ACE Treatment Research Articles

Acetylcorynoline inhibits microglia activation by regulating EGFR/MAPK signaling to promote functional recovery of injured mouse spinal cord

To investigate the effect of acetylcorynoline (Ace) for promoting functional recovery of injured spinal cord in rats and explore the underlying mechanism. Rat models of spinal cord injury (SCI) were treated with intraperitoneal injection of different concentrations of Ace, with the sham-operated rats as the control group. After the treatment, the changes in motor function of the rats and the area of spinal cord injury were assessed with BBB score and HE staining, and the changes in pro-inflammatory cytokine levels and microglial activation were determined using PCR, ELISA and immunofluorescence staining. In a lipopolysaccharide (LPS)-treated BV2 cell model, the effects of different concentrations of Ace or DMSO on microglial activation and inflammatory cytokine production were observed. Network pharmacology analysis was performed to predict the target protein and signaling mechanism that mediated the inhibitory effect of Ace on microglia activation, and AutoDock software was used for molecular docking between Ace and the target protein. A signaling pathway blocker (Osimertinib) was used to verify the signaling mechanism in rat models of SCI and LPS-treated BV2 cell model. In rat models of SCI, Ace treatment significantly increased the BBB score, reduced the area of spinal cord injury, and lowered the number of activated microglia cells and the levels of pro-inflammatory cytokines (P < 0.05). The cell experiments showed that Ace treatment significantly lower the level of cell activation and the production of inflammatory cytokines in LPS-treated BV2 cells (P < 0.05). Network pharmacology analysis suggested that EGFR was the main target of Ace, and they bound to each other via hydrogen bonds as shown by molecular docking. Western blotting confirmed that Ace inhibited the activation of the EGFR/MAPK signaling pathway in injured mouse spinal cord tissue and in LPS-treated BV2 cells, and its inhibitory effect was comparable to that of Osimertinib. In rat models of SCI, treatment with Ace can inhibit microglia-mediated inflammatory response by regulating the EGFR/MAPK pathway, thus promoting tissue repair and motor function recovery.

Combined toxicity of acetamiprid and cadmium to larval zebrafish (Danio rerio) based on metabolomic analysis

Emerging contaminants, such as neonicotinoid pesticide acetamiprid (Ace), are frequently detected in the water environment, which can interact with existing heavy metal cadmium (Cd) to produce unpredicted influence. Limited studies have evaluated the effects of multiple pollutant exposures on aquatic animals. Here, we characterized the joint toxicity of Ace and Cd exposure to zebrafish (Danio rerio). The results revealed that Cd and its combined exposure with Ace had an inhibitory effect on the growth of larval zebrafish and induced morphological defects. Combined exposure to high doses of Ace and Cd could significantly reduce the levels of TG, glucose, and pyruvate in larval zebrafish. Untargeted metabolomics revealed that Cd treatment (285) produced more differentially expressed metabolites (DEMs) than Ace treatment (115), and combined treatment produced the most DEMs (294). The KEGG pathway enrichment analysis showed that they could disrupt riboflavin metabolism, amino acid metabolism, and glycolipid metabolism in the larvae of D. rerio. ELISA showed that VB2, FMN, and FAD levels were significantly increased. In addition, gene expression analysis exhibited that the mRNA levels of essential genes related to glycolipid metabolism were substantially affected, such as PK, PEPckc, PPAR-α, and FABP6. Furthermore, targeted amino acid metabolomics confirmed that both single exposure to Cd and combined exposure to Ace and Cd altered the levels of amino acids in larvae, including ALA, ARG, MET, PRO, TYR, VAL, GLY, ORN, and PHE. Taken together, exposure to Ace and Cd, alone or in combination, exerted harmful effects on the individual development, riboflavin metabolism, glycolipid metabolism, and amino acid metabolism disorder of D. rerio. These findings highlighted that more attention should be paid to the compound toxicity of chemical mixtures to aquatic organisms.

Standardized Astragalus Mongholicus Bunge-Curcuma Aromatica Salisb. Extract Efficiently Suppresses Colon Cancer Progression Through Gut Microbiota Modification in CT26-Bearing Mice.

Altered gut microbiota and a damaged colon mucosal barrier have been implicated in the development of colon cancer. Astragalus mongholicus Bunge-Curcuma aromatica Salisb. (ACE) is a common herbal drug pair that widely used clinically to treat cancer. However, whether the anti-cancer effect of ACE is related to gut microbiota remains unclear yet. We standardized ACE and investigated the effects of ACE on tumour suppression and analyze the related mechanisms on gut microbiota in CT26 colon cancer-bearing mice in the present study. Firstly, four flavonoids (calycosin-7-glucoside, ononin, calycosin, formononetin) and three astragalosides (astragaloside A, astragaloside II, astragaloside I) riched in Astragalus mongholicus Bunge, three curcumins (bisdemethoxycurcumin, demethoxycurcumin, curcumin) and four essential oils (curdione, curzerene, germacrone and β-elemene) from Curcuma aromatica Salisb., in concentrations from 0.08 to 2.07 mg/g, were examined in ACE. Then the results in vivo studies indicated that ACE inhibited solid tumours, liver and spleen metastases of colon cancer while simultaneously reducing pathological tissue damage. Additionally, ACE regulated gut microbiota dysbiosis and the short chain fatty acid content in the gut, repaired intestinal barrier damage. ACE treatment suppressed the overgrowth of conditional pathogenic gut bacteria, including Escherichia-Shigella, Streptococcus and Enterococcus, while the probiotic gut microbiota like Lactobacillus, Roseburia, Prevotellaceae_UCG-001 and Mucispirillum were increased. More interestingly, the content level of SCFAs such as propionic acid and butyric acid was increased after ACE administration, which further mediates intestinal SDF-1/CXCR4 signalling pathway to repair the integrity of the intestinal barrier, decrease Cyclin D1 and C-myc expressions, eventually suppress the tumor the growth and metastasis of colon cancer. To sum up, the present study demonstrated that ACE could efficiently suppress colon cancer progression through gut microbiota modification, which may provide a new explanation of the mechanism of ACE against colon cancer.

ACETATE AMELIORATES GLUCOSE DYSREGULATION AND NEUROBEHAVIOURAL DEFICIT IN DEXAMETHASONE PLUS SCOPOLAMINE-TREATED MICE: GUT-HEART-BRAIN CROSSTALK

Objective: Cardiometabolic disorders have been shown to be associated with the etiology of neurodegenerative diseases but the mechanisms are elusive. There is increasing evidence that the gut microbiota-derived short-chain fatty acids (SCFAs) plays key role in mediating the beneficial effects of the gut microbiome in maintenance of host health. This study was designed to investigate whether SCFA, acetate, would mitigate dexamethasone plus scopolamine-induced dysmetabolism and cognitive decline. Design and method: Male mice (n = 6/group) received (p.o.) vehicle, dexamethasone with scopolamine (DEX; 0.2 mg/kg + SC; 3.0 mg/kg), DEX+SC with sodium acetate (ACE; 200 mg/kg) and DEX+SC with donepezil hydrochloride (DP; 1.0 mg/kg) for 7 days. Morris water maze was used to examine spatial learning and memory while Y-maze was used to determine working and cognitive memory respectively. Oral glucose tolerance test was carried. Results: Degenerative changes such as weight loss, reduced exploratory/working memory, frontal-dependent motor deficits, cognitive decline, memory dysfunction and anxiety during behavioural assessments were noticed in DEX+SC-treated mice compared to control. Furthermore, DEX+SC treatment led to impaired glucose tolerance, elevated 1-hour postload glucose response and increased triglyceride-glucose index. Likewise oxidative impairment was indicated by depleted plasma, cardiac and brain glutathione reductase, nitric oxide and elevated lipid peroxidation (malondialdehyde). Cholinergic deficits characterized by increased neural acetylcholinestrase (AChE) expression and elevated uric acid, lactate dehydrogenase, lactate the plasma, cardiac and neural tissues of the DEX+SC-treated mice further implied cardiac dysfunction alongside the degenerative changes. Consequently, proteolysis was evident by observed diminshed Nissl profiles in axons and dendrites of neurons which correspond to apoptotic changes observed in H&amp;E staining of prefrontal cortex and hippocampal sections. Conclusions: Interestingly, ACE treatment ameliorated the DEX+SC-induced behavioural deficits and cardiometabolic dysfunctions in mice. The effects of ACE treatment were comparable to the DP in DEX+SC-treated rats. Hence, ACE prevents neural and cardiac oxidative damage, behavioural deficits and glucose deregulation. Furthermore, ACE could be a potential AChE inhibitor. These findings suggest that the gut microbiota-derived SCFA, acetate, would be a cost effective therapeutic target for inhibition of neuro-cardiac degenerative processes and behavioural deficits through the gut-heart-brain crosstalk

Treatment with acetate during late pregnancy protects dams against testosterone-induced renal dysfunction

Cardiometabolic diseases are complicated by renal damage. Gestational hyperandrogenism causes gestational metabolic dysfunction that is associated with fetal and maternal tissue derangements as well as post-partum maternal androgen excess. Acetate (Ace) conferred hepatoprotection in pregnant rats exposed to excess testosterone (Tes). The effect of excess androgenic exposure on maternal kidney during and after pregnancy is not clear. Therefore, this study investigated the effect of late gestational and post-gestational testosterone exposure on renal functions and plausible renoprotective role of gestational Ace treatment in dams. Thirty pregnant Wistar rats were grouped (n = 10/group) and treated (sc) with olive oil, testosterone propionate (0.5 mg/kg) with or without acetate (200 mg/kg sodium acetate; p.o) between gestational days 14 and 19. Data were obtained from half of the animals on gestational day 20. Data were also obtained from the other half (dams) after treatment of animals which received Tes with or without prior gestational acetate treatment with post-gestational Tes (sc; 0.5 mg/kg) for the last 6 days of an 8-week postpartum period. Biochemical and statistical analyses were performed with appropriate methods and SPSS statistical software respectively. Late gestational excess Tes led to low placental weight (p = 0.0001, F = 205.7), poor fetal outcomes, creatinine (p = 0.0001, F = 385.4), urea (p = 0.0001, F = 300.9) and renal uric acid (UA) (p = 0.0001, F = 123.2), gamma-glutamyl transferase (GGT) (p = 0.004, F = 26.9), malondialdehyde (p = 0.0001, F = 45.96), and lactate dehydrogenase (LDH) (p = 0.0002, F = 150.7). Postpartum Tes exposure also caused elevated plasma testosterone (p = 0001, F = 22.15), creatinine (p = 0.0002, F = 15.2), urea (p = 0.01, F = 13.8) and renal UA (p = 0.0001, 226.8), adenosine deaminase (p = 0001, F = 544.7), GGT (p = 0.0002, F = 401.4) and LDH (p = 0.01, F = 23.7). However, gestational acetate treatment ameliorated the renal effects of gestational and post-gestational Tes exposure. Taken together, gestational acetate would pre-programme dams against renal dysfunction caused by Tes exposure.

Implementation of a Cardio Oncology Protocol in Uruguay

Introduction Survival of hemato oncologic patients has significantly improved in the last 50 years due to more intensive treatments and directed therapies. This has led to a paradigm shift focused not only in achieving cure but also addressing survivors' complications such as treatment toxicities and second malignancies. Cardiac toxicity is one of the most frequent long-term complications after cancer treatment leading to a significant burden in morbidity and mortality. Anthracyclines are type 1 cardiotoxic drugs. Risk of cardiotoxicity depends on patient characteristics and drug combinations as well as anthracyclines cumulative doses. Treatment of many hematologic malignancies often includes anthracyclines. Cardiac toxicity may limit oncologic treatment along with a negative impact on functional prognosis of survivors. Cardio oncology is an emerging field aimed at prophylaxis, early detection and proper treatment in order to improve quality of life in cancer survivors. This is the first Uruguayan experience in the implementation of a cardio oncology protocol. Methods This is a prospective interventional study conducted by a multidisciplinary team formed by hematologists and cardiologists. Inclusion criteria were patients older than 18 years old with hematologic malignancies who received anthracycline treatment between march 2017 and march 2019, treated at our institution. All patients gave their informed consent. This protocol was approved by our institution Ethical Committee. Patients who entered the protocol were followed at the Cardio Oncology Unit. Trans thoracic echocardiogram (TTE) were performed using the same equipment and by experimented operators. Left ventricular ejection fraction (LVEF) by Simpson and Global Longitudinal Strain (GLS) were measured. Figure 1 shows the algorithm used. We defined cardiotoxicity as the decrease of LVEF greater than 10% (relative to baseline LVEF) to a threshold inferior to 53%; or a relative reduction of GLS greater than 15%. Results We created a Cardio Oncology Unit (COU) at our institution with hematologists and cardiologists. Forty-four patients were included (table 1). Protocol compliance was 70%. Seven percent (3/44) of patients presented structural cardiopathy and 20% (9/44) were defined as high risk (figure 1). Cardiotoxicity was diagnosed in 16% (7/44) of patients. The diagnosis was made using LVEF decrease in every case, no patient was diagnosed based on GLS. Mean time of onset was 3 months (1-6). Mean doxorubicin dose was 115 mg/m2 (50-200). Four of the patients were asymptomatic and 3 presented with heart failure. Two patients required suspension of anthracyclines due to cardiotoxicity. Six of the 7 patients diagnosed with cardiotoxicity were treated with Beta blockers and ACE inhibitors and treatment was well tolerated. Of these patients, two died due to their oncologic disease, three improved their LVEF, one maintained the LVEF stable in spite of continuing on anthracyclines. Structural cardiopathy was associated with greater risk of cardiotoxicity (p=0.013). Conclusions We present the results of the implementation of a Cardio Oncology prospective protocol at our institution. The incidence of cardiotoxicity evidenced was greater than expected according to anthracycline used doses, with early onset during treatment. We identified structural cardiopathy as a risk factor for cardiotoxicity. Our results highlight the relevance of cardiologic follow up in patients receiving anthracyclines and makes us question whether prophylaxis would be beneficial for high risk patients. We strongly believe that cardiotoxicity is a major problem for hemato oncologic patients, and that a multidisciplinary approach with health care protocols is the best way to address it. Disclosures No relevant conflicts of interest to declare.

ANALYSIS OF THE TREATMENT IN COMBINATION OF ACE INHIBITORS OR ARBS IN THE CARDIOVASCULAR MORTALITY

Objective: To analyze the combination in randomized clinical trials (RCTs) that described the second drug of choice for antihypertensive treatment (angiotensin-converting enzyme inhibitors – ACEIs or angiotensin receptor blockers - ARBs), by intention to treat. Design and method: Systematic review and metanalysis of the RCTs. A database search between 1966 and December 2018 identified eligible RCTs (PubMed, Embase, Scopus, Web of Science/ Web of Knowledge). Risk ratios and their 95% confidence intervals of four outcomes were estimated by a random-effects model. The heterogeneity index of the studies was calculated through I2 test. The risk of bias was assessed using the Risk of Bias (RoB1), from Cochrane Collaboration. All data were analyzed by two independent evaluators (E.B. and B.E.) and the discrepancies were solved by a third evaluator (W.S.B). Results: 46 eligible RCTs were identified. The ACE treatment in combination reduced cardiovascular mortality (−15%), total mortality, stroke and AMI (p < 0.001). The methodological quality of the included studies pointed to an unclear risk of bias. Conclusions: The ACE inhibitors, in combination, present a reduction in cardiovascular mortality, while the ARBs in combination, do not demonstrate this reduction.

PROTECTIVE ROLE OF CRUDE EXTRACT OF AMORPHOPHALLUS CAMPANULATUS AGAINST ETHANOL-INDUCED OXIDATIVE RENAL DAMAGE

Objective: The current study investigates the nephroprotective effect of Amorphophallus campanulatus against chronic alcohol-induced oxidative stress and tissue damage.Methods: The rats were simultaneously supplemented with ethanolic extract of A. campanulatus along with ethanol (40% w/v)2 g/kg body weight/day for 30 days to evaluate the nephroprotective effect against alcohol toxicity. Renal antioxidant enzymes, serum urea, creatinine, and pro-inflammatory cytokines were assayed biochemically. Histomorphological and histochemical alterations were detected by Hematoxylin and Eosin, periodic acid Schiff, and Feulgen and Picrosirius stain, respectively. The degree of apoptotic cell death was examined by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay technique.Results: Serum urea, creatinine, pro-inflammatory cytokines, tissue TBARS, and activity of glutathione metabolizing enzymes were significantly (p&lt;0.01) elevated, whereas cytosolic and mitochondrial superoxide dismutase, catalase, and levels of reduced glutathione were significantly (p&lt;0.001) decreased in the EtOH group compared to control. However, ethanolic extract of A. campanulatus (ACE) supplementation to the EtOH rats reversed these effects to normal levels. Furthermore, degenerative changes in renal cells with alcohol treatment were minimized to nearness in architecture by ACE supplementation. Glycogen and deoxyribonucleic acid depletion, excess fibrosis due to collagen deposition, and increased apoptotic cell number were also restricted by ACE supplementation, with the higher dose being more promising.Conclusion: Thus ethanol-induced nephrotoxicity was attenuated by ACE treatment by the antioxidative and antiapoptotic property of the extract. Such effects of the extract may be due to the probable presence of different bioactive components in the tuber. Hence, it can be used as a regular nutrient or therapeutic agent to protect the renal cells.

PROTECTIVE ROLE OF CRUDE EXTRACT OF AMORPHOPHALLUS CAMPANULATUS AGAINST ETHANOL-INDUCED OXIDATIVE RENAL DAMAGE

Objective: The current study investigates the nephroprotective effect of Amorphophallus campanulatus against chronic alcohol-induced oxidative stress and tissue damage.Methods: The rats were simultaneously supplemented with ethanolic extract of A. campanulatus along with ethanol (40% w/v)2 g/kg body weight/day for 30 days to evaluate the nephroprotective effect against alcohol toxicity. Renal antioxidant enzymes, serum urea, creatinine, and pro-inflammatory cytokines were assayed biochemically. Histomorphological and histochemical alterations were detected by Hematoxylin and Eosin, periodic acid Schiff, and Feulgen and Picrosirius stain, respectively. The degree of apoptotic cell death was examined by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay technique.Results: Serum urea, creatinine, pro-inflammatory cytokines, tissue TBARS, and activity of glutathione metabolizing enzymes were significantly (p&lt;0.01) elevated, whereas cytosolic and mitochondrial superoxide dismutase, catalase, and levels of reduced glutathione were significantly (p&lt;0.001) decreased in the EtOH group compared to control. However, ethanolic extract of A. campanulatus (ACE) supplementation to the EtOH rats reversed these effects to normal levels. Furthermore, degenerative changes in renal cells with alcohol treatment were minimized to nearness in architecture by ACE supplementation. Glycogen and deoxyribonucleic acid depletion, excess fibrosis due to collagen deposition, and increased apoptotic cell number were also restricted by ACE supplementation, with the higher dose being more promising.Conclusion: Thus ethanol-induced nephrotoxicity was attenuated by ACE treatment by the antioxidative and antiapoptotic property of the extract. Such effects of the extract may be due to the probable presence of different bioactive components in the tuber. Hence, it can be used as a regular nutrient or therapeutic agent to protect the renal cells.

Prevention of microalbuminuria using early intervention with renin-angiotensin system inhibitors in patients with type 2 diabetes: A systematic review.

Hypothesis/objectives:Early prevention of diabetic nephropathy by way of blocking the renin-angiotensin system (RAS) in patients with normoalbuminuria seems rational, but trials have so far shown conflicting results. The present meta-analysis was undertaken to investigate if such treatment can prevent development of microalbuminuria.Materials and methods:We searched MEDLINE, EMBASE and the Cochrane Library (2 June 2014) for randomised controlled trials, with a population of patients with type 2 diabetes and normoalbuminuria, comparing angiotensin-converting enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs) to placebo. Studies had to have at least 50 participants in each arm and one year of follow-up. Random and fixed effect models were performed as well as trial sequential analysis.Results:Six trials were included in the analysis (n=16,921). Overall risk of bias was variable. In a fixed model analysis ACE or ARB treatment was superior to placebo in relation to prevention of development of microalbuminuria, risk ratio 0.84 (95% confidence interval (CI) 0.79–0.88) p<0.001, I2=23%, similar to random model results. Treatment also showed a trend towards a reduction in all-cause mortality(p=0.07).Conclusions:We conclude that in patients with type 2 diabetes and normoalbuminuria, early intervention with ACEis or ARBs reduces the risk for development of microalbuminuria.

Effects and molecular mechanisms of the antidiabetic fraction of Acorus calamus L. on GLP-1 expression and secretion in vivo and in vitro

Ethnopharmacological relevanceThe radix of Acorus calamus L. (AC) is widely used in diabetes therapies in traditional folk medicine from America and Indonesia, and we have previously reported that the ethyl acetate fraction of AC (ACE) acts as an antidiabetic through insulin sensitizing, insulin releasing and alpha-glucosidase inhibitory activities. The present study is designed to investigate the effects and molecular mechanisms of ACE on glucagon-like peptide-1 (GLP-1) expression and secretion related to its hypoglycemic effects. Materials and methodsThe hypoglycemic effect of ACE (100mg/kg, i.g.) was confirmed by testing blood glucose levels or via oral glucose tolerance test (OGTT) in streptozotocin (STZ) induced hyperglycemic mice, db/db diabetic mice and diet-induced obese (DIO) mice. Plasma insulin, GLP-1 levels and intestinal GLP-1 related gene expression were determined in STZ-induced and db/db diabetic mice. The in vitro effects of ACE (12.5μg/ml) on the expression and secretion of GLP-1 were detected in NCI-H716 intestinal L-cells, and the correlation between ACE and molecules in the Wnt signaling pathway was further explored. ResultsACE (100mg/kg) significantly lowered fasting blood glucose in STZ-induced and db/db diabetic mice and improved the OGTT in DIO mice. Insulin releasing and islet protective effects, along with the increased secretion of GLP-1, were observed. The expression of proglucagon gene (gcg) and post-translational processing gene prohormone convertase 3 (pc3) and the GLP-1 content in the culture medium of L-cells notably increased after the ACE treatment (12.5μg/ml). At the same time, β-catenin nuclear translocation occurred, and its downstream protein cyclin D1 was activated, showing the involvement of Wnt signaling. ConclusionsACE might activate Wnt signaling to increase the gene expression of gcg and pc3 and exert incretin effects, including insulinotropic and islet protection, to lower blood glucose levels via elevated GLP-1 secretion either directly or indirectly.

Anti-atherosclerosis and hyperlipidemia effects of herbal mixture, Artemisia iwayomogi Kitamura and Curcuma longa Linne, in apolipoprotein E-deficient mice

Ethnopharmacolgical relevanceArtemisiaiwayomogi Kitamura and Curcuma longa Linne. (ACE) has been popularly used to treat atherosclerosis as well as hyperlipidemia in the Asian countries. ObjectiveAntiatherosclerotic and anti-hyperlipidemic effects of ACE were evaluated at protein and gene expression level by using apoE−/− mice. MethodApoprotein E deficient (apoE−/−) mice were randomly divided into five groups and fed freely Western diet (WD) which contained ACE (50, 100 and 200mg/kg) or curcumin (50mg/kg). The C57/BLJ mice were used as normal and which were fed the WD. After 10 weeks of being fed the WD, the atherosclerosis related mediators and hyperlipidemia induced hepatic steatosis were analyzed in serum, aorta tissue or hepatic tissues. ResultsTen-week feeding of WD considerably increased the serum lipid profiles including total cholesterol (TC), low density lipoprotein, high density lipoprotein (HDL), triglyceride, TC/HDL ratio and glucose, and also elevated the total reactive oxygen species (ROS) and inflammatory cytokines (tumor necrosis factor-α, TNF-α; and interlukin-6, IL-6) in the serum levels. ACE treatment significantly resolved these alterations. The aortic lesion formation was significantly decreased as were lipid formations by ACE treatment. Moreover, ACE not only caused significant decreases of the lipid drops on the hepatic tissues, but also restored the antioxidant components. The gene expression levels including SREBP‐1c, FAS, SCD‐1, PPAR-α, CPT‐1, IL-6, IL-1β and TNF-α in hepatic tissue were altered by Western diet fed in apoE−/− mice, while ACE treatment significantly normalized those alterations. ConclusionsThe ACE treatment is beneficial for atherosclerosis in arterial area and hyperlipidemia induced hepatic tissue steatosis.

Actinidia callosa peel (kiwi fruit) ethanol extracts protected neural cells apoptosis induced by methylglyoxal through Nrf2 activation

Context: Methylglyoxal (MG) is a reactive dicarbonyl compound generated as an intermediate of glycolysis during the physical glycation in the diabetic condition. MG itself has been commonly implicated in the development of diabetic neuropathy. Several active compounds in Actinidia callosa have been found to inhibit glycation and MG-protein reaction.Objective: This study investigated the protective effects of A. callosa (kiwi fruits) peel ethanol extracts (ACE) on MG-induced Neuro-2A cell apoptosis.Materials and methods: The Neuro-2A cells pre-treated by ACE (50–200 μg/mL) or allyl-isothiocyanate (AITC) (50 μM) for 6 h, in turn, the cells were treated with MG (250 μM) for 24 h.Results: ACE or AITC treatment markedly inhibited the generation of reactive oxygen species (ROS) and the elevation of caspase-3 and capase-9 levels induced by MG in Neuro-2A cells. ACE and AITC elevated Bcl2 and inhibited Bax expressions in MG-induced Neuro-2A cells. ACE elevated Nrf2 transcriptional activity and nuclear translocation in MG-induced Neuro-2A cells. Nrf2 down-stream molecules including HO-1 and GCL were elevated by ACE or AITC treatment in MG-induced Neuro-2A cells. The protective effects of ACE on MG-induced Neuro-2A apoptosis were attenuated while Nrf2 knockdown.Discussion and conclusion: We established the first evidence that ACE might contribute to the prevention of the development of diabetic neuropathy by blocking the MG-mediated intracellular glycation system.

Prophylactic Role of Averrhoa carambola (Star Fruit) Extract against Chemically Induced Hepatocellular Carcinoma in Swiss Albino Mice.

Liver cancer remains one of the severe lethal malignancies worldwide and hepatocellular carcinoma (HCC) is the most common form. The current study was designed to evaluate the prophylactic role of the fruit of Averrhoa carambola (star fruit or Kamrak) on diethylnitrosamine- (DENA-) induced (15 mg/kg b.wt.; single i.p. injection) and CCl4-promoted (1.6 g/kg b.wt. in corn oil thrice a week for 24 weeks) liver cancer in Swiss albino mice. Administration of ACE was made orally at a dose of 25 mg/kg b.wt/day for 5 consecutive days and it was withdrawn 48 hrs before the first administration of DENA (preinitiational stage). CCl4 was given after 2 weeks of DENA administration. A cent percent tumor incidence was noted in carcinogen treated animals while ACE administration resulted in a considerable reduction in tumor incidence, tumor yield, and tumor burden. Further, ACE treatment brings out a significant reduction in lipid peroxidation (P < 0.001) along with an elevation in the activities of enzymatic antioxidants (superoxide dismutase, P < 0.001, and catalase, P < 0.001), nonenzymatic antioxidant (reduced glutathione, P < 0.001), and total proteins (P < 0.001) when compared to the carcinogen treated control. These results demonstrate that ACE prevents the DENA/CCl4 induced adverse physical and biochemical alterations during hepatic carcinogenesis in mice. This study suggests the prophylactic role of Averrhoa carambola against hepatocellular carcinoma in mice; therefore, it could be employed for the further screening as a good chemopreventive natural supplement against cancer.

Abstract 18532: New Prognostic Factors in Heart Failure With Preserved Ejection Fraction: The KaRen Study

KaRen was a prospective multicentre study identifying predictors of outcome in patients with Heart Failure and preserved Ejection Fraction (HFpEF). Method: 539 patients were included following an acute HF presentation accompanied with BNP&gt; 100 pg/mL or NT-proBNP&gt;300 pg/mL and LVEF &gt; 45%. 438 patients were reassessed after 4 -8 weeks clinically, biologically and by ECG and echocardiography. ECG (18 variables) and echo (117 variables) were analysed in core centres. Patients were followed for vital status and hospitalisation every 6 months during a minimum of 18 months. The primary endpoint was time to all-cause death or first HF hospitalisation. A Cox proportional hazard modelling was applied. The multivariable model included univariable covariates at and below the significance level p=0.15 added by age and gender. Patients: The mean age was 76± 9 years and 57% were women. A history of HF was found in 40.4 %. Patients′ history included hypertension in 78.5%, atrial tachyarrhythmia in 58%, anemia in 47.2%, diabetes in 31.3%, renal dysfunction in 37.9%. At the acute event, LVEF was 56±7 %. Of the patients 6.1 % had first degree AV block and 14.9% had QRS width &gt; 120 ms. Right bundle branch block (BBB) was present in 6.6% and Left BBB in 3.7%. Results: During a mean follow-up time of 21.6 months a primary outcome event occurred in 204 patients (46.5%) , consisting of 101 deaths (23%) and 142 HF-hospitalizations (32.5%). Candidate predictors of outcome are: First degree AV block was the only dyssynchrony criteria independently predicting outcome (p=0.04); tricuspid regurgitation (mean±standard deviation = 2.87±0.64 m/s, p=0.0009) and mean e’ velocity &gt; 5.5cm/s (mean±standard deviation = 7.95±2.58, p=0.0009) were the two echocardiographic predictors. Ongoing ACE (ARB) treatment was the only positive predictor of outcome. CONCLUSION: The KaRen study recruited a representative population of HFpEF patients with a high rate of clinical events (23% deaths).First degree atrio-ventricular block and increased pulmonary arterial pressures and left ventricular diastolic dysfunction were independently associated with outcome. These novel data may provide new information improving the management of HFpEF patients.

Therapy Contamination as a Measure of Therapist Treatment Adherence in a Trial of Cognitive Behaviour Therapy versus Befriending for Psychosis

High quality randomized controlled trials (RCT) of psychotherapeutic interventions should ensure that the therapy being tested is what is actually delivered. However, contamination of one therapy into the other, a critical component of treatment adherence, is seldom measured in psychotherapy trials of psychosis. The aim of the study was to determine whether a purpose-designed measure, the ACE Treatment Integrity Measure (ATIM) could detect therapy contaminations within a controlled trial of cognitive behavioural therapy (CBT) versus Befriending for first-episode psychosis and to compare the ATIM to a more traditional adherence measure, the Cognitive Therapy Scale (CTS). Therapy sessions were audio-recorded and at least one therapy session from 53 of the 62 participants in the RCT was rated by an independent rater using the CTS and ATIM. Ninety-nine therapy sessions were rated. All Befriending sessions and all but three CBT sessions were correctly identified. The ATIM showed that 29 of the 99 (29%) sessions were contaminated by techniques from the other therapy. Within the CBT sessions, 19 of the 51 sessions (37%) were contaminated by one or more Befriending techniques. Of the Befriending sessions, 10 of 48 (21%) were contaminated by ACE techniques. The mean CTS score was higher in the CBT than the Befriending group. The ATIM was able to detect contaminations and revealed more meaningful, fine-grained analysis of what therapy techniques were being delivered and what contaminations occurred. The study highlights the benefit of employing purpose-designed measures that include contamination when assessing treatment adherence.

Comparison of polyvinyl alcohol coated nasal packing with non-absorbable nasal packing

A number of different nasal packing materials are available for prevention of nasal bleeding after endoscopic sinus surgery. Polyvinyl alcohol (PVA) coated nasal packing is an expandable packing for use in rhinological surgery. This innovative surf- ace treatment helps to reduce the possibility of adherence to tissue and of blood clotting within the sponge. The present study investigated the effects of PVA coated packing and non-absorbable packing with respect to pain, healing site and postoperative bleeding following endoscopic sinus surgery. Patients between 18-80 years of age undergoing sinus surgery were enrolled. Each patient`s ethmoid cavities were randomised to receive PVA coated packing material or the standard non-absorbable sinus packs. The remaining nasal packing material was removed on the 2nd day in the clinic. We determined visual analog scale score, bleeding time and wound healing status. A single rhinologist graded postoperative endoscopic appearance. Length of follow-up was 3 months. Thirty three patients were recruited. There was a significant difference in the bleeding time between the two groups, but pain and wound healing were not significantly different between the two groups. PVA-coated nasal packing presents comparable characteristics with traditional nasal packing.

Evaluation of the radioprotective effect of Ageratum conyzoides Linn. extract in mice exposed to different doses of gamma radiation

The effect of various doses (0, 25, 50, 75, 100, 125, 150, 300, 600 and 900 mg kg(-1)) of the alcoholic extract of the plant Ageratum conyzoides Linn. (ACE), on the alteration of radiation-induced mortality in mice exposed to 10 Gy of gamma radiation was studied. The acute toxicity studies showed that the drug was non-toxic up to a dose of 3000 mg kg(-1), the highest dose that could be tested for acute toxicity. Administration of ACE resulted in a dose-dependent decline in radiation-induced mortality up to a dose of 75 mg kg(-1), the dose at which the highest number of survivors (70.83%) was observed. Thereafter, the number of survivors declined with increasing doses of ACE and a nadir was reached at 900 mg kg(-1) ACE. Since the number of survivors was highest for 75 mg kg(-1) ACE, this was considered the optimum dose for radioprotection and used in further studies in which mice were treated with 75 mg kg(-1) ACE before exposure to 6, 7, 8, 9, 10 and 11 Gy of gamma radiation. The treatment of mice with 75 mg kg(-1) ACE reduced the severity of symptoms of radiation sickness and mortality at all exposure doses, and a significant increase in survival was observed compared with the non-treated irradiated group. The ACE treatment effectively protected mice against the gastrointestinal as well as bone marrow related death, as revealed by the increased number of survivors at all irradiation doses. The dose reduction factor was found to be 1.3. To understand the mechanism of action, various doses of ACE were evaluated for their in-vitro scavenging action on 1,1-diphenyl-2-picrylhydrazyl (DPPH), a chemically stable free radical. ACE was found to scavenge DPPH radicals in a concentration-dependent manner, indicating that the radioprotection afforded by ACE may be in part due to the scavenging of reactive oxygen species induced by ionizing radiation.

Is nitrate reduction to nitrite possible in glucose-amended alkaline saline soil under aerobic conditions?

A phylogenetic analysis of the archaeal community in the soil of the former Lake Texcoco showed that some of the clones identified were affiliated to Archeae that reduce nitrate (NO 3 −) to nitrite (NO 2 −) and NO 2 − to unknown products under aerobic conditions. Previous research suggested that this indeed might occur when an easily decomposable C-substrate is available, but little is known about the factors that control the possible processes involved. The sandy clay loam soil with pH 10 and electrolytic conductivity 56 dS m −1 was spiked with 1000 mg glucose-C kg −1 soil (GLUCOSE pre-treatment), 200 mg NO 3 −-N kg −1 soil (NITRATE pre-treatment), or left unamended (CONTROL pre-treatment) and conditioned for eight days. Pre-treated soil was then added with 1000 mg glucose-C kg −1 soil and 200 mg NO 3 −-N kg −1 soil and amended with ammonium (NH 4 +) (AMM treatment) and l-glutamine (GLUT treatment), acetylene (C 2H 2) (ACE treatment), oxygen (O 2) (OXI treatment), left untreated (CON treatment) or sterilized. No abiotic factors affected concentrations of NH 4 +, NO 2 − or NO 3 −. In the CONTROL pre-treatment, concentration of NO 3 − decreased 170 mg N kg −1 soil within 72 h, in the GLUCOSE pre-treatment with 182 mg N kg −1 soil within 2 h and in the NITRATE pre-treatment with 272 mg N kg −1 soil within 168 h. Mean concentration of NO 2 − was 3.2 mg N kg −1 soil in unamended soil, 5.7 mg N kg −1 soil in the CONTROL pre-treatment, but >20 mg kg −1 soil in the GLUCOSE pre-treatment and ≥40 mg kg −1 in the NITRATE pre-treatment. The application of NO 3 − and glucose increased the mean concentration of NH 4 + compared to the unamended soil independently of pre-treatment. It was found that microorganisms in the alkaline saline soil of the former Lake Texcoco can reduce concentrations of NO 3 − while releasing NO 2 − under aerobic conditions when an easy decomposable substrate is available without it being directly related to microbial activity and this being more outspoken when glucose or nitrate were previously added.

Artificial cold exposure induced stroke in renovascular hypertensive rats and its association with cold-inducible RNA binding protein mRNA expression in brain tissue and blood pressure

Background High incidence of stroke at interchange period of autumn and winter was demonstrated by epidemiological survey, and the specific causes should be further investigated. Objective To investigate the influence of artificial cold exposure on the incidence of stroke in renovascular hypertensive rats (RHR), and analyze the association with blood pressure and cold-inducible RNA binding protein (CIRP) mRNA expression in brain tissue. Design A completely randomized grouping design, a randomized control animal trial. Settings Lab of Neurology, the First Affiliated Hospital of Sun Yat-sen University; Department of Chemistry, Open laboratory of Chemical Biology, Institute of Molecular Technology for Drug Discovery and Synthesis, University of Hong Kong. Materials Male SD rats ( n = 460), weighing 80–100 g were obtained from Guangdong Province Health Animal Unit. A modified RXZ-300A intelligent artificial climate cabinet (Ningbo Jiangnan Instrument Co., Ltd., China). Methods The experiment were processed in the Lab of Neurology, the First Affiliated Hospital of Sun Yat-sen University and the Open Laboratory of Chemical Biology, Institute of Molecular Technology for Drug Discovery and Synthesis, University of Hong Kong from October 2004 to November 2005. Rats ( n = 400) were operated to establish 2-kidney 2-clip RHR model as described previously. The sham-operated rats ( n = 60) served as normotensive controls. Eight weeks later, 300 of RHR were randomly selected according to their systolic blood pressure (SBP) and divided into 3 sub-groups ( n = 100 per group): mild hypertensive group (SBP of 160–200 mm Hg), moderate hypertensive group (SBP of 200–220 mm Hg) and severe hypertensive group (SBP > 220 mm Hg). Each group was further divided into two groups ( n = 50) under ACE and non-ACE. Normal sham-operated SD rats ( n = 60), SBP < 140 mm Hg, were randomly divided into two groups: Sham-operated control group ( n = 30) under ACE and non-ACE. To establish the ACE and non-ACE treatment, rats were housed individually in artificial climate cabinet, and ACE was designed as three cycles of 12-hour light of 22 °C (7:00–19:00) and 12-hour dark of 4 °C(19:00–7:00). The non-ACE group was kept at 22 °C throughout the experiment. Main outcome measures Blood Pressure changes were measured and stroke symptom were observed; Expression of the CIRP were examined by reverse transcription-polymerase chain reaction. Results Finally 360 rats were involved in the analysis of results. ▪ Incidence of stroke: The incidence of stroke in 2k2c RHR was significantly higher after a three-day intermittent (12-hour) ACE (29.3%) as compared with that in non-ACE (17.3%) ( P < 0.05). Furthermore, the severe hypertensive 2k2c RHR (BP > 220 mm Hg) was found to have much higher incidence of stroke (66%, 33/50) than the mild (8%, 4/50) and moderate (18%) hypertensive 2k2c RHR. ▪ CIRP mRNA in brain tissue: ACE treatment stimulated the mRNA expression of CIRP in non-stroke 2k2c RHR but not in stroke 2k2c RHR ( P < 0.05). Conclusion High blood pressure and low expression of CIRP are associated with ACE induced stroke.