Rise In Plasma Levels Research Articles

Impact of Nicotine Exposure and Withdrawal on Plasma Glucose, Insulin and Glycated Haemoglobin in High-Fat Diet Fed Wistar Rats

Background to the study: Nicotine, which is the most abundant constituent of tobacco cigarette is one of the most commonly abused drugs. The duo of obesity and tobacco smoking increases the risk of cardiometabolic disorders. Methodology: The experiment involved 48 male wistar rats separated into 4 groups of 8 rats each. All the animals were placed on high-fat diet (Margarine; blue band) in addition to the different doses of nicotine in the experimental groups. Group 1 served as control and received distilled water, Groups 2, 3 and 4 received 200µg/kg, 400µg/kg and 800µg/kg of nicotine oral solution respectively. The experimental groups were placed on their respective doses of nicotine solution for an initial four weeks. Thereafter, four animals in each group were sacrificed and blood samples collected to determine their nicotine exposure plasma levels of glucose, insulin and glycated hemoglobin. The remaining four animals in each group continued without nicotine for another four weeks after which they were sacrificed and blood samples collected to determine their nicotine withdrawal plasma levels of glucose, insulin and glycated hemoglobin. Results: The results showed that exposure to the three concentrations of nicotine (200, 400 and 800µg/kg respectively) significantly caused a rise in plasma insulin levels but dose-dependent reduction in both glucose and glycated haemoglobin compared to their control groups. Four weeks after withdrawal of initial 200µg/kg nicotine there were no significant changes in the levels of plasma glucose, insulin and glycated haemoglobin compared to the nicotine exposed groups. Withdrawal, after initial exposure to 400µg/kg of nicotine was associated with significant rise in both the plasma glucose and glycated haemoglobin but no significant change in insulin compared to their respective nicotine exposed groups. Cessation, after initial exposure 800µg/kg of nicotine resulted in significant rise in plasma levels of glucose, ..........

Soluble factors and suppressive monocytes can predict early development of sepsis in acute-on-chronic liverfailure.

Patients with acute‐on‐chronic liver failure (ACLF) have a high probability of developing systemic inflammation and sepsis due to immune dysregulation. Fifty‐nine patients with ACLF (12 without and 19 with systemic inflammation, and 28 with sepsis) were serially monitored for clinical and immunological changes at baseline, 6 hours, 24 hours, day 3, and day 7 following hospitalization. Ten healthy controls were also included. At all time points, soluble plasma factors and monocyte functions were studied. Patients with ACLF and systemic inflammation showed higher interleukin (IL)–6, vascular endothelial growth factor‐a, monocyte chemoattractant protein 1, and macrophage inflammatory protein 1β than patients with no systemic inflammation. Patients with ACLF with sepsis had raised (p < 0.001) levels of IL‐1Ra, IL‐18, and triggering receptor expressed on myeloid cells 1 (TREM1) compared to patients with ACLF‐systemic inflammation. Five of the 19 (26.3%) patients with systemic inflammation developed sepsis within 48–72 hours with a rapid rise in plasma levels of IL‐1Ra (1203–35,000 pg/ml), IL‐18 (48–114 pg/ml), and TREM1 (1273–4865 pg/ml). Monocytes of patients with ACLF with systemic inflammation and sepsis showed reduced human leukocyte antigen–DR but increased programmed death ligand 1 (PD‐L1) and T‐cell immunoglobulin and mucin domain‐containing protein 3 (TIM3) (p < 0.04) expression with increased ETosis by monocytes at baseline and until day 7. Conclusion: High and rising levels of plasma IL‐1Ra, IL‐18, TREM1 soluble factors, and increased suppressive monocytes (PDL1+ve, TIM3+ve) at baseline can stratify patients with ACLF at high risk of developing sepsis within 48–72 hours of hospitalization.

Chronic Inflammatory Status Observed in Patients with Type 2 Diabetes Induces Modulation of Cytochrome P450 Expression and Activity.

Diabetes mellitus is a metabolic disease that causes a hyperglycemic status which leads, over time, to serious damage to the heart, blood vessels, eyes, kidneys and nerves. The most frequent form of diabetes is type 2 diabetes mellitus (T2DM) which is often part of a metabolic syndrome (hyperglycaemia, hypertension, hypercholesterolemia, abdominal obesity) that usually requires the use of several medications from different drug classes to bring each of these conditions under control. T2DM is associated with an increase in inflammatory markers such as interleukin-6 (IL-6) and the tumor necrosis factor alpha (TNF-α). Higher levels of IL-6 and TNF-α are associated with a downregulation of several drug metabolizing enzymes, especially the cytochrome P450 (P450) isoforms CYP3As and CYP2C19. A decrease in these P450 isoenzymes may lead to unexpected rise in plasma levels of substrates of these enzymes. It could also give rise to a mismatch between the genotypes determined for these enzymes, the predicted phenotypes based on these genotypes and the phenotypes observed clinically. This phenomenon is described as phenoconversion. Phenoconversion typically results from either a disease (such as T2DM) or concomitant administration of medications inducing or inhibiting (including competitive or non-competitive inhibition) a P450 isoenzyme used by other substrates for their elimination. Phenoconversion could have a significant impact on drug effects and genotypic-focused clinical outcomes. As the aging population is exposed to polypharmacy along with inflammatory comorbidities, consideration of phenoconversion related to drug metabolizing enzymes is of importance when applying pharmacogenomic results and establishing personalized and more precise drug regimens.

Study in the Effect of Yavavati in the Management of Dyslipidemia

Dyslipidemia is considered as metabolic disorders related to lipoprotein metabolism, manifested as rise in plasma levels of total Cholesterol, Triglyceride (TGs), or both, or a decrease in high density lipoprotein level or all three together that contributes to the formation of atherosclerosis. It can be included under santarpanjanyavyadhi. Various conditions like Shonitabhishyandana, Rasagata SnehaVriddhi (raised plasma lipid levels), Rasaraktagata Snehavriddhi (raised plasma and blood lipid levels), Medovriddhi (elevation of generalized fat), Medoroga (obesity), Aam Medodhatu (abnormal form of adipose tissue) can be correlated with Dyslipidemia due to resemblance of their etiopathogenesis and clinical features. Total 30 patients of dyslipidemia fulfilling the diagnostic criteria were selected and treated with Yavavati 1.5 gm twice a day before meal with lukewarm water for 30 days. In this study it was observed that incidence of Dyslipidemia was more in advanced ages,female gender, middle socioeconomic group individuals having vatapittajaprakruti, madhyamagni and madhyamaakruti. In present study, sedentary lifestyle, day sleep, association of other diseases like hypertension, DM, hypothyroidism and hemiplegia are the main causative factors for Dyslipidemia. Yavavati showed significant improvement in BMI, total cholesterol, S.Triglicerides, S.VLDL and HDL level. This improvement may be due to its ruksha, lekhana, kaphamedahar, agnivadhaka and apatarpana properties of Yavavati. Hence from this study it can be concluded that, Yavavati is effective and can be safely used in the management of Dyslipidemia.

Why is the therapeutic effect of acute antimigraine drugs delayed? A review of controlled trials and hypotheses about the delay of effect.

In randomised controlled trials (RCTs) of oral drug treatment of migraine attacks, efficacy is evaluated after 2hours. The effect of oral naratriptan 2.5mg with a maximum blood concentration (Tmax ) at 2hours increases from 2 to 4hours in RCTs. To check whether such a delayed effect is also present for other oral antimigraine drugs, we hand-searched the literature for publications on RCTs reporting efficacy. Two triptans, 3 nonsteroidal anti-inflammatory drugs (NSAIDs), a triptan combined with an NSAID and a calcitonin gene-related peptide receptor antagonist were evaluated for their therapeutic gain with determination of time to maximum effect (Emax ). Emax was compared with known Tmax from pharmacokinetic studies to estimate the delay to pain-free. The delay in therapeutic gain varied from 1-2hours for zolmitriptan 5mg to 7hours for naproxen 500mg. An increase in effect from 2 to 4hours was observed after eletriptan 40mg, frovatriptan 2.5mg and lasmiditan 200mg, and after rizatriptan 10mg (Tmax =1h) from 1 to 2hours. This strongly indicates a general delay of effect in oral antimigraine drugs. A review of 5 possible effects of triptans on the trigemino-vascular system did not yield a simple explanation for the delay. In addition, Emax for triptans probably depends partly on the rise in plasma levels and not only on its maximum. The most likely explanation for the delay in effect is that a complex antimigraine system with more than 1 site of action is involved.

Cholestasis-associated glucocorticoid overexposure does not increase atherogenesis.

Chronic glucocorticoid overexposure predisposes to the development of atherosclerotic cardiovascular disease in humans. Cholestatic liver disease is associated with increased plasma glucocorticoid levels. Here, we determined - in a preclinical setting - whether the chronic presence of cholestatic liver disease also induces a concomitant negative impact on atherosclerosis susceptibility. Hereto, regular chow diet-fed atherosclerosis-susceptible hypercholesterolemic apolipoprotein E (APOE)-knockout mice were treated with the bile duct toxicant alpha-naphthylisothiocyanate (ANIT) for 8 weeks. ANIT exposure induced the development of fibrotic cholestatic liver disease as evident from collagen deposits and compensatory bile duct hyperproliferation within the liver and the rise in plasma levels of bilirubin (+60%; P < 0.01) and bile acids (10-fold higher; P < 0.01). Adrenal weights (+22%; P < 0.01) and plasma corticosterone levels (+72%; P < 0.01) were increased in ANIT-treated mice. In contrast, atherosclerosis susceptibility was not increased in response to ANIT feeding, despite the concomitant increase in plasma free cholesterol (+30%; P < 0.01) and cholesteryl ester (+42%; P < 0.001) levels. The ANIT-induced hypercorticosteronemia coincided with marked immunosuppression as judged from the 50% reduction (P < 0.001) in circulating lymphocyte numbers. However, hepatic glucocorticoid signaling was not enhanced after ANIT treatment. It thus appears that the immunosuppressive effect of glucocorticoids is uncoupled from their metabolic effect under cholestatic disease conditions. In conclusion, we have shown that cholestatic liver disease-associated endogenous glucocorticoid overexposure does not increase atherosclerosis susceptibility in APOE-knockout mice. Our studies provide novel preclinical evidence for the observations that the hypercholesterolemia seen in cholestatic human subjects does not translate into a higher risk for atherosclerotic cardiovascular disease.

Daily, circadian and seasonal changes of rhodopsin-like encephalic photoreceptor and its involvement in mediating photoperiodic responses of Gambel’s white-crowned Sparrow, Zonotrichia leucophrys gambelii

Extra-retinal, non-pineal, encephalic photoreceptors (EP) play important roles in mediating development of the reproductive system by the annual change in day length (photoperiodic gonadal response – PGR) in birds. However, the distribution of rhodopsin-like EPs and their functional daily, circadian and seasonal changes are still unclear in the avian brain. This study identifies two novel groups of rhodopsin-immunoreactive cells in the nucleus paraventricularis magnocellularis (PVN) of the hypothalamus and in the medial basal hypothalamus (MBH) in a seasonally breeding species, Gambel’s white-crowned sparrow (Zonotrichia leucophrys gambelii). In the PVN, rhodopsin-ir cell number showed both daily and circadian changes with more labeled cells apparent in the night phase in photosensitive birds, while only circadian changes were observed involving fewer labeled cells in the night phase in photorefractory birds. Single long day photo-stimulation significantly decreased the rhodopsin-ir cell number only in photosensitive birds, coincident with a rise in plasma levels of luteinizing hormone (LH). In the MBH, rhodopsin-ir cell number did not show daily, circadian or single long day induced changes in either photoperiodic states. But, overall these rhodopsin expressing neurons significantly increased from photosensitive to photorefractory states. In the median eminence (ME), more intense rhodopsin-ir was detected in photorefractory birds compared to photosensitive birds. For expression of GnRH and vasoactive intestinal polypeptide (VIP), seasonal differences were found with opposite relationships, consistent with previous studies. Our results suggest different roles of the two groups of rhodopsin-like EPs in the regulation of PGR in white-crowned sparrows.

Activity of the hypothalamic–pituitary–adrenal axis of prenatally stressed male rats in experimental model of depression

The hypothalamic-pituitary-adrenal (HPA) axis activity changes were examined in the adult, prenatally stressed male rats in the experimental depression model--the paradigm of "learned helplessness". It was shown that in males descending from intact mothers a depressive-like state was accompanied by an increase in HPA activity. The expression of corticotrophin-releasing hormone (CRH) in the hypothalamic paraventricular nucleus (PVN) increases, coupled with a rise in plasma levels of ACTH and corticosterone as well as in adrenal weight. At the same time in males born from mothers stressed during the last week of pregnancy we observed a decrease in activity of both the central (hypothalamus) and the peripheral (adrenal cortex) parts of regulation of this hormonal axis similar to that revealed for these animals in our previous study in "stress-restress" paradigm. It is concluded that prenatal stress modifies the sensitivity of animals to the inescapable intense stress impact, which manifests itself in a specific pattern of the HPA axis activity after stress load.

Plasma levels of follicle-stimulating and luteinizing hormones during the reproductive cycle of wild and cultured Senegalese sole (Solea senegalensis)

The intensive culture of the Senegalese sole (Solea senegalensis) is hampered by the low or null fertilization rates exhibited by the first generation (F1) of reared males. To investigate the regulation of the reproductive processes in this species by the pituitary gonadotropins follicle-stimulating and luteinizing hormones (Fsh and Lh, respectively), we developed a highly sensitive and specific enzyme-linked immunosorbent assay (ELISA) for Lh measurements. Quantification of the Fsh and Lh plasma levels in cultured sole using the Lh ELISA developed here, and a previously developed ELISA for Fsh, indicated that in both males and females circulating Fsh steadily increased during autumn and winter and prior to the major spawning in spring, whereas an Lh surge occurred specifically during spawning. The increase in Fsh was associated with a rise of plasma levels of the steroid hormones testosterone (T), 11-ketotestosterone (11-KT) and estradiol-17β (E2), but that of Lh was concomitant with a strong decline of the levels of E2 in females and of 11-KT in males, possibly reflecting a rapid steroidogenic shift promoting the final maturation of gametes. Comparison of the plasma levels of gonadotropins and steroids between wild and F1 fish during autumn and spring revealed that F1 males showed significantly lower plasma Lh titres compared to wild males, whereas the levels of T and 11-KT were similar or more elevated in the F1 fish. These data suggest that an impaired Lh secretion during spawning, and perhaps altered Lh-mediated mechanisms in the testis, may be underlying causes for the low reproductive performance of Senegalese sole F1 males.

Anti-inflammatory, Antithrombotic and Cardiac Remodeling Preventive Effects of Eugenol in Isoproterenol-Induced Myocardial Infarction in Wistar Rat.

This study aimed to evaluate the antithrombotic, anti-inflammatory and anti-cardiac remodeling properties of eugenol in isoproterenol-induced myocardial infarction in rats. Male Wistar rats were randomly divided into four groups, control, iso [100mg/kg body weight was injected subcutaneously into rats at an interval of 24h for 2days (6th and 7th day) to induce MI] and pretreated animals with clopidogrel (0.2mg/kg) and eugenol (50mg/kg) orally for 7days and intoxicated with isoproterenol (Iso+Clop) and (Iso+EG) groups. Isoproterenol-induced myocardial infarcted rats showed notable changes in the ECG pattern, increase in heart weight index, deterioration in the hemodynamic function and rise in plasma level of troponin-T, CK-MB and LDH and ALT by 316, 74, 172 and 45%, respectively, with histological myocardium necrosis and cells inflammatory infiltration. In addition, significant increases in plasma levels of inflammatory biomarkers such as fibrinogen, α1, α2, β1, β2 and γ globulins with decrease level of albumin were observed in infarcted rats as compared to normal ones. Else, the angiotensin-converting enzyme (ACE) activity in plasma, kidney and heart of the isoproterenol-induced rats was significantly increased by 34, 47 and 93%, respectively, as compared to normal group. However, the administration of eugenol induced a clear improvement in cardiac biomarkers injury, reduced inflammatory mediators proteins, increased heart activities of superoxide dismutase and glutathione peroxidase with reduce in thiobarbituric acid-reactive substances content and inhibition of ventricular remodeling process through inhibition of ACE activity. Overall, eugenol evidences high preventive effects from cardiac remodeling process.

Reward and Toxicity of Cocaine Metabolites Generated by Cocaine Hydrolase.

Butyrylcholinesterase (BChE) gene therapy is emerging as a promising concept for treatment of cocaine addiction. BChE levels after gene transfer can rise 1000-fold above those in untreated mice, making this enzyme the second most abundant plasma protein. For months or years, gene transfer of a BChE mutated into a cocaine hydrolase (CocH) can maintain enzyme levels that destroy cocaine within seconds after appearance in the blood stream, allowing little to reach the brain. Rapid enzyme action causes a sharp rise in plasma levels of two cocaine metabolites, benzoic acid (BA) and ecgonine methyl ester (EME), a smooth muscle relaxant that is mildly hypotensive and, at best, only weakly rewarding. The present study, utilizing Balb/c mice, tested reward effects and cardiovascular effects of administering EME and BA together at molar levels equivalent to those generated by a given dose of cocaine. Reward was evaluated by conditioned place preference. In this paradigm, cocaine (20mg/kg) induced a robust positive response but the equivalent combined dose of EME+BA failed to induce either place preference or aversion. Likewise, mice that had undergone gene transfer with mouse CocH (mCocH) showed no place preference or aversion after repeated treatments with a near-lethal 80mg/kg cocaine dose. Furthermore, a single administration of that same high cocaine dose failed to affect blood pressure as measured using the noninvasive tail-cuff method. These observations confirm that the drug metabolites generated after CocH gene transfer therapy are safe even after a dose of cocaine that would ordinarily be lethal.

Saussurea lappa root extract accelerates the reversion of liver fibrosis induced by carbon tetrachloride in rats

Background and aim of work Liver fibrosis is a major health problem associated with high morbidity and mortality, particularly in Egypt. It is mainly regulated by hepatic stellate cells, which acquire a fibrogenic character in response to oxidant stress and inflammatory cytokines. We tried to test the efficacy of Saussurea lappa ( Sl ) root extract on the reversion of the already established liver fibrosis as this extract was reported to have anti-inflammatory and antioxidant activities. Materials and methods A total of 24 albino rats were divided into four groups: negative control group, carbon tetrachloride (CCl 4 ) fibrosis model group, spontaneous resolution group, CCl 4 followed by Sl root extract group. In all rats, serum alanine transaminase, aspartate transaminase, liver malonaldehyde and liver reduced glutathione were measured. Histopathological assessment were carried out through haematoxylin and eosin (H&E), sirius red staining and α-smooth muscle actin immunohistochemical staining with evaluation of the fibrosis grade and percentage of the area occupied by collagen fibres. Results Administration of Sl root extract for 4 weeks, after 8 weeks of CCl 4 injection, caused a significant decrease in CCl 4 -induced rise in plasma levels of alanine transaminase and aspartate transaminase, liver malonaldehyde and the percentage of collagen area and an increase in liver glutathione with almost preserved liver architecture, less inflammatory infiltration, less collagen deposition, fewer thinner septa, less bridging fibrosis and less positive reaction for α-smooth muscle actin as compared with the spontaneous resolution group. Conclusion These data indicate that Sl root extract can accelerate matrix degradation and reversion from liver fibrosis induced by CCl 4 in rats. This might be through antioxidant, anti-inflammatory activities and through inhibition of the activated hepatic stellate cells or probably inducing their apoptosis.

Effects of quercetin on LPS-induced disseminated intravascular coagulation (DIC) in rabbits

IntroductionQuercetin is widely distributed in plants and has been reported to have effects of anti-inflammation and anti-thrombosis. In this study, we evaluated the protective effect of quercetin on LPS-induced experimental DIC in rabbits, and tried to clarify its mechanism against DIC. Materials and MethodsLPS-induced DIC model in rabbits was established through continuous infusion of 100 ug·kg-1·h-1 LPS for a period of 6h. Six groups were divided: quercetin-treated groups (0.5, 1.0, and 2.0mg·kg-1·h-1, respectively), LPS-control group, heparin-control group (100IU·kg-1·h-1), and saline-control group. APTT, PT, and plasma FIB level were measured, the plasma levels of ALT, BUN, and TNF-α were detected, and the activity of Protein C and ATIII was recorded. ResultsA continuous injection of LPS induced a gradual impairment of hemostatic parameters, a rise in plasma level of TNF-α, and damage in renal and hepatic function. The intravenous administration of quercetin significantly attenuated the increase of APTT, PT, ALT, BUN, and TNF-α, and the decrease of plasma FIB level and activity of Protein C and ATIII. ConclusionQuercetin may have a protective effect against LPS-induced DIC in rabbits through anti-inflammation and anticoagulation.

Virtual Histology and the Morphologic Assessment of Cardiac Allograft Vasculopathy

To the Editor: We read with great interest the paper by Arora et al. reporting the results of a12-month multicenter Scandinavian study on the qualitative evaluation of the influence of everolimus on cardiac allograft vasculopathy (CAV) morphology among heart transplant (HTx) recipients with a long follow up of >5 years post-HTx. (1Arora S Erikstad I Ueland T et al.Virtual histology assessment of cardiac allograft vasculopathy following introduction of everolimus—Results of a multicenter trial.Am J Transplant. 2012; 12: 2700-2709Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar). With the use of virtual histology (VH) (2Prasad A Cipher DJ Mohandas A Roesle M Brilakis ES Banerjee S Reproducibility of intravascular ultrasound virtual histology analysis.Cardiovasc Revasc Med. 2008; 9: 71-77Crossref PubMed Scopus (27) Google Scholar,3Hernandez JM de Prada JA Burgos V et al.Virtual histology intravascular ultrasound assessment of cardiac allograft vasculopathy from 1 to 20 years after heart transplantation.J Heart Lung Transplant. 2009; 28: 156-162Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar), the authors revealed a significant increase in calcified and necrotic tissue component in intimal lesions of the everolimus group of HTx patients compared to controls, while the overall plaque volume was not affected at all. Calcified and necrotic components of the plaques were considered by the authors as a result of the inflammatory tissue component of the plaque, and their findings on VH were indeed accompanied by a parallel rise in plasma levels of the markers for endothelial cell activation vWF and VCAM. Intriguing in this study is that the increase in calcified and necrotic components was more prominent in those patients who had a longer time since HTx (>5 years). As recognized also by the authors, CAV lesions are pathologically heterogeneous and can be characterized by a prevalence of fibrous/ fibrocellular pattern or a more atheroma-like pattern. Studies on native atherosclerotic plaques have shown that the cellular microenvironment differs significantly in these two type of lesions and that they can also be affected differently by everolimus (4Li X de Winter RJ van der Wal AC The iatrogenic pathology of percutaneous interventions in coronary arteries.Minerva Medica. 2012; 103: 487-502PubMed Google Scholar). Here, the question comes up whether the results of this study could have been influenced by the specific morphological types of CAV lesions. These were not classified by the authors, but proliferation signal inhibitors (PSIs) could influence one type of lesion more than the other. We have recently evaluated pathologically 70 coronary plaques from heart transplanted pts who died because of CAV (5Castellani C Angelini A de Boer O et al.Intraplaque haemorrhage as a trigger of lesion progression in cardiac allograft vasculopathy.J Heart Lung Transplant. 2012; 31: 5275Abstract Full Text Full Text PDF Google Scholar). With the use of conventional histology and immunohistochemistry, we could identify intraplaque hemorrhages in 60% of CAV lesions, which was even more than the 30.4% of plaque hemorrhages that we observed in the coronary plaques of the same patients in their explanted native heart (p = 0.01). Such intraplaque hemorrhages can be responsible for necrotic core enlargement as was detected in the everolimus treated patients, and this process favors deposition of calcification on the long term. We believe that the lack of reduction of plaque volume in everolimus patients represents not just the inability of the PSI to inhibit the myofibroproliferative response, but can be also attributed to another mechanism of CAV evolution, namely intraplaque hemorrages. Today, we still need pathological evaluation of plaque morphology in patients with CAV. It will be a challenge for in vivo imaging techniques including IVUS to visualize plaque components like inflammation, angiogenesis and hemorrhages, to further unravel the pathophysiological mechanism of PSI in CAV development. The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

As proteínas de relógios e o eixo hipotálamo-hipófise-gonadal de fêmeas de roedores

The components of hypothalamus-pituitary-gonadal axis release their products in a circadian-temporal window; this is crucial for the reproductive success in either spontaneous or inducible ovulators. The preovulatory surge of luteinizing hormone (LH) is preceded by a hypersecretion of the gonadotrophin-releasing hormone (GnRH). In rodents, it is already known that the timed, preovulatory activation of GnRH-secreting neurons depends on a complex interacting neuroendocrine mechanism involving two cyclic signals: an ovarian estradiol rise in plasma levels during the follicular phase of the estrous cycle and a neural signal from the suprachiasmatic nuclei (SCN). Evidences supporting the hypothesis that the hypothalamic-pituitary axis function depends on the integrity of an autoregulatory loop of expression of clock proteins on each of its components are increasing. This review discusses these evidences

Inhibition of immobilization stress-induced anorexia, behavioral deficits, and plasma corticosterone secretion by injected leptin in rats

Leptin, originally identified as an anti-obesity hormone, also has an important role in the regulation of mood and emotion. The present study was designed to monitor effects of injected leptin on immobilization stress-induced anorexia, behavioral deficits, and plasma corticosterone secretion in rats. Exposure to 2 h immobilization stress decreased food intake and body weight in saline-injected animals. Animals exposed to open field, elevated plus maze, and light–dark transition tests the day following immobilization exhibited anxiety-like behavior. Leptin injected at doses of 0.1 and 0.5 mg/kg also decreased food intake and body weight in unstressed animals and elicited anxiolytic effects at dose of 0.5 mg/kg, monitored on the following day. Immobilization-induced decreases in food intake, body weight, as well as stress-induced behavioral deficits in the open field, elevated plus maze, and light–dark transition test were reversed by exogenous leptin in a dose-dependent (0.1–0.5 mg/kg) manner. Acute exposure to 2 h immobilization produced a fourfold rise in plasma levels of corticosterone. Animals injected with leptin at a dose of 0.1 mg/kg, but not at dose of 0.5 mg/kg, exhibited a marginal increase in plasma corticosterone. Immobilization-induced increases of plasma corticosterone were reversed by leptin injected at doses of 0.1 or 0.5 mg/kg. The data suggest that exogenous leptin can reduce stress perception, resulting in an inhibition of stress effects on the activity of hypothalamic-pituitary-adrenal axis and behavior. The reported pharmacological effects of leptin represent an innovative approach for the treatment of stress-related disorders.

Correlation of Peripheral Arterial Blood Flow with Plasma Chemerin and VEGF in Diabetic Peripheral Vascular Disease

Progressive vasodegeneration in microvascular beds is the major underlying factor in initiation and progression of diabetic complications. Chemerin shows a strong correlation with various facets of the metabolic syndrome, which is associated with dysregulated angiogenesis. VEGF is shown to have an angiogenic role in certain cardiovascular risk factors, including diabetes. Ankle/brachial index is a known approach for assessing lower-limb peripheral vascular disease. This study aimed to elucidate the correlation of ankle/brachial index as a marker of peripheral blood flow with biomarkers of angiogenesis, plasma chemerin and VEGF, in diabetic peripheral vascular disease. Ninety age- and sex-matched females were enrolled in the study: 30 were controls, while 60 had Type 2 diabetes, of whom 30 had controlled diabetes (group II) and 30 had diabetes with peripheral vascular disease (group III) diagnosed by an abnormal ankle/brachial index. Plasma levels of chemerin and VEGF were measured. There was a significant decrease of the ankle/brachial index and significant increase in plasma chemerin and VEGF in diabetic patients with peripheral vascular disease (p < 0.05). A positive correlation was observed between ankle/brachial index, plasma chemerin and VEGF in diabetic patients with peripheral vascular disease. Linear regression analysis revealed that neither chemerin nor VEGF were predictors for ankle/brachial index in diabetic peripheral vascular disease. This study elucidates, for the first time, the rise of plasma levels of chemerin and VEGF, and their positive correlation with ankle/brachial index in diabetic peripheral vascular disease. These findings denote their angiogenic effect of improving the peripheral blood flow in diabetic peripheral vascular disease. Further studies are warranted to examine the exact role of these two biomarkers in diabetic vasculopathy.

Tityus zulianus venom induces massive catecholamine release from PC12 cells and in a mouse envenomation model

Scorpion envenomation is a public health problem in Venezuela, mainly produced by Tityus discrepans (TD) and Tityus zulianus (TZ). Accidents by these two species differ clinically. Thus, TZ envenomation is associated with high mortality in children due to cardiopulmonary disorders, as a result of, excessive amounts of plasma catecholamines (Epinephrine) release from adrenal medulla, probably via the voltage-gated sodium-channel activated by specific scorpion toxins. This Epi release is, in part responsible, for some of the envenomation clinical consequences, resembling those described for patients presenting catecholamine-releasing tumors (pheochromocytoma). In this work, BALB/c mice and rat pheochromocytoma-derived PC12 cells were used to provide in vivo and in vitro models, respectively, on which the basis for the TZ-mediated catecholamine release mechanism could be elucidated. In mice, TZ venom increased, at 1h post-injection, the Epi plasma levels in 4000%, which remained elevated for 24h. A significant rise in plasma levels of the catecholamine catabolite 3-Methoxy-4-Hydroxy-Phenyl-Glycol (MHPG) was also observed. In [3H]dopamine-loaded PC12 cells, TZ venom potentiated the carbamylcholine (CC)-mediated release of [3H]dopamine, as shown by the leftward shift in the CC-dose-response curves. Moreover, TZ venom also displayed the maximal [3H]dopamine releasing activity compared to TD venom, with significant reduction of the EC50 for CC. The nicotinic-acetylcholine receptor (nAChR) blocker hexamethonium induced a significant inhibition of the [3H]dopamine release produced by CC in PC12 cells but the TZ-elicited release of [3H]dopamine was 70% hexamethonium-insensitive, suggesting unidentified TZ toxins affecting other regulatory mechanisms of catecholamine secretion.

C-Peptide Ameliorates Kidney Injury Following Hemorrhagic Shock

Reperfusion injury following hemorrhagic shock is accompanied by the development of a systemic inflammatory state that may lead to organ failure. Insulin connecting peptide (C-peptide) has been shown to exert anti-inflammatory effects in sepsis and myocardial ischemia-reperfusion injury and to ameliorate renal dysfunction in diabetic animals. Hence, we investigated the effect of C-peptide on kidney injury after hemorrhagic shock. We hypothesized that C-peptide would exert renoprotective effects by blunting inflammation. Hemorrhagic shock was induced in male rats (3-4 months old) by withdrawing blood from the femoral artery to a mean arterial pressure of 50 mmHg. Animals were kept in shock for 3 h, at which time they were rapidly resuscitated by returning their shed blood. At the time of resuscitation and every hour thereafter, one group of animals received C-peptide (280 nmol/kg), whereas another group received vehicle. Hemorrhagic shock resulted in significant rise in plasma levels of creatinine and elevated kidney neutrophil infiltration as evaluated by myeloperoxidase activity in vehicle-treated rats in comparison with sham rats, thus suggesting kidney injury. Treatment with C-peptide significantly attenuated the rise in creatinine and kidney myeloperoxidase activity when compared with vehicle group. At a molecular level, these effects of C-peptide were associated with reduced expression of the c-Fos subunit and reduced activation of the proinflammatory kinases, extracellular signal-regulated kinase 1/2 (ERK 1/2), and c-Jun N-terminal kinase and subsequently reduced DNA binding of activator protein 1 in the kidney. Thus, our data suggest that C-peptide may exert renoprotective effects after hemorrhagic shock by modulating activator protein 1 signaling.

Antihepatotoxic activity of Saussurea lappa extract on D‐galactosamine and lipopolysaccharide‐induced hepatitis in mice

The effects of aqueous-methanol extract of Saussurea lappa Clarke root (Sl.Cr) was investigated against D-galactosamine (D-GalN) and lipopolysaccharide (LPS)-induced hepatitis in mice. Co-administration of D-GalN (700 mg/kg) and LPS (1 microg/kg) significantly raised the plasma transaminase levels (ALT/AST) as compared to the control group (p < 0.05). Pretreatment of mice with different doses of Sl.Cr (150, 300 and 600 mg/kg) significantly prevented the D-GalN and LPS-induced rise in plasma levels of ALT and AST in a dose-dependent manner (p < 0.05). Post-treatment with Sl.Cr (600 mg/kg) significantly restricted the progression of hepatic damage induced by D-GalN and LPS (p < 0.05). The improvement in plasma enzyme levels was further verified by histopathology of the liver, which showed improved architecture, absence of parenchyma congestion, decreased cellular swelling and apoptotic cells in treatment groups as compared to the toxin group of animals. These data indicate that the Sl.Cr exhibits hepatoprotective effect in mice and this study rationalize the traditional use of this plant in liver disorders.