Hadar; Chen, Jieli; Zhang, Chunling; Chopp, Michael; Jiang, Hao

    2014-01-01

    Pituitary adenylate cyclase activating peptide (PACAP), a potent neuropeptide which crosses the blood–brain barrier, is known to provide neuroprotection in rat stroke models of middle cerebral artery occlusion (MCAO) by mechanism(s) which deserve clarification. We confirmed that following i.v. injection of 30 ng/kg of PACAP38 in rats exposed to 2 h of MCAO focal cerebral ischemia and 48 h reoxygenation, 50 % neuroprotection was measured by reduced caspase-3 activity and volume of cerebral infarction. Similar neuroprotective effects were measured upon PACAP38 treatment of oxygen–glucose deprivation and reoxygenation of brain cortical neurons. The neuroprotection was temporally associated with increased expression of brain-derived neurotrophic factor, phosphorylation of its receptor—tropomyosin-related kinase receptor type B (trkB), activation of phosphoinositide 3-kinase and Akt, and reduction of extracellular signal-regulated kinases 1/2 phosphorylation. PACAP38 increased expression of neuronal markers beta-tubulin III, microtubule-associated protein-2, and growth-associated protein-43. PACAP38 induced stimulation of Rac and suppression of Rho GTPase activities. PACAP38 down-regulated the nerve growth factor receptor (p75NTR) and associated Nogo-(Neurite outgrowth-A) receptor. Collectively, these in vitro and in vivo results propose that PACAP exhibits neuroprotective effects in cerebral ischemia by three mechanisms: a direct one, mediated by PACAP receptors, and two indirect, induced by neurotrophin release, activation of the trkB receptors and attenuation of neuronal growth inhibitory signaling molecules p75NTR and Nogo receptor. PMID:22678884

  15. Multimodal neuroprotection induced by PACAP38 in oxygen-glucose deprivation and middle cerebral artery occlusion stroke models.

    PubMed

    Lazarovici, Philip; Cohen, Gadi; Arien-Zakay, Hadar; Chen, Jieli; Zhang, Chunling; Chopp, Michael; Jiang, Hao

    2012-11-01

    Pituitary adenylate cyclase activating peptide (PACAP), a potent neuropeptide which crosses the blood-brain barrier, is known to provide neuroprotection in rat stroke models of middle cerebral artery occlusion (MCAO) by mechanism(s) which deserve clarification. We confirmed that following i.v. injection of 30 ng/kg of PACAP38 in rats exposed to 2 h of MCAO focal cerebral ischemia and 48 h reoxygenation, 50 % neuroprotection was measured by reduced caspase-3 activity and volume of cerebral infarction. Similar neuroprotective effects were measured upon PACAP38 treatment of oxygen-glucose deprivation and reoxygenation of brain cortical neurons. The neuroprotection was temporally associated with increased expression of brain-derived neurotrophic factor, phosphorylation of its receptor-tropomyosin-related kinase receptor type B (trkB), activation of phosphoinositide 3-kinase and Akt, and reduction of extracellular signal-regulated kinases 1/2 phosphorylation. PACAP38 increased expression of neuronal markers beta-tubulin III, microtubule-associated protein-2, and growth-associated protein-43. PACAP38 induced stimulation of Rac and suppression of Rho GTPase activities. PACAP38 downregulated the nerve growth factor receptor (p75(NTR)) and associated Nogo-(Neurite outgrowth-A) receptor. Collectively, these in vitro and in vivo results propose that PACAP exhibits neuroprotective effects in cerebral ischemia by three mechanisms: a direct one, mediated by PACAP receptors, and two indirect, induced by neurotrophin release, activation of the trkB receptors and attenuation of neuronal growth inhibitory signaling molecules p75(NTR) and Nogo receptor.

  16. Presence of pituitary adenylate cyclase-activating polypeptide (PACAP) in the plasma and milk of ruminant animals.

    PubMed

    Czegledi, Levente; Tamas, Andrea; Borzsei, Rita; Bagoly, Terez; Kiss, Peter; Horvath, Gabriella; Brubel, Reka; Nemeth, Jozsef; Szalontai, Balint; Szabadfi, Krisztina; Javor, Andras; Reglodi, Dora; Helyes, Zsuzsanna

    2011-05-15

    Milk contains a variety of proteins and peptides that possess biological activity. Growth factors, such as growth hormone, insulin-like, epidermal and nerve growth factors are important milk components which may regulate growth and differentiation in various neonatal tissues and also those of the mammary gland itself. We have recently shown that pituitary adenylate cyclase-activating polypeptide (PACAP), an important neuropeptide with neurotrophic actions, is present in the human milk in much higher concentration than in the plasma of lactating women. Investigation of growth factors in the milk of domestic animals is of utmost importance for their nutritional values and agricultural significance. Therefore, the aim of the present study was to determine the presence and concentration of PACAP in the plasma and milk of three ruminant animal species. Furthermore, the presence of PACAP and its specific PAC1 receptor were investigated in the mammary glands. Radioimmunoassay measurements revealed that PACAP was present in the plasma and the milk of the sheep, goat and the cow in a similar concentration to that measured previously in humans. PACAP38-like immunoreactivity (PACAP38-LI) was 5-20-fold higher in the milk than in the plasma samples of the respective animals, a similar serum/milk ratio was found in all the three species. The levels did not show significant changes within the examined 3-month-period of lactation after delivery. Similar PACAP38-LI was measured in the homogenates of the sheep mammary gland samples taken 7 and 30 days after delivery. PAC1 receptor expression was detected in these udder biopsies by fluorescent immunohistochemistry suggesting that this peptide might have an effect on the mammary glands themselves. These data show that PACAP is present in the milk of various ruminant domestic animal species at high concentrations, the physiological implications of which awaits further investigation. Copyright © 2010 Elsevier Inc. All rights reserved.

  17. Correlation between oocyte number and follicular fluid concentration of pituitary adenylate cyclase-activating polypeptide (PACAP) in women after superovulation treatment.

    PubMed

    Koppan, M; Varnagy, A; Reglodi, D; Brubel, R; Nemeth, J; Tamas, A; Mark, L; Bodis, J

    2012-11-01

    Follicular growth, ovulation, and luteinization are influenced by interactions of peptide and steroid hormone-signaling cascades in the ovary. Pituitary adenylate cyclase-activating polypeptide (PACAP) plays an important role in the regulation of several endocrine processes and is present in ovarian follicular fluid (FF). However, little is known about PACAP in FF with regard to maturation, ovulation, fertilization, and successful pregnancy. The aim of this pilot study was to investigate whether there is a correlation between PACAP concentration in FF and ovarian response to superovulation treatment in infertile women, performed in volunteers (n = 132; aged between 20 and 35). After treatment, the number of harvested oocytes was recorded and PACAP immunoreactivity in FF was measured by radioimmunoassay. All the corresponding PACAP concentrations were below 290 fmol/ml in cases when the number of harvested oocytes exceeded 14 per patient, while in all cases above 290 fmol/ml, the number of oocytes was below 14. Using these cutoff values, we determined three study groups: high-PACAP concentration, high-oocyte number, and low-PACAP concentration-low-oocyte number groups. Median values of PACAP concentration in these groups were 411.2, 106.5, and 101.0 fmol/ml, respectively, while the median values of harvested oocytes were 5.5, 19.0, and 5.0, respectively. Differences were significant, indicating a correlation between concentration of PACAP in FF and the number of recruited oocytes. Higher concentrations of PACAP in FF might be associated with lower number of developing oocytes, while low concentrations of PACAP might correlate with a markedly higher number of ova retrieved, thus predicting a higher chance for ovarian hyperstimulation. Our present study is among the first few human clinical studies with direct conclusions drawn for possible clinical impact of PACAP.

  18. PACAP Protects Against Salsolinol-Induced Toxicity in Dopaminergic SH-SY5Y Cells: Implication for Parkinson’s Disease

    PubMed Central

    Brown, Dwayne; Tamas, Andrea; Reglodi, Dora; Tizabi, Yousef

    2013-01-01

    Pituitary adenylate cyclase-activating polypeptide (PACAP) is an endogenous 38 amino acid containing neuropeptide with various cytoprotective functions including neuroprotection. Administration of PACAP has been shown to reduce damage induced by ischemia, trauma or exogenous toxic substances. Moreover, mice deficient in PACAP are more vulnerable to damaging insults. In this study we sought to determine whether PACAP may also be protective against salsolinol-induced toxicity in SH-SY5Y cells and if so, elucidate its mechanism(s) of action. Salsolinol (SALS) is an endogenous dopamine metabolite with selective toxicity to nigral dopaminergic neurons, which are directly implicated in Parkinson’s disease (PD). SH-SY5Y cells, derived from human neuroblastoma cells express high levels of dopaminergic activity and are used extensively as a model to study these neurons. Exposure of SH-SY5Y cells to 400uM SALS for 24 h resulted in approximately 50% cell death that was mediated by apoptosis as determined by cell flow cyotmetry and increases in caspase 3 levels. Cellular toxicity was also associated with reductions in brain-derived neurotrophic factor (BDNF) and phosphorylated cyclic AMP response element-binding (p-CREB) protein. Pretreatment with PACAP dose-dependently attenuated SALS-induced toxicity and the associated apoptosis and the chemical changes. PACAP receptor antagonist PACAP 6-38 in turn, dose-dependently blocked the effects of PACAP. Neither PACAP nor PACAP antagonist had any effect of its own on cellular viability. These results suggest protective effects of PACAP in a cellular model of PD. Hence, PACAP or its agonists could be of therapeutic benefit in PD. PMID:23625270

  19. Lycopene ameliorates atrazine-induced oxidative damage in adrenal cortex of male rats by activation of the Nrf2/HO-1 pathway.

    PubMed

    Abass, Marwa Ahmed; Elkhateeb, Shereen Ahmed; Abd El-Baset, Samia Adel; Kattaia, Asmaa Alhosiny; Mohamed, Eman Mosallam; Atteia, Hebatallah Husseini

    2016-08-01

    Atrazine (ATZ) is one of the most commonly used herbicides contaminating plants, soil and water resources. Several strategies have been used to counteract ATZ toxicity. Here, we tested the hypothesis that lycopene could ameliorate ATZ-induced toxicity in the adrenal cortex. For this purpose, 35 adult male albino rats were randomized into five equal groups: untreated control, vehicle control (received 0.5 mL corn oil/day), lycopene (treated with lycopene dissolved in 0.5 mL corn oil, 10 mg/kg b.w./day), ATZ (received ATZ dissolved in 0.5 mL corn oil 300 mg/kg b.w./day), and ATZ + lycopene (treated with ATZ and lycopene at the same previously mentioned doses). All treatments were given by oral gavage for 4 weeks. We found that ATZ exposure significantly increased relative adrenal weight, plasma ACTH levels, and adrenal oxidative stress as manifested by elevated malondialdehyde levels, decreased reduced glutathione content and depressed antioxidant enzyme activities in adrenal cortex tissues with respect to control groups. Furthermore, the transcription of adrenal cortex nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), nuclear factor kappa B, and caspase-3 genes was increased significantly compared with the control groups. This was accompanied with DNA fragmentation and structural and ultrastructural changes in zona glomerulosa and zona fasiculata of the adrenal cortex. Notably, all these changes were partially ameliorated in rats treated concomitantly with ATZ and lycopene. Our results showed that lycopene exerts protective effects against ATZ-induced toxicity in rat adrenal cortex. These effects may be attributed to the antioxidative property of lycopene and its ability to activate the Nrf2/HO-1 pathway.

  20. Natural amelioration of Zinc oxide nanoparticle toxicity in fenugreek (Trigonella foenum-gracum) by arbuscular mycorrhizal (Glomus intraradices) secretion of glomalin.

    PubMed

    Ghasemi Siani, Narges; Fallah, Seyfollah; Pokhrel, Lok Raj; Rostamnejadi, Ali

    2017-03-01

    Owing to rising production and use of engineered nanoparticles (ENPs) in the myriad of consumer applications, ENPs are being released into the environment where their potential fate and effects have remained unclear. With naturally occurring arbuscular mycorrhizal fungus (AMF; Glomus intraradices) in soils, their influence (positive or negative) on ENPs toxicity in plants is not well documented. Herein, we investigated potential influence of AMF on the growth and development in fenugreek (Trigonella foenum-graecum) under varied Zinc oxide nanoparticles (ZnONPs) treatments (0, 125, 250, 375 and 500 μg g(-1)). Results showed that in the absence of AMF, increasing ZnONPs concentrations caused significant decline in root nodule number and biomass in fenugreek. In non-AMF plants, shoot length, and biomass of both root and shoot decreased at ≥375 μg g(-1) of ZnONPs treatment; while Zn uptake by shoot and root increased as a function of ZnONPs treatments. Interestingly, AMF colonization in roots significantly diminished at 375 μg g(-1) ZnONPs treatment compared to controls. More importantly, AMF inoculation ameliorated inhibitory effects of ZnONPs by promoting secretion of glycoprotein called glomalin-a potent metal chelator-within the rhizosphere, which significantly reduced (by almost half) Zn uptake by root and subsequent translocation to the shoot. AMF inoculation (high glomalin secretion)-mediated low Zn uptake might have been stimulatory to promote root and shoot growth in fenugreek. The results highlight significant protective roles of rhizospheric AMF through glomalin secretion thereby ameliorating nanotoxicity in plants, and underscore the need to include soil-microbial interactions when assessing nanophytotoxicology and risks. Furthermore, potential positive implications to other organisms in the food chain can be inferred due to low tropic transfer of ENPs and/or associated toxic dissolved ions in the presence of naturally occurring soil fingi.

  1. Effect of virgin coconut oil enriched diet on the antioxidant status and paraoxonase 1 activity in ameliorating the oxidative stress in rats - a comparative study.

    PubMed

    Arunima, S; Rajamohan, T

    2013-09-01

    Virgin coconut oil (VCO) extracted by wet processing is popular among the scientific field and society nowadays. The present study was carried out to examine the comparative effect of VCO with copra oil (CO), olive oil (OO) and sunflower oil (SFO) on endogenous antioxidant status and paraoxonase 1 activity in ameliorating the oxidative stress in rats. Male Sprague-Dawley rats were fed different oils at 8% level for 45 days along with the synthetic diet. Results revealed that dietary VCO improved the antioxidant status compared to other three oil fed groups (P < 0.05), which is evident from the increased activities of catalase, superoxide dismutase, glutathione peroxidase and glutathione reductase in tissues. Concentration of reduced glutathione was also found to be increased significantly in liver (532.97 mM per 100 g liver), heart (15.77 mM per 100 g heart) and kidney (1.58 mM per 100 g kidney) of VCO fed rats compared to those fed with CO, OO and SFO (P < 0.05). In addition, the activity of paraoxonase 1 was significantly increased in VCO fed rats compared to other oil fed groups (P < 0.05). Furthermore, VCO administration prevented the oxidative stress, which is indicated by the decreased formation of lipid peroxidation and protein oxidation products like malondialdehyde, hydroperoxides, conjugated dienes and protein carbonyls in serum and tissues compared to other oil fed rats (P < 0.05). Wet processing of VCO retains higher amounts of biologically active unsaponifiable components like polyphenols (84 mg per 100 g oil) and tocopherols (33.12 μg per 100 g oil) etc. compared to other oils (P < 0.05). From these observations, it is concluded that VCO has a beneficial role in improving antioxidant status and hence preventing lipid and protein oxidation.

  2. Yhhu981, a novel compound, stimulates fatty acid oxidation via the activation of AMPK and ameliorates lipid metabolism disorder in ob/ob mice

    PubMed Central

    Zeng, Hong-liang; Huang, Su-ling; Xie, Fu-chun; Zeng, Li-min; Hu, You-hong; Leng, Ying

    2015-01-01

    Aim: Defects in fatty acid metabolism contribute to the pathogenesis of insulin resistance and obesity. In this study, we investigated the effects of a novel compound yhhu981 on fatty acid metabolism in vitro and in vivo. Methods: The capacity to stimulate fatty acid oxidation was assessed in C2C12 myotubes. The fatty acid synthesis was studied in HepG2 cells using isotope tracing. The phosphorylation of AMPK and acetyl-CoA carboxylase (ACC) was examined with Western blot analysis. For in vivo experiments, ob/ob mice were orally treated with yhhu981 acutely (300 mg/kg) or chronically (150 or 300 mg·kg−1·d−1 for 22 d). On the last day of treatment, serum and tissue samples were collected for analysis. Results: Yhhu981 (12.5–25 μmol/L) significantly increased fatty acid oxidation and the expression of related genes (Sirt1, Pgc1α and Mcad) in C2C12 myotubes, and inhibited fatty acid synthesis in HepG2 cells. Furthermore, yhhu981 dose-dependently increased the phosphorylation of AMPK and ACC in both C2C12 myotubes and HepG2 cells. Compound C, an AMPK inhibitor, blocked fatty acid oxidation in yhhu981-treated C2C12 myotubes and fatty acid synthesis decrease in yhhu981-treated HepG2 cells. Acute administration of yhhu981 decreased the respiratory exchange ratio in ob/ob mice, whereas chronic treatment with yhhu981 ameliorated the lipid abnormalities and ectopic lipid deposition in skeletal muscle and liver of ob/ob mice. Conclusion: Yhhu981 is a potent compound that stimulates fatty acid oxidation, and exerts pleiotropic effects on lipid metabolism by activating AMPK. PMID:25732571

  3. PACAP is transiently expressed in anterior pituitary gland of rats: in situ hybridization and cell immunoblot assay studies.

    PubMed

    Heinzlmann, Andrea; Kirilly, Eszter; Meltzer, Kinga; Szabó, Eniko; Baba, Akemichi; Hashimoto, Hitoshi; Köves, Katalin

    2008-04-01

    In this work the expression of PACAP (pituitary adenylate cyclase activating polypeptide) in rat anterior pituitary was demonstrated for the first time using in situ hybridization. The number of cells showing PACAP signal in intact male rats was negligible similarly to that of diestrous rats. In proestrous rats sacrificed at 10h there was a moderate increase in the expression and after a decrease at 16 h and 18 h, there was a transient peak at 20 h and then the number of labeled cells was declined again (22 h). In the cell immunoblot assay study it was observed that the number of PACAP blot forming (PACAP releasing) cells in an anterior pituitary cell culture changed according to a similar pattern as the number of PACAP expressing cells. The number of blots was also the highest when the animals were sacrificed in the evening of proestrus at 20h. The results obtained by in situ hybridization and cell immunoblot assay well correlate with each other. The above-mentioned results support our hypothesis that the enhanced expression and secretion of PACAP in the pituitary gland may be involved in ceasing the LH surge.

  4. Momordica charantia polysaccharides ameliorate oxidative stress, hyperlipidemia, inflammation, and apoptosis during myocardial infarction by inhibiting the NF-κB signaling pathway.

    PubMed

    Raish, Mohammad

    2017-04-01

    The polysaccharide extract of Momordica charantia has various biological activities; however, its effect on endothelial dysfunction in myocardial infarction remains unclear. To elucidate this, myocardial infarction was induced in rats using isoproterenol (ISP). Pretreatment with M. charantia polysaccharides (MCP; 150 or 300mg/kg) for 25days significantly inhibited increases in heart weight, the heart-weight-to-body-weight ratio, and infarction size, and ameliorated the increased serum levels of aspartate transaminase, creatine kinase, lactate dehydrogenase, total cholesterol, triglycerides, very-low-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. In addition, MCP enhanced the activity of superoxide dismutase, catalase, and non-protein sulfhydryls, and decreased the level of lipid peroxidation. Moreover, MCP pretreatment downregulated the expression of proinflammatory cytokines (tumor necrosis factor alpha, interleukin (IL)-6, and IL-10), inflammatory markers (nitric oxide, myeloperoxidase, and inducible nitric oxide synthase), and apoptotic markers (caspase-3 and BAX), and upregulated Bcl-2 expression. Pretreatment with MCP reduced myonecrosis, edema, and inflammatory cell infiltration, and restored cardiomyocytes architecture. This myocardial protective effect could be related to the enhancement of the antioxidant defense system through the nuclear factor kappa B (NF-kB) pathways, and to anti-apoptosis through regulation of Bax, caspase-3, and Bcl-2. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Anti-convulsant action and amelioration of oxidative stress by Glycyrrhiza glabra root extract in pentylenetetrazole- induced seizure in albino rats.

    PubMed

    Chowdhury, Bimalendu; Bhattamisra, Subrat K; Das, Mangala C

    2013-01-01

    The aim of the present study was to evaluate the anti-convulsant potential of aqueous and ethanol e xtract of Glycyrrhiza glabra (AEGG and EEGG) and its action on markers of oxidant stress in albino rats. The aqueous and ethanol extract of Glycyrrhiza glabra was tested at three doses viz. 100, 200, and 400 mg/kg i.p. for its anti-convulsant activity using pentylenetetrazole (PTZ)-induced seizure in rat. The effect of EEGG (400 mg/kg, i.p.) on oxidative stress markers like malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) of rat brain tissue homogenate was tested. The onset of seizure was delayed (P < 0.01) by all the three doses of EEGG, but the duration of convulsion was reduced (P < 0.01) only in higher dose level (200 and 400 mg/ kg), whereas AEGG up to 400 mg/kg did not alter any of the parameters significantly. Biochemical analysis of rat brain tissue revealed that MDA was increased (P < 0.01), whereas SOD and CAT were decreased (P < 0.01) in PTZ-induced seizure rat, whereas pre-treatment with EEGG (400 mg/kg) decreased (P < 0.01) the MDA and increased (P < 0.01) both SOD and CAT, indicating attenuation of lipid peroxidation due to increase in antioxidant enzymes. The results demonstrated that EEGG poses anti-convulsant potential and ameliorates ROS induced neuronal damage in PTZ-induced seizure.

  6. Dehydroepiandrosterone ameliorates H2O2-induced Leydig cells oxidation damage and apoptosis through inhibition of ROS production and activation of PI3K/Akt pathways.

    PubMed

    Ding, Xiao; Wang, Dian; Li, Longlong; Ma, Haitian

    2016-01-01

    Dehydroepiandrosterone (DHEA) is widely used as a nutritional supplement, and administration of DHEA produces a number of beneficial effects in the elderly. Many researchers have suggested that DHEA exerts it function after conversion into more biologically active hormones in peripheral target cells. The actions of DHEA in Leydig cells, a major target cell of DHEA biotransformation in males, are not clear. The present study found that DHEA increased cell viability and decreased reactive oxygen species (ROS) and malondialdehyde contents in H2O2-induced Leydig cells. DHEA significantly increased the activities of superoxide dismutase, catalase and peroxidase, and decreased the DNA damage in H2O2-induced Leydig cells. Apoptosis was significant decreased in H2O2-induced Leydig cells after DHEA treatment. DHEA inhibited the loss of mitochondrial membrane potential (ΔΨm) and the upregulation of the caspase-3 protein level induced by H2O2 in Leydig cells. DHEA also reversed the decrease in PI3K and p-Akt protein levels induced by H2O2. These data showed that DHEA could ameliorate H2O2-induced oxidative damage by increasing anti-oxidative enzyme activities, which resulted in reduced ROS content, and decreased apoptosis, mainly by preventing the loss of ΔΨm and inhibiting caspase-3 protein levels via activation of PI3K/Akt signaling pathways. These results increase our understanding of the molecular mechanism of the anti-ageing effect of DHEA.

  7. Hydroalcoholic extract of cyperus rotundus ameliorates H2O2-induced human neuronal cell damage via its anti-oxidative and anti-apoptotic machinery.

    PubMed

    Kumar, K Hemanth; Khanum, Farhath

    2013-01-01

    Hydrogen peroxide (H(2)O(2)), a major reactive oxygen species produced during oxidative stress, has been implicated in the pathophysiology of various neurodegenerative conditions. Cyperus rotundus is a traditional medicinal herb that has recently found applications in food and confectionary industries. In the current study, the neuroprotective effects of Cyperus rotundus rhizome extract (CRE) through its antioxidant and anti-apoptotic machinery to attenuate H(2)O(2)-induced cell damage on human neuroblastoma SH-SY5Y cells have been explored. The results obtained demonstrate that pretreatment of cells with CRE for 2 h before administration of H(2)O(2) for 24 h ameliorates the cytotoxicity induced by H(2)O(2) as evidenced by MTT and LDH assays. CRE exhibited potent antioxidant activity by regulating the enzymes/proteins levels such as SOD, CAT, GPx, GR, HSP-70, Caspase-3, and Bcl-2. The pretreatment restored H(2)O(2)-induced cellular, nuclear, and mitochondrial morphologies as well as increased the expression of Brain derived nerve growth factor (BDNF). The anti-oxidant and anti-apoptotic potentials of the plant extract may account for its high content of phenolics, flavonoids, and other active principles. Taken together, our findings suggest that CRE might be developed as an agent for neurodegeneration prevention or therapy.

  8. Ameliorating effect of chicory (Cichorium intybus L.)-supplemented diet against nitrosamine precursors-induced liver injury and oxidative stress in male rats.

    PubMed

    Hassan, Hanaa A; Yousef, Mokhtar I

    2010-01-01

    The current study was carried out to elucidate the modulating effect of chicory (Cichorium intybus L.)-supplemented diet against nitrosamnine-induced oxidative stress and hepatotoxicity in male rats. Rats were divided into four groups and treated for 8 weeks as follow: group 1 served as control; group 2 fed on chicory-supplemented diet (10% w/w); group 3 received simultaneously nitrosamine precursors [sodium nitrite (0.05% in drinking water) plus chlorpromazine (1.7 mg/kg body weight)] and group 4 received nitrosamine precursors and fed on chicory-supplemented diet. The obtained results revealed that rats received nitrosamine precursors showed a significant increase in liver TBARS and total lipids, total cholesterol, bilirubin, and enzymes activity (AST, ALT, ALP and gamma-GT) in both serum and liver. While a significant decrease in the levels of GSH, GSH-Rx, SOD, catalase, total protein and albumin was recorded. On the other hand, chicory-supplemented diet succeeded to modulate these observed abnormalities resulting from nitrosamine compounds as indicated by the reduction of TBARS and the pronounced improvement of the investigated biochemical and antioxidant parameters. So, it could be concluded that chicory has a promising role and it worth to be considered as a natural substance for ameliorating the oxidative stress and hepatic injury induced by nitrosamine compounds.

  9. Ameliorative effect of dietary genistein on diabetes induced hyper-inflammation and oxidative stress during early stage of wound healing in alloxan induced diabetic mice.

    PubMed

    Eo, Hyeyoon; Lee, Hea-Ji; Lim, Yunsook

    2016-09-23

    Among the diabetic complications, diabetic foot ulcer due to delayed wound healing is one of the most significant clinical problems. Early inflammatory stage is important for better prognosis during wound healing. Thus, regulation of inflammatory response during early stage of wound healing is main target for complete cutaneous recovery. This study investigated the role of genistein supplementation in inflammation and oxidative stress, which are related to NLRP3 inflammasome, NFκB and Nrf2 activation, during cutaneous wound healing in alloxan-induced diabetic mice. Mice with diabetes with fasting blood glucose (FBG) levels > 250 mg/dl were fed diets with AIN-93G rodent diet containing 0%, 0.025% (LG) or 0.1% (HG) genistein. After 2 weeks of genistein supplementation, excisional wounds were made by biopsy punches (4 mm). Genistein supplementation improved fasting glucose levels and wound closure rate. Moreover, genistein supplementation restored NLRP3 inflammasome (NLRP3, ASC and caspase-1) at the basal level and ameliorated both inflammation (TNFα, iNOS, COX2 and NFκB) and antioxidant defense system (Nrf2, HO-1, GPx, and catalase) during early stage of wound healing in diabetic mice. Taken together, genistein supplementation would be a potential therapeutic nutrient in prevention and treatment of delayed wound healing by modulation of inflammation and oxidative stress during inflammatory stage. Copyright © 2016. Published by Elsevier Inc.

  10. High-Fat Diet Augments VPAC1 Receptor-Mediated PACAP Action on the Liver, Inducing LAR Expression and Insulin Resistance.

    PubMed

    Nakata, Masanori; Zhang, Boyang; Yang, Yifei; Okada, Takashi; Shintani, Norihito; Hashimoto, Hitoshi; Yada, Toshihiko

    2016-01-01

    Pituitary adenylate cyclase-activating polypeptide (PACAP) acts on multiple processes of glucose and energy metabolism. PACAP potentiates insulin action in adipocytes and insulin release from pancreatic β-cells, thereby enhancing glucose tolerance. Contrary to these effects at organ levels, PACAP null mice exhibit hypersensitivity to insulin. However, this apparent discrepancy remains to be solved. We aimed to clarify the mechanism underlying the antidiabetic phenotype of PACAP null mice. Feeding with high-fat diet (HFD) impaired insulin sensitivity and glucose tolerance in wild type mice, whereas these changes were prevented in PACAP null mice. HFD also impaired insulin-induced Akt phosphorylation in the liver in wild type mice, but not in PACAP null mice. Using GeneFishing method, HFD increased the leukocyte common antigen-related (LAR) protein tyrosine phosphatase in the liver in wild type mice. Silencing of LAR restored the insulin signaling in the liver of HFD mice. Moreover, the increased LAR expression by HFD was prevented in PACAP null mice. HFD increased the expression of VPAC1 receptor (VPAC1-R), one of three PACAP receptors, in the liver of wild type mice. These data indicate that PACAP-VPAC1-R signaling induces LAR expression and insulin resistance in the liver of HFD mice. Antagonism of VPAC1-R may prevent progression of HFD-induced insulin resistance in the liver, providing a novel antidiabetic strategy.

  11. High-Fat Diet Augments VPAC1 Receptor-Mediated PACAP Action on the Liver, Inducing LAR Expression and Insulin Resistance

    PubMed Central

    Nakata, Masanori; Zhang, Boyang; Yang, Yifei; Okada, Takashi; Shintani, Norihito; Hashimoto, Hitoshi

    2016-01-01

    Pituitary adenylate cyclase-activating polypeptide (PACAP) acts on multiple processes of glucose and energy metabolism. PACAP potentiates insulin action in adipocytes and insulin release from pancreatic β-cells, thereby enhancing glucose tolerance. Contrary to these effects at organ levels, PACAP null mice exhibit hypersensitivity to insulin. However, this apparent discrepancy remains to be solved. We aimed to clarify the mechanism underlying the antidiabetic phenotype of PACAP null mice. Feeding with high-fat diet (HFD) impaired insulin sensitivity and glucose tolerance in wild type mice, whereas these changes were prevented in PACAP null mice. HFD also impaired insulin-induced Akt phosphorylation in the liver in wild type mice, but not in PACAP null mice. Using GeneFishing method, HFD increased the leukocyte common antigen-related (LAR) protein tyrosine phosphatase in the liver in wild type mice. Silencing of LAR restored the insulin signaling in the liver of HFD mice. Moreover, the increased LAR expression by HFD was prevented in PACAP null mice. HFD increased the expression of VPAC1 receptor (VPAC1-R), one of three PACAP receptors, in the liver of wild type mice. These data indicate that PACAP-VPAC1-R signaling induces LAR expression and insulin resistance in the liver of HFD mice. Antagonism of VPAC1-R may prevent progression of HFD-induced insulin resistance in the liver, providing a novel antidiabetic strategy. PMID:28044141

  12. Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) Pathway Is Induced by Mechanical Load and Reduces the Activity of Hedgehog Signaling in Chondrogenic Micromass Cell Cultures.

    PubMed

    Juhász, Tamás; Szentléleky, Eszter; Somogyi, Csilla Szűcs; Takács, Roland; Dobrosi, Nóra; Engler, Máté; Tamás, Andrea; Reglődi, Dóra; Zákány, Róza

    2015-07-29

    Pituitary adenylate cyclase activating polypeptide (PACAP) is a neurohormone exerting protective function during various stress conditions either in mature or developing tissues. Previously we proved the presence of PACAP signaling elements in chicken limb bud-derived chondrogenic cells in micromass cell cultures. Since no data can be found if PACAP signaling is playing any role during mechanical stress in any tissues, we aimed to investigate its contribution in mechanotransduction during chondrogenesis. Expressions of the mRNAs of PACAP and its major receptor, PAC1 increased, while that of other receptors, VPAC1, VPAC2 decreased upon mechanical stimulus. Mechanical load enhanced the expression of collagen type X, a marker of hypertrophic differentiation of chondrocytes and PACAP addition attenuated this elevation. Moreover, exogenous PACAP also prevented the mechanical load evoked activation of hedgehog signaling: protein levels of Sonic and Indian Hedgehogs and Gli1 transcription factor were lowered while expressions of Gli2 and Gli3 were elevated by PACAP application during mechanical load. Our results suggest that mechanical load activates PACAP signaling and exogenous PACAP acts against the hypertrophy inducing effect of mechanical load.

  13. Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) Pathway Is Induced by Mechanical Load and Reduces the Activity of Hedgehog Signaling in Chondrogenic Micromass Cell Cultures

    PubMed Central

    Juhász, Tamás; Szentléleky, Eszter; Szűcs Somogyi, Csilla; Takács, Roland; Dobrosi, Nóra; Engler, Máté; Tamás, Andrea; Reglődi, Dóra; Zákány, Róza

    2015-01-01

    Pituitary adenylate cyclase activating polypeptide (PACAP) is a neurohormone exerting protective function during various stress conditions either in mature or developing tissues. Previously we proved the presence of PACAP signaling elements in chicken limb bud-derived chondrogenic cells in micromass cell cultures. Since no data can be found if PACAP signaling is playing any role during mechanical stress in any tissues, we aimed to investigate its contribution in mechanotransduction during chondrogenesis. Expressions of the mRNAs of PACAP and its major receptor, PAC1 increased, while that of other receptors, VPAC1, VPAC2 decreased upon mechanical stimulus. Mechanical load enhanced the expression of collagen type X, a marker of hypertrophic differentiation of chondrocytes and PACAP addition attenuated this elevation. Moreover, exogenous PACAP also prevented the mechanical load evoked activation of hedgehog signaling: protein levels of Sonic and Indian Hedgehogs and Gli1 transcription factor were lowered while expressions of Gli2 and Gli3 were elevated by PACAP application during mechanical load. Our results suggest that mechanical load activates PACAP signaling and exogenous PACAP acts against the hypertrophy inducing effect of mechanical load. PMID:26230691

  14. Ameliorative potential of Solanum trilobatum leaf extract and fractions on lipid profile and oxidative stress in experimental diabetes.

    PubMed

    Ahmed, KhaderSyed Zameer; Sidhra, Syed Zameer Ahmed; Ponmurugan, Ponnusamy; Kumar, Balasubramanian Senthil

    2016-09-01

    Solanum trilobatum Linn is a medicinal plants used in India from many centuries to cure various diseases. The purpose of the study is to evaluate the ameliorative potential of the ethanolic leaf extract and fractions of Solanum trilobatum (St) against alloxan induced diabetic rats. Solanum trilobatum leaf extract and fractions were administered orally at two different concentration (100-200mg/kg body weight) to alloxan induced diabetic rats. The antidiabetic efficacy was validated through various biochemical parameters, enzyme assays, renal markers and antioxidant properties were also determined. The phytochemical analyses of St leaves were done by estimating their Chlorophyll, carotenoids, total sugar, protein, amino acid and minerals contents. The results revealed that the leaf extracts and fractions of St were efficient anti hyperglycemic agents and posses potent nephro-protective activity. However, the extracts of St leaves at a concentration of 200mg/kg bw exhibit higher efficacy in all tested concentrations. From the result it can be concluded that the leaf extracts of St can be a potential candidate in treating the hyperglycemic conditions and justifies its use in ethano medicine and can be exploits in the management of diabetes.

  15. Sulforaphane ameliorates the development of experimental autoimmune encephalomyelitis by antagonizing oxidative stress and Th17-related inflammation in mice.

    PubMed

    Li, Bin; Cui, Wei; Liu, Jia; Li, Ru; Liu, Qian; Xie, Xiao-Hua; Ge, Xiao-Li; Zhang, Jing; Song, Xiu-Juan; Wang, Ying; Guo, Li

    2013-12-01

    Sulforaphane (SFN) is an organosulfur compound present in vegetables and has potent anti-oxidant and anti-inflammatory activities. This study was aimed at investigating the effect of treatment with SFN on inflammation and oxidative stress, and the potential mechanisms underlying the action of SFN in experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. Treatment with SFN significantly inhibited the development and severity of EAE in mice, accompanied by mitigating inflammatory infiltration and demyelination in the spinal cord of mice. The protective effect of SFN was associated with significantly improved distribution of claudin-5 and occludin, and decreased levels of MMP-9 expression, preserving the blood-brain barrier. Furthermore, the protection of SFN was also related to decreased levels of oxidative stress in the brains of mice by enhanced activation of the Nrf2/ARE pathway and increased levels of anti-oxidant HO-1 and NQO1 expression. In addition, treatment with SFN inhibited antigen-specific Th17 responses and enhanced IL-10 responses. Our data indicated that treatment with SFN inhibited EAE development and severity in mice by its anti-oxidant activity and antagonizing autoimmune inflammation. Our findings suggest that SFN and its analogues may be promising reagents for intervention of multiple sclerosis and other autoimmune diseases. © 2013.

  16. Standardized Bacopa monnieri extract ameliorates acute paraquat-induced oxidative stress, and neurotoxicity in prepubertal mice brain.

    PubMed

    Hosamani, Ravikumar; Krishna, Gokul; Muralidhara

    2016-12-01

    Bacopa monnieri (BM), an ayurvedic medicinal plant, has attracted considerable interest owing to its diverse neuropharmacological properties. Epidemiological studies have shown significant correlation between paraquat (PQ) exposure and increased risk for Parkinson's disease in humans. In this study, we examined the propensity of standardized extract of BM to attenuate acute PQ-induced oxidative stress, mitochondrial dysfunctions, and neurotoxicity in the different brain regions of prepubertal mice. To test this hypothesis, prepubertal mice provided orally with standardized BM extract (200 mg/kg body weight/day for 4 weeks) were challenged with an acute dose (15 mg/kg body weight, intraperitoneally) of PQ after 3 hours of last dose of extract. Mice were sacrificed after 48 hours of PQ injection, and different brain regions were isolated and subjected to biochemical determinations/quantification of central monoamine (dopamine, DA) levels (by high-performance liquid chromatography). Oral supplementation of BM for 4 weeks resulted in significant reduction in the basal levels of oxidative markers such as reactive oxygen species (ROS), malondialdehyde (MDA), and hydroperoxides (HP) in various brain regions. PQ at the administered dose elicited marked oxidative stress within 48 hours in various brain regions of mice. However, BM prophylaxis significantly improved oxidative homeostasis by restoring PQ-induced ROS, MDA, and HP levels and also by attenuating mitochondrial dysfunction. Interestingly, BM supplementation restored the activities of cholinergic enzymes along with the restoration of striatal DA levels among the PQ-treated mice. Based on these findings, we infer that BM prophylaxis renders the brain resistant to PQ-mediated oxidative perturbations and thus may be better exploited as a preventive approach to protect against oxidative-mediated neuronal dysfunctions.

  17. Protective effect of berberine, an isoquinoline alkaloid ameliorates ethanol-induced oxidative stress and memory dysfunction in rats.

    PubMed

    Patil, Shaktipal; Tawari, Santosh; Mundhada, Dharmendra; Nadeem, Sayyed

    2015-09-01

    Memory impairment induced by ethanol in rats is a consequence of changes in the CNS that are secondary to impaired oxidative stress and cholinergic dysfunction. Treatment with antioxidants and cholinergic agonists are reported to produce beneficial effects in this model. Berberine, an isoquinoline alkaloid is reported to exhibit antioxidant effect and cholinesterase (ChE) inhibitor activity. However, no report is available on the influence of berberine on ethanol-induced memory impairment. Therefore, we tested its influence against cognitive dysfunction in ethanol-induced rats using Morris water maze paradigm. Lipid peroxidation and glutathione levels as parameter of oxidative stress and cholinesterase (ChE) activity as a marker of cholinergic function were assessed in the cerebral cortex and hippocampus. Forty five days after ethanol treated rats showed a severe deficit in learning and memory associated with increased lipid peroxidation, decreased glutathione, and elevated ChE activity. In contrast, chronic treatment with berberine (25-100mg/kg, p.o., once a day for 45days) improved cognitive performance, and lowered oxidative stress and ChE activity in ethanol treated rats. In another set of experiments, berberine (100mg/kg) treatment during training trials also improved learning and memory, and lowered oxidative stress and ChE activity. Chronic treatment (45days) with vitamin C, and donepezil during training trials also improved ethanol-induced memory impairment and reduced oxidative stress and/or cholinesterase activity. In conclusion, the present study demonstrates that treatment with berberine prevents the changes in oxidative stress and ChE activity, and consequently memory impairment in ethanol treated rats.

  18. Melatonin can Ameliorate Radiation-Induced Oxidative Stress and Inflammation-Related Deterioration of Bone Quality in Rat Femur.

    PubMed

    Çakir, Zelal Ünlü; Demirel, Can; Kilciksiz, Sevil Cagiran; Gürgül, Serkan; Zincircioğlu, S Burhanedtin; Erdal, Nurten

    2016-06-01

    The aim of the present study was to evaluate the radioprotective effects of melatonin on the biomechanical properties of bone in comparison to amifostine (WR-2721). Forty Sprague Dawley rats were divided equally into 5 groups namely; control (C), irradiation (R; single dose of 50 Gy), irradiation + WR-2721 (R + WR-2721; irradiation + 200 mg/kg WR-2721) radiation + melatonin 25 mg/kg (R + M25; irradiation + 25 mg/kg melatonin), and radiation + melatonin 50 mg/kg (R + M50; irradiation + 50 mg/kg melatonin). In order to measure extrinsic (organ-level mechanical properties of bone; the ultimate strength, deformation, stiffness, energy absorption capacity) and intrinsic (tissue-level mechanical properties of bone; ultimate stress, ultimate strain, elastic modulus, toughness) features of the bone, a three-point bending (TPB) test was performed for biomechanical evaluation. In addition, a bone mineral density (BMD) test was carried out. The BMD and extrinsic properties of the diaphyseal femur were found to be significantly higher in the R + M25 group than in group R (p < 0.05). A significant increase was observed in R + M50 (p < 0.05) in comparison to group R in the cross-sectional area of the femoral shaft and elastic modulus parameter. The protective effect of melatonin was similar to that of WR-2721. Thus, biomechanical quality of irradiated bone can be ameliorated by free radical scavenger melatonin.

  19. Methanol extract of Nymphaea lotus ameliorates carbon tetrachloride-induced chronic liver injury in rats via inhibition of oxidative stress.

    PubMed

    Oyeyemi, Ifeoluwa T; Akanni, Olubukola O; Adaramoye, Oluwatosin A; Bakare, Adekunle A

    2017-01-01

    Nymphaea lotus (NL) is an aquatic perennial plant used traditionally in the management of various liver diseases. In this study, the protective effect of methanol extract of NL against carbon tetrachloride (CCl4)-induced chronic hepatotoxicity in rats was investigated. Male Wistar rats were assigned into six groups of five rats each. Group I received corn oil (0.5 mL p.o.) and served as control, group II received CCl4 (1 mL/kg i.p., 1:3 in corn oil), group III received NL (200 mg/kg), and groups IV, V, and VI received CCl4+NL (50, 100, and 200 mg/kg, respectively) for 6 weeks. Twenty-four hours after the last exposure, rats were bled and killed. The activities of alanine aminotransaminase (ALT), aspartate aminotransferase (AST), and levels of total bilirubin (TB) in the serum, thiobarbituric acid reactive substances (TBARS), superoxide dismutase, catalase, glutathione peroxidase (GPx) and glutathione (GSH) in the liver, and histopathology of the liver were determined using standard procedures. NL significantly (p<0.05) lowered the levels of ALT, AST, and TB and exhibited antioxidant potentials in rats exposed to CCl4 relative to the control values. Specifically, NL at 100 and 200 mg/kg significantly (p<0.05) increased CCl4-induced decrease in hepatic GSH and GPx and also decreased the level of hepatic TBARS in CCl4-intoxicated rats. Histopathological findings revealed cellular infiltration and fibrosis in rats that received CCl4 only, which were ameliorated in rats that received NL+CCl4. The data suggest that NL exhibited hepatoprotective effects in CCl4-intoxicated rats via antioxidative mechanism.

  20. Swertiamarin ameliorates oleic acid induced lipid accumulation and oxidative stress by attenuating gluconeogenesis and lipogenesis in hepatic steatosis.

    PubMed

    Patel, Tushar P; Rawal, Komal; Soni, Sanket; Gupta, Sarita

    2016-10-01

    Swertiamarin, a bitter secoiridoid glycoside, is an antidiabetic drug with lipid lowering activity meliorates insulin resistance in Type 2 Diabetes condition. Therefore, the study was designed to explore the antioxidant and hypolipidemic activity of swertiamarin in ameliorating NAFLD caused due to hepatic lipid accumulation, inflammation and insulin resistance. Steatosis was induced in HepG2 cells by supplementing 1mM oleic acid (OA) for 24h which was marked by significant accumulation of lipid droplets. This was determined by Oil Red O (ORO) staining and triglyceride accumulation. Swertiamarin (25μg/ml) decreased triglyceride content by 2 folds and effectively reduced LDH release (50%) activity by protecting membrane integrity thus, preventing apoptosis evidenced by reduced cleavage of Caspase 3 and PARP1. We observed that swertiamarin significantly increased the expressions of major insulin signaling proteins like Insulin receptor (IR), PI(3)K, pAkt with concomitant reduction in p307 IRS-1. AMPK was activated by swertiamarin action, thus restoring insulin sensitivity in hepatocytes. In addition, qPCR results confirmed OA up-regulated Sterol Regulatory Element Binding Protein (SREBP)-1c and fatty acid synthase (FAS), resulting in increased fatty acid synthesis. Swertiamarin effectively modulated PPAR-α, a major potential regulator of carbohydrate metabolism which, in turn, decreased the levels of the gluconeogenic enzyme PEPCK, further restricting hepatic glucose production and fatty acid synthesis. Cumulatively, swertiamarin targets potential metabolic regulators AMPK and PPAR-α, through which it regulates hepatic glycemic burden, fat accumulation, insulin resistance and ROS in hepatic steatosis which emphasizes clinical significance of swertiamarin in regulating metabolism and as a suitable candidate for treating NAFLD.

  1. Endoplasmic Reticulum Stress-Induced Autophagy Provides Cytoprotection from Chemical Hypoxia and Oxidant Injury and Ameliorates Renal Ischemia-Reperfusion Injury

    PubMed Central

    Chandrika, Bhavya B.; Yang, Cheng; Ou, Yang; Feng, Xiaoke; Muhoza, Djamali; Holmes, Alexandrea F.; Theus, Sue; Deshmukh, Sarika; Haun, Randy S.; Kaushal, Gur P.

    2015-01-01

    We examined whether endoplasmic reticulum (ER) stress-induced autophagy provides cytoprotection from renal tubular epithelial cell injury due to oxidants and chemical hypoxia in vitro, as well as from ischemia-reperfusion (IR) injury in vivo. We demonstrate that the ER stress inducer tunicamycin triggers an unfolded protein response, upregulates ER chaperone Grp78, and activates the autophagy pathway in renal tubular epithelial cells in culture. Inhibition of ER stress-induced autophagy accelerated caspase–3 activation and cell death suggesting a pro-survival role of ER stress-induced autophagy. Compared to wild-type cells, autophagy-deficient MEFs subjected to ER stress had enhanced caspase–3 activation and cell death, a finding that further supports the cytoprotective role of ER stress-induced autophagy. Induction of autophagy by ER stress markedly afforded cytoprotection from oxidants H2O2 and tert-Butyl hydroperoxide and from chemical hypoxia induced by antimycin A. In contrast, inhibition of ER stress-induced autophagy or autophagy-deficient cells markedly enhanced cell death in response to oxidant injury and chemical hypoxia. In mouse kidney, similarly to renal epithelial cells in culture, tunicamycin triggered ER stress, markedly upregulated Grp78, and activated autophagy without impairing the autophagic flux. In addition, ER stress-induced autophagy markedly ameliorated renal IR injury as evident from significant improvement in renal function and histology. Inhibition of autophagy by chloroquine markedly increased renal IR injury. These studies highlight beneficial impact of ER stress-induced autophagy in renal ischemia-reperfusion injury both in vitro and in vivo. PMID:26444017

  2. Endoplasmic Reticulum Stress-Induced Autophagy Provides Cytoprotection from Chemical Hypoxia and Oxidant Injury and Ameliorates Renal Ischemia-Reperfusion Injury.

    PubMed

    Chandrika, Bhavya B; Yang, Cheng; Ou, Yang; Feng, Xiaoke; Muhoza, Djamali; Holmes, Alexandrea F; Theus, Sue; Deshmukh, Sarika; Haun, Randy S; Kaushal, Gur P

    2015-01-01

    We examined whether endoplasmic reticulum (ER) stress-induced autophagy provides cytoprotection from renal tubular epithelial cell injury due to oxidants and chemical hypoxia in vitro, as well as from ischemia-reperfusion (IR) injury in vivo. We demonstrate that the ER stress inducer tunicamycin triggers an unfolded protein response, upregulates ER chaperone Grp78, and activates the autophagy pathway in renal tubular epithelial cells in culture. Inhibition of ER stress-induced autophagy accelerated caspase-3 activation and cell death suggesting a pro-survival role of ER stress-induced autophagy. Compared to wild-type cells, autophagy-deficient MEFs subjected to ER stress had enhanced caspase-3 activation and cell death, a finding that further supports the cytoprotective role of ER stress-induced autophagy. Induction of autophagy by ER stress markedly afforded cytoprotection from oxidants H2O2 and tert-Butyl hydroperoxide and from chemical hypoxia induced by antimycin A. In contrast, inhibition of ER stress-induced autophagy or autophagy-deficient cells markedly enhanced cell death in response to oxidant injury and chemical hypoxia. In mouse kidney, similarly to renal epithelial cells in culture, tunicamycin triggered ER stress, markedly upregulated Grp78, and activated autophagy without impairing the autophagic flux. In addition, ER stress-induced autophagy markedly ameliorated renal IR injury as evident from significant improvement in renal function and histology. Inhibition of autophagy by chloroquine markedly increased renal IR injury. These studies highlight beneficial impact of ER stress-induced autophagy in renal ischemia-reperfusion injury both in vitro and in vivo.

  3. Growth Hormone Ameliorates the Radiotherapy-Induced Ovarian Follicular Loss in Rats: Impact on Oxidative Stress, Apoptosis and IGF-1/IGF-1R Axis

    PubMed Central

    Mahran, Yasmen F.; El-Demerdash, Ebtehal; Nada, Ahmed S.; El-Naga, Reem N.; Ali, Azza A.; Abdel-Naim, Ashraf B.

    2015-01-01

    Radiotherapy is one of the standard cytotoxic therapies for cancer. However, it has a profound impact on ovarian function leading to premature ovarian failure and infertility. Since none of the currently available methods for fertility preservation guarantees future fertility, the need for an effective radioprotective agent is highly intensified. The present study investigated the mechanisms of the potential radioprotective effect of growth hormone (GH) on γ irradiation-induced ovarian failure and the impact of the insulin like growth factor 1 (IGF-1) in the underlying protection. Immature female Sprague-Dawley rats were either exposed to single whole body irradiation (3.2 Gy) and/or treated with GH (1 mg/kg s.c). Experimental γ-irradiation produced an array of ovarian dysfunction that was evident by assessment of hormonal changes, follicular development, proliferation marker (PCNA), oxidative stress as well as apoptotic markers. In addition, IGF-1/IGF-1R axis expression was assessed using real-time PCR and immunolocalization techniques. Furthermore, after full maturity, fertility assessment was performed. GH significantly enhanced follicular development and restored anti-Mullerian hormone serum level as compared with the irradiated group. In addition, GH significantly ameliorated the deleterious effects of irradiation on oxidative status, PCNA and apoptosis. Interestingly, GH was shown to enhance the ovarian IGF-1 at transcription and translation levels, a property that contributes significantly to its radioprotective effect. Finally, GH regained the fertility that was lost following irradiation. In conclusion, GH showed a radioprotective effect and rescued the ovarian reserve through increasing local IGF-1 level and counteracting the oxidative stress-mediated apoptosis. PMID:26465611

  4. Growth Hormone Ameliorates the Radiotherapy-Induced Ovarian Follicular Loss in Rats: Impact on Oxidative Stress, Apoptosis and IGF-1/IGF-1R Axis.

    PubMed

    Mahran, Yasmen F; El-Demerdash, Ebtehal; Nada, Ahmed S; El-Naga, Reem N; Ali, Azza A; Abdel-Naim, Ashraf B

    2015-01-01

    Radiotherapy is one of the standard cytotoxic therapies for cancer. However, it has a profound impact on ovarian function leading to premature ovarian failure and infertility. Since none of the currently available methods for fertility preservation guarantees future fertility, the need for an effective radioprotective agent is highly intensified. The present study investigated the mechanisms of the potential radioprotective effect of growth hormone (GH) on γ irradiation-induced ovarian failure and the impact of the insulin like growth factor 1 (IGF-1) in the underlying protection. Immature female Sprague-Dawley rats were either exposed to single whole body irradiation (3.2 Gy) and/or treated with GH (1 mg/kg s.c). Experimental γ-irradiation produced an array of ovarian dysfunction that was evident by assessment of hormonal changes, follicular development, proliferation marker (PCNA), oxidative stress as well as apoptotic markers. In addition, IGF-1/IGF-1R axis expression was assessed using real-time PCR and immunolocalization techniques. Furthermore, after full maturity, fertility assessment was performed. GH significantly enhanced follicular development and restored anti-Mullerian hormone serum level as compared with the irradiated group. In addition, GH significantly ameliorated the deleterious effects of irradiation on oxidative status, PCNA and apoptosis. Interestingly, GH was shown to enhance the ovarian IGF-1 at transcription and translation levels, a property that contributes significantly to its radioprotective effect. Finally, GH regained the fertility that was lost following irradiation. In conclusion, GH showed a radioprotective effect and rescued the ovarian reserve through increasing local IGF-1 level and counteracting the oxidative stress-mediated apoptosis.

  5. Pectinase-treated Panax ginseng ameliorates hydrogen peroxide-induced oxidative stress in GC-2 sperm cells and modulates testicular gene expression in aged rats

    PubMed Central

    Kopalli, Spandana Rajendra; Cha, Kyu-Min; Jeong, Min-Sik; Lee, Sang-Ho; Sung, Jong-Hwan; Seo, Seok-Kyo; Kim, Si-Kwan

    2015-01-01

    Background To investigate the effect of pectinase-treated Panax ginseng (GINST) in cellular and male subfertility animal models. Methods Hydrogen peroxide (H2O2)-induced mouse spermatocyte GC-2spd cells were used as an in vitro model. Cell viability was measured using MTT assay. For the in vivo study, GINST (200 mg/kg) mixed with a regular pellet diet was administered orally for 4 mo, and the changes in the mRNA and protein expression level of antioxidative and spermatogenic genes in young and aged control rats were compared using real-time reverse transcription polymerase chain reaction and western blotting. Results GINST treatment (50 μg/mL, 100 μg/mL, and 200 μg/mL) significantly (p < 0.05) inhibited the H2O2-induced (200 μM) cytotoxicity in GC-2spd cells. Furthermore, GINST (50 μg/mL and 100 μg/mL) significantly (p < 0.05) ameliorated the H2O2-induced decrease in the expression level of antioxidant enzymes (peroxiredoxin 3 and 4, glutathione S-transferase m5, and glutathione peroxidase 4), spermatogenesis-related protein such as inhibin-α, and specific sex hormone receptors (androgen receptor, luteinizing hormone receptor, and follicle-stimulating hormone receptor) in GC-2spd cells. Similarly, the altered expression level of the above mentioned genes and of spermatogenesis-related nectin-2 and cAMP response element-binding protein in aged rat testes was ameliorated with GINST (200 mg/kg) treatment. Taken together, GINST attenuated H2O2-induced oxidative stress in GC-2 cells and modulated the expression of antioxidant-related genes and of spermatogenic-related proteins and sex hormone receptors in aged rats. Conclusion GINST may be a potential natural agent for the protection against or treatment of oxidative stress-induced male subfertility and aging-induced male subfertility. PMID:27158240

  6. Protective property of mulberry digest against oxidative stress - A potential approach to ameliorate dietary acrylamide-induced cytotoxicity.

    PubMed

    Zhang, Linxia; Xu, Yang; Li, Yuting; Bao, Tao; Gowd, Vemana; Chen, Wei

    2017-09-01

    The aim of this study was investigating the protective effect of mulberry digest (MBD) on acrylamide-induced oxidative stress. Composition analysis of MBD revealed that it contained six major phenolic compounds (quercetin-3-O-rutinoside, quercetin hexoside, quercetin rhamnosylhexoside hexoside, kaempferol rhamnosylhexoside, cyanidin-3-O-glucoside and cyanidin-3-O-rutinoside). After in vitro digestion, the contents of two anthocyanins were both decreased significantly, while the contents of four flavonoid glycosides were all increased. In addition, MBD was found to successfully suppress acrylamide-induced ROS overproduction, restore the mitochondrial membrane potential, and inhibit the mitochondrial membrane lipid peroxidation and glutathione depletion. More interestingly, the protective effect of MBD against acrylamide-induced oxidative damage was enhanced compared with mulberry fruits without digestion (MBE). Further study revealed that MBD enhanced the cell resistance capacity to acrylamide-induced oxidative stress, rather than its direct reaction with acrylamide. Overall, our results indicate that MBD provides a potent protection against acrylamide-induced oxidative stress. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Ameliorative effect of septilin, an ayurvedic preparation against gamma-irradiation-induced oxidative stress and tissue injury in rats.

    PubMed

    Mansour, Heba Hosny; Ismael, Naglaa El-Sayed Rifaat; Hafez, Hafez Farouk

    2014-04-01

    Ionizing radiation is known to induce multiple organ dysfunctions directly related to an increase of cellular oxidative stress, due to overproduction of reactive oxygen species (ROS). This study was aimed to investigate the effect of septilin (an ayurvedic poly-herbal formulation containing the principal herbs, namely Commiphora wightii, Trinospora cordifolia, Rubia cardifolia, Emblica officinalis, Saussurea lappa and Glycyrrhiza glabra) against whole body gamma-irradiation-induced oxidative damage in hepatic and brain tissues in rats. Administration of septilin for 5 days (100 mg/kg) prior to radiation resulted in a significant increase in both superoxide dismutase (SOD) activity and total glutathione (GSH) level in hepatic and brain tissues, while serum high-density lipoprotein-cholesterol (HDL) was reduced by gamma-irradiation. Also, septilin resulted in a significant decrease in NO(x), nitric oxide and malondialdehyde (MDA) levels in hepatic and brain tissues and a significant decrease in serum triglycerides, low-density lipoprotein-cholesterol (LDL) and total cholesterol levels and serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) levels and alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT) activities, as well as serum tumor necrosis factor-alpha (TNF-alpha), compared to irradiated group. In conclusion, data obtained from this study indicated that septilin exhibited potential antioxidant activity and showed radioprotective effect against gamma-radiation by preventing oxidative stress and scavenging free radicals.

  8. To Analyze the Amelioration of Phenobarbital Induced Oxidative Stress by Erucin, as Indicated by Biochemical and Histological Alterations.

    PubMed

    Arora, Rohit; Bhushan, Sakshi; Kumar, Rakesh; Mannan, Rahul; Kaur, Pardeep; Singh, Bikram; Sharma, Ritika; Vig, Adarsh Pal; Singh, Balbir; Singh, Amrit Pal; Arora, Saroj

    2016-01-01

    Phenobarbital is a commonly employed antidepressant and anti-epileptic drug. The cancer promoting activity of this genotoxic xenobiotic is often ignored. It is responsible for oxidative stress leading to modulation in xenobiotic and antioxidative enzymes. Glucosinolates and more specifically their hydrolytic products are known for their antioxidative and anticancer activities. The present study involves the analysis of hepatoprotective effect of erucin (isolated from Eruca sativa (Mill.) Thell.) against phenobarbital mediated hepatic damage in male wistar rats. The liver homogenate was analyzed for oxidative stress (superoxide dismutase, catalase, guaiacol peroxidase, ascorbate peroxidase, glutathione reductase and lactate dehydrogenase), other oxidative parameters (thiobarbituric acid reactive species, conjugated dienes and lipid hydroperoxide), phase I enzymes (NADPH-cytochrome P450 reductase, NADH-cytochrome b5 reductase, cytochrome P420, cytochrome P450 and cytochrome b5), phase II enzymes (γ-glutamyl transpeptidase, DT-diaphorase and glutathione-S-transferase), serum parameters (alkaline phosphatase, serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, direct bilirubin and total bilirubin) and certain histological parameters. Erucin accorded protection from phenobarbital induced hepatic damage by normalizing antioxidative enzymes, other oxidative parameters, phase I, II, and serum parameters. Erucin, an analogue of sulforaphane has the potential to act as an anticancer agent by regulating various biochemical parameters.

  9. Amelioration of diabetes-induced neurobehavioral and neurochemical changes by melatonin and nicotinamide: implication of oxidative stress-PARP pathway.

    PubMed

    Jangra, Ashok; Datusalia, Ashok Kumar; Khandwe, Shriya; Sharma, Shyam Sunder

    2013-12-01

    Diabetes associated hyperglycemia results in generation of reactive oxygen species which induces oxidative stress and initiate massive DNA damage leading to overactivation of poly (ADP-ribose) polymerase (PARP). In this study, we have elucidated the involvement of oxidative stress-PARP pathway using pharmacological interventions (melatonin, as an anti-oxidant and nicotinamide, as a PARP inhibitor) in diabetes-induced neurobehavioral and neurochemical alterations. Sprague-Dawley rats were rendered diabetic by a single intraperitoneal injection of streptozotocin. Behavioral and cognitive deficits were assessed after 8weeks of diabetes induction using a functional observation battery, passive avoidance and rotarod test. Acetylcholinesterase activity was significantly decreased in hippocampus of diabetic rats as compared to control rats. Diabetic animals showed significant increase in malondialdehyde levels and reduction in NAD levels in hippocampus. Glutamate and GABA levels were also altered in hippocampus of the diabetic animals. Two week treatment with melatonin (3 and 10mg/kg) and nicotinamide (300 and 1000mg/kg) alone and in combination significantly improved the neurobehavioral parameters which were altered in diabetes. Neurotransmitter (glutamate and GABA) levels were improved by these interventions. Our results emphasize that simultaneous inhibition of oxidative stress-PARP overactivation cascade can be beneficial in treatment of diabetes associated CNS changes.

  10. The Chinese herbal formula Free and Easy Wanderer ameliorates oxidative stress through KEAP1-NRF2/HO-1 pathway.

    PubMed

    Hong, Chunlan; Cao, Jingming; Wu, Ching-Fen; Kadioglu, Onat; Schüffler, Anja; Kauhl, Ulrich; Klauck, Sabine M; Opatz, Till; Thines, Eckhard; Paul, Norbert W; Efferth, Thomas

    2017-09-14

    Posttraumatic stress disorder (PTSD) gains a lot of attention due to high prevalence and strong psychological upset, but the etiology remains undefined and effective treatment is quite limited. Growing studies demonstrated the involvement of oxidative stress in various psychiatry diseases, suggesting anti-oxidation therapy might be a strategy for PTSD treatment. Free and Easy Wanderer (FAEW) is a poly-herbal drug clinically used in China for hundreds of years in the treatment of psychiatric disorder. We hypothesized that FAEW exerts clinical effects through the activity against oxidative stress with fluoxetine as antidepressant control drug. Our results revealed that FAEW significantly reduced both endogenous and H2O2-induced exogenous ROS levels in the human glioblastoma T98G and neuroblastoma SH-SY5Y cell lines. Transcriptome-wide microarray analysis indicated NRF2/HO-1 as the common target of FAEW and fluoxetine. Western blotting assay proved that the two drugs promoted NRF2 release from KEAP1 in the cytoplasm and translocation to the nuclei in a KEAP1-dependent manner, the expression of the protein HO-1 increased accordingly, suggesting the participation of KEAP1-NRF2/HO-1 pathway. The chemical constituents of FAEW (i.e. paeoniflorin, baicalin) bound to KEAP1 in silico, which hence might be the effective substances of FAEW. In conclusion, FAEW counteracted H2O2-induced oxidative stress through KEAP1-NRF2/HO-1 pathway.

  11. Citrus flavanones prevent systemic inflammation and ameliorate oxidative stress in C57BL/6J mice fed high fat diet

    USDA-ARS?s Scientific Manuscript database

    It was investigated the preventive effects of the flavanones hesperidin, eriocitrin and eriodictyol on the oxidative stress and systemic inflammation induced by high-fat diet in C57BL/6J mice. The mice received a standard diet (9.5% kcal from fat), high-fat diet (45% kcal from fat) or high fat diet ...

  12. Melatonin ameliorates cognitive impairment induced by sleep deprivation in rats: role of oxidative stress, BDNF and CaMKII.

    PubMed

    Zhang, Lei; Zhang, Hu-Qin; Liang, Xiang-Yan; Zhang, Hai-Feng; Zhang, Ting; Liu, Fang-E

    2013-11-01

    Sleep deprivation (SD) has been shown to induce oxidative stress which causes cognitive impairment. Melatonin, an endogenous potent antioxidant, protects neurons from oxidative stress in many disease models. The present study investigated the effect of melatonin against SD-induced cognitive impairment and attempted to define the possible mechanisms involved. SD was induced in rats using modified multiple platform model. Melatonin (15 mg/kg) was administered to the rats via intraperitoneal injection. The open field test and Morris water maze were used to evaluate cognitive ability. The cerebral cortex (CC) and hippocampus were dissected and homogenized. Nitric oxide (NO) and malondialdehyde (MDA) levels and the superoxide dismutase (SOD) enzyme activity of hippocampal and cortical tissues (10% wet weight per volume) were performed to determine the level of oxidative stress. The expression of brain-derived neurotrophic factor (BDNF) and calcium-calmodulin dependent kinase II (CaMKII) proteins in CC and hippocampus was assayed by means of immunohistochemistry. The results revealed that SD impairs cognitive ability, while melatonin treatment prevented these changes. In addition, melatonin reversed SD-induced changes in NO, MDA and SOD in both of the CC and hippocampus. The results of immunoreactivity showed that SD decreased gray values of BDNF and CaMKII in CC and hippocamal CA1, CA3 and dentate gyrus regions, whereas melatonin improved the gray values. In conclusion, our results suggest that melatonin prevents cognitive impairment induced by SD. The possible mechanism may be attributed to its ability to reduce oxidative stress and increase the levels of CaMKII and BDNF in CC and hippocampus.

  13. Pituitary adenylate cyclase-activating polypeptide (PACAP) mimics neuroendocrine and behavioral manifestations of stress: Evidence for PKA-mediated expression of the corticotropin-releasing hormone (CRH) gene.

    PubMed

    Agarwal, Anika; Halvorson, Lisa M; Legradi, Gabor

    2005-07-29

    The physiologic response to stress is highly dependent on the activation of corticotropin-releasing hormone (CRH) neurons by various neurotransmitters. A particularly rich innervation of hypophysiotropic CRH neurons has been detected by nerve fibers containing the neuropeptide PACAP, a potent activator of the cAMP-protein kinase A (PKA) system. Intracerebroventricular (icv) injections of PACAP also elevate steady-state CRH mRNA levels in the paraventricular nucleus (PVN), but it is not known whether PACAP effects can be associated with acute stress responses. Likewise, in cell culture studies, pharmacologic activation of the PKA system has stimulated CRH gene promoter activity through an identified cAMP response element (CRE); however, a direct link between PACAP and CRH promoter activity has not been established. In our present study, icv injection of 150 or 300 pmol PACAP resulted in robust phosphorylation of the transcription factor CREB in the majority of PVN CRH neurons at 15 to 30 min post-injection and induced nuclear Fos labeling at 90 min. Simultaneously, plasma corticosterone concentrations were elevated in PACAP-injected animals, and significant increases were observed in face washing, body grooming, rearing and wet-dog shakes behaviors. We investigated the effect of PACAP on human CRH promoter activity in alphaT3-1 cells, a PACAP-receptor expressing cell line. Cells were transiently transfected with a chloramphenicol acetyltransferase (CAT) reporter vector containing region - 663/+124 of the human CRH gene promoter then treated for with PACAP (100 nM) or with the adenylate cyclase activating agent, forskolin (2.5 muM). Both PACAP and forskolin significantly increased wild-type hCRH promoter activity relative to vehicle controls. The PACAP response was abolished in the CRE-mutant construct. Pretreatment of transfected cells with the PKA blocker, H-89, completely prevented both PACAP- and forskolin-induced increases in CRH promoter activity. Furthermore

  14. Pituitary adenylate cyclase-activating polypeptide (PACAP) has a neuroprotective function in dopamine-based neurodegeneration in rat and snail parkinsonian models

    PubMed Central

    Kiss, Tibor; Jungling, Adel

    2017-01-01

    ABSTRACT Pituitary adenylate cyclase-activating polypeptide (PACAP) rescues dopaminergic neurons from neurodegeneration and improves motor changes induced by 6-hydroxy-dopamine (6-OHDA) in rat parkinsonian models. Recently, we investigated the molecular background of the neuroprotective effect of PACAP in dopamine (DA)-based neurodegeneration using rotenone-induced snail and 6-OHDA-induced rat models of Parkinson's disease. Behavioural activity, monoamine (DA and serotonin), metabolic enzyme (S-COMT, MB-COMT and MAO-B) and PARK7 protein concentrations were measured before and after PACAP treatment in both models. Locomotion and feeding activity were decreased in rotenone-treated snails, which corresponded well to findings obtained in 6-OHDA-induced rat experiments. PACAP was able to prevent the behavioural malfunctions caused by the toxins. Monoamine levels decreased in both models and the decreased DA level induced by toxins was attenuated by ∼50% in the PACAP-treated animals. In contrast, PACAP had no effect on the decreased serotonin (5HT) levels. S-COMT metabolic enzyme was also reduced but a protective effect of PACAP was not observed in either of the models. Following toxin treatment, a significant increase in MB-COMT was observed in both models and was restored to normal levels by PACAP. A decrease in PARK7 was also observed in both toxin-induced models; however, PACAP had a beneficial effect only on 6-OHDA-treated animals. The neuroprotective effect of PACAP in different animal models of Parkinson's disease is thus well correlated with neurotransmitter, enzyme and protein levels. The models successfully mimic several, but not all etiological properties of the disease, allowing us to study the mechanisms of neurodegeneration as well as testing new drugs. The rotenone and 6-OHDA rat and snail in vivo parkinsonian models offer an alternative method for investigation of the molecular mechanisms of neuroprotective agents, including PACAP. PMID:28067625

  15. Pituitary adenylate cyclase activating polypeptide (PACAP) and its receptors are present and biochemically active in the central nervous system of the pond snail Lymnaea stagnalis.

    PubMed

    Pirger, Zsolt; Laszlo, Zita; Hiripi, Laszlo; Hernadi, Laszlo; Toth, Gabor; Lubics, Andrea; Reglodi, Dora; Kemenes, Gyorgy; Mark, Laszlo

    2010-11-01

    PACAP is a highly conserved adenylate cyclase (AC) activating polypeptide, which, along with its receptors (PAC1-R, VPAC1, and VPAC2), is expressed in both vertebrate and invertebrate nervous systems. In vertebrates, PACAP has been shown to be involved in associative learning, but it is not known if it plays a similar role in invertebrates. To prepare the way for a detailed investigation into the possible role of PACAP and its receptors in a suitable invertebrate model of learning and memory, here, we undertook a study of their expression and biochemical role in the central nervous system of the pond snail Lymnaea stagnalis. Lymnaea is one of the best established invertebrate model systems to study the molecular mechanisms of learning and memory, including the role of cyclic AMP-activated signaling mechanisms, which crucially depend on the learning-induced activation of AC. However, there was no information available on the expression of PACAP and its receptors in sensory structures and central ganglia of the Lymnaea nervous system known to be involved in associative learning or whether or not PACAP can actually activate AC in these ganglia. Here, using matrix-assisted laser desorption ionization time of flight (MALDI-TOF) and immunohistochemistry, we established the presence of PACAP-like peptides in the cerebral ganglia and the lip region of Lymnaea. The MALDI-TOF data indicated an identity with mammalian PACAP-27 and the presence of a squid-like PACAP-38 highly homologous to vertebrate PACAP-38. We also showed that PACAP, VIP, and maxadilan stimulated the synthesis of cAMP in Lymnaea cerebral ganglion homogenates and that this effect was blocked by the appropriate general and selective PACAP receptor antagonists.

  16. PACAP Inhibits β-cell Mass Expansion in a Mouse Model of Type II Diabetes: Persistent Suppressive Effects on Islet Density

    PubMed Central

    Inoue, Hiroaki; Shintani, Norihito; Sakurai, Yusuke; Higashi, Shintaro; Hayata-Takano, Atsuko; Baba, Akemichi; Hashimoto, Hitoshi

    2012-01-01

    Pituitary adenylate cyclase-activating polypeptide (PACAP) is a potent insulinotropic G-protein-coupled receptor ligand, for which morphoregulative roles in pancreatic islets have recently been suggested. Here, we evaluated the effects of pancreatic overexpression of PACAP on morphometric changes of islets in a severe type II diabetes model. Following cross-breeding of obese-diabetic model KKAy mice with mice overexpressing PACAP in their pancreatic β-cells, the resulting KKAy mice with or without PACAP transgene (PACAP/+:Ay/+ or Ay/+ mice) were fed with a high-fat diet up to the age of 11 months. Pancreatic sections from 5- to 11-month-old littermates were examined. Histomorphometric analyses revealed significant suppression of islet mass expansion in PACAP/+:Ay/+ mice compared with Ay/+ mice at 11 months, but no significant difference between PACAP/+ and +/+ (wild-type) mice, as previously reported. The suppressed islet mass in PACAP/+:Ay/+ mice was due to a decrease in islet density but not islet size. In addition, the density of tiny islets (<0.001 mm2) and of insulin-positive clusters in ductal structures were markedly decreased in PACAP/+:Ay/+ mice compared with Ay/+ mice at 5 months of age. In contrast, PACAP overexpression caused no significant effects on the level of aldehyde-fuchsin reagent staining (a measure of β-cell granulation) or the volume and localization of glucagon-positive cells in the pancreas. These results support previously reported inhibitory effects of PACAP on pancreatic islet mass expansion, and suggest it has persistent suppressive effects on pancreatic islet density which may be related with ductal cell-associated islet neogenesis in type II diabetes. PMID:23483824

  17. PACAP Inhibits β-cell Mass Expansion in a Mouse Model of Type II Diabetes: Persistent Suppressive Effects on Islet Density.

    PubMed

    Inoue, Hiroaki; Shintani, Norihito; Sakurai, Yusuke; Higashi, Shintaro; Hayata-Takano, Atsuko; Baba, Akemichi; Hashimoto, Hitoshi

    2013-01-01

    Pituitary adenylate cyclase-activating polypeptide (PACAP) is a potent insulinotropic G-protein-coupled receptor ligand, for which morphoregulative roles in pancreatic islets have recently been suggested. Here, we evaluated the effects of pancreatic overexpression of PACAP on morphometric changes of islets in a severe type II diabetes model. Following cross-breeding of obese-diabetic model KKA(y) mice with mice overexpressing PACAP in their pancreatic β-cells, the resulting KKA(y) mice with or without PACAP transgene (PACAP/+:A(y)/+ or A(y)/+ mice) were fed with a high-fat diet up to the age of 11 months. Pancreatic sections from 5- to 11-month-old littermates were examined. Histomorphometric analyses revealed significant suppression of islet mass expansion in PACAP/+:A(y)/+ mice compared with A(y)/+ mice at 11 months, but no significant difference between PACAP/+ and +/+ (wild-type) mice, as previously reported. The suppressed islet mass in PACAP/+:A(y)/+ mice was due to a decrease in islet density but not islet size. In addition, the density of tiny islets (<0.001 mm(2)) and of insulin-positive clusters in ductal structures were markedly decreased in PACAP/+:A(y)/+ mice compared with A(y)/+ mice at 5 months of age. In contrast, PACAP overexpression caused no significant effects on the level of aldehyde-fuchsin reagent staining (a measure of β-cell granulation) or the volume and localization of glucagon-positive cells in the pancreas. These results support previously reported inhibitory effects of PACAP on pancreatic islet mass expansion, and suggest it has persistent suppressive effects on pancreatic islet density which may be related with ductal cell-associated islet neogenesis in type II diabetes.

  18. Long-term enhancement of REM sleep by the pituitary adenylyl cyclase-activating polypeptide (PACAP) in the pontine reticular formation of the rat.

    PubMed

    Ahnaou, A; Basille, M; Gonzalez, B; Vaudry, H; Hamon, M; Adrien, J; Bourgin, P

    1999-11-01

    In rats, rapid eye movement (REM) sleep can be elicited by microinjection of vasoactive intestinal polypeptide (VIP) into the oral pontine reticular nucleus (PnO). In the present study, we investigated whether this area could also be a REM-promoting target for a peptide closely related to VIP: the pituitary adenylyl cyclase-activating polypeptide (PACAP). When administered into the posterior part of the PnO, but not in nearby areas, of freely moving chronically implanted rats, PACAP-27 and PACAP-38 (0.3 and 3 pmol) induced a marked enhancement (60-85% over baseline) of REM sleep for 8 h that could be prevented by prior infusion of the antagonist PACAP-(6-27) (3 pmol) into the same site. Moreover, injections of PACAP into the centre of the posterior PnO resulted in REM sleep enhancement which could last for up to 11 consecutive days. Quantitative autoradiography using [125I]PACAP-27 revealed the presence in the PnO of specific binding sites with high affinity for PACAP-27 and PACAP-38 (IC50 = 2.4 and 3.2 nM, respectively), but very low affinity for VIP (IC50 > 1 microM). These data suggest that PACAP within the PnO may play a key role in REM sleep regulation, and provide evidence for long-term (several days) mechanisms involved in such a control. PAC1 receptors which have a much higher affinity for PACAP than for VIP might mediate this long-term action of PACAP on REM sleep.

  19. Pituitary adenylate cyclase-activating polypeptide (PACAP) has a neuroprotective function in dopamine-based neurodegeneration in rat and snail parkinsonian models.

    PubMed

    Maasz, Gabor; Zrinyi, Zita; Reglodi, Dora; Petrovics, Dora; Rivnyak, Adam; Kiss, Tibor; Jungling, Adel; Tamas, Andrea; Pirger, Zsolt

    2017-02-01

    Pituitary adenylate cyclase-activating polypeptide (PACAP) rescues dopaminergic neurons from neurodegeneration and improves motor changes induced by 6-hydroxy-dopamine (6-OHDA) in rat parkinsonian models. Recently, we investigated the molecular background of the neuroprotective effect of PACAP in dopamine (DA)-based neurodegeneration using rotenone-induced snail and 6-OHDA-induced rat models of Parkinson's disease. Behavioural activity, monoamine (DA and serotonin), metabolic enzyme (S-COMT, MB-COMT and MAO-B) and PARK7 protein concentrations were measured before and after PACAP treatment in both models. Locomotion and feeding activity were decreased in rotenone-treated snails, which corresponded well to findings obtained in 6-OHDA-induced rat experiments. PACAP was able to prevent the behavioural malfunctions caused by the toxins. Monoamine levels decreased in both models and the decreased DA level induced by toxins was attenuated by ∼50% in the PACAP-treated animals. In contrast, PACAP had no effect on the decreased serotonin (5HT) levels. S-COMT metabolic enzyme was also reduced but a protective effect of PACAP was not observed in either of the models. Following toxin treatment, a significant increase in MB-COMT was observed in both models and was restored to normal levels by PACAP. A decrease in PARK7 was also observed in both toxin-induced models; however, PACAP had a beneficial effect only on 6-OHDA-treated animals. The neuroprotective effect of PACAP in different animal models of Parkinson's disease is thus well correlated with neurotransmitter, enzyme and protein levels. The models successfully mimic several, but not all etiological properties of the disease, allowing us to study the mechanisms of neurodegeneration as well as testing new drugs. The rotenone and 6-OHDA rat and snail in vivo parkinsonian models offer an alternative method for investigation of the molecular mechanisms of neuroprotective agents, including PACAP.

  20. Possible role of PACAP and its PAC1 receptor in the differential regulation of pituitary LHbeta- and FSHbeta-subunit gene expression by pulsatile GnRH stimulation.

    PubMed

    Kanasaki, Haruhiko; Purwana, Indri N; Miyazaki, Kohji

    2013-02-01

    The pituitary gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), are mainly under the control of hypothalamic gonadotropin-releasing hormone (GnRH), which regulates male and female gonadal function. GnRH is released in a pulsatile manner from the hypothalamus, and the frequency of GnRH pulses determines the dominance of output of LH and FSH from pituitary gonadotrophs. That is, more rapid pulses of GnRH preferentially increase synthesis and secretion of LH, whereas FSH is preferentially stimulated by slower GnRH pulses. The detailed mechanisms underlying this phenomenon remain unknown. Pituitary adenylate cyclase-activating polypeptide (PACAP) was originally identified as a hypothalamic activator of cAMP production in pituitary cells. PACAP is produced within the pituitary gonadotroph as well as in the central nervous system. PACAP stimulates gonadotropin alpha-, LHbeta-, and FSHbeta-subunits as well as receptors for GnRH in the pituitary gonadotropin-secreting cells. In addition, its own receptor, PACAP type I receptor (PAC1R), is also regulated by PACAP in gonadotrophs. GnRH stimulates expression of PACAP as well as PAC1R, and lower frequencies of GnRH pulses preferentially increase PACAP and PAC1R expression in gonadotrophs. Increasing concentrations of PACAP further increase the levels of gonadotropin subunit and that increasing amounts of PAC1R in gonadotrophs potentiates the effects of PACAP or GnRH on gonadotropin subunit expression. In addition, we have observed that GnRH-increased FSHbeta-subunit expression was prevented in the presence of PAC1R antagonist. These observations suggest the involvement of locally produced PACAP and its PAC1R in the differential regulation of specific gonadotropin subunit expression by pulsatile GnRH stimulation. Here, we review the possible involvement of PACAP and its PAC1R in gonadotropin control on the basis of our observations with gonadotroph cell lines.

  1. Igf1 and Pacap rescue cerebellar granule neurons from apoptosis via a common transcriptional program

    PubMed Central

    Maino, B; D’Agata, V; Severini, C; Ciotti, MT; Calissano, P; Copani, A; Chang, Y-C; DeLisi, C; Cavallaro, S

    2015-01-01

    A shift of the delicate balance between apoptosis and survival-inducing signals determines the fate of neurons during the development of the central nervous system and its homeostasis throughout adulthood. Both pathways, promoting or protecting from apoptosis, trigger a transcriptional program. We conducted whole-genome expression profiling to decipher the transcriptional regulatory elements controlling the apoptotic/survival switch in cerebellar granule neurons following the induction of apoptosis by serum and potassium deprivation or their rescue by either insulin-like growth factor-1 (Igf1) or pituitary adenylyl cyclase-activating polypeptide (Pacap). Although depending on different upstream signaling pathways, the survival effects of Igf1 and Pacap converged into common transcriptional cascades, thus suggesting the existence of a general transcriptional program underlying neuronal survival. PMID:26941962

  2. Central Control of Feeding Behavior by the Secretin, PACAP, and Glucagon Family of Peptides

    PubMed Central

    Sekar, Revathi; Wang, Lei; Chow, Billy Kwok Chong

    2017-01-01

    Constituting a group of structurally related brain-gut peptides, secretin (SCT), pituitary adenylate cyclase-activating peptide (PACAP), and glucagon (GCG) family of peptide hormones exert their functions via interactions with the class B1 G protein-coupled receptors. In recent years, the roles of these peptides in neuroendocrine control of feeding behavior have been a specific area of research focus for development of potential therapeutic drug targets to combat obesity and metabolic disorders. As a result, some members in the family and their analogs have already been utilized as therapeutic agents in clinical application. This review aims to provide an overview of the current understanding on the important role of SCT, PACAP, and GCG family of peptides in central control of feeding behavior. PMID:28223965

  3. Pepsin Egg White Hydrolysate Ameliorates Obesity-Related Oxidative Stress, Inflammation and Steatosis in Zucker Fatty Rats

    PubMed Central

    Garcés-Rimón, M.; González, C.; Uranga, J. A.; López-Miranda, V.; López-Fandiño, R.; Miguel, M.

    2016-01-01

    The aim of this work was to evaluate the effect of the administration of egg white hydrolysates on obesity-related disorders, with a focus on lipid metabolism, inflammation and oxidative stress, in Zucker fatty rats. Obese Zucker rats received water, pepsin egg white hydrolysate (750 mg/kg/day) or Rhizopus aminopeptidase egg white hydrolysate (750 mg/kg/day) for 12 weeks. Lean Zucker rats received water. Body weight, solid and liquid intakes were weekly measured. At the end of the study, urine, faeces, different organs and blood samples were collected. The consumption of egg white hydrolysed with pepsin significantly decreased the epididymal adipose tissue, improved hepatic steatosis, and lowered plasmatic concentration of free fatty acids in the obese animals. It also decreased plasma levels of tumor necrosis factor-alpha and reduced oxidative stress. Pepsin egg white hydrolysate could be used as a tool to improve obesity-related complications. PMID:26985993

  4. Perillyl alcohol as a protective modulator against rat hepatocarcinogenesis via amelioration of oxidative damage and cell proliferation.

    PubMed

    Sultana, S; Nafees, S; Khan, A Q

    2013-11-01

    In the present study, we have evaluated the chemopreventive effects of perillyl alcohol (POH) against diethylnitrosamine-initiated and 2-AAF (2-acetylaminofluorine)-promoted hepatocarcinogenesis in Wistar rats. Efficacy of POH against 2-AAF-induced hepatotoxicity was evaluated in terms of biochemical estimation of antioxidant enzyme activities, histopathological changes and expression levels of proliferative markers. 2-AAF is a potent hepatotoxicant and a hepatic carcinogen that induces its effect by causing oxidative stress. Pre-treatment of POH prevented oxidative stress and tumour incidences. POH suppressed 2-AAF-induced early tumour markers, namely ornithine decarboxylase activity, thymidine phosphorylase and proliferating cell nuclear antigen (PCNA) protein and also suppressed the expression of pro-apoptotic protein P53. Histopathological findings revealed that POH-pretreated groups showed marked recovery. From our results, it could be concluded that POH markedly protects against chemically induced liver cancer and acts possibly by virtue of its antioxidant and antiproliferative activities.

  5. CTRP5 ameliorates palmitate-induced apoptosis and insulin resistance through activation of AMPK and fatty acid oxidation.

    PubMed

    Yang, Won-Mo; Lee, Wan

    2014-09-26

    Lipotoxicity resulting from a high concentration of saturated fatty acids is closely linked to development of insulin resistance, as well as apoptosis in skeletal muscle. CTRP5, an adiponectin paralog, is known to activate AMPK and fatty acid oxidation; however, the effects of CTRP5 on palmitate-induced lipotoxicity in myocytes have not been investigated. We found that globular domain of CTRP5 (gCTRP5) prevented palmitate-induced apoptosis and insulin resistance in myocytes by inhibiting the activation of caspase-3, reactive oxygen species accumulation, and IRS-1 reduction. These beneficial effects of gCTRP5 are mainly attributed to an increase in fatty acid oxidation through phosphorylation of AMPK. These results provide a novel function of CTRP5, which may have preventive and therapeutic potential in management of obesity, insulin resistance, and type 2 diabetes mellitus.

  6. Antioxidant treatment ameliorates experimental diabetes-induced depressive-like behaviour and reduces oxidative stress in brain and pancreas.

    PubMed

    Réus, Gislaine Z; Dos Santos, Maria Augusta B; Abelaira, Helena M; Titus, Stephanie E; Carlessi, Anelise S; Matias, Beatriz I; Bruchchen, Livia; Florentino, Drielly; Vieira, Andriele; Petronilho, Fabricia; Ceretta, Luciane B; Zugno, Alexandra I; Quevedo, João

    2016-03-01

    Studies have shown a relationship between diabetes mellitus (DM) and the development of major depressive disorder. Alterations in oxidative stress are associated with the pathophysiology of both diabetes mellitus and major depressive disorder. This study aimed to evaluate the effects of antioxidants N-acetylcysteine and deferoxamine on behaviour and oxidative stress parameters in diabetic rats. To this aim, after induction of diabetes by a single dose of alloxan, Wistar rats were treated with N-acetylcysteine or deferoxamine for 14 days, and then depressive-like behaviour was evaluated. Oxidative stress parameters were assessed in the prefrontal cortex, hippocampus, amygdala, nucleus accumbens and pancreas. Diabetic rats displayed depressive-like behaviour, and treatment with N-acetylcysteine reversed this alteration. Carbonyl protein levels were increased in the prefrontal cortex, hippocampus and pancreas of diabetic rats, and both N-acetylcysteine and deferoxamine reversed these alterations. Lipid damage was increased in the prefrontal cortex, hippocampus, amygdala and pancreas; however, treatment with N-acetylcysteine or deferoxamine reversed lipid damage only in the hippocampus and pancreas. Superoxide dismutase activity was decreased in the amygdala, nucleus accumbens and pancreas of diabetic rats. In diabetic rats, there was a decrease in catalase enzyme activity in the prefrontal cortex, amygdala, nucleus accumbens and pancreas, but an increase in the hippocampus. Treatment with antioxidants did not have an effect on the activity of antioxidant enzymes. In conclusion, animal model of diabetes produced depressive-like behaviour and oxidative stress in the brain and periphery. Treatment with antioxidants could be a viable alternative to treat behavioural and biochemical alterations induced by diabetes. Copyright © 2015 John Wiley & Sons, Ltd.

  7. Melatonin ameliorates oxidative stress, modulates death receptor pathway proteins, and protects the rat cerebrum against bisphenol-A-induced apoptosis.

    PubMed

    El-Missiry, Mohamed A; Othman, Azza I; Al-Abdan, Monera A; El-Sayed, Aml A

    2014-12-15

    Epidemiological reports have indicated a correlation between the increasing of bisphenol-A (BPA) levels in the environment and the incidence of neurodegenerative diseases. In the present study, the protective effect of melatonin on oxidative stress and the death receptor apoptotic proteins in the cerebrum of the bisphenol-A-treated rats were examined. Adult male rats were orally administered melatonin (10mg/kg bw) concurrently with BPA (50mg/kg bw) 3 days a week for 6 weeks. BPA exposure resulted in significant elevations of oxidative stress, as evidenced by the increased malondialdehyde level and the decreased glutathione level and superoxide dismutase activity in the cerebrum. BPA caused an upregulation of p53 and CD95-Fas and activation of capsases-3 and 8, resulting in cerebral cell apoptosis. Melatonin significantly attenuated the BPA-evoked brain oxidative stress, modulated apoptotic-regulating proteins and protected against apoptosis. These data suggest that melatonin modulated important steps in the death receptor apoptotic pathway which likely related to its redox control properties. Melatonin is a promising pharmacological agent for preventing the potential neurotoxicity of BPA following occupational or environmental exposures.

  8. Ameliorative Effect of Zinc Oxide Nanoparticles on Antioxidants and Sperm Characteristics in Streptozotocin-Induced Diabetic Rat Testes.

    PubMed

    Afifi, Mohamed; Almaghrabi, Omar A; Kadasa, Naif Mohammed

    2015-01-01

    The present study investigated the impact of zinc oxide nanoparticles (ZnONPs) on the oxidative status and sperm characteristics in diabetic rat testicular tissue. Forty male albino rats were used in this study; 10 of them served as a control and 30 rats were injected with a single dose (100 mg/kg) of streptozotocin intraperitoneally. They were subdivided into diabetic, diabetic + ZnONPs (10 mg/kg B.W.), and diabetic and cotreated with ZnONPs + insulin groups. The sperm count and motility were assessed. The activity and mRNA expression of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GRD), and Glutathion-S-Transferase (GST) were determined in the testicular tissue. Malondialdehyde (MDA) and reduced glutathione (GSH) levels were estimated in the testicular tissue. Sperm count and motility increased in ZnONPs treated diabetic rats. A significant increase in the activity and mRNA expression of SOD, CAT, GPx, GRD, and GST was shown in ZnONPs treated diabetic rats. MDA significantly decreased, while GSH increased in testicular tissue of ZnONPs treated diabetic rats. It was concluded that ZnONPs either alone or in combination with insulin have the ability to increase the sperm count and motility and protect the testicular tissue against the oxidative stress induced by diabetes in rats.

  9. Can garlic oil ameliorate diabetes-induced oxidative stress in a rat liver model? A correlated histological and biochemical study.

    PubMed

    Abdultawab, Hanem Saad; Ayuob, Nasra N

    2013-09-01

    This study aimed to characterise the structural changes in liver of an alloxan-induced diabetic rat and to explain such changes in terms of the biochemical changes in free radicals and antioxidants. In addition, it aimed to determine the potential ability of garlic oil to alter these changes. The study groups were: control (n=12), alloxan-induced diabetic rats (n=10) and alloxan-induced diabetic rats treated with garlic oil (10 mg/kg body weight (n=10)). Markers of oxidative stress were assessed. Small pieces of the liver were processed for transmission electron microscopic study. Garlic oil caused a significant decrease in levels of LPO in plasma (0.26 vs 0.53), erythrocyte lysate (14.4 vs 24.8) and liver tissue homogenate (1.04 vs 2.08), whereas those of thiols were significantly elevated (1.2 vs 0.46), (24 vs 15) in plasma and erythrocyte lysate respectively. SOD activity and G-S-T activity were significantly elevated in erythrocyte lysate (5.7 vs 3.3) (377 vs 179) and liver homogenate (1.4 vs 0.5) (752 vs 623) respectively after garlic oil administration. Ultrastructural study of the liver confirmed the ability of garlic to retard lipid peroxidation of cellular membranes induced by oxidative stress associated with diabetes. Therefore, garlic could normalise oxidative stress in alloxan-induced diabetic rats.

  10. Glycyrrhizin ameliorates insulin resistance, hyperglycemia, dyslipidemia and oxidative stress in fructose-induced metabolic syndrome-X in rat model.

    PubMed

    Sil, Rajarshi; Ray, Doel; Chakraborti, Abhay Sankar

    2013-02-01

    This study investigates if glycyrrhizin, a constituent of licorice (Glycyrrhiza glabra) root, is able to treat the complications (insulin resistance, hyperglycemia, dyslipidemia and oxidative stress) of metabolic syndrome. Metabolic syndrome was induced in rats by feeding a fructose-enriched (60%) diet for six weeks, after which single dose of glycyrrhizin (50 mg/kg body weight) was administered intraperitoneally. Different biochemical parameters from blood were estimated during three weeks after treatment. Then the rats were sacrificed to collect skeletal muscle tissue. Glycyrrhizin reduced the enhanced levels of blood glucose, insulin and lipids in metabolic syndrome group. Increased advanced glycation end products of hemoglobin, glycohemoglobin, hemoglobin-mediated iron release and iron-mediated free radical reactions (arachidonic acid and deoxyribose degradation) in metabolic syndrome were inhibited by glycyrrhizin treatment. Reduced activities of enzymatic antioxidants (superoxide dismutase and catalase) and elevated oxidative stress markers (malonaldehyde, fructosamine, hemoglobin carbonyl content and DNA damage) in metabolic syndrome were reversed to almost normal levels by glycyrrhizin. The decreased levels of peroxisome proliferator activated receptor gamma (PPARgamma) and glucose transporter 4 (GLUT4) proteins in skeletal muscle of metabolic syndrome group were elevated by glycyrrhizin, indicating improved fatty acid oxidation and glucose homeostasis.

  11. Ameliorative Effect of Zinc Oxide Nanoparticles on Antioxidants and Sperm Characteristics in Streptozotocin-Induced Diabetic Rat Testes

    PubMed Central

    Afifi, Mohamed; Almaghrabi, Omar A.; Kadasa, Naif Mohammed

    2015-01-01

    The present study investigated the impact of zinc oxide nanoparticles (ZnONPs) on the oxidative status and sperm characteristics in diabetic rat testicular tissue. Forty male albino rats were used in this study; 10 of them served as a control and 30 rats were injected with a single dose (100 mg/kg) of streptozotocin intraperitoneally. They were subdivided into diabetic, diabetic + ZnONPs (10 mg/kg B.W.), and diabetic and cotreated with ZnONPs + insulin groups. The sperm count and motility were assessed. The activity and mRNA expression of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GRD), and Glutathion-S-Transferase (GST) were determined in the testicular tissue. Malondialdehyde (MDA) and reduced glutathione (GSH) levels were estimated in the testicular tissue. Sperm count and motility increased in ZnONPs treated diabetic rats. A significant increase in the activity and mRNA expression of SOD, CAT, GPx, GRD, and GST was shown in ZnONPs treated diabetic rats. MDA significantly decreased, while GSH increased in testicular tissue of ZnONPs treated diabetic rats. It was concluded that ZnONPs either alone or in combination with insulin have the ability to increase the sperm count and motility and protect the testicular tissue against the oxidative stress induced by diabetes in rats. PMID:26581756

  12. Transcriptomics and proteomics analyses of the PACAP38 influenced ischemic brain in permanent middle cerebral artery occlusion model mice

    PubMed Central

    2012-01-01

    Introduction The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is considered to be a potential therapeutic agent for prevention of cerebral ischemia. Ischemia is a most common cause of death after heart attack and cancer causing major negative social and economic consequences. This study was designed to investigate the effect of PACAP38 injection intracerebroventrically in a mouse model of permanent middle cerebral artery occlusion (PMCAO) along with corresponding SHAM control that used 0.9% saline injection. Methods Ischemic and non-ischemic brain tissues were sampled at 6 and 24 hours post-treatment. Following behavioral analyses to confirm whether the ischemia has occurred, we investigated the genome-wide changes in gene and protein expression using DNA microarray chip (4x44K, Agilent) and two-dimensional gel electrophoresis (2-DGE) coupled with matrix assisted laser desorption/ionization-time of flight-mass spectrometry (MALDI-TOF-MS), respectively. Western blotting and immunofluorescent staining were also used to further examine the identified protein factor. Results Our results revealed numerous changes in the transcriptome of ischemic hemisphere (ipsilateral) treated with PACAP38 compared to the saline-injected SHAM control hemisphere (contralateral). Previously known (such as the interleukin family) and novel (Gabra6, Crtam) genes were identified under PACAP influence. In parallel, 2-DGE analysis revealed a highly expressed protein spot in the ischemic hemisphere that was identified as dihydropyrimidinase-related protein 2 (DPYL2). The DPYL2, also known as Crmp2, is a marker for the axonal growth and nerve development. Interestingly, PACAP treatment slightly increased its abundance (by 2-DGE and immunostaining) at 6 h but not at 24 h in the ischemic hemisphere, suggesting PACAP activates neuronal defense mechanism early on. Conclusions This study provides a detailed inventory of PACAP influenced gene expressions and protein targets

  13. Piracetam ameliorated oxygen and glucose deprivation-induced injury in rat cortical neurons via inhibition of oxidative stress, excitatory amino acids release and P53/Bax.

    PubMed

    He, Zhi; Hu, Min; Zha, Yun-hong; Li, Zi-cheng; Zhao, Bo; Yu, Ling-ling; Yu, Min; Qian, Ying

    2014-05-01

    Our previous work has demonstrated that piracetam inhibited the decrease in amino acid content induced by chronic hypoperfusion, ameliorated the dysfunction of learning and memory in a hypoperfusion rat model, down-regulated P53, and BAX protein, facilitated the synaptic plasticity, and may be helpful in the treatment of vascular dementia. To explore the precise mechanism, the present study further evaluated effects of piracetam on Oxygen and glucose deprivation (OGD)-induced neuronal damage in rat primary cortical cells. The addition of piracetam to the cultured cells 12 h before OGD for 4 h significantly reduced neuronal damage as determined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and lactate dehydrogenase release experiments. Piracetam also lowered the levels of malondialdehyde, nitrogen monoxidum, and xanthine oxidase which was increased in the OGD cells, and enhanced the activities of superoxide dismutase and glutathione peroxidase, which were decreased in the OGD cells. We also demonstrated that piracetam could decrease glutamate and aspartate release when cortical cells were subjected to OGD. Furthermore, Western blot study demonstrated that piracetam attenuated the increased expression of P53 and BAX protein in OGD cells. These observations demonstrated that piracetam reduced OGD-induced neuronal damage by inhibiting the oxidative stress and decreasing excitatory amino acids release and lowering P53/Bax protein expression in OGD cells.

  14. Effects of berberine on amelioration of hyperglycemia and oxidative stress in high glucose and high fat diet-induced diabetic hamsters in vivo.

    PubMed

    Liu, Cong; Wang, Zhuo; Song, Yulong; Wu, Dan; Zheng, Xuan; Li, Ping; Jin, Jin; Xu, Nannan; Li, Ling

    2015-01-01

    This study investigated the effects of berberine on amelioration of hyperglycemia and hyperlipidemia and the mechanism involved in high glucose and high fat diet-induced diabetic hamsters. Golden hamsters fed with high glucose and high fat diet were medicated with metformin, simvastatin, and low or high dose of berberine (50 and 100 mg·kg(-1)) for 6 weeks. The results showed that the body weights were significantly lower in berberine-treated groups than control group. Histological analyses revealed that the treatment of berberine inhibited hepatic fat accumulation. Berberine significantly reduced plasma total cholesterol, triglyceride, free fatty acid, low density lipoprotein cholesterol, malondialdehyde, thiobarbituric acid-reactive substance, and 8-isoprostane level but significantly increased plasma superoxide dismutase activity. Glucose and insulin levels were significantly reduced in metformin and berberine-treated groups. Glucose tolerance tests documented that berberine-treated mice were more glucose tolerant. Berberine treatment increased expression of skeletal muscle glucose transporter 4 mRNA and significantly decreased liver low density lipoprotein receptor mRNA expression. The study suggested that berberine was effective in lowering blood glucose and lipids levels, reducing the body weight, and alleviating the oxidative stress in diabetic hamsters, which might be beneficial in reducing the cardiovascular risk factors in diabetes.

  15. Evaluation of the Effectiveness of Piper cubeba Extract in the Amelioration of CCl4-Induced Liver Injuries and Oxidative Damage in the Rodent Model

    PubMed Central

    AlSaid, Mansour; Mothana, Ramzi; Raish, Mohammad; Al-Sohaibani, Mohammed; Al-Yahya, Mohammed; Ahmad, Ajaz; Al-Dosari, Mohammed; Rafatullah, Syed

    2015-01-01

    Background. Liver diseases still represent a major health burden worldwide. Moreover, medicinal plants have gained popularity in the treatment of several diseases including liver. Thus, the present study was to evaluate the effectiveness of Piper cubeba fruits in the amelioration of CCl4-induced liver injuries and oxidative damage in the rodent model. Methods. Hepatoprotective activity was assessed using various biochemical parameters like SGOT, SGPT, γ-GGT, ALP, total bilirubin, LDH, and total protein. Meanwhile, in vivo antioxidant activities as LPO, NP-SH, and CAT were measured in rat liver as well as mRNA expression of cytokines such as TNFα, IL-6, and IL-10 and stress related genes iNOS and HO-1 were determined by RT-PCR. The extent of liver damage was also analyzed through histopathological observations. Results. Treatment with PCEE significantly and dose dependently prevented drug induced increase in serum levels of hepatic enzymes. Furthermore, PCEE significantly reduced the lipid peroxidation in the liver tissue and restored activities of defense antioxidant enzymes NP-SH and CAT towards normal levels. The administration of PCEE significantly downregulated the CCl4-induced proinflammatory cytokines TNFα and IL-6 mRNA expression in dose dependent manner, while it upregulated the IL-10 and induced hepatoprotective effect by downregulating mRNA expression of iNOS and HO-1 gene. PMID:25654097

  16. Fucoidan ameliorates steatohepatitis and insulin resistance by suppressing oxidative stress and inflammatory cytokines in experimental non-alcoholic fatty liver disease.

    PubMed

    Heeba, Gehan H; Morsy, Mohamed A

    2015-11-01

    Fucoidan, a sulfated polysaccharide derived from brown seaweeds, possesses a wide range of pharmacological properties. In the present study, we investigated the therapeutic effect of fucoidan on non-alcoholic fatty liver disease (NAFLD) in rats. Rats were fed a high-fat diet (HFD) for 12 weeks to induce NAFLD. Oral administrations of fucoidan (100mg/kg, orally), metformin (200mg/kg, orally) or the vehicle were started in the last four weeks. Results showed that administration of fucoidan for 4 weeks attenuated the development of NAFLD as evidenced by the significant decrease in liver index, serum liver enzymes activities, serum total cholesterol and triglycerides, fasting serum glucose, insulin, insulin resistance, and body composition index. Further, fucoidan decreased hepatic malondialdehyde as well as nitric oxide concentrations, and concomitantly increased hepatic reduced glutathione level. In addition, the effect of fucoidan was accompanied with significant decrease in hepatic mRNA expressions of tumor necrosis factor-α, interleukins-1β and matrix metalloproteinase-2. Furthermore, histopathological examination confirmed the effect of fucoidan. In conclusion, fucoidan ameliorated the development of HFD-induced NAFLD in rats that may be, at least partly, related to its hypolipidemic, insulin sensitizing, antioxidant and anti-inflammatory mechanisms.

  17. Effects of Berberine on Amelioration of Hyperglycemia and Oxidative Stress in High Glucose and High Fat Diet-Induced Diabetic Hamsters In Vivo

    PubMed Central

    Liu, Cong; Wang, Zhuo; Song, Yulong; Wu, Dan; Zheng, Xuan; Li, Ping; Jin, Jin; Xu, Nannan; Li, Ling

    2015-01-01

    This study investigated the effects of berberine on amelioration of hyperglycemia and hyperlipidemia and the mechanism involved in high glucose and high fat diet-induced diabetic hamsters. Golden hamsters fed with high glucose and high fat diet were medicated with metformin, simvastatin, and low or high dose of berberine (50 and 100 mg·kg−1) for 6 weeks. The results showed that the body weights were significantly lower in berberine-treated groups than control group. Histological analyses revealed that the treatment of berberine inhibited hepatic fat accumulation. Berberine significantly reduced plasma total cholesterol, triglyceride, free fatty acid, low density lipoprotein cholesterol, malondialdehyde, thiobarbituric acid-reactive substance, and 8-isoprostane level but significantly increased plasma superoxide dismutase activity. Glucose and insulin levels were significantly reduced in metformin and berberine-treated groups. Glucose tolerance tests documented that berberine-treated mice were more glucose tolerant. Berberine treatment increased expression of skeletal muscle glucose transporter 4 mRNA and significantly decreased liver low density lipoprotein receptor mRNA expression. The study suggested that berberine was effective in lowering blood glucose and lipids levels, reducing the body weight, and alleviating the oxidative stress in diabetic hamsters, which might be beneficial in reducing the cardiovascular risk factors in diabetes. PMID:25705654

  18. Abresham ameliorates dyslipidemia, hepatic steatosis and hypertension in high-fat diet fed rats by repressing oxidative stress, TNF-α and normalizing NO production.

    PubMed

    Nepal, Saroj; Malik, Salma; Sharma, Ashok Kumar; Bharti, Saurabh; Kumar, Narender; Siddiqui, Khalid Mehmood; Bhatia, Jagriti; Kumari, Santosh; Arya, Dharamvir Singh

    2012-11-01

    This study was aimed to investigate whether standardized hydroalcoholic extract of abresham (AB) ameliorates dyslipidemia, hepatic steatosis and associated hypertension in rats fed with high-cholesterol/high-fat diet (HFD). HFD (55% calorie from fat and 2% cholesterol) were fed for 45 days to induce dyslipidemia, hepatic steatosis and associated hypertension. After confirmation of hypercholesterolemia (total cholesterol >150 mg/dl) on 30th day, different doses of AB (200-800 mg/kg/day) were administered for next 15 days. HFD administration for 45 days led to cardiometabolic syndrome characterized by significant increase in body weight, total cholesterol, triglyceride, low density lipoprotein cholesterol, TNF-α levels along with decrease in high density lipoprotein cholesterol and serum NO level. Furthermore, HFD resulted in significant increase in systolic arterial pressure, diastolic arterial pressure and mean arterial pressure. In addition, morphological studies revealed hepatic steatosis along with swelling of mitochondria and loss of cristae in hepatocyte and periarteritis in aorta. Treatment with AB for 15 days positively modulated the altered parameters in dose-dependent fashion, though maximum effect was seen at 800 mg/kg. These findings suggest that AB guard against cardiometabolic syndrome in HFD fed rats. It attenuates dyslipidemia, hepatic steatosis and associated hypertension by decreasing oxidative stress, TNF-α and normalizing NO production.

  19. Interaction of PACAP with Sonic hedgehog reveals complex regulation of the hedgehog pathway by PKA.

    PubMed

    Niewiadomski, Pawel; Zhujiang, Annie; Youssef, Mary; Waschek, James A

    2013-11-01

    Sonic hedgehog (Shh) signaling is essential for proliferation of cerebellar granule cell progenitors (cGCPs) and its aberrant activation causes a cerebellar cancer medulloblastoma. Pituitary adenylate cyclase activating polypeptide (PACAP) inhibits Shh-driven proliferation of cGCPs and acts as tumor suppressor in murine medulloblastoma. We show that PACAP blocks canonical Shh signaling by a mechanism that involves activation of protein kinase A (PKA) and inhibition of the translocation of the Shh-dependent transcription factor Gli2 into the primary cilium. PKA is shown to play an essential role in inhibiting gene transcription in the absence of Shh, but global PKA activity levels are found to be a poor predictor of the degree of Shh pathway activation. We propose that the core Shh pathway regulates a small compartmentalized pool of PKA in the vicinity of primary cilia. GPCRs that affect global PKA activity levels, such as the PACAP receptor, cooperate with the canonical Shh signal to regulate Gli protein phosphorylation by PKA. This interaction serves to fine-tune the transcriptional and physiological function of the Shh pathway.

  20. Up-regulation of heme oxygenase-1 contributes to the amelioration of aluminum-induced oxidative stress in Medicago sativa.

    PubMed

    Cui, Weiti; Zhang, Jing; Xuan, Wei; Xie, Yanjie

    2013-10-15

    In this report, pharmacological, histochemical and molecular approaches were used to investigate the effect of heme oxygenase-1 (HO-1) up-regulation on the alleviation of aluminum (Al)-induced oxidative stress in Medicago sativa. Exposure of alfalfa to AlCl3 (0-100 μM) resulted in a dose-dependent inhibition of root elongation as well as the enhancement of thiobarbituric acid reactive substances (TBARS) content. 1 and 10 μM (in particular) Al(3+) increased alfalfa HO-1 transcript or its protein level, and HO activity in comparison with the decreased changes in 100 μM Al-treated samples. After recuperation, however, TBARS levels in 1 and 10 μM Al-treated alfalfa roots returned to control values, which were accompanied with the higher levels of HO activity. Subsequently, exogenous CO, a byproduct of HO-1, could substitute for the cytoprotective effects of the up-regulation of HO-1 in alfalfa plants upon Al stress, which was confirmed by the alleviation of TBARS and Al accumulation, as well as the histochemical analysis of lipid peroxidation and loss of plasma membrane integrity. Theses results indicated that endogenous CO generated via heme degradation by HO-1 could contribute in a critical manner to its protective effects. Additionally, the pretreatments of butylated hydroxytoluene (BHT) and hemin, an inducer of HO-1, exhibited the similar cytoprotective roles in the alleviation of oxidative stress, both of which were impaired by the potent inhibitor of HO-1, zinc protoporphyrin IX (ZnPP). However, the Al-induced inhibition of root elongation was not influenced by CO, BHT and hemin, respectively. Together, the present results showed up-regulation of HO-1 expression could act as a mechanism of cell protection against oxidative stress induced by Al treatment.

  1. Anti-convulsant action and amelioration of oxidative stress by Glycyrrhiza glabra root extract in pentylenetetrazole- induced seizure in albino rats

    PubMed Central

    Chowdhury, Bimalendu; Bhattamisra, Subrat K.; Das, Mangala C.

    2013-01-01

    Objectives: The aim of the present study was to evaluate the anti-convulsant potential of aqueous and ethanol e xtract of Glycyrrhiza glabra (AEGG and EEGG) and its action on markers of oxidant stress in albino rats. Materials and Methods: The aqueous and ethanol extract of Glycyrrhiza glabra was tested at three doses viz. 100, 200, and 400 mg/kg i.p. for its anti-convulsant activity using pentylenetetrazole (PTZ)-induced seizure in rat. The effect of EEGG (400 mg/kg, i.p.) on oxidative stress markers like malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) of rat brain tissue homogenate was tested. Results: The onset of seizure was delayed (P < 0.01) by all the three doses of EEGG, but the duration of convulsion was reduced (P < 0.01) only in higher dose level (200 and 400 mg/ kg), whereas AEGG up to 400 mg/kg did not alter any of the parameters significantly. Biochemical analysis of rat brain tissue revealed that MDA was increased (P < 0.01), whereas SOD and CAT were decreased (P < 0.01) in PTZ-induced seizure rat, whereas pre-treatment with EEGG (400 mg/kg) decreased (P < 0.01) the MDA and increased (P < 0.01) both SOD and CAT, indicating attenuation of lipid peroxidation due to increase in antioxidant enzymes. Conclusion: The results demonstrated that EEGG poses anti-convulsant potential and ameliorates ROS induced neuronal damage in PTZ-induced seizure. PMID:23543836

  2. Iron reduction by deferoxamine leads to amelioration of adiposity via the regulation of oxidative stress and inflammation in obese and type 2 diabetes KKAy mice.

    PubMed

    Tajima, Soichiro; Ikeda, Yasumasa; Sawada, Kaori; Yamano, Noriko; Horinouchi, Yuya; Kihira, Yoshitaka; Ishizawa, Keisuke; Izawa-Ishizawa, Yuki; Kawazoe, Kazuyoshi; Tomita, Shuhei; Minakuchi, Kazuo; Tsuchiya, Koichiro; Tamaki, Toshiaki

    2012-01-01

    Iron is an essential trace metal for most organisms. However, excess iron causes oxidative stress through production of highly toxic hydroxyl radicals via the Fenton/Haber-Weiss reaction. Iron storage in the body is reported to be associated with fat accumulation and type 2 diabetes mellitus. We investigated the role of iron in adiposity by using KKAy mice and obese and diabetic model mice. Eight-week-old KKAy mice were divided into two groups and treated with deferoxamine (DFO), an iron chelator agent, or a vehicle for 2 wk. DFO treatment diminished fat iron concentration and serum ferritin levels in KKAy mice. Fat weight and adipocyte size were reduced significantly in DFO-treated mice compared with vehicle-treated mice. Macrophage infiltration into fat was also decreased in DFO-treated mice compared with vehicle-treated mice. Superoxide production and NADPH oxidase activity in fat, as well as urinary 8-hydroxy-2'-deoxyguanosine excretion, were decreased in KKAy mice after DFO treatment while p22(phox) expression in adipose tissue was diminished in such mice. Ferritin expression in the fat of DFO-treated KKAy mice was decreased. In addition, F4/80-positive cells also presented through both p22(phox) and ferritin expression. The mRNA expression levels of inflammatory cytokines were also reduced in fat tissue of DFO-treated mice. These findings suggest that reduction of iron levels ameliorates adipocyte hypertrophy via suppression of oxidative stress, inflammatory cytokines, and macrophage infiltration, thereby breaking a vicious cycle in obesity.

  3. Paeoniflorin attenuates amyloid-beta peptide-induced neurotoxicity by ameliorating oxidative stress and regulating the NGF-mediated signaling in rats.

    PubMed

    Lan, Zhou; Chen, Lvyi; Fu, Qiang; Ji, Weiwei; Wang, Shuyuan; Liang, Zhaohui; Qu, Rong; Kong, Lingyi; Ma, Shiping

    2013-03-01

    Paeoniflorin is a monoterpene glycoside isolated from the aqueous extract of the dry root of Paeonia. It has been identified to exhibit many pharmacological effects including enhancing the cognitive ability, producing anti-depressant-like effect and reducing the MTPT-induced toxicity. In our previous study, it has shown that paeoniflorin improved the cognitive ability and attenuated the oxidative stress in the Aβ(1-42)-treated rats. In order to further elucidate the possible molecular mechanisms of paeoniflorin on the cognitive ability, rats were injected with Aβ(1-42) (1 μg/μL) and later with paeoniflorin (15 mg/kg and 30 mg/kg, i.p.) and donepezil hydrochloride (2mg/kg, i.p.) daily for 20 days in this study. The results showed that the long-term treatment of paeoniflorin or donepezil enhanced the cognitive performances in the Morris water maze test, restored the decreased activities of superoxide dismutase and catalase and the increased level of malondialdehyde, and reversed the alterations of matrix metallopeptidase-9 and tissue-inhibitor of metalloproteinase-1 in the hippocampus of Aβ(1-42)-treated rats. Paeoniflorin also up-regulated the activity of choline acetyltrasferase and the expression of tyrosine kinase A receptor, and down-regulated the activity of acetylcholine esterase in the hippocampus of Aβ(1-42)-treated rats. These results demonstrate that paeoniflorin ameliorates the spatial learning and memory deficits by attenuating oxidative stress and regulating the nerve growth factor-mediated signaling to reinforce cholinergic functions in the hippocampus of the Aβ(1-42)-treated rats.

  4. Targeting oxidative/nitrergic stress ameliorates motor impairment, and attenuates synaptic mitochondrial dysfunction and lipid peroxidation in two models of Huntington's disease.

    PubMed

    Pérez-De La Cruz, Verónica; Elinos-Calderón, Diana; Robledo-Arratia, Yolanda; Medina-Campos, Omar N; Pedraza-Chaverrí, José; Ali, Syed F; Santamaría, Abel

    2009-05-16

    In this study, we reproduced two toxic models resembling some motor/kinetic deficits of Huntington's disease induced by bilateral intrastriatal injections of either quinolinic acid (QUIN, 120 nmol/microl per side) or 3-nitropropionic acid (3-NP, 250 nmol/microl per side) to rats. Motor skills (including total distance walked/traveled and total horizontal and vertical activities) were evaluated in a box-field system at 1 and 7 days post-lesion. In order to investigate whether these alterations were associated with the oxidative/nitrergic stress evoked by the nitrogen reactive species peroxynitrite (ONOO(-)) in the striatum, some rats were pretreated with the ONOO(-) decomposition catalyst iron porphyrinate (Fe(TPPS), 10 mg/kg, i.p.) 120 min prior to toxins infusion. With the aim to further characterize some possible mechanisms by which motor tasks were affected and/or preserved, biochemical analysis of peroxidative damage to lipids and mitochondrial dysfunction were both assessed in synaptic membranes isolated from the striata of QUIN-, 3-NP- and/or Fe(TPPS)-treated animals. Our results show that targeting oxidative/nitrergic stress by Fe(TPPS) in these toxic models results in amelioration of motor deficits linked to inhibition of peroxidative damage and recovery of mitochondrial function in synaptic membranes. Based on these findings, we hypothesize that the protection exerted by Fe(TPPS) on the biochemical markers analyzed reflects the possible preservation of the functional status of the nerve tissue by limiting the deleterious actions of ONOO(-), further accounting for partial recovery of integrative motor functions.

  5. Effect of Withania somnifera (Ashwagandha) root extract on amelioration of oxidative stress and autoantibodies production in collagen-induced arthritic rats.

    PubMed

    Khan, Mahmood Ahmad; Subramaneyaan, Mythily; Arora, Vinod Kumar; Banerjee, Basu Dev; Ahmed, Rafat Sultana

    2015-06-01

    Rheumatoid arthritis is an inflammatory autoimmune disorder. Withania somnifera Dunal (Solanaceae) (WS), is a common medicinal plant used in traditional systems of medicine for the treatment of arthritis, and is an ingredient of anti-arthritic polyherbal formulations such as Habb-e-Asgand® and Arthritin™. In the present study, we evaluated the antioxidant and anti-arthritic activity of aqueous extract of WS root (WSAq) in collagen-induced arthritic (CIA) rats. CIA rats were treated by using three doses of WSAq (100, 200, 300 mg/kg b. wt., orally) and methotrexate (MTX, 0.25 mg/kg b. wt. i.p.) as a standard reference drug for 20 days. The anti-arthritic effect was assayed by measuring the arthritic index, autoantibodies such as rheumatoid factor (RF), anti-cyclic citrullinated peptide antibody (a-CCP), anti-nuclear antibody (ANA), anti-collagen type II antibody (a-CII) and inflammatory marker like C-reactive protein (CRP). The oxidative stress parameters were also measured. Treatment with WSAq resulted in a dose-dependent reduction in arthritic index, autoantibodies and CRP (p < 0.05) with maximum effect at dose of 300 mg/kg b. wt. and the results were comparable to that of MTX-treated rats. Similarly, oxidative stress in CIA rats was ameliorated by treatment with different doses of WSAq, as evidenced by a decrease in lipid peroxidation and glutathione-S-transferase activity and an increase in the glutathione content and ferric-reducing ability of plasma (p < 0.05). The results showed that WSAq exhibited antioxidant and anti-arthritic activity and reduced inflammation in CIA rats and suggests the potential use of this plant in the treatment of arthritis.

  6. Chrysin protects against cisplatin-induced colon. toxicity via amelioration of oxidative stress and apoptosis: probable role of p38MAPK and p53.

    PubMed

    Khan, Rehan; Khan, Abdul Quaiyoom; Qamar, Wajhul; Lateef, Abdul; Tahir, Mir; Rehman, Muneeb U; Ali, Farrah; Sultana, Sarwat

    2012-02-01

    Cisplatin, an antineoplastic drug, is widely used as a foremost therapy against numerous forms of cancer but it has pronounced adverse effects viz., nephrotoxicity, ototoxicity etc. CDDP-induced emesis and diarrhea are also marked toxicities that may be due to intestinal injury. Chrysin (5,7-dihydroxyflavone), a natural flavone commonly found in many plants possesses multiple biological activities, such as antioxidant, anti-inflammatory and anti-cancer effects. In the present study, we investigated the protective effect of chrysin against CDDP-induced colon toxicity. The plausible mechanism of CDDP-induced colon toxicity and damage includes oxidative stress, activation of p38MAPK and p53, and colonic epithelial cell apoptosis via upregulating the expression of Bak and cleaved caspase-3. Chrysin was administered to Wistar rats once daily for 14 consecutive days at the doses of 25 and 50 mg/kg body weight orally in corn oil. On day 14, a single intraperitoneal injection of cisplatin was given at the dose of 7.5 mg/kg body weight and animals were euthanized after 24 h of cisplatin injection. Chrysin ameliorated CDDP-induced lipid peroxidation, xanthine oxidase activity, glutathione depletion, decrease in antioxidant (catalase, glutathione reductase, glutathione peroxidase and glucose-6 phosphate dehydrogenase) and phase-II detoxifying (glutathione-S-transferase and quinone reductase) enzyme activities. Chrysin also attenuated goblet cell disintegration, expression of phospho-p38MAPK and p53, and apoptotic tissue damage which were induced by CDDP. Histological findings further supported the protective effects of chrysin against CDDP-induced colonic damage. The results of the present study suggest that the protective effect of chrysin against CDDP-induced colon toxicity was related with attenuation of oxidative stress, activation of p38MAPK and p53, and apoptotic tissue damage.

  7. 17β-estradiol ameliorates light-induced retinal damage in Sprague-Dawley rats by reducing oxidative stress.

    PubMed

    Wang, Shaolan; Wang, Baoying; Feng, Yan; Mo, Mingshu; Du, Fangying; Li, Hongbo; Yu, Xiaorui

    2015-01-01

    Oxidative stress is considered as a major cause of light-induced retinal neurodegeneration. The protective role of 17β-estradiol (βE2) in neurodegenerative disorders is well known, but its underlying mechanism remains unclear. Here, we utilized a light-induced retinal damage model to explore the mechanism by which βE2 exerts its neuroprotective effect. Adult male and female ovariectomized (OVX) rats were exposed to 8,000 lx white light for 12 h to induce retinal light damage. Electroretinogram (ERG) assays and hematoxylin and eosin (H&E) staining revealed that exposure to light for 12 h resulted in functional damage to the rat retina, histological changes, and retinal neuron loss. However, intravitreal injection (IVI) of βE2 significantly rescued this impaired retinal function in both female and male rats. Based on the level of malondialdehyde (MDA) production (a biomarker of oxidative stress), an increase in retinal oxidative stress followed light exposure, and βE2 administration reduced this light-induced oxidative stress. Quantitative reverse-transcriptase (qRT)-PCR indicated that the messenger RNA (mRNA) levels of the antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (Gpx) were downregulated in female OVX rats but were upregulated in male rats after light exposure, suggesting a gender difference in the regulation of these antioxidant enzyme genes in response to light. However, βE2 administration restored or enhanced the SOD and Gpx expression levels following light exposure. Although the catalase (CAT) expression level was insensitive to light stimulation, βE2 also increased the CAT gene expression level in both female OVX and male rats. Further examination indicated that the antioxidant proteins thioredoxin (Trx) and nuclear factor erythroid 2-related factor 2 (Nrf2) are also involved in βE2-mediated antioxidation and that the cytoprotective protein heme oxygenase-1 (HO-1) plays a key role in the endogenous defense mechanism

  8. Amelioration of radiation-induced oxidative stress and biochemical alteration by SOD model compounds in pre-treated gamma-irradiated rats.

    PubMed

    Abou-Seif, Mosaad A M; El-Naggar, Mohammad M; El-Far, Mohammad; Ramadan, Mohsen; Salah, N

    2003-11-01

    The role of metalloelements in tissue maintenance, function and response to injury offer a new approach to decreasing and/or treating radiation injury. We investigated the roles of CuL(2)SO(4), [MnL(2)O](2)Cl(4)(H(2)O)(2) and [(VL(2)O)(VL(2)H(2)O)]Cl(6) complexes (L=2-methylaminopyridine) of SOD-mimetic activities, in ameliorating the radiation-induced oxidative stress and alterations in some biochemical parameters in liver, kidney, spleen and brain in pretreated female rats exposed to gamma-irradiation. Both untreated-rats and rats treated with the above complexes were subjected to whole-body gamma-irradiation (6 Gy). 5'-Nucleotidase (5'-NT), acetylcholinesterase (AChE), adenosne triphosphatase (ATPase), superoxide dismutase (SOD), catalase (CAT) and glutathione reductase (GSSG-R) were assessed as well as liver DNA and RNA contents and total protein concentration were estimated in tissue homogenates of the above organs. The same parameters were assessed in non-irradiated treated rats and normal control rats. Results were compared to irradiated non-treated and normal control rats. Pretreatment of gamma-irradiated rats with Mn(IV) or V(IV) complex produced a significant decrease in liver 5'-NT activity compared to the corresponding value of the untreated irradiated rats. In contrast, liver DNA and RNA contents and brain AChE and ATPase activities were significantly increased in irradiated rat group pre-treated with these metal complexes. Cu II, Mn IV or V IV complex inoculation prior to irradiation of normal rats exhibited a significant increase in SOD, CAT, GSSG-R activities and protein content of liver, kidney, spleen and brain homogenates compared with that of the untreated irradiated rats. The treatment of non-irradiated rats with these complexes produced a highly significant increase in mean activities of SOD and CAT, with no changes in other parameters vs. controls. Cu(II), Mn(IV) and V(IV) 2-methylaminopyridine complexes offer a physiological approach to

  9. Geraniol, alone and in combination with pioglitazone, ameliorates fructose-induced metabolic syndrome in rats via the modulation of both inflammatory and oxidative stress status.

    PubMed

    Ibrahim, Sherehan M; El-Denshary, Ezzedin S; Abdallah, Dalaal M

    2015-01-01

    Geraniol (GO) potent antitumor and chemopreventive effects are attributed to its antioxidant and anti-inflammatory properties. In the current study, the potential efficacy of GO (250 mg/kg) in ameliorating metabolic syndrome (MetS) induced by fructose in drinking water was elucidated. Moreover, the effect of pioglitazone (5 and 10 mg/kg; PIO) and the possible interaction of the co-treatment of GO with PIO5 were studied in the MetS model. After 4 weeks of treatment, GO and/or PIO reduced the fasting blood glucose and the glycemic excursion in the intraperitoneal glucose tolerance test. GO and PIO5/10 restrained visceral adiposity and partly the body weight gain. The decreased level of peroxisome proliferator activated receptor (PPAR)-γ transcriptional activity in the visceral adipose tissue of MetS rats was increased by single treatment regimens. Though GO did not affect MetS-induced hyperinsulinemia, PIO5/10 lowered it. Additionally, GO and PIO5/10 suppressed glycated hemoglobin and the receptor for advanced glycated end products (RAGE). These single regimens also ameliorated hyperuricemia, the disrupted lipid profile, and the elevated systolic blood pressure evoked by MetS. The rise in serum transaminases, interleukin-1β, and tumor necrosis factor-α, as well as hepatic lipid peroxides and nitric oxide (NO) was lowered by the single treatments to different extents. Moreover, hepatic non-protein thiols, as well as serum NO and adiponectin were enhanced by single regimens. Similar effects were reached by the combination of GO with PIO5; however, a potentiative interaction was noted on fasting serum insulin level, while synergistic effects were reflected as improved insulin sensitivity, as well as reduced RAGE and triglycerides. Therefore, GO via the transcriptional activation of PPAR-γ reduces inflammation and free radical injury produced by MetS. Thereby, these effects provide novel mechanistic insights on GO management of MetS associated critical risk factors

  10. Chrysin protects against cisplatin-induced colon. toxicity via amelioration of oxidative stress and apoptosis: Probable role of p38MAPK and p53

    SciTech Connect

    Khan, Rehan; Khan, Abdul Quaiyoom; Qamar, Wajhul; Lateef, Abdul; Tahir, Mir; Rehman, Muneeb U; Ali, Farrah; Sultana, Sarwat

    2012-02-01

    Cisplatin, an antineoplastic drug, is widely used as a foremost therapy against numerous forms of cancer but it has pronounced adverse effects viz., nephrotoxicity, ototoxicity etc. CDDP-induced emesis and diarrhea are also marked toxicities that may be due to intestinal injury. Chrysin (5,7-dihydroxyflavone), a natural flavone commonly found in many plants possesses multiple biological activities, such as antioxidant, anti-inflammatory and anti-cancer effects. In the present study, we investigated the protective effect of chrysin against CDDP-induced colon toxicity. The plausible mechanism of CDDP-induced colon toxicity and damage includes oxidative stress, activation of p38MAPK and p53, and colonic epithelial cell apoptosis via upregulating the expression of Bak and cleaved caspase-3. Chrysin was administered to Wistar rats once daily for 14 consecutive days at the doses of 25 and 50 mg/kg body weight orally in corn oil. On day 14, a single intraperitoneal injection of cisplatin was given at the dose of 7.5 mg/kg body weight and animals were euthanized after 24 h of cisplatin injection. Chrysin ameliorated CDDP-induced lipid peroxidation, xanthine oxidase activity, glutathione depletion, decrease in antioxidant (catalase, glutathione reductase, glutathione peroxidase and glucose-6 phosphate dehydrogenase) and phase-II detoxifying (glutathione-S-transferase and quinone reductase) enzyme activities. Chrysin also attenuated goblet cell disintegration, expression of phospho-p38MAPK and p53, and apoptotic tissue damage which were induced by CDDP. Histological findings further supported the protective effects of chrysin against CDDP-induced colonic damage. The results of the present study suggest that the protective effect of chrysin against CDDP-induced colon toxicity was related with attenuation of oxidative stress, activation of p38MAPK and p53, and apoptotic tissue damage. Highlights: ► Cisplatin-induced colon toxicity is associated with oxidative stress and

  11. Rutin ameliorates cyclophosphamide induced oxidative stress and inflammation in Wistar rats: role of NFκB/MAPK pathway.

    PubMed

    Nafees, Sana; Rashid, Summya; Ali, Nemat; Hasan, Syed Kazim; Sultana, Sarwat

    2015-04-25

    Cyclophosphamide is a potent anticancer agent. However its clinical use is restricted because of its marked organ toxicity associated with increased oxidative stress and inflammation. The present study was designed to demonstrate the protective effects of rutin, a naturally occurring bioflavonoid against the hepatotoxicity induced by CP. Rats were subjected to oral pretreatment of rutin (50 and 100 mg/kg b wt) against hepatotoxicity induced by i.p. injection of CP (150 mg/kg b wt) and were sacrificed after 24 h. Hepatoprotective effects of rutin were associated with upregulation of antioxidant enzyme activities and down regulation of serum toxicity markers. Rutin was able to down regulate the levels of inflammatory markers like TNF-α, IL-6 and expressions of p38-MAPK, NFκB, i-NOS and COX-2. Histopathological changes further confirmed the biochemical and immunohistochemical results showing that CP caused significant structural damage to liver which were reversed by pretreatment of rutin. Therefore, our study revealed that rutin may be a promising modulator in attenuating CP induced oxidative stress, inflammation and hepatotoxicity via targeting NFκB and MAPK pathway.

  12. SIRT1 ameliorates oxidative stress induced neural cell death and is down-regulated in Parkinson's disease.

    PubMed

    Singh, Preeti; Hanson, Peter S; Morris, Christopher M

    2017-06-02

    Sirtuins (SIRTs) are NAD(+) dependent lysine deacetylases which are conserved from bacteria to humans and have been associated with longevity and lifespan extension. SIRT1, the best studied mammalian SIRT is involved in many physiological and pathological processes and changes in SIRT1 have been implicated in neurodegenerative disorders, with SIRT1 having a suggested protective role in Parkinson's disease. In this study, we determined the effect of SIRT1 on cell survival and α-synuclein aggregate formation in SH-SY5Y cells following oxidative stress. Over-expression of SIRT1 protected SH-SY5Y cells from toxin induced cell death and the protection conferred by SIRT1 was partially independent of its deacetylase activity, which was associated with the repression of NF-кB and cPARP expression. SIRT1 reduced the formation of α-synuclein aggregates but showed minimal co-localisation with α-synuclein. In post-mortem brain tissue obtained from patients with Parkinson's disease, Parkinson's disease with dementia, dementia with Lewy bodies and Alzheimer's disease, the activity of SIRT1 was observed to be down-regulated. These findings suggests a negative effect of oxidative stress in neurodegenerative disorders and possibly explain the reduced activity of SIRT1 in neurodegenerative disorders. Our study shows that SIRT1 is a pro-survival protein that is downregulated under cellular stress.

  13. Ameliorative effects of 5-hydroxymethyl-2-furfural (5-HMF) from Schisandra chinensis on alcoholic liver oxidative injury in mice.

    PubMed

    Li, Wei; Qu, Xin-Nan; Han, Ye; Zheng, Si-Wen; Wang, Jia; Wang, Ying-Ping

    2015-01-22

    The aim of this paper is to evaluate the protective effect of 5-hydroxymethyl-2-furfural (5-HMF) on acute alcohol-induced liver oxidative injury in mice. 5-HMF, a maillard reaction product, was isolated from the fruits of Schisandra chinensis for animal experiments. Experimental ICR mice were pretreated with different doses of 5-HMF (7.5, 15, and 30 mg/kg) for seven days by gavage feeding. Biochemical markers and enzymatic antioxidants from serum and liver tissue were examined. Our results showed that the activities of ALT (alanine aminotransferase), AST (aspartate transaminase), TC (total cholesterol), TG (triglyceride), L-DLC (low density lipoprotein) in serum and the levels of MDA (malondialdehyde) in liver tissue, decreased significantly (p < 0.05) in the 5-HMF-treated group compared with the alcohol group. On the contrary, enzymatic antioxidants CAT (catalase), GSH-Px (glutathione peroxidase), and GSH SOD (superoxide dismutase) were markedly elevated in liver tissue treated with 5-HMF (p < 0.05). Furthermore, the hepatic levels of pro-inflammatory response marker tumor necrosis factor-alpha (TNF-α) and interleukin-1β (IL-1β) were significantly suppressed (p < 0.05). Histopathological examination revealed that 5-HMF (30 mg/kg) pretreatment noticeably prevented alcohol-induced hepatocyte apoptosis and fatty degeneration. It is suggested that the hepatoprotective effects exhibited by 5-HMF on alcohol-induced liver oxidative injury may be due to its potent antioxidant properties.

  14. Ameliorative Effects of 5-Hydroxymethyl-2-furfural (5-HMF) from Schisandra chinensis on Alcoholic Liver Oxidative Injury in Mice

    PubMed Central

    Li, Wei; Qu, Xin-Nan; Han, Ye; Zheng, Si-Wen; Wang, Jia; Wang, Ying-Ping

    2015-01-01

    The aim of this paper is to evaluate the protective effect of 5-hydroxymethyl-2-furfural (5-HMF) on acute alcohol-induced liver oxidative injury in mice. 5-HMF, a maillard reaction product, was isolated from the fruits of Schisandra chinensis for animal experiments. Experimental ICR mice were pretreated with different doses of 5-HMF (7.5, 15, and 30 mg/kg) for seven days by gavage feeding. Biochemical markers and enzymatic antioxidants from serum and liver tissue were examined. Our results showed that the activities of ALT (alanine aminotransferase), AST (aspartate transaminase), TC (total cholesterol), TG (triglyceride), L-DLC (low density lipoprotein) in serum and the levels of MDA (malondialdehyde) in liver tissue, decreased significantly (p < 0.05) in the 5-HMF-treated group compared with the alcohol group. On the contrary, enzymatic antioxidants CAT (catalase), GSH-Px (glutathione peroxidase), and GSH SOD (superoxide dismutase) were markedly elevated in liver tissue treated with 5-HMF (p < 0.05). Furthermore, the hepatic levels of pro-inflammatory response marker tumor necrosis factor-alpha (TNF-α) and interleukin-1β (IL-1β) were significantly suppressed (p < 0.05). Histopathological examination revealed that 5-HMF (30 mg/kg) pretreatment noticeably prevented alcohol-induced hepatocyte apoptosis and fatty degeneration. It is suggested that the hepatoprotective effects exhibited by 5-HMF on alcohol-induced liver oxidative injury may be due to its potent antioxidant properties. PMID:25622257

  15. Nigella sativa (black cumin) ameliorates potassium bromate-induced early events of carcinogenesis: diminution of oxidative stress.

    PubMed

    Khan, Naghma; Sharma, Sonia; Sultana, Sarwat

    2003-04-01

    Potassium bromate (KBrO3) is a potent nephrotoxic agent. In this paper, we report the chemopreventive effect of Nigella sativa (black cumin) on KBrO3-mediated renal oxidative stress, toxicity and tumor promotion response in rats. KBrO3 (125 mg/kg body weight, intraperitoneally) enhances lipid peroxidation, gamma-glutamyl transpeptidase, hydrogen peroxide and xanthine oxidase with reduction in the activities of renal antioxidant enzymes and renal glutathione content. A marked increase in blood urea nitrogen and serum creatinine has also been observed. KBrO3 treatment also enhances ornithine decarboxylase (ODC) activity and [3H] thymidine incorporation into renal DNA. Prophylaxis of rats orally with Nigella sativa extract (50 mg/kg body weight and 100 mg/kg body weight) resulted in a significant decrease in renal microsomal lipid peroxidation (P < 0.001), gamma-glutamyl transpeptidase (P < 0.001), H2O2 (P < 0.001) and xanthine oxidase (P < 0.05). There was significant recovery of renal glutathione content (P < 0.01) and antioxidant enzymes (P < 0.001). There was also reversal in the enhancement of blood urea nitrogen, serum creatinine, renal ODC activity and DNA synthesis (P < 0.001). Data suggest that Nigella sativa is a potent chemopreventive agent and may suppress KBrO3-mediated renal oxidative stress, toxicity and tumour promotion response in rats.

  16. Thymol Ameliorates Cadmium-Induced Phytotoxicity in the Root of Rice (Oryza sativa) Seedling by Decreasing Endogenous Nitric Oxide Generation.

    PubMed

    Wang, Ting-Ting; Shi, Zhi Qi; Hu, Liang-Bin; Xu, Xiao-Feng; Han, Fengxiang X; Zhou, Li-Gang; Chen, Jian

    2017-08-30

    Thymol has been developed as medicine and food preservative due to its immune-regulatory effect and antimicrobial activity, respectively. However, little is currently known about the role of thymol in the modulation of plant physiology. In the present study, we applied biochemical and histochemical approaches to investigate thymol-induced tolerance in rice (Oryza sativa) seedlings against Cd (cadmium) stress. Thymol at 20 μM recovered root growth completely upon CdCl2 exposure. Thymol pronouncedly decreased Cd-induced ROS accumulation, oxidative injury, cell death, and Cd(2+) accumulation in roots. Pharmaceutical experiments suggested that endogenous NO mediated Cd-induced phytotoxicity. Thymol decreased Cd-induced NO accumulation by suppressing the activity of NOS (nitric oxide synthase) and NR (nitrate reductase) in root. The application of NO donor (SNP, sodium nitroprusside) resulted in the increase in endogenous NO level, which in turn compromised the alleviating effects of thymol on Cd toxicity. Such findings may helpful to illustrate the novel role of thymol in the modulation of plant physiology, which may be applicable to improve crop stress tolerance.

  17. Intravesical PAC1 Receptor Antagonist, PACAP(6–38), Reduces Urinary Bladder Frequency and Pelvic Sensitivity in NGF-OE Mice

    PubMed Central

    Girard, Beatrice M.; Malley, Susan E.; Mathews, Morgan M.; May, Victor

    2017-01-01

    Chronic NGF overexpression (OE) in the urothelium, achieved through the use of a highly urothelium-specific uroplakin II promoter, stimulates neuronal sprouting in the urinary bladder, produces increased voiding frequency and non-voiding contractions, and referred somatic sensitivity. Additional NGF-mediated pleiotropic changes might contribute to increased voiding frequency and pelvic hypersensitivity in NGF-OE mice such as neuropeptide/receptor systems including PACAP(Adcyap1) and PAC1 receptor (Adcyap1r1). Given the presence of PAC1-immunoreactive fibers and the expression of PAC1 receptor expression in bladder tissues, and PACAP-facilitated detrusor contraction, whether PACAP/receptor signaling contributes to increased voiding frequency and somatic sensitivity was evaluated in NGF-OE mice. Intravesical administration of the PAC1 receptor antagonist, PACAP(6–38) (300 nM), significantly (p ≤ 0.01) increased intercontraction interval (2.0-fold) and void volume (2.5-fold) in NGF-OE mice. Intravesical instillation of PACAP(6–38) also decreased baseline bladder pressure in NGF-OE mice. PACAP(6–38) had no effects on bladder function in WT mice. Intravesical administration of PACAP(6–38) (300 nM) significantly (p ≤ 0.01) reduced pelvic sensitivity in NGF-OE mice but was without effect in WT mice. PACAP/receptor signaling contributes to the increased voiding frequency and pelvic sensitivity observed in NGF-OE mice. PMID:27146136

  18. Sudden infant death syndrome (SIDS) in African Americans: polymorphisms in the gene encoding the stress peptide pituitary adenylate cyclase-activating polypeptide (PACAP).

    PubMed

    Cummings, Kevin J; Klotz, Cherise; Liu, Wei-Qiao; Weese-Mayer, Debra E; Marazita, Mary L; Cooper, Margaret E; Berry-Kravis, Elizabeth M; Tobias, Rose; Goldie, Cameron; Bech-Hansen, N Torben; Wilson, Richard Ja

    2009-03-01

    Mice lacking pituitary adenylate cyclase-activating polypeptide (PACAP) are prone to sudden death in the second post-natal week, having respiratory and metabolic disturbances reminiscent of the human Sudden Infant Death Syndrome (SIDS). Here we test the hypothesis that the human PACAP gene is a site of genetic variance associated with SIDS in a cohort of 92 victims and 92 matched controls. Using polymerase chain reaction and sequencing, we examined the PACAP gene in 92 SIDS cases (46 Caucasians and 46 African Americans) and 92 race- and gender-matched controls. We found no significant associations between PACAP and SIDS in Caucasians. However, in the African Americans, a non-synonymous single nucleotide polymorphism (i.e. an aspartic acid/glycine coding variant, rs2856966) within exon 2 of PACAP was significantly associated with SIDS (p = 0.004), as were haplotypes containing this polymorphism (p < 0.0001). Glycine was three times more likely at this location in the African-American SIDS victims (17 cases) than African-American controls (5 cases). These data are the first to suggest an association between a variant within the coding region of the PACAP gene and SIDS. Based on these findings, further investigations are warranted into the functional importance of PACAP signaling in neonatal survival and the role of PACAP-signaling abnormalities in SIDS.

  19. Pituitary adenylate cyclase activating polypeptide (PACAP) dilates cerebellar arteries through activation of large-conductance Ca(2+)-activated (BK) and ATP-sensitive (K ATP) K (+) channels.

    PubMed

    Koide, Masayo; Syed, Arsalan U; Braas, Karen M; May, Victor; Wellman, George C

    2014-11-01

    Pituitary adenylate cyclase activating polypeptide (PACAP) is a potent vasodilator of numerous vascular beds, including cerebral arteries. Although PACAP-induced cerebral artery dilation is suggested to be cyclic AMP (cAMP)-dependent, the downstream intracellular signaling pathways are still not fully understood. In this study, we examined the role of smooth muscle K(+) channels and hypothesized that PACAP-mediated increases in cAMP levels and protein kinase A (PKA) activity result in the coordinate activation of ATP-sensitive K(+) (KATP) and large-conductance Ca(2+)-activated K(+) (BK) channels for cerebral artery dilation. Using patch-clamp electrophysiology, we observed that PACAP enhanced whole-cell KATP channel activity and transient BK channel currents in freshly isolated rat cerebellar artery myocytes. The increased frequency of transient BK currents following PACAP treatment is indicative of increased intracellular Ca(2+) release events termed Ca(2+) sparks. Consistent with the electrophysiology data, the PACAP-induced vasodilations of cannulated cerebellar artery preparations were attenuated by approximately 50 % in the presence of glibenclamide (a KATP channel blocker) or paxilline (a BK channel blocker). Further, in the presence of both blockers, PACAP failed to cause vasodilation. In conclusion, our results indicate that PACAP causes cerebellar artery dilation through two mechanisms: (1) KATP channel activation and (2) enhanced BK channel activity, likely through increased Ca(2+) spark frequency.

  20. Intravesical PAC1 Receptor Antagonist, PACAP(6-38), Reduces Urinary Bladder Frequency and Pelvic Sensitivity in NGF-OE Mice.

    PubMed

    Girard, Beatrice M; Malley, Susan E; Mathews, Morgan M; May, Victor; Vizzard, Margaret A

    2016-06-01

    Chronic NGF overexpression (OE) in the urothelium, achieved through the use of a highly urothelium-specific uroplakin II promoter, stimulates neuronal sprouting in the urinary bladder, produces increased voiding frequency and non-voiding contractions, and referred somatic sensitivity. Additional NGF-mediated pleiotropic changes might contribute to increased voiding frequency and pelvic hypersensitivity in NGF-OE mice such as neuropeptide/receptor systems including PACAP(Adcyap1) and PAC1 receptor (Adcyap1r1). Given the presence of PAC1-immunoreactive fibers and the expression of PAC1 receptor expression in bladder tissues, and PACAP-facilitated detrusor contraction, whether PACAP/receptor signaling contributes to increased voiding frequency and somatic sensitivity was evaluated in NGF-OE mice. Intravesical administration of the PAC1 receptor antagonist, PACAP(6-38) (300 nM), significantly (p ≤ 0.01) increased intercontraction interval (2.0-fold) and void volume (2.5-fold) in NGF-OE mice. Intravesical instillation of PACAP(6-38) also decreased baseline bladder pressure in NGF-OE mice. PACAP(6-38) had no effects on bladder function in WT mice. Intravesical administration of PACAP(6-38) (300 nM) significantly (p ≤ 0.01) reduced pelvic sensitivity in NGF-OE mice but was without effect in WT mice. PACAP/receptor signaling contributes to the increased voiding frequency and pelvic sensitivity observed in NGF-OE mice.

  1. Expression and significance of TIMP-3, PACAP and VIP in vaginal wall tissues of patients with stress urinary incontinence

    PubMed Central

    Fan, Bo; Jin, Xiaohua; Shi, Yi; Zhu, Hailiang; Zhou, Wenjun; Tu, Wenjian; Ding, Li

    2017-01-01

    The objective of the present study was to investigate whether tissue inhibitor of metalloproteinase-3 (TIMP-3), pituitary adenylate cyclase-activating polypeptide (PACAP), and vasoactive intestinal peptide (VIP) participate in the occurrence of female stress urinary incontinence (SUI) by measuring the expression levels of TIMP-3, PACAP, and VIP in the vaginal wall and analyzing their correlation to understand the pathogenesis of female SUI. Forty female patients who were admitted to our hospital for tension-free obturator tape surgery for treatment of SUI from April, 2012 to December, 2015 were selected as the study group. Forty patients who underwent vaginal or total abdominal hysterectomy for treatment of non-estrogen-related diseases during the same period were selected as the control group. Tissue samples from the anterior vaginal wall, located at twelve o'clock, were taken from both groups. The expression levels of TIMP-3, PACAP and VIP were detected by immunohistochemistry, and the correlation of integral optical density (IOD) among expressions of TIMP-3, PACAP, and VIP was investigated. The expression of TIMP-3 in vaginal wall tissues of the study group was lower than that of the control group (P<0.05). The expression of PACAP and VIP in vaginal tissues of the study group were lower than those of the control group (P<0.05). In the study group, the IOD of PACAP expression was significantly and positively correlated with that of VIP (r=0.873, P<0.05), the IOD of PACAP expression was significantly and positively correlated with that of TIMP-3 (r=0.802, P<0.05), and the IOD of VIP expression was significantly and positively correlated with that of TIMP-3 (r=0.716, P<0.05). In conclusion, TIMP-3, PACAP and VIP jointly participate in the occurrence of female SUI. Increasing the expression of TIMP-3, PACAP, and VIP, repairing neurons, and enhancing the elasticity of vaginal wall tissues may become a new way to treat female SUI. PMID:28352341

  2. Betulinic acid ameliorates endothelium-dependent relaxation in L-NAME-induced hypertensive rats by reducing oxidative stress.

    PubMed

    Fu, Jia-Yin; Qian, Ling-Bo; Zhu, Lie-Gang; Liang, Hao-Te; Tan, Yi-Nuo; Lu, Han-Ti; Lu, Jian-Feng; Wang, Hui-Ping; Xia, Qiang

    2011-10-09

    Zizyphi Spinosi semen (ZSS) is one of the most widely used traditional Chinese herbs with protective effects on the cardiovascular system. It is not clear whether betulinic acid (BA), the key active constituent of ZSS, has beneficial cardiovascular effects on N(ω)-nitro-L-arginine methyl ester hydrochloride (L-NAME)-induced hypertensive rats. The objective of this study was to investigate the effect of BA on endothelium-dependent vasorelaxation in isolated aortic rings from L-NAME-induced hypertensive rats and its underlying mechanisms. Male Sprague-Dawley rats were injected with L-NAME (15 mg/kg/d, i.p.) for 4 weeks to induce hypertension. After treatment with L-NAME for 2 weeks, rats with mean blood pressure >120 mm Hg measured by tail-cuff method were considered hypertensive and then injected with BA (0.8, 4, 20 mg/kg/d, i.p.) for the last 2 weeks. The effect of BA on the tension of rat thoracic aortic rings was measured in an organ bath system. The levels of nitric oxide (NO), reactive oxygen species (ROS), and the activity of superoxide dismutase (SOD) and nitric oxide synthase (NOS) in aortas were assayed. We found that BA (0.1-100 μM) evoked a concentration-dependent vasorelaxation in endothelium-intact normal rat aortic rings, which was significantly attenuated by pretreatment with L-NAME (100 μM) or methylene blue (MB, 10 μM), but not by indomethacin (10 μM). Pretreatment with EC(50) (1.67 μM) concentration of BA enhanced the acetylcholine (ACh)-induced vasorelaxation, which was also markedly reversed by both L-NAME and MB. The blood pressure in hypertensive rats increased to 135.22±5.38 mm Hg (P<0.01 vs. control group), which was markedly attenuated by high dose of BA. The ACh-induced vasorelaxation in hypertensive rat aortic rings was impaired, which was markedly improved by chronic treatment with BA (20 mg/kg/d) for 2 weeks. The increase of ROS level and the decrease of NO level, SOD and eNOS activities in hypertensive rat aortas were all

  3. Ginsenoside Rg5 Ameliorates Cisplatin-Induced Nephrotoxicity in Mice through Inhibition of Inflammation, Oxidative Stress, and Apoptosis.

    PubMed

    Li, Wei; Yan, Meng-Han; Liu, Ying; Liu, Zhi; Wang, Zi; Chen, Chen; Zhang, Jing; Sun, Yin-Shi

    2016-09-13

    Although cisplatin is an effective anti-cancer agent that is widely used for treating various types of malignant solid tumors, the nephrotoxicity induced by cisplatin severely limits its clinical application. The present study was designed to explore the potential protective effect of ginsenoside Rg5, a rare ginsenoside generated during steaming ginseng, on cisplatin-induced nephrotoxicity in a mouse experimental model. The possible mechanisms underlying this nephroprotective effect were also investigated for the first time. Rg5 was given at doses of 10 and 20 mg/kg for 10 consecutive days. On Day 7, a single nephrotoxic dose of cisplatin (25 mg/kg) was injected to mice. Cisplatin administration resulted in renal dysfunction as evidenced by increase in serum creatinine (CRE) and blood urea nitrogen (BUN) levels. In addition, cisplatin increased the level of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), the makers of lipid peroxidation, and depleted glutathione (GSH) content and superoxide dismutase (SOD) activity in renal tissues. These effects were associated with the significantly increased levels of cytochrome P450 E1 (CYP2E1), 4-hydroxynonenal (4-HNE), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, nuclear factor-kappa B (NF-κB) p65, and cyclooxygenase-2 (COX-2) in renal tissues. However, pretreatment with ginsenoside Rg5 significantly attenuated the renal dysfunction, oxidative stress and inflammation response induced by cisplatin. Furthermore, ginsenoside Rg5 supplementation inhibited activation of apoptotic pathways through increasing Bcl-2 and decreasing Bax expression levels. Histopathological examination further confirmed the nephroprotective effect of Rg5. Collectively, these results clearly suggest that Rg5-mediated alleviation of cisplatin-induced nephrotoxicity may be related to its anti-oxidant, anti-apoptotic and anti-inflammatory effects.

  4. (-)-Epicatechin improves mitochondrial-related protein levels and ameliorates oxidative stress in dystrophic δ-sarcoglycan null mouse striated muscle.

    PubMed

    Ramirez-Sanchez, Israel; De los Santos, Sergio; Gonzalez-Basurto, Silvia; Canto, Patricia; Mendoza-Lorenzo, Patricia; Palma-Flores, Carlos; Ceballos-Reyes, Guillermo; Villarreal, Francisco; Zentella-Dehesa, Alejandro; Coral-Vazquez, Ramon

    2014-12-01

    Muscular dystrophies (MDs) are a group of heterogeneous genetic disorders characterized by progressive striated muscle wasting and degeneration. Although the genetic basis for many of these disorders has been identified, the exact mechanism of disease pathogenesis remains unclear. The presence of oxidative stress (OS) is known to contribute to the pathophysiology and severity of the MD. Mitochondrial dysfunction is observed in MD, and probably represents an important determinant of increased OS. Experimental antioxidant therapies have been implemented with the aim of protecting against disease progression, but results from clinical trials have been disappointing. In this study, we explored the capacity of the cacao flavonoid (-)-epicatechin (Epi) to mitigate OS by acting as a positive regulator of mitochondrial structure/function endpoints and redox balance control systems in skeletal and cardiac muscles of dystrophic, δ-sarcoglycan (δ-SG) null mice. Wild-type or δ-SG null 2.5-month-old male mice were treated via oral gavage with either water (controls) or Epi (1 mg·kg(-1) , twice daily) for 2 weeks. The results showed significant normalization of total protein carbonylation, recovery of the glutathione/oxidized glutathione ratio and enhanced superoxide dismutase 2, catalase and citrate synthase activities with Epi treatment. These effects were accompanied by increases in the protein levels of thioredoxin, glutathione peroxidase, superoxide dismutase 2, catalase, and mitochondrial endpoints. Furthermore, we found decreases in heart and skeletal muscle fibrosis, accompanied by an improvement in skeletal muscle function, with treatment. These results warrant further investigation of Epi as a potential therapeutic agent to mitigate MD-associated muscle degeneration. © 2014 FEBS.

  5. (−)-EPICATECHIN IMPROVES MITOCHONDRIAL RELATED PROTEIN LEVELS AND AMELIORATES OXIDATIVE STRESS IN DYSTROPHIC DELTA SARCOGLYCAN NULL MOUSE STRIATED MUSCLE

    PubMed Central

    Ramirez-Sanchez, Israel; De los Santos, Sergio; Gonzalez-Basurto, Silvia; Canto, Patricia; Mendoza-Lorenzo, Patricia; Palma-Flores, Carlos; Ceballos-Reyes, Guillermo; Villarreal, Francisco; Zentella-Dehesa, Alejandro; Coral-Vazquez, Ramon

    2014-01-01

    Muscular dystrophies (MD) are a group of heterogeneous genetic disorders characterized by progressive striated muscle wasting and degeneration. Although the genetic basis for many of these disorders has been identified, the exact mechanism for disease pathogenesis remains unclear. The presence of oxidative stress (OS) is known to contribute to the pathophysiology and severity of the MD. Mitochondrial dysfunction is observed in MD and likely represents an important determinant of increased OS. Experimental antioxidant therapies have been implemented with the aim of protecting against disease progression, but results from clinical trials have been disappointing. In this study, we explored the capacity of the cacao flavonoid (−)-epicatechin (Epi) to mitigate OS by acting as a positive regulator of mitochondrial structure/function endpoints and redox balance control systems in skeletal and cardiac muscles of dystrophic, δ-sarcoglycan (δ-SG) null mice. Wild type or δ-SG null 2.5 month old male mice were treated via oral gavage with either water (control animals) or Epi (1 mg/kg, twice/day) for 2 weeks. Results evidence a significant normalization of total protein carbonylation, recovery of reduced/oxidized glutathione (GSH/GSSG ratio) and enhanced superoxide dismutase 2, catalase and citrate synthase activities with Epi treatment. These effects were accompanied by increases in protein levels for thiolredoxin, glutathione peroxidase, superoxide dismutase 2, catalase and mitochondrial endpoints. Furthermore, we evidence decreases in heart and skeletal muscle fibrosis, accompanied with an improvement in skeletal muscle function with treatment. These results warrant the further investigation of Epi as a potential therapeutic agent to mitigate MD associated muscle degeneration. PMID:25284161

  6. Glycyrrhizin ameliorates oxidative stress and inflammation in hippocampus and olfactory bulb in lithium/pilocarpine-induced status epilepticus in rats.

    PubMed

    González-Reyes, Susana; Santillán-Cigales, Juan Jair; Jiménez-Osorio, Angélica Saraí; Pedraza-Chaverri, José; Guevara-Guzmán, Rosalinda

    2016-10-01

    Glycyrrhizin (GL) is a triterpene present in the roots and rhizomes of Glycyrrhiza glabra that has anti-inflammatory, hepatoprotective and neuroprotective effects. Recently, it was demonstrated that GL produced neuroprotective effects on the postischemic brain as well as on the kainic acid injury model in rats. In addition to this, GL also prevented excitotoxic effects on primary cultures. The aims of the present study were to evaluate GL scavenging properties and to investigate GL's effect on oxidative stress and inflammation in the lithium/pilocarpine-induced seizure model in two cerebral regions, hippocampus and olfactory bulb, at acute time intervals (3 or 24h) after status epilepticus (SE). Fluorometric methods showed that GL scavenged three reactive oxygen species: hydrogen peroxide, peroxyl radicals and superoxide anions. In contrast, GL was unable to scavenge peroxynitrite, hydroxyl radicals, singlet oxygen and 2,2-diphenil-1-picrylhydrazyl (DPPH) radicals suggesting that GL is a weak scavenger. Additionally, administration of GL (50mg/kg, i.p.) 30min before pilocarpine administration significantly suppressed oxidative stress. Moreover, malondialdehyde levels were diminished and glutathione levels were maintained at control values in both cerebral regions at 3 and 24 after SE. At 24h after SE, glutathione S-transferase and superoxide dismutase activity increased in the hippocampus, while both glutathione reductase and glutathione peroxidase activity were unchanged in the olfactory bulb at that time. In addition, GL suppressed the induction of the proinflammatory cytokines interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α) in both cerebral regions evaluated. These results suggest that GL confers protection against pilocarpine damage via antioxidant and anti-inflammatory effects.

  7. Protective role of lithium in ameliorating the aluminium-induced oxidative stress and histological changes in rat brain.

    PubMed

    Bhalla, Punita; Dhawan, D K

    2009-06-01

    This study was carried out to investigate the effects of lithium (Li) supplementation on aluminium (Al) induced changes in antioxidant defence system and histoarchitecture of cerebrum and cerebellum in rats. Al was administered in the form of aluminium chloride (100 mg/kg b.wt./day, orally) and Li was given in the form of Li carbonate through diet (1.1 g/kg diet, daily) for a period of 2 months. Al treatment significantly enhanced the levels of lipid peroxidation and reactive oxygen species in both the cerebrum and cerebellum, which however were decreased following Li supplementation. The enzyme activities of catalase, superoxide dismutase (SOD) and glutathione reductase (GR) were significantly increased in both the regions following Al treatment. Li administration to Al-fed rats decreased the SOD, catalase and GR enzyme activities in both the regions; however, in cerebellum the enzyme activities were decreased in comparison to normal controls also. Further, the specific activity of glutathione-s-transferase and the levels of total and oxidized glutathione were significantly decreased in cerebrum and cerebellum following Al treatment, which however showed elevation upon Li supplementation. The levels of reduced glutathione were significantly decreased in cerebrum but increased in cerebellum following Al treatment, which however were normalized upon Li supplementation but in cerebellum only. Apart from the biochemical changes, disorganization in the layers of cerebrum and vacuolar spaces were also observed following Al treatment indicating the structural damage. Similarly, the loss of purkinje cells was also evident in cerebellum. Li supplementation resulted in an appreciable improvement in the histoarchitecture of both the regions. Therefore, the study shows that Li has a potential to exhibit neuroprotective role in conditions of Al-induced oxidative stress and be explored further to be treated as a promising drug against neurotoxicity.

  8. Amelioration of ozone-induced oxidative damage in wheat plants grown under high carbon dioxide: Role of antioxidant enzymes

    SciTech Connect

    Rao, M.V.; Hale, B.A.; Ormrod, D.P.

    1995-10-01

    O{sub 3}-induced in growth, oxidative damage to protein, and specific activities of certain antioxidant enzymes were investigated in wheat plants (Triticum aestivum L. cv Roblin) grown under ambient or high CO{sub 2}. High CO{sub 2} enhanced shoot biomass. The shoot biomass was relatively unaffected in plants grown under a combination of high CO{sub 2} and O{sub 3}. O{sub 3} exposure under ambient CO{sub 2} decreased photosynthetic pigments, soluble proteins, and ribulose-1,5-bisphosphate carboxylase/oxygenase protein and enhanced oxidative damage to proteins, but these effects were not observed in plants exposed to O{sub 3} under high CO{sub 2}. O{sub 3} exposure initially enhanced the specific activities of superoxide dismutase, peroxidase, glutathione reductase, and ascorbate peroxidase irrespective of growth in ambient or high CO{sub 2}. O{sub 3} exposure initially enhanced the specific activities of superoxide dismutase, peroxidase, glutathione reductase, and ascorbate peroxidase irrespective of growth in ambient or high CO{sub 2}. However, the specific activities decreased in plants with prolonged exposure to O{sub 3} under ambient CO{sub 2} but not in plants exposed to O{sub 3} under high CO{sub 2}. Native gels revealed preferential changes in the isoform composition of superoxide dismutase, peroxidases, and ascorbate peroxidase of plants grown under a combination of high CO{sub 2} and O{sub 3}. Furthermore, growth under high CO{sub 2} and O{sub 3} led to the synthesis of one new isoform of glutathione reductase. This could explain why plants grown under a combination of high CO{sub 2} and O{sub 3} are capable of resisting O{sub 3}-induced damage to growth and proteins compared to plants exposed to O{sub 3} under ambient CO{sub 2}. 66 refs., 8 figs., 1 tab.

  9. Amelioration of Prallethrin-Induced Oxidative Stress and Hepatotoxicity in Rat by the Administration of Origanum majorana Essential Oil

    PubMed Central

    Mossa, Abdel-Tawab H.; Refaie, Amel A.; Ramadan, Amal; Bouajila, Jalloul

    2013-01-01

    This study was carried out to evaluate the adverse effects of exposure to prallethrin on oxidant/antioxidant status and liver dysfunction biomarkers and the protective role of Origanum majorana essential oil (EO) in rat. Male rats were divided into 4 groups: (i) received only olive oil (ii) treated with 64.0 mg/kg body weight prallethrin (1/10 LD50) in olive oil via oral route daily for 28 days, (iii) treated with 64.0 mg/kg body weight prallethrin (1/10 LD50) and EO (160 μL/kg b.wt.) in olive oil and (iv) received EO (160 μL/kg b.wt.) in olive oil via oral route twice daily for 28 days. Prallethrin treatment caused decrease in body weight gain and increase in relative liver weight. There was a significant increase in the activity of serum marker enzymes, aspartate transaminase, alanine transaminase, and alkaline phosphatase. It caused increase in thiobarbituric acid reactive substances and reduction in the activities of superoxide dismutase, catalase, and glutathione-S-transferase in liver. Consistent histological changes were found in the liver of prallethrin treatment. EO showed significant protection with the depletion of serum marker enzymes and replenishment of antioxidant status and brought all the values to near normal, indicating the protective effect of EO. We can conclude that prallethrin caused oxidative damage and liver injury in male rat and co-administration of EO attenuated the toxic effect of prallethrin. These results demonstrate that administration of EO may be useful, easy, and economical to protect human against pyrethroids toxic effects. PMID:24381944

  10. Ginsenoside Rg5 Ameliorates Cisplatin-Induced Nephrotoxicity in Mice through Inhibition of Inflammation, Oxidative Stress, and Apoptosis

    PubMed Central

    Li, Wei; Yan, Meng-Han; Liu, Ying; Liu, Zhi; Wang, Zi; Chen, Chen; Zhang, Jing; Sun, Yin-Shi

    2016-01-01

    Although cisplatin is an effective anti-cancer agent that is widely used for treating various types of malignant solid tumors, the nephrotoxicity induced by cisplatin severely limits its clinical application. The present study was designed to explore the potential protective effect of ginsenoside Rg5, a rare ginsenoside generated during steaming ginseng, on cisplatin-induced nephrotoxicity in a mouse experimental model. The possible mechanisms underlying this nephroprotective effect were also investigated for the first time. Rg5 was given at doses of 10 and 20 mg/kg for 10 consecutive days. On Day 7, a single nephrotoxic dose of cisplatin (25 mg/kg) was injected to mice. Cisplatin administration resulted in renal dysfunction as evidenced by increase in serum creatinine (CRE) and blood urea nitrogen (BUN) levels. In addition, cisplatin increased the level of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), the makers of lipid peroxidation, and depleted glutathione (GSH) content and superoxide dismutase (SOD) activity in renal tissues. These effects were associated with the significantly increased levels of cytochrome P450 E1 (CYP2E1), 4-hydroxynonenal (4-HNE), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, nuclear factor-kappa B (NF-κB) p65, and cyclooxygenase-2 (COX-2) in renal tissues. However, pretreatment with ginsenoside Rg5 significantly attenuated the renal dysfunction, oxidative stress and inflammation response induced by cisplatin. Furthermore, ginsenoside Rg5 supplementation inhibited activation of apoptotic pathways through increasing Bcl-2 and decreasing Bax expression levels. Histopathological examination further confirmed the nephroprotective effect of Rg5. Collectively, these results clearly suggest that Rg5-mediated alleviation of cisplatin-induced nephrotoxicity may be related to its anti-oxidant, anti-apoptotic and anti-inflammatory effects. PMID:27649238

  11. Silymarin Prevents Restraint Stress-Induced Acute Liver Injury by Ameliorating Oxidative Stress and Reducing Inflammatory Response.

    PubMed

    Kim, Sou Hyun; Oh, Dal-Seok; Oh, Ji Youn; Son, Tae Gen; Yuk, Dong Yeon; Jung, Young-Suk

    2016-04-01

    Silymarin is a flavonoid extracted from the milk thistle Silybum marianum. It has been reported to prevent liver injuries induced by various chemicals or toxins. Our recent study suggested that silymarin induces hepatic synthesis of glutathione by increasing cysteine availability, which may consequently contribute to increased antioxidant capacity of the liver. In the present study, we investigated the effects of silymarin on acute liver injury induced by restraint stress. Silymarin (100 mg/kg) was orally administered to BALB/c mice every 12 h (3 times in total). After the last dose, mice were subjected to restraint stress for 6 h, and serum levels of aspartate and alanine aminotransferases, and hepatic levels of lipid peroxidation were determined. Hepatic levels of sulfur-containing metabolites such as methionine, S-adenosylmethionine, cysteine, and glutathione were also measured. The level of pro-inflammatory mediators in both liver and serum was determined. To study the mechanism of the effects of silymarin, we assessed Jun N-terminal kinase (JNK) activation and apoptotic signaling. Restraint stress induced severe oxidative stress and increased mRNA levels of pro-inflammatory mediators; both effects of restraint stress were significantly inhibited by silymarin. Moreover, administration of silymarin significantly prevented acute liver injury induced by restraint stress by blocking JNK activation and subsequently apoptotic signaling. In conclusion, these results suggest that the inhibition of restraint stress-induced liver injury by silymarin is due at least in part to its anti-oxidant activity and its ability to suppress the inflammatory response.

  12. One-month strawberry-rich anthocyanin supplementation ameliorates cardiovascular risk, oxidative stress markers and platelet activation in humans.

    PubMed

    Alvarez-Suarez, José M; Giampieri, Francesca; Tulipani, Sara; Casoli, Tiziana; Di Stefano, Giuseppina; González-Paramás, Ana M; Santos-Buelga, Celestino; Busco, Franco; Quiles, Josè L; Cordero, Mario D; Bompadre, Stefano; Mezzetti, Bruno; Battino, Maurizio

    2014-03-01

    Strawberries are an important fruit in the Mediterranean diet because of their high content of essential nutrients and beneficial phytochemicals, which seem to exert beneficial effects in human health. Healthy volunteers were supplemented daily with 500 g of strawberries for 1 month. Plasma lipid profile, circulating and cellular markers of antioxidant status, oxidative stress and platelet function were evaluated at baseline, after 30 days of strawberry consumption and 15 days after the end of the study. A high concentration of vitamin C and anthocyanins was found in the fruits. Strawberry consumption beneficially influenced the lipid profile by significantly reducing total cholesterol, low-density lipoprotein cholesterol and triglycerides levels (-8.78%, -13.72% and -20.80%, respectively; P<.05) compared with baseline period, while high-density lipoprotein cholesterol remained unchanged. Strawberry supplementation also significant decreased serum malondialdehyde, urinary 8-OHdG and isoprostanes levels (-31.40%, -29.67%, -27.90%, respectively; P<.05). All the parameters returned to baseline values after the washout period. A significant increase in plasma total antioxidant capacity measured by both ferric reducing ability of plasma and oxygen radical absorbance capacity assays and vitamin C levels (+24.97%, +41.18%, +41.36%, respectively; P<.05) was observed after strawberry consumption. Moreover, the spontaneous and oxidative hemolysis were significant reduced (-31.7% and -39.03%, respectively; P<.05), compared to the baseline point, which remained stable after the washout period. Finally, strawberry intake significant decrease (P<.05) the number of activated platelets, compared to both baseline and washout values. Strawberries consumption improves plasma lipids profile, biomarkers of antioxidant status, antihemolytic defenses and platelet function in healthy subjects, encouraging further evaluation on a population with higher cardiovascular disease risk.

  13. Epac2 contributes to PACAP-induced astrocytic differentiation through calcium ion influx in neural precursor cells

    PubMed Central

    Seo, Hyunhyo; Lee, Kyungmin

    2016-01-01

    Astrocytes play a critical role in normal brain functions and maintaining the brain microenvironment, and defects in astrocytogenesis during neurodevelopment could give rise to severe mental illness and psychiatric disorders. During neuro-embryogenesis, astrocytogenesis involves astrocytic differentiation of neural precursor cells (NPCs) induced by signals from ciliary neurotrophic factor (CNTF) or pituitary adenylate cyclase-activating peptide (PACAP). However, in contrast to the CNTF signaling pathway, the exact mechanism underlying astrocytic differentiation induced by PACAP is unknown. In the present study, we aimed to verify a signaling pathway specific to PACAP-induced astrocytogenesis, using exchange protein directly activated by cAMP2 (Epac2)-knockout mice. We found that PACAP could trigger astrocytic differentiation of NPCs via Epac2 activation and an increase in the intracellular calcium concentration via a calcium ion influx. Taken together, we concluded that astrocytogenesis stimulated by PACAP occurs through a novel signaling pathway independent from CNTF-JAK/STAT signaling, that is the well-known pathway of astrocytogenesis. [BMB Reports 2016; 49(2): 128-133] PMID:26645637

  14. Bushen-Yizhi formula ameliorates cognition deficits and attenuates oxidative stress-related neuronal apoptosis in scopolamine-induced senescence in mice

    PubMed Central

    HOU, XUE-QIN; WU, DIAN-WEI; ZHANG, CHUN-XIA; YAN, RONG; YANG, CONG; RONG, CUI-PING; ZHANG, LEI; CHANG, XIANG; SU, RU-YU; ZHANG, SHI-JIE; HE, WEN-QING; QU, ZHAO; LI, SHI; SU, ZI-REN; CHEN, YUN-BO; WANG, QI; FANG, SHU-HUAN

    2014-01-01

    Bushen-Yizhi formula (BSYZ), a traditional Chinese medicine formula consisting of six herbs has been reported to possess a neuroprotective effect. The present study aimed to investigate the effects of BSYZ on learning and memory abilities, as well as oxidative stress and neuronal apoptosis in the hippocampus of scopolamine (SCOP)-induced senescence in mice, in order to reveal whether BSYZ is a potential therapeutic agent for Alzheimer’s disease (AD). A high-performance liquid chromatography (HPLC) fingerprint was applied to provide a chemical profile of BSYZ. Extracts of BSYZ were orally administered to mice with SCOP-induced memory impairment for two weeks. The learning and memory abilities were determined by the Morris water maze test. The oxidant stress-related indices, such as activity of superoxide dismutase (SOD) and levels of glutathione (GSH) and malondialdehyde (MDA) were examined in hippocampus of SCOP-treated mice. The cell death ratio was assessed by TUNEL staining, while apoptotic-related proteins including Bcl-2 and Bax were determined by immunofluorescent staining and western blot analysis. Caspase-3 was determined by western blot analysis. Consequently, a chromatographic condition, which was conducted at 35°C with a flow rate of 0.8 ml/min on the Gemini C18 column with mobile phase of acetonitrile and water-phosphoric acid (100:0.1, v/v), was established to yield common fingerprint chromatography under 203 nm with a similarity index of 0.986 within 10 batches of BSYZ samples. BSYZ at a dose of 2.92 g/kg significantly improved the cognitive ability, restored the abnormal activity of SOD and increased the levels of MDA and GSH induced by SCOP. Moreover, the neural apoptosis in the hippocampus of SCOP-treated mice was reversed by BSYZ by regulating the expression of Bcl-2, Bax and caspase-3. The results demonstrated that BSYZ had neuroprotective effects in SCOP-induced senescence in mice by ameliorating oxidative stress and neuronal apoptosis in the

  15. PACAP Interacts with PAC1 Receptors to Induce Tissue Plasminogen Activator (tPA) Expression and Activity in Schwann Cell-Like Cultures

    PubMed Central

    Castorina, Alessandro; Waschek, James A.; Marzagalli, Rubina; Cardile, Venera; Drago, Filippo

    2015-01-01

    Regeneration of peripheral nerves depends on the abilities of rejuvenating axons to migrate at the injury site through cellular debris and altered extracellular matrix, and then grow along the residual distal nerve sheath conduit and reinnervate synaptic targets. Considerable evidence suggest that glial cells participate in this process, although the mechanisms remain to be clarified. In cell culture, regenerating neurites secrete PACAP, a peptide shown to induce the expression of the protease tissue plasminogen activator (tPA) in neural cell types. In the present studies, we tested the hypothesis that PACAP can stimulate peripheral glial cells to produce tPA. More specifically, we addressed whether or not PACAP promoted the expression and activity of tPA in the Schwann cell line RT4-D6P2T, which shares biochemical and physical properties with Schwann cells. We found that PACAP dose- and time-dependently stimulated tPA expression both at the mRNA and protein level. Such effect was mimicked by maxadilan, a potent PAC1 receptor agonist, but not by the PACAP-related homolog VIP, suggesting a PAC1-mediated function. These actions appeared to be mediated at least in part by the Akt/CREB signaling cascade because wortmannin, a PI3K inhibitor, prevented peptide-driven CREB phosphorylation and tPA increase. Interestingly, treatment with BDNF mimicked PACAP actions on tPA, but acted through both the Akt and MAPK signaling pathways, while causing a robust increase in PACAP and PAC1 expression. PACAP6-38 totally blocked PACAP-driven tPA expression and in part hampered BDNF-mediated effects. We conclude that PACAP, acting through PAC1 receptors, stimulates tPA expression and activity in a Akt/CREB-dependent manner to promote proteolytic activity in Schwann-cell like cultures. PMID:25658447

  16. Ventilatory and cardiovascular actions of centrally and peripherally administered trout pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) in the unanaesthetized trout.

    PubMed

    Le Mével, J-C; Lancien, F; Mimassi, N; Conlon, J M

    2009-12-01

    In mammals, pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are involved in cardiovascular and respiratory regulation. Several studies have demonstrated the presence of PACAP, VIP and their receptors in various tissues of teleost fish, including the brain, but little is known about their respiratory and cardiovascular effects. The present study was undertaken to compare the central and peripheral actions of graded doses (25-100 pmol) of trout PACAP and trout VIP on ventilatory and cardiovascular variables in the unanaesthetized rainbow trout. Compared with vehicle, only intracerebroventricular injection of PACAP significantly (P<0.05) elevated the ventilation frequency and the ventilation amplitude, but both peptides significantly increased the total ventilation (total ventilation). However, the maximum hyperventilatory effect of PACAP was approximately 2.5-fold higher than the effect of VIP at the 100 pmol dose (PACAP, (total ventilation)=+5407+/-921 arbitrary units, a.u.; VIP, (total ventilation)=+2056+/-874 a.u.; means +/- s.e.m.). When injected centrally, only PACAP produced a significant increase in mean dorsal aortic blood pressure (P(DA)) (100 pmol: +21%) but neither peptide affected heart rate (f(H)). Intra-arterial injections of either PACAP or VIP were without effect on the ventilatory variables. PACAP was without significant action on P(DA) and f(H) while VIP significantly elevated P(DA) (100 pmol: +36%) without changing f(H). In conclusion, the selective central hyperventilatory actions of exogenously administered trout PACAP, and to a lesser extent VIP, suggest that the endogenous peptides may be implicated in important neuroregulatory functions related to the central control of ventilation in trout.

  17. Epigallocatechin 3-Gallate Ameliorates Bile Duct Ligation Induced Liver Injury in Mice by Modulation of Mitochondrial Oxidative Stress and Inflammation

    PubMed Central

    Su, Rong; Xie, Haiyang; Zhou, Lin; Zheng, Shusen

    2015-01-01

    Cholestatic liver fibrosis was achieved by bile duct ligation (BDL) in mice. Liver injury associated with BDL for 15 days included significant reactive oxygen/nitrogen species generation, liver inflammation, cell death and fibrosis. Administration of Epigallocatechin 3-Gallate (EGCG) in animals reduced liver fibrosis involving parenchymal cells in BDL model. EGCG attenuated BDL-induced gene expression of pro-fibrotic markers (Collagen, Fibronectin, alpha 2 smooth muscle actin or SMA and connective tissue growth factor or CTGF), mitochondrial oxidative stress, cell death marker (DNA fragmentation and PARP activity), NFκB activity and pro-inflammatory cytokines (TNFα, MIP1α, IL1β, and MIP2). EGCG also improved BDL induced damages of mitochondrial electron transport chain complexes and antioxidant defense enzymes such as glutathione peroxidase and manganese superoxide dismutase. EGCG also attenuated hydrogen peroxide induced cell death in hepatocytes in vitro and alleviate stellate cells mediated fibrosis through TIMP1, SMA, Collagen 1 and Fibronectin in vitro. In conclusion, the reactive oxygen/nitrogen species generated from mitochondria plays critical pathogenetic role in the progression of liver inflammation and fibrosis and this study indicate that EGCG might be beneficial for reducing liver inflammation and fibrosis. PMID:25955525

  18. Trigonella foenum-graecum ameliorates acrylamide-induced toxicity in rats: Roles of oxidative stress, proinflammatory cytokines, and DNA damage.

    PubMed

    Abdel-Daim, Mohamed M; Abd Eldaim, Mabrouk A; Hassan, Abeer G A

    2015-06-01

    Acrylamide is a hazardous substance inducing oxidative stress. Based on some evidence on the antioxidant properties of fenugreek, Trigonella foenum-graecum, this study was conducted to investigate the protective effect of fenugreek seed oil against acrylamide toxicity. Thirty-two male Wistar rats were randomly assigned into four groups. The control group was given normal saline. The second group was administered acrylamide (20 mg/kg bw orally). The third and fourth groups were administered acrylamide (20 mg/kg bw) and supplemented with 2.5% and 5% fenugreek seed oil in their diets, respectively. Acrylamide intoxication significantly increased serum levels of LDH, AST, ALT, APL, γ-GT, cholesterol, uric acid, urea, creatinine, 8-oxo-2'-deoxyguanosine, interleukin 1 beta, interleukin 6, and tumor necrosis factor α. Moreover, it increased hepatic, renal, and brain lipid peroxidation, while it impaired the activities and concentrations of the antioxidant biomarkers. Fenugreek oil supplementation normalized the altered serum parameters, prevented lipid peroxidation, and enhanced the antioxidant biomarker concentrations and activities in the hepatic, renal, and brain tissues of acrylamide-intoxicated rats in a dose-dependent manner. Thus, these results indicate that Trigonella foenum-graecum oil has a protective effect against acrylamide-induced toxicity through its free radical scavenging and potent antioxidant activities.

  19. Amelioration of particulate matter-induced oxidative damage by vitamin c and quercetin in human bronchial epithelial cells.

    PubMed

    Jin, Xiaoting; Su, Ruijun; Li, Ruijin; Song, Li; Chen, Meilan; Cheng, Long; Li, Zhuoyu

    2016-02-01

    Exposure to fine particulate matter (PM2.5) has a close association with respiratory damage. Vitamin c and quercetin have been documented to possess antioxidant and anti-inflammation properties. However, their potential protective effects against PM2.5-induced respiratory damage have not been evaluated yet. Hence, the study was aimed to investigate their protective effects and delineate the possible mechanisms. The results indicated that PM2.5 depleted the cell viability of 16HBE cells, elevated reactive oxygen species (ROS) generation, and inhibited mitochondrial genes expressions, including fusion proteins Mfn1 and OPA1, along with biogenesis markers SIRT1 and p53R2. Additionally, the damage of mitochondrial morphology was observed upon PM2.5 exposure using both JC-1 and MitoTracker Red staining. Expressions of mitochondrial respiratory chain genes including NDUFS2 and UQCRI1 were also attenuated by PM2.5 exposure. Furthermore, PM2.5 promoted the mRNA levels of NADPH oxidase and inflammation cytokines. However, the addition of vitamin c or quercetin strikingly antagonized the PM2.5-induced toxic effects. Collectively, these findings suggest that vitamin c and quercetin have repressive roles in respiratory oxidative damage incurred by PM2.5, which provide the theoretical basis about intervention and control of food nutrients on PM2.5-induced human adverse health. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. Chromium-induced nephrotoxicity and ameliorative effect of carvedilol in rats: Involvement of oxidative stress, apoptosis and inflammation.

    PubMed

    Sahu, Bidya Dhar; Koneru, Meghana; Bijargi, Shriharsh R; Kota, Anudeep; Sistla, Ramakrishna

    2014-11-05

    Nephrotoxicity is a major adverse effect of chromium poisoning. In the present study, we investigated the potential renoprotective effect and underlying mechanisms of carvedilol, a non-specific β-adrenergic blocker using rat model of potassium dichromate-induced nephrotoxicity. Rats were pretreated with carvedilol (10mg/kg) for 21days. A single subcutaneous injection of potassium dichromate (15mg/kg, s.c.) resulted in a significant increase in the levels of blood urea nitrogen and serum creatinine, markers related to oxidative stress, nitrosative stress, apoptosis and inflammation accompanied with histopathological changes in kidney tissues. Exploration of the underlying renoprotective mechanisms of carvedilol revealed that carvedilol attenuated nuclear translocation and DNA binding activity of NF-κB (p65) in kidney tissues. The serum levels of TNF-α and the renal expression of iNOS and tissue nitrites were significantly decreased in carvedilol plus potassium dichromate administered rats. Carvedilol pretreatment significantly attenuated the potassium dichromate-induced DNA damage, decreased the p53, Bax and cleaved caspase-3 expression and increased the Bcl-2 expression. Moreover, pretreatment with carvedilol significantly restored the renal tissue antioxidant and mitochondrial respiratory enzyme activities and decreased the elevated lipid peroxidation biomarkers to normal. These results were further supported and confirmed by histopathological findings. In conclusion, the findings of the present study demonstrated that carvedilol is an effective chemoprotectant against potassium dichromate-induced nephrotoxicity in rats. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  1. Polydatin ameliorates renal ischemia/reperfusion injury by decreasing apoptosis and oxidative stress through activating sonic hedgehog signaling pathway.

    PubMed

    Meng, Qiu-Hong; Liu, Hong-Bao; Wang, Jian-Bo

    2016-10-01

    Polydatin, a glucoside of resveratrol, recently has been demonstrated possibly to exert its biological effects by targeting sonic hedgehog (Shh). However, whether Shh signaling pathway is involved in the therapeutic effects of polydatin for renal ischemia/reperfusion (I/R) injury has not been evaluated. Our results showed that I/R induced the secretion of Shh, upregulated Patched and Smoothened, and enhanced the nuclear translocation and target gene transcription of Glioblastoma 1 in renal I/R injury models, which were further upregulated after the administration of polydatin significantly and in turn exerted prominent nephroprotective effects against cell apoptosis and oxidative stress. The treatment with cyclopamine (a specific inhibitor of Smoothened) or 5E1 (an anti-Shh antibody) not only markedly inhibited the activation of the Shh pathway, but also dramatically suppressed the nephroprotective effects of polydatin above-mentioned. These results advance our knowledge that polydatin can provide protection for kidneys against I/R injury by enhancing antioxidant capacity and decreasing cell apoptosis through activating Shh signaling pathway.

  2. Melatonin and vitamin C ameliorate alcohol-induced oxidative stress and eNOS expression in rat kidney.

    PubMed

    Sönmez, Mehmet Fatih; Narin, Figen; Akkuş, Derya; Türkmen, Ayşegül Burçin

    2012-01-01

    The aim of this study was to investigate the preventive effects of melatonin and vitamin C as antioxidants on renal injury in chronic alcohol consumption. A total of 24 adult male Wistar rats weighing 200-250 g were used in the study. Rats were divided into four equal groups. Group I (control): rats were not fed on alcohol; Group II: rats were fed on alcohol; Group III: rats were fed on alcohol and 40 mg/kg vitamin C; and Group IV: rats were fed on alcohol and 4 mg/kg melatonin. Light microscopic examination revealed atrophic renal corpuscles, dilatation and congestion of the peritubular vessels, and renal corpuscles with obscure Bowman's space and a few foamy-appearing tubules due to alcohol consumption were observed. Expression of endothelial nitric oxide synthase (eNOS) was localized to glomerulus, distal, and collector tubules. eNOS staining decreased in alcohol treatment group and melatonin and vitamin C encore increased expression pattern of eNOS. Alcohol consumption increased malondialdehyde (MDA) level and superoxide dismutase (SOD) and catalase (CAT) activities significantly in the alcohol consumption groups compared with that in the control group, while in melatonin give group just MDA level was decreased statistically significant and SOD and CAT activities were also decreased numerically compared with the alcohol consumption groups. These results indicated that chronic alcohol consumption caused renal damage by increased lipid peroxidation and melatonin and vitamin C administration produced in some degree protection against alcohol-induced damage.

  3. Amelioration of oxidative stress in bio-membranes and macromolecules by non-toxic dye from Morinda tinctoria (Roxb.) roots.

    PubMed

    Bhakta, Dipita; Siva, Ramamoorthy

    2012-06-01

    Plant dyes have been in use for coloring and varied purposes since prehistoric times. A red dye found in the roots of plants belonging to genus Morinda is a well recognized coloring ingredient. The dye fraction obtained from the methanolic extract of the roots of Morinda tinctoria was explored for its role in attenuating damages caused by H(2)O(2)-induced oxidative stress. The antioxidant potential of the dye fraction was assessed through DPPH radical scavenging, deoxyribose degradation and inhibition of lipid peroxidation in mice liver. It was subsequently screened for its efficiency in extenuating damage incurred to biomembrane (using erythrocytes and their ghost membranes) and macromolecules (pBR322 DNA, lipids and proteins) from exposure to hydrogen peroxide. In addition, the non-toxic nature of the dye was supported by the histological evaluation conducted on the tissue sections from the major organs of Swiss Albino mice as well as effect on Hep3B cell line (human hepatic carcinoma). The LC-MS confirms the dye fraction to be morindone. Our study strongly suggests that morindone present in the root extracts of M. tinctoria, in addition to being a colorant, definitely holds promise in the pharmaceutical industry. Copyright © 2012 Elsevier Ltd. All rights reserved.

  4. Pien Tze Huang Gan Bao ameliorates carbon tetrachloride-induced hepatic injury, oxidative stress and inflammation in rats.

    PubMed

    Zhao, Jinyan; Hu, Haixia; Wan, Yun; Zhang, Yuchen; Zheng, Liangpu; Hong, Zhenfeng

    2017-05-01

    Liver damage results from a variety of insults, including hepatitis and chemical toxicity from alcohol, drugs and other toxins. The present study evaluated the hepatoprotective effects and potential mechanisms of action of the Traditional Chinese Medicine Pien Tze Huang Gan Bao (GB) in a rat model of carbon tetrachloride (CCl4)-induced liver injury. Sixty male Sprague-Dawley rats were randomly divided into six different groups: i) Control, ii) CCl4 injury model and groups treated with iii) silymarin as a positive drug control, iv) 150 mg/kg GB, v) 300 mg/kg GB and vi) 600 mg/kg GB. Control rats received no treatment, while the remaining ones were intraperitoneally injected with CCl4 (2 ml/kg) to induce acute liver disease. Silymarin or GB was orally administered prior to CCl4 treatment in various treatment groups for 7 days. Animals were sacrificed 24 h post-CCl4 injection. It was revealed that GB significantly reduced serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma glutamyl transpeptidase and total bilirubin levels in the serum induced by CCl4. BG also prevented CCl4-induced changes in liver tissues, as revealed by histopathological analysis. CCl4-induced reductions in endogenous liver antioxidant enzyme activities of superoxide dismutase, glutathione and glutathione peroxidase as well as increases in malondialdehyde and thiobarbituric acid reactive substances were inhibited by GB treatment. Activated NF-κB in liver tissues was also significantly increased by CCl4, which was attenuated by GB as indicated by immunohistochemical and PCR analysis. Furthermore, CCl4-mediated increases in the inflammatory factors tumor necrosis factor-alpha and interleukin-1β secretion into the serum and their expression in liver tissues were reversed following GB treatment, as revealed by ELISA and PCR, respectively. These findings suggested that GB protects against CCl4-induced hepatic injury, inflammation and oxidative damage in rats and may

  5. Rutin ameliorates diabetic neuropathy by lowering plasma glucose and decreasing oxidative stress via Nrf2 signaling pathway in rats.

    PubMed

    Tian, Ruifeng; Yang, Wenqing; Xue, Qiang; Gao, Liang; Huo, Junli; Ren, Dongqing; Chen, Xiaoyan

    2016-01-15

    Rutin exhibits antidiabetic, antioxidant and anti-inflammatory properties, which makes rutin an attractive candidate for diabetic complications. The present study was designed to investigate the potential effect of rutin on diabetic neuropathy. After induction of diabetic neuropathy, rutin (5mg/kg, 25mg/kg and 50mg/kg) were daily given to the diabetic rats for 2 weeks. At the end of rutin administration, rutin produced a significant inhibition of mechanical hyperalgesia, thermal hyperalgesia and cold allodynia, as well as partial restoration of nerve conduction velocities in diabetic rats. Furthermore, rutin significantly increased Na(+), K(+)-ATPase activities in sciatic nerves and decreased caspase-3 expression in dorsal root ganglions (DRG). In addition, rutin significantly decreased plasma glucose, attenuated oxidative stress and neuroinflammation. Further studies showed that rutin significantly increased hydrogen sulfide (H2S) level, up-regulated the expression of nuclear factor-E2-related factor-2 (Nrf2) and heme oxygenase-1 (HO-1) in DRG. The evidences suggest the beneficial effect of rutin on diabetic neuropathy. Additionally, insulin (2 IU) and BG-12 (15mg/kg) were used to investigate the mechanisms underlying the beneficial effect of rutin on diabetic neuropathy. Insulin achieved lower plasma glucose and BG-12 achieved comparable Nrf2 expression than/to rutin (50mg/kg), respectively. In contrast, the beneficial effect of insulin and BG-12 was inferior to that of rutin (50mg/kg), suggesting that both lowered plasma glucose and Nrf2 signaling contribute to the beneficial effect of rutin on diabetic neuropathy. In conclusion, rutin produces significant protection in diabetic neuropathy, which makes it an attractive candidate for the treatment of diabetic neuropathy. Copyright © 2015 Elsevier B.V. All rights reserved.

  6. Amelioration of diet-induced nonalcoholic steatohepatitis in rats by Mn-salen complexes via reduction of oxidative stress.

    PubMed

    Rezazadeh, Alireza; Yazdanparast, Razieh; Molaei, Mahsa

    2012-02-29

    Nonalcoholic steatohepatitis (NASH), a progressive stage of nonalcoholic fatty liver disease (NAFLD), is characterized by steatosis (accumulation of triacylglycerols within hepatocytes) along with inflammation and ballooning degeneration. It has been suggested that oxidative stress may play an important role in the progress of NAFLD to NASH. The aim of present study was to determine whether antioxidant supplementations using EUK-8, EUK-134 and vitamin C could improve the biochemical and histological abnormalities associated with diet-induced NASH in rats. NASH was induced in male N-Mary rats by feeding a methionine - choline deficient (MCD) diet. The rats were fed eit