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Zika, dengue, and Yellow fever are transmitted primarily by Aedes aegypti mosquitoes. Investigations to find more natural but highly effective pesticidal agents against Ae. aegypti have increased in the last few years. Plant-based compounds have been the source of several current pesticides and have provided models for creation of synthetic derivatives like the pyrethroids. Plants continue to be a rich source for potential new active ingredients. The aim of this study is to increase knowledge on V. dioscoridis and to present the results of the cytotoxic and insecticidal activities of various extracts of its roots and volatile compound compositions of roots. The hexane and chloroform extracts, HM1 and CM1 respectively, exhibited cytotoxicity with IC50 values of 128.4 and 86.93 mg/mL against the HepG2 cell line. Because CM1 had higher cytotoxicity across the studied concentration range, it was also tested against the HUVEC cell line. Extracts HM1 and CM1 were also tested for their insecticidal activities. CM1 was found to be the more active (mortality (\%) = 96.7\% +/- 5.8 at 5 mu g/mosquito), consistent with its cytotoxic activity. Since these active extracts were nonpolar, the chemical composition of the volatile compounds of the roots were analyzed by GC-MS analysis. About 87.7\% of the essential oil were characterized. The major compound was beta-eudesmol (9.2\%), following by camphene (8.9\%), bornyl acetate (8.2\%) and maaliol (7.6\%). This is the first study on the HepG2 and HUVEC cytotoxicity and insecticidal activity of V. dioscoridis. Further studies on the potential of this plant to define the spectrum of activity and examine potential therapeutic agents is warranted. (C) 2021 SAAB. Published by Elsevier B.V. All rights reserved.

Clinical intervention of pain is often accompanied by changes in affective behaviors, so both assays of affective and sensorial aspects of nociception play an important role in the development of novel analgesics. Although positive allosteric modulation (PAM) of α7 nicotinic acetylcholine receptors (nAChRs) has been recognized as a novel approach for the relief of sensorial aspects of pain, their effects on affective components of pain remain unclear. Therefore, we investigated whether PAM-4, a highly selective α7-nAChR PAM, attenuates inflammatory and neuropathic pain, as well as the concomitant depressive/anxiety comorbidities. The anti-nociceptive activity of PAM-4 was assessed in mice using the formalin test and chronic constriction injury (CCI)-induced neuropathic pain model. The anxiolytic- and antidepressant-like activity of PAM-4 was evaluated using the marble burying test and forced swimming test. Acute systemic administration of PAM-4 dose-dependently reversed formalin-induced paw licking behavior and CCI-induced mechanical allodynia without development of any motor impairment. PAM-4 reversed the decreased swimming time and number of buried marbles in CCI-treated mice, suggesting that this ligand attenuates chronic pain-induced depression-like behavior and anxiogenic-like effects. The effects of PAM-4 were inhibited by the α7-selective antagonist methyllycaconitine, indicating molecular mechanism mediated by α7-nAChRs. Indeed, electrophysiological recordings showed the PAM-4 enhances human α7 nAChRs with higher potency and efficacy compared to rat α7 nAChRs. These findings suggest that PAM-4 reduces both sensorial and affective behaviors induced by chronic pain in mice by α7-nAChR potentiation. PAM-4 deserves further investigations for the management of chronic painful conditions with comorbidities.

We aimed to investigate the hypothesis that sigma receptor ligands, haloperidol and ifenprodil, attenuate hypoxia-induced striatal dopamine release in vitro and determine the possible mechanisms.Extracellular concentrations of dopamine were measured using acute brain slices method under hypoxic, aglycemic and ischemic conditions. Sigma receptor ligands haloperidol and ifenprodil attenuate striatal dopamine release induced by hypoxia in contrast to aglycemia and ischemia. To determine the possible contribution of glutamatergic system on this effect, we compared the effect of NMDA receptor antagonist MK-801 and haloperidol in hypoxia induced by Na-K-ATPaz enzyme inhibitor ouabain. Also, we compared the effect of dopamine uptake blocker nomifensine and haloperidol to determine the role of dopamine transporter on this effect.Haloperidol and nomifensine almost completely abolish ouabain-induced dopamine release unlike MK-801. Different effects of sigma ligands and glutamate receptor antagonists on the hypoxia and ouabain induced dopamine release show that glutamate receptor blockade is partial involved in inhibitory effect of sigma ligand on dopamine release under hypoxic conditions. Similar effect of dopamine uptake blocker nomifensine and sigma receptor ligand haloperidol on ouabain induced dopamine release supports the possibility that inhibition of reverse dopamine transport by sigma ligands might be involved in their protective effect.Data in this study suggest that sigma ligands may be a new therapeutic intervention for the management of hypoxic conditions.

Objective: In present study, we aimed to clarify effect of aging on the susceptibility of brain tissue to neurodegeneration induced by ischemia.Methods: Damage induced by oxygen-glucose deprivation...

Background: Natural phenolic compounds in medicinal herbs and dietary plants are antioxidants which play therapeutic or preventive roles in different pathological situations, such as oxidative stress and inflammation. One of the most studied phenolic compounds in the last decade is chlorogenic acid (CGA), which is a potent antioxidant found in certain foods and drinks. Objective: This review focuses on the anti-inflammatory and antinociceptive bioactivities of CGA, and the putative mechanisms of action are described. Ethnopharmacological reports related to these bioactivities are also reviewed. Materials and Methods: An electronic literature search was conducted by authors up to October 2019. Original articles were selected. Results: CGA has been shown to reduce inflammation and modulate inflammatory and neuropathic pain in animal models. Conclusion: The consensus of the literature search was that systemic CGA may facilitate pain management via bolstering antioxidant defenses against inflammatory insults.

Although L-DOPA revolutionized in the treatment of Parkinson's disease, most patients developed motor complications after several years of treatment. Adjunctive therapy to L-DOPA with drugs related to dopaminergic signaling may reduce its dose without decreasing the therapeutic efficiency and thus ameliorates its adverse effects. It has been shown that 3,4-diaminopyridine (3,4-DAP), a K channel blocker, increased dopamine release from striatal slices by increasing neuronal firing in striatal dopaminergic terminals. The current study investigates whether 3,4-DAP may enhance L-DOPA-induced dopamine (DA) release from striatal slices by increasing neuronal firing in striatal dopaminergic terminals. The effects of L-DOPA and 3,4-DAP on spontaneous DA and DOPAC release were tested in vitro, on acute rat striatal slices prepared from non-treated and 6-hydroxydopamine-pre-treated rats. DA and DOPAC levels were determined by HPLC methods. When 3,4-diaminopyridine was combined with L-DOPA, the observed effect was considerably greater than the increases induced by L-DOPA or 3,4-DAP alone in normoxic and neurodegenerative conditions produced by FeSO4 and 6-hydroxydopamine. Furthermore, L-DOPA plus 3,4-DAP also ameliorated DOPAC levels in neurodegenerative conditions. These data indicate that 3,4 DAP plus L-DOPA activates striatal dopaminergic terminals by increasing the DA release and, thus, could be considered as a promising finding in treatment of acute and chronic injury in dopaminergic neurons.

Aim In the present study, we investigated the long-term effects of exenatide treatment on serum fasting ghrelin levels in patients with type 2 diabetes mellitus. Methods Type 2 diabetic patients, who were using metformin with and without the other antihyperglycemic drugs on a stable dose for at least 3 months, were enrolled in the study. BMI>35 kg/m2 and HbA1c>7.0% were the additional inclusion criteria. Oral antihyperglycemic drugs, other than metformin, were stopped, and metformin treatment was continued at 2000 mg per day. Exenatide treatment was initiated at 5 µg per dose subcutaneously (sc) twice daily, and after one month, the dose of exenatide was increased to 10 µg twice daily. Changes in anthropometric variables, glycemic control, lipid parameters and total ghrelin levels were evaluated at baseline and following 12 weeks of treatment. Results Thirty-eight patients (male/female = 7/31) entered the study. The mean age of patients was 50.5 ± 8.8 years with a mean diabetes duration of 8.5 ± 4.9 years. The mean BMI was 41.6 ± 6.3 kg/m2 and the mean HbA1c of patients was 8.9 ± 1.4%. The mean change in the weight of patients was −5.6 kg and the percentage change in weight was −5.2 ± 3.7% following 12 weeks of treatment. BMI, fasting plasma glucose and HbA1c levels of patients were decreased significantly (P P P = 0.024). Conclusion These results suggest that the effects of exenatide on weight loss may be related with the suppression of serum fasting ghrelin levels, which is an orexigenic peptide.

To assess the vitreous and serum levels of neuron-specific enolase (NSE), S100B and malondialdehyde (MDA) in proliferative diabetic retinopathy (PDR) cases and investigate the correlation between preoperative and postoperative anatomical and clinical features. The study group included patients who had pars plana vitrectomy (PPV) for PDR. The control group included non-diabetic individuals who underwent PPV surgery for vitreoretinal interface disorders. Samples of serum were taken from all participants preoperatively, while vitreous samples were taken during the PPV. Vitreous and serum levels of NSE, S100B and MDA were measured, and comparisons were made between the groups. The study group consisted of 56 eyes of 56 cases with PDR. The control group consisted of 20 eyes of 20 cases. The concentrations of vitreous NSE, S100B and MDA were significantly higher than the control group (p

Background and Purpose Orthosteric agonists and positive allosteric modulators (PAMs) of the α7 nicotinic ACh receptor (nAChR) represent novel therapeutic approaches for pain modulation. Moreover, compounds with dual function as allosteric agonists and PAMs, known as ago-PAMs, add further regulation of receptor function. Experimental Approach Initial studies examined the α7 ago-PAM, GAT107, in the formalin, complete Freund's adjuvant (CFA), LPS inflammatory pain models, the chronic constriction injury neuropathic pain model and the tail flick and hot plate acute thermal nociceptive assays. Additional studies examined the locus of action of GAT107 and immunohistochemical markers in the dorsal horn of the spinal cord in the CFA model. Key Results Complementary pharmacological and genetic approaches confirmed that the dose-dependent antinociceptive effects of GAT107 were mediated through α7 nAChR. However, GAT107 was inactive in the tail flick and hot plate assays. In addition, GAT107 blocked conditioned place aversion elicited by acetic acid injection. Furthermore, intrathecal, but not intraplantar, injections of GAT107 reversed nociception in the CFA model, suggesting a spinal component of action. Immunohistochemical evaluation revealed an increase in the expression of astrocyte-specific glial fibrillary acidic protein and phosphorylated p38MAPK within the spinal cords of mice treated with CFA, which was attenuated by intrathecal GAT107 treatment. Importantly, GAT107 did not elicit motor impairment and continued to produce antinociceptive effects after subchronic administration in both phases of the formalin test. Conclusions and Implications Collectively, these results provide the first proof of principle that α7 ago-PAMs represent an effective pharmacological strategy for treating inflammatory and neuropathic pain.

Introduction: One of the preferable flavors in oral nicotine delivery systems is menthol which masks the harshness of tobacco. However, possible interactions between oral menthol and nicotine on intake and preference remain unclear. Therefore, we aimed to determine the impact of menthol on oral nicotine consumption. Methods: Adult Sprague Dawley female and male rats (n = 8 per group) were given a choice of water or drug solution by using two-bottle free choice paradigm for 2 weeks: vehicle (5% ethanol), nicotine (20 mg/L), menthol (1 g/L) and mentholated nicotine groups. At the end of the study, plasma nicotine levels were determined. Results: When rats were given a choice of nicotine or water, nicotine intake was similar between female and male rats. Menthol addition to nicotine solution significantly increased nicotine intake and preference in male but not female rats without a considerable effect on total fluid intake and body weight change in either sex. The average nicotine intake in male rats was 0.5 +/- 0.05 and 1.4 +/- 0.12 mg/kg/day for nicotine and menthol-nicotine combination (p .05), respectively. Plasma nicotine levels were not significantly different between the groups in either male (nicotine group: 20.8 +/- 4.9, mentholated nicotine group: 31.9 +/- 3.2 ng/mL) or female (nicotine group: 24.0 +/- 3.3, mentholated nicotine group: 17.8 +/- 2.9 ng/mL) rats (p >.05). Conclusions: Menthol increases oral nicotine consumption in male, but not female, rats. Canada Research Chair in Pharmacogenomics Training and Education Core of the National Institute on Drug Abuse of the National Institutes of Health (NIH) (P50DA036105) Center for Tobacco Products of the US Food and Drug Administration Canadian Institutes of Health Research (FDN-154294) Rat für Forschung und Technologieentwicklung

Purpose: To investigate the olfaction and taste functions in obese female patients and the association between serum ghrelin and leptin levels compared with healthy controls. Methods: Fifty-two obese women, who have a body mass index >30 kg/m(2), and 15 healthy women were included in the study. After 8 hrs fasting, blood samples were taken for serum biochemical parameters, ghrelin, and leptin level measurement. For the quantitative assessment of olfactory function, all participants underwent an N-butanol threshold test and odor identification test using 12 Sniffin' Sticks (R) fragrance sticks. The gustatory function was tested by administering a whole-mouth above threshold test using sucrose solutions. Results: The sucrose taste threshold score in obese women was significantly higher than the controls (P = 0.004). We found positively significant correlation between serum ghrelin levels and n-butanol threshold scores in obese women (r = 0.300, P = 0.031). N-butanol smell threshold was not significantly different between the two groups (P = 0.149), while the Sniffin' Sticks smell test scores were significantly lower in obese women compared with the controls (P = 0.007). Serum leptin levels were also significantly higher in obese women (P < 0.001) although there was no significant difference in serum ghrelin levels between the two groups (P = 0.768). There was no correlation between serum leptin levels and Sniffin' Sticks scores, n-butanol, and sucrose taste threshold scores in obese women. Conclusions: These results might suggest that leptin, which is an anorexigenic peptide, may have a negative effect on taste and smell functions. More studies are warranted to elucidate the exact role of ghrelin secretion on olfaction and taste functions.

Aglepristone is a safe and effective abortifacient, which is being widely used in small animal practice during the last years. Although no side effetcs have been reported in clinical studies, there is no information available about the effects of aglepristone on oxidative stress parameters. The objective of this study was to investigate the effects of aglepristone treatment on oxidative stress parameters, which are Malondialdehyt (MDA), Superoxide Dismutase (SOD) ve reduced Glutathione (GSH), in mid-gestation termination in rabbits. Fifteen healthy New Zealand White rabbit, 12 months of age, were included the the study. They were given to fertile bucks and the mating day was recorded as the 0 day of pregnancy. The does were randomly divided into Yrd.Doc.Dr., Uludag Universitesi Veteriner Fakultesi Fizyoloji Anabilim Dali Gorukle Kampusu/BURSA Aras.Gor.Dr., Uludag Universitesi Tip Fakultesi Deney Hayvanlari Yetistirme Uygulama Merkezi Gorukle Kampusu /BURSA Aras.Gor., Uludag Universitesi Tip Fakultesi Farmakoloji Anabilim Dali Gorukle Kampusu/BURSA4* Doc.Dr.,Uludag Universitesi Veteriner Fakultesi Dogum ve Jinekoloji Anabilim Dali Gorukle Kampusu/BURSA, rgozalp@uludag.edu.trthree groups. In Group I (control) the does were injected with 0.9% NaCl at dose of 1ml/3kg on day 15 and 16 post-mating. In Group II and Group III, aglepristone (Alizin®) was applied at a dose of 10mg/kg dose ofsubcutaneously, on day 15 and on days 15-16 days post-mating, respectively. MDA, SOD and GSH levels were measured from collected blood samples. A marked increase of MDA in Group III, was statistically significant with Group I (p

The aim of this study was to evaluate different antioxidants-supplemented freeze-dried egg yolk based extenders for the post-thawing quality and incubation resilience of goat spermatozoa. Pooled semen were diluted in a two-step dilution method to a final concentration of 1/5 (semen/extender) in control and antoxidant supplemented freeze-dried extenders (methionine, cysteamine and butylated hydroxytoluene). Semen samples were assessed for sperm motility, plasma membrane functional integrity using hypoosmotic swelling test (HOST), damaged acrosome using FITC-Pisum sativum agglutinin (PSA-FITC) and DNA integrity using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). Membrane lipid peroxidation status was also analyzed using the malondialdehyde (MDA) concentration. In the study, antioxidant supplemented freeze-dried egg yolk based extenders have beneficial effect on goat sperm parameters. In addition, we achieved a higher quality in post thawed goat semen even after 6 h incubation when the extender was supplemented by 5 mM BHT or cysteamine.

Aim. To investigate the effect of exenatide treatment on serum ghrelin levels in obese female patients with type 2 diabetes mellitus.Methods. Fourteen female patients with type 2 diabetes mellitus being treated with metformin and exenatide were enrolled. A mixed meal test was applied to the patients while continuing with their daily medications. Blood samples were taken before and at 60, 120, and 180 minutes following mixed meal test to measure serum total ghrelin, glucose, and insulin levels. The following week, exenatide treatment of the patients was paused for 24 hours and the same experimental procedures were repeated.Results. Serum ghrelin levels were suppressed significantly at 180 minutes with exenatide treatment compared with baseline (294.4±57.5versus234.5±59.4 pg/mL) (p<0.001). Serum ghrelin levels at 180 minutes were statistically different when percentage change in serum ghrelin levels after mixed meal tests with and without exenatide usage were compared (p=0.001). Estimated total area under the curve values for serum ghrelin concentrations was also significantly lower with exenatide compared with omitted treatment (p=0.035).Conclusion. These results suggest that the effect of exenatide on weight loss may be related with the suppression of serum ghrelin levels, which is an orexigenic peptide.

Orthosteric agonists and positive allosteric modulators (PAMs) of the α7 nicotinic ACh receptor (nAChR) represent novel therapeutic approaches for pain modulation. Moreover, compounds with dual function as allosteric agonists and PAMs, known as ago-PAMs, add further regulation of receptor function.Initial studies examined the α7 ago-PAM, GAT107, in the formalin, complete Freund's adjuvant (CFA), LPS inflammatory pain models, the chronic constriction injury neuropathic pain model and the tail flick and hot plate acute thermal nociceptive assays. Additional studies examined the locus of action of GAT107 and immunohistochemical markers in the dorsal horn of the spinal cord in the CFA model.Complementary pharmacological and genetic approaches confirmed that the dose-dependent antinociceptive effects of GAT107 were mediated through α7 nAChR. However, GAT107 was inactive in the tail flick and hot plate assays. In addition, GAT107 blocked conditioned place aversion elicited by acetic acid injection. Furthermore, intrathecal, but not intraplantar, injections of GAT107 reversed nociception in the CFA model, suggesting a spinal component of action. Immunohistochemical evaluation revealed an increase in the expression of astrocyte-specific glial fibrillary acidic protein and phosphorylated p38MAPK within the spinal cords of mice treated with CFA, which was attenuated by intrathecal GAT107 treatment. Importantly, GAT107 did not elicit motor impairment and continued to produce antinociceptive effects after subchronic administration in both phases of the formalin test.Collectively, these results provide the first proof of principle that α7 ago-PAMs represent an effective pharmacological strategy for treating inflammatory and neuropathic pain.

Oxidative stress occurs following the impairment of pro-oxidant/antioxidant balance in chronic wounds and leads to harmful delays in healing progress. A fine balance between oxidative stress and endogenous antioxidant defense system may be beneficial for wound healing under redox control. This study tested the hypothesis that oxidative stress in wound area can be controlled with systemic antioxidant therapy and therefore wound healing can be accelerated. We used chlorogenic acid (CGA), a dietary antioxidant, in experimental diabetic wounds that are characterized by delayed healing. Additionally, we aimed to understand possible side effects of CGA on pivotal organs and bone marrow during therapy. Wounds were created on backs of streptozotocin-induced diabetic rats. CGA (50 mg/kg/day) was injected intraperitoneally. Animals were sacrificed on different days. Biochemical and histopathological examinations were performed. Side effects of chronic antioxidant treatment were tested. CGA accelerated wound healing, enhanced hydroxyproline content, decreased malondialdehyde/nitric oxide levels, elevated reduced-glutathione, and did not affect superoxide dismutase/catalase levels in wound bed. While CGA induced side effects such as cyto/genotoxicity, 15 days of treatment attenuated blood glucose levels. CGA decreased lipid peroxidation levels of main organs. This study provides a better understanding for antioxidant intake on diabetic wound repair and possible pro-oxidative effects.

Previous studies showed that chlorogenic acid (CGA) accelerates wound healing via its antioxidant activity. We aimed to investigate the effect of CGA in an experimental epigastric abdominal skin flap model in nondiabetic and diabetic rats. Rats were firstly divided into 2 groups: nondiabetic and diabetic. Diabetes was induced by streptozotocin. Then, 4 subgroups were created for each group: vehicle as well as 0.2 mg/0.5 mL, 1 mg/0.5 mL, and 5 mg/0.5 mL CGA treatments. Right epigastric artery-based abdominal skin flaps were elevated and sutured back into their original position. Chlorogenic acid or vehicle was injected once into the femoral arteries by leaving the epigastric artery as the single artery feeding the flaps during the injection. On postoperative day 7, flap survivals were evaluated, and the rats were killed. Distal flap tissues were collected for histopathological and biochemical assays. Chlorogenic acid showed greater flap survival in both nondiabetic and diabetic rats. Capillary density was increased, and necrosis was reduced in the CGA-treated rats. Chlorogenic acid decreased malondialdehyde levels as well as increased reduced glutathione and superoxide dismutase levels in the flap tissues. This study showed that CGA significantly improved flap survival by its antioxidant activities with intra-arterial local injections.

Chlorogenic acid (CGA) is a well-known natural antioxidant in human diet. To understand the effects of CGA on wound healing by enhancing antioxidant defense in the body, the present study sought to investigate the potential role of systemic CGA therapy on wound healing and oxidative stress markers of the skin. We also aimed to understand whether chronic CGA treatment has side effects on pivotal organs or rat bone marrow during therapy. Full-thickness experimental wounds were created on the backs of rats. CGA (25, 50, 100, 200 mg/kg) or vehicle was administered intraperitoneally for 15 days. All rats were sacrificed on the 16th day. Biochemical, histopathological, and immunohistochemical examinations were performed. Possible side effects were also investigated. The results suggested that CGA accelerated wound healing in a dose-dependent manner. CGA enhanced hydroxyproline content, decreased malondialdehyde and nitric oxide levels. and elevated reduced glutathione, superoxide dismutase, and catalase levels in wound tissues. Epithelialization, angiogenesis, fibroblast proliferation, and collagen formation increased by CGA while polymorph nuclear leukocytes infiltration decreased. CGA modulated matrix metalloproteinase-9 and tissue inhibitor-2 expression in biopsies. Otherwise, high dose of CGA increased lipid peroxidation of liver and kidney without affecting the heart and muscle samples. Chronic CGA increased micronuclei formation and induced cytotoxicity in the bone marrow. In conclusion, systemic CGA has beneficial effects in improving wound repair. Antioxidant, free radical scavenger, angiogenesis, and anti-inflammatory effects of CGA may ameliorate wound healing. High dose of CGA may induce side effects. In light of these observations, CGA supplementation or dietary CGA may have benefit on wound healing.

There has been considerable interest in understanding the effects of antioxidants in flap survival during diabetes. Previous studies showed that chlorogenic acid (CGA) exhibits potent antioxidant effects. We aimed to determine the effects of systemic CGA treatment on skin flap survival in an experimental random-pattern dorsal skin flap model in diabetic rats. Twenty-eight male Wistar rats were divided into four groups: phosphate buffered saline (PBS)-treated or CGA-treated nondiabetic rats, PBS-treated or CGA-treated diabetic rats. Diabetes was induced by streptozotocin (45 mg/kg). Caudally based bipedicled dorsal skin flaps were elevated. CGA (100 mg/kg) or PBS (mL/kg; as vehicle) was administered intraperitoneally once daily. On postoperative day 7, flap survival, regional blood perfusion and microangiography were evaluated. The malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD) and nitric oxide (NO) levels were evaluated from the flap tissue. Capillary density and vascular endothelial growth factor (VEGF) expression were assessed. Harmful effects of diabetes on flap survival were observed. CGA attenuated these effects and allowed greater survival and blood perfusion. CGA decreased MDA and NO levels and increased GSH and SOD levels. CGA elevated capillary density and VEGF expression. This study showed that peripherally administered CGA significantly improved flap survival in diabetic and nondiabetic rats.