Biochemical Actions Research Articles

Biosynthesis and molecular actions of specialized 1,4-naphthoquinone natural products produced by horticultural plants.

The 1,4-naphthoquinones (1,4-NQs) are a diverse group of natural products found in every kingdom of life. Plants, including many horticultural species, collectively synthesize hundreds of specialized 1,4-NQs with ecological roles in plant–plant (allelopathy), plant–insect and plant–microbe interactions. Numerous horticultural plants producing 1,4-NQs have also served as sources of traditional medicines for hundreds of years. As a result, horticultural species have been at the forefront of many basic studies conducted to understand the metabolism and function of specialized plant 1,4-NQs. Several 1,4-NQ natural products derived from horticultural plants have also emerged as promising scaffolds for developing new drugs. In this review, the current understanding of the core metabolic pathways leading to plant 1,4-NQs is provided with additional emphasis on downstream natural products originating from horticultural species. An overview on the biochemical mechanisms of action, both from an ecological and pharmacological perspective, of 1,4-NQs derived from horticultural plants is also provided. In addition, future directions for improving basic knowledge about plant 1,4-NQ metabolism are discussed.

Etiology and drug resistance of non-typhi Salmonella in Henan province, 2011-2015

Objective: To analyze the serotypes and antibiotic resistance phenotypes of non-typhi Salmonella strains in Henan province from 2011 to 2015. Methods: The stool samples were collected from diarrhea patients, and enriched with SBG enrichment broth and the pathogen isolation was conducted with CHROMAgar selective culture medium at 37 ℃ for 18-24 hours using KIA/MIU biochemical action and API20E biochemical system slab to identify Salmonella strains. The serotypes of all the positive strains were detected with SSI Salmonella typing sera. According to K-B drug susceptibility testing method published by USA clinical and Laboratory Standards Institute (CLSI), the antibiotics resistant phenotype of the positive strains were analyzed. Results: A total of 1 351 strains of non-typhi Salmonella were isolated, in which 811 were from males, 540 were from females. The ratio of men to women was 1.5∶1. Children and young adults were mainly affected. The pathogen isolation was mainly in May-October during a year. The 1 351 strains of non-typhi Salmonlla were divided into 58 serotypes. S. enteritidis, S. typhimurium, S. agona, S. derby, S. indiana, S. senftenberg and S. thompson ranked 1st-7th. The drug-resistance rate of the 1 351 strains was 46.1% to synthetic broad-spectrum penicillin ampicillin (AMP), 19.5% and 21.2% to the three generation cephalosporin ceftazidime (CAZ) and cefotaxime (CTX), 8.8% to the four generation cephalosporins cefepime (FEP), 58.7% to the one generation of quinolones nalidixic acid (NAL), 14.7% to the three generation fluoroquinolone ciprofloxacin (CIP) and norfloxacin (NOR), 25.0% and 35.6% to aminoglycoside antibiotic gentamicin (GEN) and streptomycin (STR), 35.4% to amphenicols (CHL), 31.7% to sulfonamide trimethoprim (TMP) and 37.8% to tetracycline (TET). Totally 879 strains were multidrug resistant (65.1%): 350 strains were resistant to 3-4 kinds of antibiotics (25.9%), 309 strains were resistant to 5-7 kinds of antibiotics (22.9%), 174 strains were resistant to 8-10 kinds of antibiotics (12.9%) and 48 strains were resistant to 11-12 kinds of antibiotics (3.6%). Conclusion: The serotypes of non-typhi Salmonella strains isolated from Henan province varied, some strains were resistant to 12 kinds of antibiotics commonly used in clinical treatment and the multidrug resistance has become serious.

THE ROLE OF AMPK AND MTOR IN THE DEVELOPMENT OF INSULIN RESISTANCE AND TYPE 2 DIABETES. THE MECHANISM OF METFORMIN ACTION (literature review)

It was analyzed the cellular and molecular links between chronic low-grade inflammation and caused by inflammation insulin resistance and type 2 diabetes. Particular emphasis is placed on the participation of AMPK and mTORC1 in the development of metabolic diseases caused by obesity. A detailed analysis of the biochemical mechanisms of action of the main drug used in the treatment of insulin resistance and type 2 diabetes — metformin.

T-3364366 Targets the Desaturase Domain of Delta-5 Desaturase with Nanomolar Potency and a Multihour Residence Time.

Delta-5 desaturase (D5D) catalyzes the conversion from dihomo-gamma linoleic acid (DGLA) to arachidonic acid (AA). DGLA and AA are common precursors of anti- and pro-inflammatory eicosanoids, respectively, making D5D an attractive drug target for inflammatory-related diseases. Despite several reports on D5D inhibitors, their biochemical mechanisms of action (MOAs) remain poorly understood, primarily due to the difficulty in performing quantitative enzymatic analysis. Herein, we report a radioligand binding assay to overcome this challenge and characterized T-3364366, a thienopyrimidinone D5D inhibitor, by use of the assay. T-3364366 is a reversible, slow-binding inhibitor with a dissociation half-life in excess of 2.0 h. The long residence time was confirmed in cellular washout assays. Domain swapping experiments between D5D and D6D support [(3)H]T-3364366 binding to the desaturase domain of D5D. The present study is the first to demonstrate biochemical MOA of desaturase inhibitors, providing important insight into drug discovery of desaturase enzymes.

Solubility of glycine and DL-nor-valine in aqueous solutions of NaNO3 and KNO3 and measurements of transfer thermodynamics

The solubility and solvation thermodynamics of the amino acids in aqueous solutions are related to their biochemical and biophysical actions in human physiology. This makes such studies to be highly relevant for academia, health and industry. In the present work solubilities of glycine and DL-nor-valine were measured under different experimental conditions by an analytical gravimetric method in aqueous NaNO3 and KNO3 solutions and the results were employed as an input in theoretical solvation investigations. Thermodynamic parameters like standard transfers Gibbs energies and entropies and other important physicochemical parameters such as molar volume, density, dipole moment, mixed solvent diameter, etc., of the experimental solutions were evaluated at 298.15K and compared with earlier values. Finally the above mentioned parameters were used to conclude ΔGt,ch0(i) i.e. chemical effects of the transfer Gibbs energies and ΤΔSt,ch0(i) i.e. chemical effects of the transfer entropy. Different factors such as nature of solute and solvent, interactions between solute and solvents, etc., which are influencing the solvation of glycine and DL-nor-valine were also characterized by different physical and analytical techniques.

IN-SILICO PRELIMINARY DOCKING SCREENING OF SOME ANTI-ALZHEIMER DRUGS

Alzheimer’s disease is an irreversible, progressive brain disease that slowly destroys cognition function. It is neurodegenerative disease & most common kind of dementia. The main purpose of this work is to perform preliminary docking screening & estimate toxic properties of some anti-Alzheimer's drugs through computational software. To assess toxic properties of some anti-Alzheimer’s drugs, through Lipinski rule of five. Drug-likeness and toxic properties of selective drugs were determined by employing Osiris server. To calculate the biological activity spectrum through prediction of activity spectra for a drug which provide intrinsic property that correspond to different pharmacological effects, physiological and biochemical mechanisms of action. The OSIRIS toxicity predictions resulted for toxicity, cLogP value, drug likeness and drug-score of each molecular imprint. These findings are relevant for the exploration of drug action of any compound of Anti- Alzheimer’s drug using both animal models and in silico strategies.

The etiological and molecular typing research of diarrheagenic Escherichia coli in Henan province in 2013

To analyze the distribution and pulsed field gel electrophoresis (PFGE) patterns of five kinds of diarrheagenic Escherichia coli (DEC) in infected diarrhea population of Henan province in 2013. Gathering 1 037 strains of E. coli of 1 037 diarrhea patients from four sentinel hospitals of multi-pathogen monitoring system in Henan province in 2013. Stool samples were cultured with Mac agar plates and using KIA/MIU biochemical action as the preliminary method to identify E. coli strains; preparation of DNA template with thermal cracking method and using multiplex PCR to detect five kinds of DEC. According to molecular typing method published by the international PulseNet bacterial infectious disease monitoring network, the PFGE molecular characteristics of DEC strains were analyzed. 125 DEC positive strains were detected in 1 037 strains of E. coli, the total detection rate was 12.05%. 90 strains were enteroaggregative E.coli (EAEC), detection rate was 8.68% (n=90); 24 strains were enteropathogenic E.coli (EPEC), detection rate was 2.31%; 7 strains were enteroinvasive E.coli (EIEC), detection rate was 0.68%; 4 strains were enterotoxigenic E.coli (ETEC), detection rate was 0.39%; enterohemorrhagic E.coli (EHEC) was not detected. 639 cases of diarrhea samples were collected from male patients, 398 cases were from female patients, 94 positive cases were from male patients, the detection rate was 14.71%.The positive number of female cases were 31 cases, the detection rate was 7.79%. 97 positive cases were detected from 782 countryside cases and 28 positive cases were detected from 255 urban area cases, with detection rate 12.40% and 10.98% respectively. In 125 cases of DEC positive samples, children below 5 years old were 83 cases, accounting for 66.4%; 53 strains of EAEC were divided into 52 molecular patterns by digestion with XbaⅠ and pulsed field gel electrophoresis, each pattern contained 1-2 strains with similarity ranged from 66.3%-100%; 18 strains of EPEC were divided into 18 molecular patterns, each pattern contains 1 strain with similarity ranged from 72.6%-94.8%; 5 strains of EIEC were divided into 5 molecular patterns, each pattern contains 1 strain with similarity ranged from 71.9%-98.5%. 2 strains of ETEC were divided into 2 molecular patterns and similarity below 70%. Through the research we could find that four kinds of DEC as a pathogenic bacteria took an important component in pathogenic spectrum of bacterial diarrhea of Henan province in 2013. Four kinds of DEC carrying different virulence genes and taking multiple PFGE patterns showed diversity and complexity characteristics.

Mode of action of triflumezopyrim: A novel mesoionic insecticide which inhibits the nicotinic acetylcholine receptor

Triflumezopyrim, a newly commercialized molecule from DuPont Crop Protection, belongs to the novel class of mesoionic insecticides. This study characterizes the biochemical and physiological action of this novel insecticide. Using membranes from the aphid, Myzus persicae, triflumezopyrim was found to displace 3H-imidacloprid with a Ki value of 43 nM with competitive binding results indicating that triflumezopyrim binds to the orthosteric site of the nicotinic acetylcholine receptor (nAChR). In voltage clamp studies using dissociated Periplaneta americana neurons, triflumezopyrim inhibits nAChR currents with an IC50 of 0.6 nM. Activation of nAChR currents was minimal and required concentrations ≥100 μM. Xenopus oocytes expressing chimeric nAChRs (Drosophila α2/chick β2) showed similar inhibitory effects from triflumezopyrim. In P. americana neurons, co-application experiments with acetylcholine reveal the inhibitory action of triflumezopyrim to be rapid and prolonged in nature. Such physiological action is distinct from other insecticides in IRAC Group 4 in which the toxicological mode of action is attributed to nAChR agonism.Mesoionic insecticides act via inhibition of the orthosteric binding site of the nAChR despite previous beliefs that such action would translate to poor insect control. Triflumezopyrim is the first commercialized insecticide from this class and provides outstanding control of hoppers, including the brown planthopper, Nilaparvata lugens, which is already displaying strong resistance to neonicotinoids such as imidacloprid.

Surveillance on the etiology and molecular epidemiology of Shigella sonnei isolated in Henan province from 2011 to 2014

To detect and analyze the distribution of virulence factors, antimicrobial resistance and pulsed field gel electrophoresis (PFGE) patterns of Shigella sonnei, isolated in Henan province from 2011 to 2014. Samples of diarrhea patients were collected and isolated with SS selective culture medium in 37 ℃ for 18-24 hours. All strains were identified under the Kligler iron agar/motility-indol-urea biochemical action and API20E biochemical system. Serological typing and prepared DNA template were carried out with thermal cracking method and multiplex PCR, to detect the virulence genes of Shigella sonnei. According to the molecular typing method and K-B drug susceptibility testing method published by the international PulseNet bacterial infectious disease monitoring network and USA clinical and Laboratory Standards Institute, antimicrobial susceptibility tests and PFGE molecular characteristics of these positive strains isolated from sentinel hospitals patients stool samples were analyzed. Among the 98 strains of Sonnei type Ⅰ and 118 strains of Sonnei type Ⅱ, all the strains carried carry different virulence genes including SHET-1B, SHET-2, ial, ipaH genes, with 4 kinds of virulence gene combination types. All the 216 strains of Shigella sonnei belonged to the multi-drug resistant strains, including 34 isolates resistant to 2-4 kinds of antibiotics(15.7%), 147 isolates to 5-8 kinds of antibiotics (68.1%), 24 to 9-10 kinds of antibiotics (11.1%), 7 to 11 kinds of antibiotics (3.2%), and 4 to 13 kinds of antibiotics (1.9%). A total of 100 strains of Shigella sonnei were divided into 31 molecular patterns, digested by XbaⅠ and PFGE. Each pattern contained 1-13 strains with similarities ranged from 68.6%-100.0%. All the Shigella sonnei strains carried virulence pathogenic factors, presenting serious status on drug resistance. PFGE fingerprinting patterns showed high polymorphism and dominant characteristics. PFGE patterns of partial strains and corresponding antidrug spectrum presented certain relevance and with same aggregation relationship.

Rhodiola rosea L. as a putative botanical antidepressant

BackgroundRhodiola rosea (R. rosea) is a botanical adaptogen with putative anti-stress and antidepressant properties. Evidence-based data supporting the effectiveness of R. rosea for depression in adults is limited, and therefore a comprehensive review of available animal and human studies suggesting a putative antidepressant action is warranted. PurposeA review of the literature was undertaken to ascertain studies of possible antidepressant mechanisms of action and studies of the safety and effectiveness of R. rosea extracts in animals and adult humans. MethodsA search of MEDLINE and the Russian state library database was conducted (up to October 2015) on R. rosea. ResultsMechanism of action: R. rosea extracts and its purified constituent, salidroside, has been shown to produce a variety of mediator interactions with several molecular networks of neuroendocrine-immune and neurotransmitter receptor systems likely to be involved in the pathophysiology of depression. A wide variety of preclinical in vivo and ex vivo studies with laboratory animals suggests the presence of several biochemical and pharmacological antidepressant-like actions. EffectivenessClinical assessment of R. rosea L. rhizome extracts in humans with various depressive syndromes is based upon results from two randomized, double-blind, placebo-controlled trials of 146 subjects with major depressive disorder and seven open-label studies totaling 714 individuals with stress-induced mild depression (diagnosed as asthenic syndrome or psychoneurosis). Overall, results of these studies suggests a possible antidepressant action for R. rosea extract in adult humans. SafetyIn contrast to most conventional antidepressants, R. rosea extract appears to be well-tolerated in short-term studies with a favorable safety profile. ConclusionsR. rosea demonstrates multi-target effects on various levels of the regulation of cell response to stress, affecting various components of the neuroendocrine, neurotransmitter receptor and molecular networks associated with possible beneficial effects on mood.

Thermodynamic Study on the Protonation Reactions of Glyphosate in Aqueous Solution: Potentiometry, Calorimetry and NMR spectroscopy.

Glyphosate [N-(phosphonomethyl)glycine] has been described as the ideal herbicide because of its unique properties. There is some conflicting information concerning the structures and conformations involved in the protonation process of glyphosate. Protonation may influence the chemical and physical properties of glyphosate, modifying its structure and the chemical processes in which it is involved. To better understand the species in solution associated with changes in pH, thermodynamic study (potentiometry, calorimetry and NMR spectroscopy) about the protonation pathway of glyphosate is performed. Experimental results confirmed that the order of successive protonation sites of totally deprotonated glyphosate is phosphonate oxygen, amino nitrogen, and finally carboxylate oxygen. This trend is in agreement with the most recent theoretical work in the literature on the subject (J. Phys. Chem. A 2015, 119, 5241-5249). The result is important because it confirms that the protonated site of glyphosate in pH range 7-8, is not on the amino but on the phosphonate group instead. This corrected information can improve the understanding of the glyphosate chemical and biochemical action.

FRET analysis using sperm-activating peptides tagged with fluorescent proteins reveals that ligand-binding sites exist as clusters.

Long-range cellular communication between the sperm and egg is critical for external fertilization. Sperm-activating peptides (SAPs) are diffusible components of the outer layer of eggs in echinoderms, and function as chemoattractants for spermatozoa. The decapeptide named speract is the best-characterized sea urchin SAP. Biochemical and physiological actions of speract have been studied with purified or chemically synthesized peptides. In this work, we prepared recombinant speract fused to a fluorescent protein (FP; FP-speract) using three color variants: a cyan (eCFP), a yellow (mVenus) and a large Stokes shift yellow (mAmetrine) FP. Although these fluorescence tags are 20 times larger than speract, competitive binding experiments using mAmetrine-speract revealed that this FP-speract has binding affinity to the receptor that is comparable (7.6-fold less) to that of non-labeled speract. Indeed, 10 nmol l(-1) eCFP-speract induces physiological sperm responses such as membrane potential changes and increases in intracellular pH and Ca(2+) concentrations similar to those triggered by 10 nmol l(-1) speract. Furthermore, FP-speract maintains its fluorescence upon binding to its receptor. Using this property, we performed fluorescence resonance energy transfer (FRET) measurements with eCFP-speract and mVenus-speract as probes and obtained a positive FRET signal upon binding to the receptor, which suggests that the speract receptor exists as an oligomer, at least as a dimer, or alternatively that a single speract receptor protein possesses multiple binding sites. This property could partially account for the positive and/or negative cooperative binding of speract to the receptor.

Mechanical Signaling in the Pathophysiology of Critical Illness Myopathy.

The complete loss of mechanical stimuli of skeletal muscles, i.e., the loss of external strain, related to weight bearing, and internal strain, related to the contraction of muscle cells, is uniquely observed in pharmacologically paralyzed or deeply sedated mechanically ventilated intensive care unit (ICU) patients. The preferential loss of myosin and myosin associated proteins in limb and trunk muscles is a significant characteristic of critical illness myopathy (CIM) which separates CIM from other types of acquired muscle weaknesses in ICU patients. Mechanical silencing is an important factor triggering CIM. Microgravity or ground based microgravity models form the basis of research on the effect of muscle unloading-reloading, but the mechanisms and effects may differ from the ICU conditions. In order to understand how mechanical tension regulates muscle mass, it is critical to know how muscles sense mechanical information and convert stimulus to intracellular biochemical actions and changes in gene expression, a process called cellular mechanotransduction. In adult skeletal muscles and muscle fibers, this process may differ, the same stimulus can cause divergent response and the same fiber type may undergo opposite changes in different muscles. Skeletal muscle contains multiple types of mechano-sensors and numerous structures that can be affected differently and hence respond differently in distinct muscles.

The role of acupuncture in managing overactive bladder; a review of the literature.

Overactive bladder (OAB) affects a considerable proportion of men and women in the United States and is associated with significant costs and quality of life (QoL) reduction. While medication remains a mainstay of treatment, there is increasing interest in the use of alternative medicine in the form of acupuncture. We reviewed the literature on the role of acupuncture in managing OAB. A narrative review was compiled after searching electronic databases (PubMed, MEDLINE, Scopus, and EMBASE) for clinical studies involving acupuncture in treating OAB. Databases were searched from the time of inception through September 2015 by a clinician for articles reporting the results related to the use of acupuncture in OAB. Key search terms were acupuncture, overactive bladder, bladder instability, urgency, urinary incontinence. Articles in English or translated into English were included. Initial animal studies suggest several biochemical mechanisms of action underlying the effect of acupuncture on OAB suppression. The experience in humans includes two case series and six comparative trials. All studies demonstrated subjective improvement in OAB symptoms, and some reported objective improvement in urodynamic studies. Notably, some comparative trials showed the benefit of acupuncture to be comparable with antimuscarinic treatment. Despite their limitations, existing studies serve as a promising foundation for suggesting a role for acupuncture as an alternative therapy for OAB. Further well-designed studies are required to investigate optimal technique and their outcomes.

Kinetically Defined Mechanisms and Positions of Action of Two New Modulators of Glucocorticoid Receptor-regulated Gene Induction

Most of the steps in, and many of the factors contributing to, glucocorticoid receptor (GR)-regulated gene induction are currently unknown. A competition assay, based on a validated chemical kinetic model of steroid hormone action, is now used to identify two new factors (BRD4 and negative elongation factor (NELF)-E) and to define their sites and mechanisms of action. BRD4 is a kinase involved in numerous initial steps of gene induction. Consistent with its complicated biochemistry, BRD4 is shown to alter both the maximal activity (Amax) and the steroid concentration required for half-maximal induction (EC50) of GR-mediated gene expression by acting at a minimum of three different kinetically defined steps. The action at two of these steps is dependent on BRD4 concentration, whereas the third step requires the association of BRD4 with P-TEFb. BRD4 is also found to bind to NELF-E, a component of the NELF complex. Unexpectedly, NELF-E modifies GR induction in a manner that is independent of the NELF complex. Several of the kinetically defined steps of BRD4 in this study are proposed to be related to its known biochemical actions. However, novel actions of BRD4 and of NELF-E in GR-controlled gene induction have been uncovered. The model-based competition assay is also unique in being able to order, for the first time, the sites of action of the various reaction components: GR < Cdk9 < BRD4 ≤ induced gene < NELF-E. This ability to order factor actions will assist efforts to reduce the side effects of steroid treatments.

Preliminary Study on the Antibacterial Activity of Six Medicinal Plants against Two Naso-Pharyngeal Pathogens—&amp;lt;i&amp;gt;Streptococccus pyogenes&amp;lt;/i&amp;gt; and &amp;lt;i&amp;gt;Pseudomonas aeruginosa&amp;lt;/i&amp;gt;

Objective: The objective is to study the antibacterial activity of six medicinal plants against two naso-pharyngeal pathogens and determination of total phenol contents in ethanol extracts of those plants. Methods: Different serial concentrations (0.05 g/mL, 0.1 g/mL, 0.2 g/mL, 0.4 g/mL) of ethanolic and acetone extracts of Piper nigrum L. (Piperaceae), Ocimum sanctum Linn., Plectranthus amboinicus L. (Lamiaceae), Ayapana triplinervis M.Vahl. (Asteraceae), Cinnamomum zeylanicum L. (Lauraceae), Allium schoenoprasum Linn. (Liliaceace) were evaluated for the antibacterial activity using disc diffusion method against gram positive Streptococcus pyogenes and gram negative Pseudomonas aeruginosa. The extracts were prepared from different parts of the plants. The total phenol content was estimated using folin-ciocaltau reagent in catechol equivalents. Results: Majority of the extracts had inhibitory effect against the tested bacteria at different concentrations. In ethanol extracts, Plectranthus amboinicus exhibited the maximum zone of inhibition (14 mm) at 0.05 g/mL concentration against Streptococcus pyogenes, and Ocimum sanctum showed highest zone of bacterial inhibition (19 mm) at 0.05 g concentration against Pseudomonas aeruginosa. In acetone extracts, Piper nigrum had the maximum zone of bacterial inhibition (17 mm) in 0.4 g/mL concentration against Streptococcus pyogenes and Cinnamomum zeylanicum and Allium schoenoprasum exhibited the highest zone of bacterial inhibition (0.4 g/mL) against Pseudomonas aeruginosa. The ethanol extract of Plectranthus amboinicus contained the highest amount of phenol (0.8 mg/mL) and Allium schoenoprasum contained the lowest amount (0.62 mg/mL). In acetone, Cinnamomum zeylanicum contained highest phenol content (0.78 mg/mL). Conclusion: All these investigations pave way to the molecular modeling of the lead phyto compounds present in the studied plants, and also in finding out their biochemical action in various metabolic pathways and reactions of infection.

Homocysteine, hyperhomocysteinemia and vascular contributions to cognitive impairment and dementia (VCID)

Homocysteine is produced physiologically in all cells, and is present in plasma of healthy individuals (plasma [HCy]: 3–10μM). While rare genetic mutations (CBS, MTHFR) cause severe hyperhomocysteinemia ([HCy]: 100–200μM), mild-moderate hyperhomocysteinemia ([HCy]: 10–100μM) is common in older people, and is an independent risk factor for stroke and cognitive impairment. As B-vitamin supplementation (B6, B12 and folate) has well-validated homocysteine-lowering efficacy, this may be a readily-modifiable risk factor in vascular contributions to cognitive impairment and dementia (VCID).Here we review the biochemical and cellular actions of HCy related to VCID. Neuronal actions of HCy were at concentrations above the clinically-relevant range. Effects of HCy <100μM were primarily vascular, including myocyte proliferation, vessel wall fibrosis, impaired nitric oxide signalling, superoxide generation and pro-coagulant actions. HCy-lowering clinical trials relevant to VCID are discussed. Extensive clinical and preclinical data support HCy as a mediator for VCID. In our view further trials of combined B-vitamin supplementation are called for, incorporating lessons from previous trials and from recent experimental work. To maximise likelihood of treatment effect, a future trial should: supply a high-dose, combination supplement (B6, B12 and folate); target the at-risk age range; and target cohorts with low baseline B-vitamin status. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock.

Bridging progestogens in pregnancy and pregnancy prevention.

Steroid hormones have been in use for more than a half a century as contraceptive agents, and only now are researchers elucidating the biochemical mechanisms of action and non-target effects. Progesterone and synthetic progestins, critical for women's health in the US and internationally, appear to have important effects on immune functioning and other diverse systems. Apart from the contraceptive world is a separate field that is devoted to understanding progesterone in other contexts. Based on research following a development timeline parallel to hormonal contraception, progesterone and 17-hydroxyprogesterone caproate are now administered to prevent preterm birth in high-risk pregnant women. Preterm birth researchers are similarly working to determine the precise biochemical actions and immunological effects of progesterone. Progesterone research in both areas could benefit from increased collaboration and bringing these two bodies of literature together. Progesterone, through actions on various hormone receptors, has lifelong importance in different organ systems and researchers have much to learn about this molecule from the combination of existing literatures, and from future studies that build on this combined knowledge base.

Effect of adipose derived nucleated cell fractions with chitosan biodegradable film on wound healing in rats

Abstract Wound healing is the interaction of a complex event in cellular and biochemical actions ending up the reestablishment of structural and functional integrity of injured tissues. In this study the effect of combination of adipose derived nucleated cell fractions (ADNCs) and chitosan film was evaluated on full thickness wounds. For excisional wound healing model twenty-four male white Wistar rats were randomized into four groups of 6 rats each: control group (CG) including creation of wounds and no treatment, ADNC group including creation of wounds and application of 1 mL ADNCs, chitosan group (CHIT) including dressing the wound with chitosan and CHIT/ADNC group including application of 1 mL ADNCs and dressing the wound with chitosan. Wound size was measured on 6, 9, 12, 15, 18 and 21 days after surgery. For incisional wound healing model twenty-four healthy male Wistar rats were randomized into four groups of 6 rats each the same way in excisional wound model. Reduction in wound area, hydroxyproline contents and biomechanical parameters indicated that there was significant difference (P > 0.05) between CHIT/ADNC group and other groups. Biomechanical testing was performed 9 days after surgery in incisional model. Quantitative histological studies and mean rank of the qualitative studies demonstrated that there was significant difference (P > 0.05) between CHIT/ADNC group and other groups. ADNCs can provide a readily accessible source of cells in large quantities that contribute to wound healing in the emerging field of regenerative medicine especially where a traumatic injury is dealt with. ADNCs with chitosan have beneficial effects on wounds repair and could be suggested for treating various types of wounds in animals and human being.

Exploring the Molecular Interactions of 7,8-Dihydroxyflavone and Its Derivatives with TrkB and VEGFR2 Proteins.

7,8-Dihydroxyflavone (7,8-DHF) is a TrkB receptor agonist, and treatment with this flavonoid derivative brings about an enhanced TrkB phosphorylation and promotes downstream cellular signalling. Flavonoids are also known to exert an inhibitory effect on the vascular endothelial growth factor receptor (VEGFR) family of tyrosine kinase receptors. VEGFR2 is one of the important receptors involved in the regulation of vasculogenesis and angiogenesis and has also been implicated to exhibit various neuroprotective roles. Its upregulation and uncontrolled activity is associated with a range of pathological conditions such as age-related macular degeneration and various proliferative disorders. In this study, we investigated molecular interactions of 7,8-DHF and its derivatives with both the TrkB receptor as well as VEGFR2. Using a combination of molecular docking and computational mapping tools involving molecular dynamics approaches we have elucidated additional residues and binding energies involved in 7,8-DHF interactions with the TrkB Ig2 domain and VEGFR2. Our investigations have revealed for the first time that 7,8-DHF has dual biochemical action and its treatment may have divergent effects on the TrkB via its extracellular Ig2 domain and on the VEGFR2 receptor through the intracellular kinase domain. Contrary to its agonistic effects on the TrkB receptor, 7,8-DHF was found to downregulate VEGFR2 phosphorylation both in 661W photoreceptor cells and in retinal tissue.