Anti-glycative and anti-inflammatory effects of protocatechuic acid in brain of mice treated by d-galactose

Protocatechuic acid (PCA) at 0.5%, 1% or 2% was supplied to d-galactose (DG) treated mice for 8 week. PCA intake at 2% increased its deposit in brain. DG treatment increased brain level of reactive oxygen species, protein carbonyl, carboxymethyllysine, pentosidine, sorbitol, fructose and methylglyoxal (P < 0.05). PCA intake, at 1% and 2%, lowered brain level of these parameters (P < 0.05). DG treatments enhanced activity and protein expression of aldose reductase (AR) and sorbitol dehydrogenase, as well as declined glyoxalase I (GLI) activity and protein expression (P < 0.05). PCA intake at 1% and 2% reduced activity and protein expression of AR (P < 0.05), and at 2% restored GLI activity and expression (P < 0.05). DG injection also elevated cyclooxygenase (COX)-2 activity and expression, and increased the release of interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha and prostaglandin E₂ in brain (P < 0.05). PCA intake decreased these cytokines (P < 0.05), and at 1% and 2% suppressed COX-2 activity and expression (P < 0.05). PCA intake at 1% and 2% also lowered DG-induced elevation in activity, mRNA expression and protein production of nuclear factor kappa B p65 (P < 0.05). These findings suggest that the supplement of protocatechuic acid might be helpful for the prevention or alleviation of aging.     

Fucoidan, a sulfated polysaccharide from brown algae, against myocardial ischemia-reperfusion injury in rats via regulating the inflammation response

The aim of the study was to determine the effects of fucoidan on rat myocardial ischemia-reperfusion (I/R) model and elucidate the potential mechanisms. Myocardial I/R injury was induced by the occlusion of left anterior descending coronary artery for 30 min followed by reperfusion for 2 h. After 2 h reperfusion, hemodynamics parameters were detected. Blood samples were collected to determine serum levels of tumor necrosis factor-α (TNF-α) and interleukin 6, 10 (IL-6, 10). Hearts were harvested to assess histopathological changes, infarct size (IS), and the content of myeloperoxidase (MPO). The expression of high-mobility group box 1 (HMGB1), phosphor-IκB-α and phosphor-nuclear factor kappa B (NF-κB) were assayed by western blot. Compared with control group, treatment with fucoidan improved left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP) and the contractility index (P < 0.05, P < 0.01). Fucoidan reduced the myocardial IS, the levels of TNF-α and IL-6, and the activity of MPO (P < 0.05, P < 0.01). Fucoidan down-regulated the expression of HMGB1, phosphor-IκB-α and NF-κB, but increased the content of IL-10 when compared with control (P < 0.05, P < 0.01). Besides, the infiltration of polymorph nuclear leukocytes (PMNs) and histopathological damages in myocardium were decreased in fucoidan treated groups (PMNs, P < 0.05, P < 0.01). These findings revealed that the administration of fucoidan could regulate the inflammation response via HMGB1 and NF-κB inactivation in I/R-induced myocardial damage.     

Beneficial effects of histidine and carnosine on ethanol-induced chronic liver injury.

Alleviative effects of histidine and carnosine in mice against ethanol-induced oxidative and inflammatory was examined. After chronic alcoholic liver injury was induced, histidine and carnosine at 0.5, 1, 2g/L were added to the drinking water for 3 weeks. Results showed that the post-intake of histidine or carnosine markedly decreased alanine aminotransferase and aspartate aminotransferase activities (P<0.05). Ethanol treatment increased malondialdehyde (MDA) level, decreased glutathione (GSH) content and catalase and glutathione peroxidase (GPX) activities, and increased cytochrome P450 2E1 (CYP2E1) activity in liver (P<0.05). The post-intake of histidine and carnosine significantly decreased MDA formations, increased GSH content, enhanced catalase and GPX activities, and suppressed CYP2E1 activity (P<0.05), in which the effects on catalase and CYP2E1 activities were dose-dependent (P<0.05). Ethanol treatment elevated hepatic levels of c-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) (P<0.05), the post-intake of histidine and carnosine significantly and dose-dependently diminished the release of CRP, IL-6, and TNF-alpha (P<0.05). Ethanol treatment caused down-regulation in both catalase and GPX mRNA expression, and up-regulated both IL-6 and TNF-alpha mRNA expression (P<0.05). Histidine and carnosine post-treatments significantly and dose-dependently upregulated catalase mRNA, and down-regulated mRNA expression of IL-6 and TNF-alpha (P<0.05). Based on the observed anti-oxidative and anti-inflammatory effects, the supplement of histidine or carnosine might be helpful for the treatment of chronic alcoholic liver injury.     

Dimethyl sulfoxide (DMSO) attenuates the inflammatory response in the in vitro intestinal Caco-2 cell model

This study aimed to investigate dose effects of dimethyl sulfoxide (DMSO) (0.05-1%) on the intestinal inflammatory response in confluent- and differentiated-Caco-2 cells stimulated with interleukin (IL)-1β or a pro-inflammatory cocktail for 24 h. Cyclooxygenase-2 (COX-2) activity was assayed by incubating inflamed cells with arachidonic acid and then measuring prostaglandin-E₂ (PGE₂) produced. Soluble mediators (IL-8, IL-6, macrophage chemoattractant protein-1 (MCP-1), and COX-2-derived PGE₂) were quantified by enzyme immunoassays and mRNA expression of 33 proteins by high throughput TaqMan Low Density Array. Data showed that DMSO decreased induced IL-6 and MCP-1 secretions in a dose-dependent manner (P < 0.05), but not IL-8; these effects were cell development- and stimulus- independent. Moreover, in IL-1β-stimulated confluent-cells, DMSO dose-dependently reduced COX-2-derived PGE₂ (P < 0.05). DMSO at 0.5% decreased significantly mRNA levels of 14 proteins involved in the inflammatory response (including IL-6, IL-1α, IL-1β, and COX-2). Thus, DMSO at low concentrations (0.1-0.5%) exhibits anti-inflammatory properties in the in vitro intestinal Caco-2 cell model. This point is important to be taken into account when assessing anti-inflammatory properties of bioactive compounds requiring DMSO as vehicle, such as phenolic compounds, in order to avoid miss-interpretation of the results.     

Phenyl methimazole suppresses dextran sulfate sodium-induced murine colitis

Ulcerative colitis is an autoimmune-inflammatory disease characterized by abnormally increased expression of Toll-like receptor-4 (TLR4) in colonic epithelial cells, increased production of pro-inflammatory cytokines (e.g., TNF-α, IL-1β, IL-6, IL-12), chemokines (e.g., IP-10), and endothelial cell adhesion molecules (e.g., VCAM-1), plus enhanced leukocyte infiltration into colonic interstitium. Previously, we have shown that phenyl methimazole (C10) markedly decreases virally-induced TLR-3 expression and signaling and potently inhibits both TNF-α-induced VCAM-1 expression and the resultant leukocyte-endothelial cell adhesion. In this study we probed the hypothesis that C10 is efficacious in a TLR-4- and VCAM-1-associated murine model [the dextran sulfate sodium (DSS) model] of human colitis. C10 was administered intraperitoneally coincident with or after DSS treatment was initiated. Macroscopic colon observations revealed that C10 significantly reversed DSS-induced shortening of the colon (P < 0.05) and reduced the presence of blood in the colon. Histological analyses of colonic tissues revealed that C10 distinctly attenuated both DSS-induced edema as well as leukocyte infiltration in the colonic mucosa and resulted in pronounced protection against DSS-induced crypt damage (P < 0.001). Northern blot analyses and immunohistochemistry of colonic tissue revealed that C10 markedly diminished DSS-induced expression of pertinent inflammatory mediators: TNF-α, IL-1β, IL-6, IL-12, IP-10, TLR-4 and VCAM-1. Most importantly, C10 significantly improved survival and protected mice against DSS-induced colitic-death: 75% by comparison to 12.5% with identical treatment with DMSO-control (log rank test: P = 0.005). These results provide direct evidence that C10 suppresses DSS-induced colitis by inhibiting expression of key inflammatory mediators and leukocyte infiltration, and is a potentially attractive therapeutic for colitis.     

Palmatine attenuates d-galactosamine/lipopolysaccharide-induced fulminant hepatic failure in mice

Palmatine is an isoquinoline alkaloid from Coptis chinensis, an herbal medicine used to treat various inflammatory diseases such as gastritis, edema and dermatitis. The present study examined the cytoprotective properties of palmatine on d(+)-galactosamine (GalN)/lipopolysaccharide (LPS)-induced fulminant hepatic failure. Mice were intraperitoneally given GalN (700 mg/kg)/LPS (10 μg/kg). Palmatine (25, 50, 100, and 200 mg/kg) was administered 1 h before GalN/LPS. GalN/LPS increased the mortality and serum aminotransferase activities. These increases were attenuated by palmatine. GalN/LPS increased hepatic lipid peroxidation and decreased the contents of reduced glutathione. Palmatine did not affect the lipid peroxidation and glutathione content. GalN/LPS increased the circulating levels of tumor necrosis factor (TNF)-α, interleukin-6 (IL-6) and IL-10. Palmatine prevented the increase of serum TNF-α and augmented that of serum IL-10. GalN/LPS treatment also increased the levels of TNF-α, IL-6 and IL-10 mRNA expression in liver tissue. Palmatine decreased the TNF-α mRNA expression and increased the IL-10 mRNA expression. Palmatine attenuated the apoptosis of hepatocytes, as evidenced by the TUNEL method and capase-3 analysis. Our data suggest that palmatine alleviates GalN/LPS-induced liver injury by modulating the cytokine response and inhibiting apoptosis.     

Long-term oral Asperosaponin VI attenuates cardiac dysfunction,myocardial fibrosis in a rat model of chronic myocardial infarction

The aim of the study was to determine the effects of Asperosaponin VI (ASA VI), a triterpene saponin isolated from Dipsacus asper Wall, on chronic myocardial infarction (MI) and possible mechanisms in rats. MI was induced by permanent ligation of the left coronary artery. Twenty-four hours after MI, the rats were administered the extract by gavage (once a day). Six weeks after MI/sham surgery, cardiac dysfunction, infarct size (IS), cardiac fibrosis, hydroxyproline concentration, the oxidative stress parameter and inflammation mediators were examined. The results indicated that ASA VI improved left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), ±dP/dt, heart weight/body weight, right ventricular weight/body weight and lung weight/body weight (P < 0.01, P < 0.05). These were accompanied by the attenuation of cardiac fibrosis, IS and hydroxyproline concentration (P < 0.01, P < 0.05). ASA VI could decrease the levels of tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6), but increase IL-10 content (P < 0.01, P < 0.05). Furthermore, it also could raise the activities of catalase, superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), but reduce malonyldialdehyde (MDA) level (P < 0.01, P < 0.05). The results indicated that ASA VI improved cardiac function and myocardial fibrosis from myocardial ischemia injury, and this cardioprotection might be attributed to reduce oxidative stress and regulate inflammation mediators.     

Effect of environmental pollutants on oxytocin synthesis and secretion from corpus luteum and on contractions of uterus from pregnant cows

Chloro-organic compounds are persistent environmental pollutants and affect many reproductive processes. Oxytocin (OT) synthesized in luteal cells is a local regulator of ovarian activity and uterine contractions. Therefore the effect of xenobiotics on the OT prohormone synthesis, secretion of OT and progesterone (P4) from luteal cells and on myometrial contractions during early pregnancy in cows was investigated.Luteal cells and myometrial strips from a cow at early pregnancy were treated with polychlorinated biphenyl 77 (PCB 77), dichlorodiphenyltrichloroethane (DDT), dichlorodiphenyldichloroethylene (DDE) and hexachlorocyclohexane (HCH) (1 or 10 ng/ml). The mRNA expression of neurophysin-I/oxytocin (NP-I/OT) and peptidyl-glycine-α-amidating mono-oxygenase (PGA) and concentration of OT and P4 were determined by RT-PCR and EIA, respectively. Moreover, the effect of xenobiotics given with P4 (12 ng/ml) on the basal and OT (10⁻⁷ M) stimulated contractions of myometrial strips was studied.Xenobiotics increased (P < 0.05) OT secretion but DDE only stimulated P4 secretion. The ratio of P4 to OT in culture medium was decreased by all xenobiotics during 9-12 weeks of pregnancy. All xenobiotics, except HCH, increased (P < 0.05) mRNA expression of NP-I/OT during all stages of pregnancy and all treatments decreased (P < 0.05) expression of mRNA for PGA during 9-12 weeks of pregnancy. Myometrial strips were relaxed (P < 0.01) after pre-incubation with P4, while each of the xenobiotics jointly with P4 increased (P < 0.01) myometrial contractions.In conclusion, the xenobiotics used increased both expression of mRNA for genes involved in OT synthesis and secretion of OT from luteal cells. This decreases the ratio of P4 to OT and presumably, in this manner, the chloro-organic compounds can influence uterine contractions and enhance risk of abortions in pregnant females.     

Liver antioxidant capacity in the early phase of acute paracetamol-induced liver injury in mice

The aim of our study was to investigate the relationship between liver antioxidant capacity and hepatic injury in the early phase of acute paracetamol intoxication in mice. Male Swiss mice were divided into groups: (1) control, that received saline, (2) paracetamol-treated group (300 mg/kg intraperitoneally). Animals were sacrificed 6, 24 and 48 h after treatment. Oxidative stress parameters were determined in blood and liver samples spectrophotometrically. Liver malondialdehyde and nitrite + nitrate level were significantly increased 6 h after paracetamol administration in comparison with control group (p < 0.05). Paracetamol induced a significant reduction in total liver superoxide dismutase (SOD) and copper/zinc SOD activity at all time intervals (p < 0.01). However, manganese SOD activity was significantly increased within 6 h (p < 0.01), while its activity progressively declined 24 and 48 h after paracetamol administration in comparison with control group (p < 0.01). Content of sulfhydryl groups in the liver was increased 24 h after paracetamol administration (p < 0.05), while its level was decreased within next 24 h when compared to control animals (p < 0.01). Our data showed that liver antioxidant capacity increases in first 24 h of paracetamol-induced liver injury were in correlation with manganese SOD activity and increase in level of sulfhydryl groups.     

Sub-acute,moderate-dose,but not short-term,low-dose dietary pre-exposure of mice to perfluorooctanoate aggravates concanavalin A-induced hepatitis

Exposure of mice to perfluorooctanoate (PFOA) evokes pronounced hepatomegaly along with significant alterations in both the histological structure and immune status of the liver. The present study was designed to evaluate the effects of this perfluorochemical on immune-mediated liver damage. In this connection, the influence of both sub-acute (10 days), moderate-dose (0.002% w/w = 3 ± 0.7 mg/kg body weight/day) and short-term (28 days), low-dose (0.00005% w/w = 70 ± 2 μg/kg body weight/day) dietary pretreatment with PFOA on the development of concanavalin A (Con A)-induced liver damage in mice was examined. With sub-acute, moderate, but not short-term, low-dose exposure, PFOA aggravated the acute liver damage caused by Con A, i.e., elevated serum levels of transaminases and led to more pronounced damage of hepatic tissue. This aggravation was associated with significantly enhanced hepatic level of interleukin-6 (IL-6), but unaltered hepatic levels of tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ) and interleukin-4 (IL-4). Moreover, hepatic DNA fragmentation was not changed by sub-acute exposure to the moderate-dose. Our findings imply that exposure to PFOA may sensitize hepatic parenchymal cells to other toxicants that activate the hepatic immune system and thereby aggravate liver injury during acute inflammation.     

Potential of long-term dietary administration of rosemary in improving the antioxidant status of rat tissues following carbon tetrachloride intoxication

In this study, 24 Wistar rats were allocated to 4 groups of 6 animals each. Groups 1 and 2 were fed a basal diet, while groups 3 and 4 were fed the basal diet supplemented further with ground rosemary at 1% level. Following 6-weeks feeding, groups 2 and 4 were injected 1 ml CCl₄/kg bw and after six hours all animals were sacrificed. Results showed that feeding rosemary before CCl₄ treatment resulted in decline (P < 0.05) of the increased aspartate transaminase, alanine transaminase and alkaline phosphatase activities and increase (P < 0.05) of the reduced cholesterol and triacylglycerols in serum. It also decreased (P < 0.05) lipid peroxidation and increased (P < 0.05) the reduced hydroxyl anion radical and hydrogen peroxide scavenging activities in serum, liver, kidney and heart tissues. In addition, it increased (P < 0.05) the reduced ABTS radical cation and the superoxide anion scavenging activities in all tissues except in heart and in kidney and heart tissues, respectively. These results suggest that dietary rosemary has the potential to become a promising functional food component.     

Estrogenic status modulates the effect of soy on hepatic responses to 7,12-dimethylbenz(a)anthracene (DMBA)

We examined the influence of estradiol (E2) status and soy protein isolate (SPI) intake on the hepatic responses altered by 7,12-dimethylbenz(a)anthracene (DMBA, a polycyclic aromatic hydrocarbon [PAH]). Sprague-Dawley rats were ovariectomized (OVX) at PND50 and infused with E2 or vehicle for 14 d and gavaged with 50 mg/kg DMBA or vehicle 24 h before sacrifice at PND64. Rats were fed an AIN-93G diet made with SPI or casein as sole protein source throughout the study. Basal AhR protein levels were reduced (P < 0.05) by SPI feeding irrespective of the E2 status. However, DMBA increased (P < 0.05) AhR-induced CYP1A1 gene expression in OVX, SPI-fed rats, but reduced (P < 0.05) CYP1A1 in OVX + E2, SPI-fed rats. Chromatin-immunoprecipitation demonstrated lower (P < 0.05) DMBA-mediated recruitment of estrogen receptor alpha to the CYP1A1 promoter by SPI feeding in the presence of E2, suggesting an estrogen-like action of SPI on DMBA-mediated signaling in the absence of E2. Further, microarray analysis (Rat 230-2.0 Affymetrix-GeneChip™) revealed 231 genes common to SPI + DMBA and SPI + E2 + DMBA (normalized to E2) treatments. AhR-activated genes (CYP1A1, CYP1A2, and NQO1) were down-regulated by SPI + E2 + DMBA compared to SPI + DMBA. Unique interactions among SPI, DMBA and E2 altered the expression profile of 316 genes, not observed by either treatment alone. Our data suggest that although E2 status does not effect soy-mediated AhR degradation, it modulates the effects of soy on many genes, including CYP1A1.     

Effect of baicalin on toll-like receptor 4-mediated ischemia/reperfusion inflammatory responses in alcoholic fatty liver condition

Alcoholic fatty liver is susceptible to secondary stresses such as ischemia/reperfusion (I/R). Baicalin is an active component extracted from Scutellaria baicalensis, which is widely used in herbal preparations for treatment of hepatic diseases and inflammatory disorders. This study evaluated the potential beneficial effect of baicalin on I/R injury in alcoholic fatty liver. Rats were fed an alcohol liquid diet or a control isocaloric diet for 5 weeks, and then subjected to 60 min of hepatic ischemia and 5 h of reperfusion. Baicalin (200 mg/kg) was intraperitoneally administered 24 and 1 h before ischemia. After reperfusion, baicalin attenuated the increases in serum alanine aminotransferase activity, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) levels in alcoholic fatty liver. The increased levels of TNF-α and IL-6 mRNA expression and inducible nitric oxide synthase and cyclooxygenase-2 protein and mRNA expressions increased after reperfusion, which were higher in ethanol-fed animals, were attenuated by baicalin. In ethanol-fed animals, baicalin attenuated the increases in toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 protein expressions and the nuclear translocation of NF-κB after reperfusion. In conclusion, our findings suggest that baicalin ameliorates I/R-induced hepatocellular damage by suppressing TLR4-mediated inflammatory responses in alcoholic fatty liver.     

Inhibition of inflammatory mediators by polyphenolic plant extracts in human intestinal Caco-2 cells

The mitogen-activated protein kinases (MAPK) and nuclear factor κB (NF-κB) are involved in transduction cascades that play a key role in inflammatory response. We tested the ability of preselected natural polyphenolic extracts (grape seed, cocoa, sugar cane, oak, mangosteen and pomegranate) to modulate intestinal inflammation using human intestinal Caco-2 cells treated for 4 h with these extracts and then stimulated by cytokines for 24 or 48 h. The effect of polyphenolic extracts, at 50 μmol of gallic acid equivalent/l, was investigated on inflammation-related cellular events: (i) NF-κB activity (cells transfected with a NF-κB-luciferase construct), (ii) activation of Erk1/2 and JNK (western blotting), (iii) secretion of interleukin 8 (IL-8) (ELISA), (iv) secretion of prostaglandin (PG) E₂ (ELISA), (v) production of NO (Griess method). Results show that: (i) sugar cane, oak and pomegranate extracts inhibited NF-κB activity (from 1.6 to 1.9-fold) (P < 0.001); (ii) pomegranate slightly inhibited Erk1/2 activation (1.3-fold) (P = 0.008); (iii) oak and pomegranate decreased NO synthesis by 1.5-fold (P < 0.001) and that of IL-8 by 10.3 and 6.7-fold respectively; (iv) pomegranate and cocoa decreased PGE₂ synthesis by 4.6 (P < 0.0001) and 2.2-fold (P = 0.001), respectively. We suggest that pomegranate extract could be particularly promising in dietary prevention of intestinal inflammation.     

Protective effects of Forsythia suspensa extract against oxidative stress induced by diquat in rats

Forsythia suspensa extract has been proved as a potential antioxidant in the recent years. The present study was undertaken to obtain the optimal antioxidant fraction in vitro and examine its antioxidative potential against diquat-induced oxidative stress in male Sprague Dawley rats in vivo. In vitro, 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging experiment indicated that the CH₂Cl₂ fraction of F. suspensa (FSC) exerted the strongest scavenging activities; forsythoside A, forythialan A and phillygenin from it might be the major antioxidant constituents. In vivo, pretreatment of rats with different doses of FSC (25, 50 and 100 mg/kg bw) and vitamin C (100 mg/kg bw, positive control) for 15 days significantly lowered the tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in plasma compared to the negative control group. Also, FSC significantly increased the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and the levels of glutathione (GSH) in plasma, liver and kidney whereas it decreased the levels of malondialdehyde (MDA) in plasma and kidney. Moreover, the protective effect of FSC (100 mg/kg bw) was better than vitamin C. These results revealed that FSC exerted a protective effect against diquat-induced oxidative stress and is worthy of becoming a potential dietary antioxidant.     

Effects of fibre-enriched diets on tissue lipid profiles of MSG obese rats

In order to investigate the influence of some fibre-enriched diets on tissue lipids in an animal model of obesity induced by the administration of monosodium glutamate (MSG), obese rats were fed diets containing 30% of Acha, Cassava, Maize and Plantain for five weeks and weight gain, feed intake and lee index were recorded. The lipid profiles of plasma, erythrocytes, kidney, heart and liver as well as hepatic 3-hydroxyl-3-methylglutaryl-CoA (HMG-CoA) reductase activity were measured. The diets significantly (p < 0.05) reduced weight gain and lee index in the obese rats. Obesity-induced increase in plasma and erythrocytes lipid levels was significantly (p < 0.05) reduced by these diets. MSG-induced obesity also resulted in a significant increase (p < 0.05) in hepatic cholesterol level which was reduced by the diets. MSG-obesity was characterised by a significant (p < 0.05) increase in cholesterol, triacylglycerol and phospholipids in kidney and this was reversed by the diets except Maize which did not reverse the increased cholesterol level. Only Acha reversed the obesity-induced increase in heart cholesterol and phospholipids. The increased activity of hepatic HMG-CoA reductase associated with obesity was also significantly (p < 0.05) reduced by the diets. In conclusion, dyslipidemia associated with MSG-induced obesity could be attenuated by consumption of fibre-enriched diets.     

Inhibiting NF-κB activation and ROS production are involved in the mechanism of silibinin's protection against D-galactose-induced senescence

Aging is featured by intelligence decline, behavioral disorders and cognitive disability. Autophagy is related to senescent development. In this study, we investigated the roles of NF-κB and autophagy in hippocampal neurons of d-galactose-induced senescent mice, and examined the protective roles of silibinin. Senescence was induced in 6-month-old mice by subcutaneous injection of d-galactose (150 mg/kg/d, for 6 weeks). Silibinin (50 mg/kg/d, intramuscular injection, for 6 weeks) or inhibitors (PDTC, 3-MA or rapamycin, 50 mg/kg/d, subcutaneous injection, for 6 weeks) were given 1 h before d-galactose exposure. Senescent control animals received vehicle for the same time. Ethological analysis, immunofluorescence staining, flow cytometric analysis, western blot and enzyme activity assays were used. Compared with senescent controls, silibinin, PDTC or rapamycin-treated mice showed upregulations of spatial recognition memory (P < 0.05), cellular oxidoreductase activities (P < 0.05) and autophagy (P < 0.05) as well as downregulations of MDA (P < 0.05) and ROS (P < 0.05) levels. We propose in d-galactose-induced murine senescence, autophagy is inhibited by NF-κB, inducing the deactivations of celluar oxidoreductases and upregulation of ROS level. The protection by autophagy and the promotion of cellular oxidoreductase activities via inhibiting NF-κB activation and ROS production are involved in the mechanism of silibinin's protection against d-galactose-induced senescence.     

Evaluation of the direct systemic and cardiopulmonary effects of diesel particles in spontaneously hypertensive rats

Recent data suggest that ultrafine pollutant particles (diameter <0.1 μm) may pass from the lung into the systemic circulation. However, the systemic and cardiorespiratory effects of translocated particles are not well known. In this study, we determined the direct acute (24 h) effect of the systemic administration of 0.01 mg/kg and 0.02 mg/kg diesel exhaust particles (DEP) on systolic blood pressure, heart rate, and both systemic and pulmonary inflammation in spontaneously hypertensive rats (SHR). Compared to the blood pressure in control group, rats exposed to DEP exhibited a dose-dependent increase in systolic blood pressure, at 0.01 mg/kg (P < 0.05) and 0.02 mg/kg (P < 0.01). Likewise, the heart rate was also dose-dependently increased at 0.01 mg/kg (P:NS) and 0.02 mg/kg (P < 0.01) compared to control SHR. DEP exposure (0.02 mg/kg) significantly elevated the number of leukocytes in blood (P < 0.05), interleukin-6 (IL-6, P < 0.005), tumor necrosis factor alpha (P < 0.05) and leukotriene B4 (LTB4, P < 0.005) concentrations in plasma. Moreover, in SHR given 0.02 mg/kg, the number of platelet was significantly reduced (P < 0.05), whereas the tail bleeding time was prolonged (P < 0.05). Pulmonary inflammations were confirmed by the presence of a significant increase in the number of macrophages (0.02 mg/kg) and neutrophils (0.01 and 0.02 mg/kg) and protein contents (0.02 mg/kg) in bronchoalveolar lavage (BAL) compared to saline-treated SHR. Also, IL-6 (0.01 mg/kg; P < 0.05 and 0.02 mg/kg; P < 0.01), LTB4 (0.02 mg/kg; P < 0.05) concentrations in BAL and the superoxide dismutase activity (0.02 mg/kg; P = 0.01) were significantly elevated compared to control group. We conclude that, in SHR, the presence of DEP in the systemic circulation leads not only to cardiac and systemic changes, but also triggers pulmonary inflammatory reaction involving IL-6, LTB4 and oxidative stress.