Tonic Effect Research Articles

Processing of dairy raw materials in healthy food products

The object of research is whey-based beverages. The most problematic areas are the limited shelf life of beverages and the risk of product stratification during storage.In the course of the study, whey pasteurization regimes are used: 84±2 °C, waiting time 15–20 s, so the shelf life of beverages is limited, since sterilization of whey beverages is impossible due to loss of biologically active substances. To prevent delamination of the beverages during the storage of the formulation, pectin is added and an additional operation – homogenization is introduced.Whey beverages with functional properties for individuals controlling body weight are obtained with improvement of organoleptic characteristics of the product. The resulting beverage is suitable, as a result of the introduction of plant components, to improve the metabolism in the body, block the synthesis of fat in adipose tissue, reduce the absorption of carbohydrates and fats in the digestive tract and remove excess fluid, accelerate the cleavage of fat molecules and transform fat into free energy. This is confirmed by the activation of pancreatic lipase. The activity of pancreatic lipase increases in 3.8...4.0 times in comparison with the control (whey).Components of the whey, as the basis of beverages, have low energy value and high biological value. L-carnitine, α-lipoic acid, stevia, gingerol and bromelain stimulate the breakdown of fats. Cinnamon increases metabolism in the body. This helps to accelerate the breakdown of fat.To increase the nutritional value and biological activity to the beverages, the introduction of fruit and berry juices (lemon, cranberry, orange, pumpkin, yostaberry juice). Biologically active substances of juices show antisclerotic, antistress, tonic, immunostimulating, antioxidant effect. Antisclerotic action of juices is associated with the antioxidant properties of vitamins C, E, β-carotene. Juices reduce the oxidation degree of the most dangerous fraction of lipoproteins, thereby slowing the growth process of atherosclerotic plaques in the vessels. Antistress, tonic, immunostimulating and antioxidant effects of juices are due to the content of polysaccharides, sulfur-containing proteins, minerals, vitamins A, E, C, group B, bioflavonoids.Whey beverages for people who control body weight are not toxic, their frequent consumption does not lead to addiction. Beverages do not contain substances prohibited by the Ministry of Health of Ukraine. Shelf life of beverages is 14 days. Beverages can be made on traditional equipment using traditional technology.

Involvement of arginine 878 together with Ca2+ in mouse aminopeptidase A substrate specificity for N-terminal acidic amino-acid residues.

Aminopeptidase A (APA) is a membrane-bound zinc metalloprotease cleaving, in the brain, the N-terminal aspartyl residue of angiotensin II to generate angiotensin III, which exerts a tonic stimulatory effect on the control of blood pressure in hypertensive animals. Using a refined APA structure derived from the human APA crystal structure, we docked the specific and selective APA inhibitor, EC33 in the presence of Ca2+. We report the presence in the S1 subsite of Arg-887 (Arg-878 in mouse APA), the guanidinium moiety of which established an interaction with the electronegative sulfonate group of EC33. Mutagenic replacement of Arg-878 with an alanine or a lysine residue decreased the affinity of the recombinant enzymes for the acidic substrate, α-L-glutamyl-β-naphthylamide, with a slight decrease in substrate hydrolysis velocity either with or without Ca2+. In the absence of Ca2+, the mutations modified the substrate specificity of APA for the acidic substrate, the mutated enzymes hydrolyzing more efficiently basic and neutral substrates, although the addition of Ca2+ partially restored the acidic substrate specificity. The analysis of the 3D models of the Arg-878 mutated APAs revealed a change in the volume of the S1 subsite, which may impair the binding and/or the optimal positioning of the substrate in the active site as well as its hydrolysis. These findings demonstrate the key role of Arg-878 together with Ca2 + in APA substrate specificity for N-terminal acidic amino acid residues by ensuring the optimal positioning of acidic substrates during catalysis.

Membrane Receptor-Induced Changes of the Protein Kinases A and C Activity May Play a Leading Role in Promoting Developmental Synapse Elimination at the Neuromuscular Junction.

Synapses that are overproduced during histogenesis in the nervous system are eventually lost and connectivity is refined. Membrane receptor signaling leads to activity-dependent mutual influence and competition between axons directly or with the involvement of the postsynaptic cell and the associated glial cell/s. Presynaptic muscarinic acetylcholine (ACh) receptors (subtypes mAChR; M1, M2 and M4), adenosine receptors (AR; A1 and A2A) and the tropomyosin-related kinase B receptor (TrkB), among others, all cooperate in synapse elimination. Between these receptors there are several synergistic, antagonic and modulatory relations that clearly affect synapse elimination. Metabotropic receptors converge in a limited repertoire of intracellular effector kinases, particularly serine protein kinases A and C (PKA and PKC), to phosphorylate protein targets and bring about structural and functional changes leading to axon loss. In most cells A1, M1 and TrkB operate mainly by stimulating PKC whereas A2A, M2 and M4 inhibit PKA. We hypothesize that a membrane receptor-induced shifting in the protein kinases A and C activity (inhibition of PKA and/or stimulation of PKC) in some nerve endings may play an important role in promoting developmental synapse elimination at the neuromuscular junction (NMJ). This hypothesis is supported by: (i) the tonic effect (shown by using selective inhibitors) of several membrane receptors that accelerates axon loss between postnatal days P5–P9; (ii) the synergistic, antagonic and modulatory effects (shown by paired inhibition) of the receptors on axonal loss; (iii) the fact that the coupling of these receptors activates/inhibits the intracellular serine kinases; and (iv) the increase of the PKA activity, the reduction of the PKC activity or, in most cases, both situations simultaneously that presumably occurs in all the situations of singly and paired inhibition of the mAChR, AR and TrkB receptors. The use of transgenic animals and various combinations of selective and specific PKA and PKC inhibitors could help to elucidate the role of these kinases in synapse maturation.

Phthalide Derivatives from Angelica Sinensis Decrease Hemoglobin Oxygen Affinity: A New Allosteric-Modulating Mechanism and Potential Use as 2,3-BPG Functional Substitutes

Angelica sinensis (AS), one of the most versatile herbal medicines remains widely used due to its multi-faceted pharmacologic activities. Besides its traditional use as the blood-nourishing tonic, its anti-hypertensive, anti-cardiovascular, neuroprotective and anti-cancer effects have been reported. Albeit the significant therapeutic effects, how AS exerts such diverse efficacies from the molecular level remains elusive. Here we investigate the influences of AS and four representative phthalide derivatives from AS on the structure and function of hemoglobin (Hb). From the spectroscopy and oxygen equilibrium experiments, we show that AS and the chosen phthalides inhibited the oxygenated Hb from transforming into the high-affinity “relaxed” (R) state, decreasing Hb’s oxygen affinity. It reveals that phthalides cooperate with the endogenous Hb modulator, 2,3-bisphosphoglycerate (2,3-BPG) to synergetically regulate Hb allostery. From the docking modeling, phthalides appear to interact with Hb mainly through its α1/α2 interface, likely strengthening four (out of six) Hb “tense” (T) state stabilizing salt-bridges. A new allosteric-modulating mechanism is proposed to rationalize the capacity of phthalides to facilitate Hb oxygen transport, which may be inherently correlated with the therapeutic activities of AS. The potential of phthalides to serve as 2,3-BPG substitutes/supplements and their implications in the systemic biology and preventive medicine are discussed.

Differential tonic inhibition and ethanol effects in the central and lateral amygdala corticotropin releasing factor receptor 1 (CRF1) circuitry

Differential tonic inhibition and ethanol effects in the central and lateral amygdala corticotropin releasing factor receptor 1 (CRF1) circuitry

Chronic, complete cervical6‐7 cord injury: distinct autonomic, cardiac and vascular deficits

Spinal cord injury (SCI) resulting in tetraplegia is a devastating, life‐changing injury causing paralysis and sensory impairment as well as autonomic dysfunction that triggers compromised cardiovascular, bowel, bladder and sexual activity. Life becomes a battle for independence as even routine bodily functions and the smallest activity of daily living become a major challenge. The human physiology, mind and spirit are wonderfully adaptable as individuals with tetraplegia find ways to adjust. However, addressing autonomic losses and cardiovascular consequences would greatly improve the quality of life for individuals living with tetraplegia. Virtually all pre‐clinical investigations of autonomic losses and cardiovascular consequences following SCI induce lesions in the thoracic region. However, cervical lesions produce distinct autonomic, cardiac and vascular deficits and result in the most dramatic autonomic outcomes and cardiovascular consequences. Specifically, although cardiovascular disease (CVD) is the leading cause of morbidity and mortality for individuals living with SCI, the magnitude of CVD risk is dependent on the level of SCI, whereby individuals with tetraplegia have a 16% greater risk of all‐cause CVD than individuals with paraplegia. Accordingly, there is a critical need for a chronic pre‐clinical model of tetraplegia. In this report, we compare resting cardiac sympathetic and parasympathetic tonus, reflex sympathetic effects (heart rate responses to sodium nitroprusside), tonic autonomic effects (responses to autonomic ganglionic blockade), cardiac responses to beta‐adrenergic stimulation and the response to angiotensin‐converting enzyme inhibition in 6 rats with chronic (4 week) complete C6‐7 transection and 6 intact sham‐transected rats. Histological examination of the heart and stellate ganglia support the profound and distinct autonomic and cardiac deficits and reliance on angiotensin to maintain cardiovascular stability following chronic, complete cervical6‐7 cord transection.Support or Funding InformationR01HL122223

Local enema treatment to inhibit FOLH1/GCPII as a novel therapy for inflammatory bowel disease

Here we evaluate the potential for local administration of a small molecule FOLH1/GCPII inhibitor 2-phosphonomethyl pentanedioic acid (2-PMPA) as a novel treatment for inflammatory bowel disease (IBD). We found that FOLH1/GCPII enzyme activity was increased in the colorectal tissues of mice with TNBS-induced colitis, and confirmed that 2-PMPA inhibited FOLH1/GCPII enzyme activity ex vivo. In order to maximize local enema delivery of 2-PMPA, we studied the effect of vehicle tonicity on the absorption of 2-PMPA in the colon. Local administration of 2-PMPA in a hypotonic enema vehicle resulted in increased colorectal tissue absorption at 30min compared to 2-PMPA administered in an isotonic enema vehicle. Furthermore, local delivery of 2-PMPA in hypotonic enema vehicle resulted in prolonged drug concentrations for at least 24h with minimal systemic exposure. Finally, daily treatment with the hypotonic 2-PMPA enema ameliorated macroscopic and microscopic symptoms of IBD in the TNBS-induced colitis mouse model, indicating the potential of FOLH1/GCPII inhibitors for the local treatment of IBD.

The Immune Effects of an African Traditional Energy Tonic in In Vitro and In Vivo Models.

Most of the African traditional medicines (ATM) are formulated as energy tonics to boost and maintain immune defences. In this study, we aimed to evaluate the immune effects of a traditional energy tonic using peripheral blood mononuclear cells (PBMCs), THP-1 monocytes, and bacteria infected rats. When tested in mitogen and peptidoglycan stimulated PBMCs, this energy tonic showed minimal cytotoxicity, while in acute toxicity studies in rats it did not exhibit any significant toxicity at doses up to 2000 mg/mL/kg. The energy tonic doses between 100 and 10 μg/mL were shown to stimulate secretion of cytokines and increase sIL-2R levels in PHA-treated PBMCs. Similar doses in PG-S. aureus-stimulated PBMCs significantly (p < 0.05) increased IL-1α, IL-2, and GM-CSF while causing a significant (p < 0.05) decrease in sIL-2R levels. NF-κβ transcriptional activity was increased in LPS stimulated THP-1 cells. In Sprague Dawley rats pretreated with the energy tonic and then infected with S. aureus, there were insignificant increases in cytokines and sIL-2R when compared to bacteria infected only and 5% Enrofloxacin treated rats. Posttreatment with energy tonic doses after infection with S. aureus did not enhance inflammatory cytokines significantly but changed the immune response profile and decreased corticosterone levels. This ATM showed promising immunomodulatory effects on isolated immune cells and modulated the immune response of rat models infected with S. aureus.

P-ВІТАМІННА АКТИВНІСТЬ ГРИБНОГО ПОРОШКУ ШИЇТАКЕ

Urgency of the research. One of the priority issues facing the modern institutions of the restaurant business is the creation of fundamentally new technologies, wide and comprehensive application of high quality foods, which have a health improving impact on the human body.In this context, using herbal ingredients which are rich in flavonoids (vitamin P) and have powerful antioxidant effects on the human body and tonic effect on the blood circulatory system is promising for the creation of health improving foodstuffs.Target setting. To use shiitake mushrooms in the health improving food technology, it is necessary to conduct researches aimed at detecting vitamin P activity in the domestic shiitake powder.Actual scientific researches and issues analysis. Over the past few decades more than hundreds various researches regarding food and therapeutic properties of the higher fungi including shiitake mushrooms have been conducted in Japan, China, the United States and the United Kingdom of Great Britain.Uninvestigated parts of general matters defining. In spite of a great number of studies on the chemical composition of shiitake mushrooms and their powders, there is a lack of data on the qualitative and quantitative flavonoid content in the powders produced from the shiitake mushrooms grown in Ukraine.The research objective. The thesis covers the results of the efficient detection of the flavonoid substances in the powders produced from the shiitake mushrooms grown in Ukraine.The statement of basic materials. The extraction of shiitake mushroom powder (Lentinus edodes) and further study on its ability to cause the vitamin P activity have been conducted. The ethanol extracts of shiitake mushrooms cultivated in Ukraine are found to contain phenolic compounds. When 70% aqueous solution of ethanol is used as an extractant, the output of of the extractive substance is twice as much as when 96% ethanol is used. 70% ethanol extract contains phenolic compounds which have the similar structure as flavonoid quercetinConclusions. The powder of shiitake mushrooms grown in Ukraine contains flavonoid substances, similar to quercetin, so it is capable of the vitamin P activity, which makes it a promising ingredient to create new health improving foodstuffs.

ИСПОЛЬЗОВАНИЕ ЧАЙНЫХ НАПИТКОВ АНТИОКСИДАНТНОЙ НАПРАВЛЕННОСТИ ДЛЯ ПРЕДУПРЕЖДЕНИЯ РАЗВИТИЯ СТРЕССОВЫХ РЕАКЦИЙ

The article is devoted to the proof of preventing the development of stress reactions due to consumption of antioxidant tea beverages, on the basis of experimental research of the intensity of lipid peroxidation in three groups of albino male rats of Wistar line weighing 180–200 g. Components of tea drinks were selected as per their pharmacological action, contributing to prevention of oxidative stress, as well as having a tonic (multivitamin) effect and high consumer properties. Ingredients for the formulation of tea drinks were selected using methods of linear programming, including functional orientation matrix. Intensity index of lipid peroxidation indicates the presence of inhibitory effects of tea drinks medicinal-technical raw materials on the processes of lipid peroxidation. It was revealed that the amount of MDA in the blood plasma of rats increased by 27.8 % as compared to the control group. The content of diethenoid-conjugates products of peroxidation in blood plasma of rats of the second group was 46.9 % higher when compared to the intact group of animals. Thus, introduction of antioxidants in the organisms of rats in the form of tea stabilizes the free-radicals oxidation of lipids during adaptation to stress. Stabilization of the processes of peroxidation can be explained by the chemical composition of the tea beverage: flavonoids (miqueliana, quercetin, kaempferol-3-O-glucuronide, afcelin, luteolin-7-glycoside, rutin, quercetin), organic acids, vitamin C; trace elements: selenium, zinc, iron. Flavonoids enhance the activity oxireductases and anti-peroxide enzymes. Trace elements – zinc, copper, iron are part of antioxidant enzymes.

Sustained Activity of Metabotropic Glutamate Receptor: Homer, Arrestin, and Beyond.

When activated, metabotropic glutamate receptors (mGlus) exert long-lasting changes within the glutamatergic synapses. One mechanism is a tonic effect of downstream signal transduction pathways via sustained activation of mGlu itself. Like many other G protein-coupled receptors (GPCRs), mGlu can exist in a constitutively active state, which persists agonist independently. In this paper, we review the current knowledge of the mechanisms underlying the constitutive activity of group I mGlus. The issues concerning Homer1a mechanism in the constitutive activity of group I mGlus and recent findings regarding the significant role of β-arrestin in sustained GPCR activity are also discussed. We propose that once in a state of sustained activation, the mGlu persistently activates downstream signaling pathways, including various adaptor proteins and kinases, such as β-arrestin and mitogen-activated protein kinases. In turn, these effector molecules bind to or phosphorylate the mGlu C-terminal binding domains and consequently regulate the activation state of the mGlu.

ранняя диагностика нарушений регуляции гемодинамики в ортостазе

The article deals with the informative content of spectral analysis of heart rate variability in the assessment of the regulatory impacts on the systemic hemodynamics during orthostatic test. It was observed that the patients who suffer from neurogenic syncope already at a young age had had a decrease in low frequency oscillations, as well as a decrease in peripheral vascular resistance during the test. It allows us to make a conclusion about the sympathetic vasomotor regulation dysfunction, even before the symptoms of orthostatic hypotension were evident. The decrease in the tonic vagal effect which follows from the depression of high-frequency oscillations, makes for increasing the chronotropic function of the heart and keeps a relative sympathetic predominance in order to maintain adequate level of blood pressure

Direct Comparison of In Vivo Fate of Second and Third-Generation CD19-Specific Chimeric Antigen Receptor (CAR)-T Cells in Patients with B-Cell Lymphoma: Reversal of Toxicity from Tonic Signaling

Although adoptive transfer of T cells with second-generation CD19-specific CARs containing CD28 or 4-1BB costimulatory endodomains shows remarkable clinical efficacy against B cell malignancies, the optimal choice of costimulatory domains in these and other CARs remains controversial. Depending on the precise CAR structure and specificity, individual endodomains may be associated with deleterious ligand-independent tonic signaling in the transduced T cell. Long et al. (Nat Med 2015) established the CD28 co-stimulatory endodomain can have a toxic tonic signaling effect, but it is unclear if tonic 4-1BB signaling may have deleterious consequences as well, and if such effects can be reversed.We therefore modeled tonic CAR signaling in T cells by transducing them with gammaretroviral vectors expressing 2nd-generation CD19.CAR constructs containing either the CD28 or 4-1BB costimulatory endodomain (in addition to the CD3-ζ chain endodomain). Compared to CAR-T cells with the CD28 endodomain alone, those with 4-1BB alone expanded 70% more slowly following transduction. Impaired expansion of 4-1BB CD19.CAR-T cells was coupled with a 4-fold increase in apoptosis and a gradual downregulation of CAR expression, and was a consequence of 4-1BB-associated tonic TRAF2-dependent signaling, leading to activation of NF-κB, upregulation of Fas and augmented Fas-dependent activation-induced T cell death (AICD). Moreover, expression of 4-1BB CAR from a gammaretroviral vector increased tonic signaling through a self-amplifying/positive feedback effect on the retroviral LTR promoter.Because of the toxicity of 4-1BB in our gammaretroviral CAR.CD19 construct (manifest by delayed expansion and increased apoptosis) we could not directly compare the in vivo fate of T cells expressing CAR.CD19 4-1BB with that of co-administered CAR.CD19 CD28 T cells in patients with lymphoma. We found, however, that the adverse effects of tonic 4-1BB costimulation could be overcome in a 3rd-generation CAR.CD19 vector, containing both CD28 and 4-1BB costimulatory molecules in tandem.We thus compared the fate of a 3rd-generation vector containing both CD28 and 4-1BB costimulatory domains with that of a 2nd-generation vector containing CD28 alone. Six patients with refractory/relapsed diffuse large B-cell lymphoma received 2 cell populations, one expressing 2nd and one expressing 3rd generation vectors. To determine whether CD28 alone was optimal (which would suggest 4-1BB is antagonistic) or whether 4-1BB had an additive or synergistic effect contributing to superior persistence and expansion of the CD28-41BB combination, patients were simultaneously infused with 1-20×106 of both 2nd and 3rd generation CAR+ T cells/m2 48-72 hours after lymphodepletion with cyclophosphamide (500 mg/m2/d) and fludarabine (30 mg/m2/d) × 3. Persistence of infused T cells was assessed in blood by CD19.CAR qPCR assays specific for each CAR. Molecular signals peaked approximately 2 weeks post infusion, remaining detectable for up to 6 months. The 3rd-generation CAR-T cells had a mean 23-fold (range 1.1 to 109-fold) higher expansion than 2nd-generation CAR-T cells and correspondingly longer persistence. Two patients had grade 2 cytokine release syndrome, with elevation of proinflammatory cytokines, including IL-6, at the time of peak expansion of T cells. Of the 5 patients evaluable for response, 2 entered complete remission (the longest ongoing for 9 months), 1 has had continued complete remission after autologous stem cell transplantation, 1 had a partial response, and 1 progressed.In conclusion, our data indicate that infusion of T cells carrying a CD19.CAR containing CD28 and 4-1BB endodomains is safe and can have efficacy at every dose level tested. Additionally, in a side-by-side comparison, the 3rdgeneration vector produced greater in vivo expansion and persistence than an otherwise identical CAR-T cell population with CD28 alone. DisclosuresRooney:Cell Medica: Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties; Viracyte: Equity Ownership. Heslop:Celgene: Patents & Royalties, Research Funding; Chimerix: Other: Endpoint adjudication committee; Viracyte: Equity Ownership; Cell Medica: Patents & Royalties: Licensing agreement EBV-specific T cells.

Liqustri lucidi Fructus inhibits hepatic injury and functions as an antioxidant by activation of AMP-activated protein kinase in vivo and in vitro

Medicinal herbs are used to treat or prevent various diseases, and function to regulate protective mechanisms as nutraceuticals. Fructus Ligustri lucidi is the fruit of Ligustrum lucidum and has been used for its tonic effects on the liver. This study was designed to examine the effects of Fructus Ligustri lucidi water extract (FLL) against severe oxidative stress and mitochondrial impairment in vivo and in vitro and to elucidate its cellular mechanisms of action. Treatment of HepG2 cells with arachidonic acid (AA) + iron successfully induced oxidative stress and apoptosis, as indicated by depletion of glutathione, formation of ROS, decreses in mitochondrial membrane potential (Δψm), and altered expression of apoptosis-related proteins, such as procaspase-3 and Bcl-xL. FLL treatment significantly blocked these pathological changes and the mitochondrial dysfunction caused by AA + iron, which were similar with the effect of aminoimidazole-carboxamide-β-d-ribofuranoside (AICAR). Moreover, FLL induced the activation of AMP-activated protein kinase (AMPK), which was mediated by its upstream kinase LKB1. Inhibition or activation of AMPK revealed the role of AMPK in cellular protection conferred by FLL in LKB1-deficient cells. In mice, oral administration of 100 mg/kg FLL activated AMPK in the liver, and protected against oxidative stress and liver injury induced by CCl4 injection. Among the components of FLL, chlorogenic acid was found to be responsible for the protection of hepatocytes against AA + iron-induced cellular damage. Overall, our results confirmed that FLL has the ability to protect hepatocytes against oxidative injury through regulation of the AMPK signaling pathway.

Neonatal Propofol and Etomidate Exposure Enhance Inhibitory Synaptic Transmission in Hippocampal Cornus Ammonis 1 Pyramidal Neurons.

Background:Propofol and etomidate are the most important intravenous general anesthetics in the current clinical use and that mediate gamma-aminobutyric acid's (GABAergic) synaptic transmission. However, their long-term effects on GABAergic synaptic transmission induced by neonatal propofol or etomidate exposure remain unclear. We investigated the long-term GABAergic neurotransmission alterations, following neonatal propofol and etomidate administration.Methods:Sprague-Dawley rat pups at postnatal days 4–6 were underwent 6-h-long propofol-induced or 5-h-long etomidate-induced anesthesia. We performed whole-cell patch-clamp recording from pyramidal cells in the cornus ammonis 1 area of acute hippocampal slices of postnatal 80–90 days. Spontaneous and miniature inhibitory GABAergic currents (spontaneous inhibitory postsynaptic currents [sIPSCs] and miniature inhibitory postsynaptic currents [mIPSCs]) and their kinetic characters were measured. The glutamatergic tonic effect on inhibitory transmission and the effect of bumetanide on neonatal propofol exposure were also examined.Results:Neonatal propofol exposure significantly increased the frequency of mIPSCs (from 1.87 ± 0.35 Hz to 3.43 ± 0.51 Hz, P < 0.05) and did not affect the amplitude of mIPSCs and sIPSCs. Both propofol and etomidate slowed the decay time of mIPSCs kinetics (168.39 ± 27.91 ms and 267.02 ± 100.08 ms vs. 68.18 ± 12.43 ms; P < 0.05). Bumetanide significantly blocked the frequency increase and reversed the kinetic alteration of mIPSCs induced by neonatal propofol exposure (3.01 ± 0.45 Hz and 94.30 ± 32.56 ms).Conclusions:Neonatal propofol and etomidate exposure has long-term effects on inhibitory GABAergic transmission. Propofol might act at pre- and post-synaptic GABA receptor A (GABAA) receptors within GABAergic synapses and impairs the glutamatergic tonic input to GABAergic synapses; etomidate might act at the postsynaptic site.

Sulfur fumigation reducing systemic exposure of ginsenosides and weakening immunomodulatory activity of ginseng

Ethnopharmacological relevanceGinseng (Ginseng Radix et Rhizoma) is used worldwide for its miracle tonic effects, especially for its immunomodulatory activities. Sulfur fumigation, a fast and convenient method to prevent pesticidal and bacterial contamination in the food industry, has been recently employed during post-harvest processing of ginseng. Our previous studies demonstrated that sulfur fumigation significantly altered the chemical profile of the bioactive ingredients in ginseng. However, the effects of sulfur fumigation on the pharmacokinetics and bioactivities of ginseng remain unknown. Aim of the studyTo examine the effects of sulfur fumigation on the pharmacokinetics and immunomodulatory activities of ginseng. Materials and methodsFor pharmacokinetic studies, male Sprague-Dawley rats exposed to single/multiple dosages of non-fumigated ginseng (NFG) and sulfur fumigated ginseng (SFG) were investigated using HPLC-MS/MS analysis. For bioactivity studies, male ICR mice were used to compare the immunomodulatory effects of NFG or SFG under both normal and cyclophosphamide (CY)-induced immunocompromised conditions using white blood cell counts, serum cytokine levels, and spleen and thymus weight indices. ResultsSulfur fumigation significantly reduced the contents of the bioactive ginsenosides in ginseng, which resulted in drastically low systemic exposure of ginsenosides in SFG-treatment group compared to NFG-treatment group. This observation was consistent with the bioactivities obtained in NFG- and SFG-treatment groups. The bioactivity studies also demonstrated the immunomodulatory effects of NFG but not SFG in the CY-induced immunosuppressed mice. ConclusionSulfur fumigation significantly reduced contents of bioactive ginsenosides in ginseng, leading to dramatic decrease in the systemic exposure of these ginsenosides in the body and detrimental reduction of immunomodulatory effects of ginseng. Our results provided scientific evidences and laid a solid foundation for the needs of thorough evaluation of the significant impact of sulfur fumigation on ginseng and other medicinal herbs.

ДОСЛІДЖЕННЯ АНАТОМІЧНОЇ БУДОВИ НАДЗЕМНИХ ОРГАНІВ PRIMULA JULIAE KUSN

Вперше здійснено дослідження особливостей анатомічної будови надземних органів первоцвіту (примули) Юлії родини первоцвіті, в результаті якого виявлено їх характерні мікроскопічні діагностичні ознаки. Встановлені мікродіагностичні ознаки дають можливість ідентифікувати лікарську рослинну сировину і можуть бути використані для розробки проекту АНД.

Evaluation of the Antimalarial Effect of Ferulago angulata (Schlecht.) Boiss. Extract and Suberosin Epoxide Against Plasmodium berghei in Comparison with Chloroquine Using in-vivo Test.

Resistance to most antimalarial drugs has encouraged the development of novel drugs. An alternative source for discovering such drugs is natural products. Some Ferulago species are used in folk medicine for their sedative, tonic and anti-parasitic effects. Besides, coumarins isolated from this genus found to have in vitro anti-leishmanicidal effect. The present study is aimed to evaluate the in-vivo antimalarial activity of Ferulago angulata (Schlecht.) Boiss. extract and suberosin epoxide, using suarian mice. A rodent malaria parasite, Plasmodium berghei was used to inoculate healthy male Swiss Albino mice of age 6-8 weeks and weight 23-27 g. Hydro-alcoholic extract of F. angulata (20, 100, 300, 600 mg/Kg) and suberosin epoxide suspension (10, 30, 50, 100 mg/Kg) were administered subcutaneously. Parameters including percentage of parasitemia, suppression of parasitemia and mean survival time were determined using standard test such as peter٬s. Chemo-protective effects were exerted by the crude extract and suberosin epoxide. Maximum effect was observed with the larger doses of the crude extract and suberosin epoxide. Suberosin epoxide increased the survival time compared to chloroquine. However, the results of this study indicate that the plant has a promising anti-plasmodial activity against plasmodium berghei. Thus, it could be considered as a potential source of new antimalarial agents. Suberosin epoxide at the dose of 100 mg/Kg possesses relatively significant antimalarial effect. Chemical derivatization of the parent compound or preparation of the modified formulation is required to improve its systemic bioavailability.

Intraindividual and Interindividual Differences in Spontaneous Eye Blinking: Relationships to Working Memory Performance and Frontal EEG Asymmetry.

The rate and timing of spontaneous eye blinking (SB) may be used to explore mechanisms of cognitive activity in infancy. In particular, SB rate is believed to reflect some dimensions of dopamine function; therefore, we hypothesized that SB rate would relate to working memory performance and to frontal electroencephalogram (EEG) asymmetry. Forty, 10-mo-old infants completed an A-not-B task while SB and EEG were measured throughout. We found that SB rate varied across phases of the task, variability in SB rate was positively related to working memory performance, and frontal EEG asymmetry was related to individual differences in the rate of SB. Results provide indirect, but convergent support for the hypothesis that SB rate reflects dopamine function early in human development. As such, these results have implications for understanding the tonic and phasic effects of dopamine on cognitive activity early in human development.

MPS 18-01 MODE OF ACTION OF RB150, AN AMINOPEPTIDASE A INHIBITOR PRODRUG AS A CENTRALLY-ACTING ANTIHYPERTENSIVE AGENT IN DOCA-SALT HYPERTENSIVE RATS

Objective: In the brain, angiotensin III (AngIII) generated from angiotensin II (AngII) by aminopeptidase A (APA) exerts a tonic stimulatory action on the control of blood pressure (BP) in hypertensive rats. Inhibition of brain APA by RB150, an orally active prodrug of the specific and selective APA inhibitor, blocks brain AngIII formation and normalizes BP in hypertensive rats. Since following blockade of brain AngIII formation by RB150, no AngII accumulation was observed, we aimed to delineate if this treatment induces the activation of another metabolic pathway of brain AngII, in particular angiotensin converting enzyme type 2 (ACE2) which converts AngII into angiotensin 1–7 (Ang1–7). Design and Method: For this purpose, RB150 and MLN4760, an ACE2 inhibitor, were administered by intracerebroventricular (ICV) route after insertion of an intracerebral cannula to alert DOCA-salt rats, a model of salt-dependent hypertension. Mean arterial blood pressure (MABP) was recorded via an arterial femoral catheter. Maximal MABP decrease and area under the curve (AUC) of the variations in MABP were calculated. Results: ICV administration of RB150 (100 μg) significantly decreased MABP compared to vehicle (−23 ± 3 mmHg vs −6 ± 2 mmHg; AUC: 17.6 ± 2 vs 2.1 ± 3). Administration of MLN4760 (10 μg) didn’t induce any significant change of MABP compared to vehicle (−10 ± 3 mmHg; AUC: 1.4 ± 2). Co-administration of MLN4760 (10 μg) with RB150 (100 μg) partially inhibits RB150-induced BP decrease. Conclusions: In conclusion, ICV administration of the ACE2 inhibitor alone has no effect on BP indicating that in DOCA-salt rats, brain Ang1–7 does not exert a tonic stimulatory effect on the control of BP. However, when conversion of brain AngII into AngIII is blocked by RB150, there is an activation of the conversion by ACE2 of brain AngII into Ang1–7, which by acting on the Mas receptor, may participate to the RB150-induced BP decrease in hypertensive rats.