Chemistry

Non-small cell lung carcinomas (NSCLC) are the predominant form of lung malignancy and the reason for the highest number of cancer-related deaths. Widespread deregulation of Akt, a serine/ threonine kinase, has been reported in NSCLC. Allosteric Akt inhibitors bind in the space separating the Pleckstrin homology (PH) and catalytic domains, typically with tryptophan residue (Trp-80). This could decrease the regulatory site phosphorylation by stabilizing the PH-in conformation. Hence, in this study, a computational investigation was undertaken to identify allosteric Akt-1 inhibitors from FDA-approved drugs. The molecules were docked at standard precision (SP) and extra-precision (XP), followed by Prime molecular mechanics-generalized Born surface area (MM-GBSA), and molecular dynamics (MD) simulations on selected hits. Post XP-docking, fourteen best hits were identified from a library of 2115 optimized FDA-approved compounds, demonstrating several beneficial interactions such as pi-pi stacking, pi-cation, direct, and water-bridged hydrogen bonds with the crucial residues (Trp-80 and Tyr-272) and several amino acid residues in the allosteric ligand-binding pocket of Akt-1. Subsequent MD simulations to verify the stability of chosen drugs to the Akt-1 allosteric site showed valganciclovir, dasatinib, indacaterol, and novobiocin to have high stability. Further, predictions for possible biological interactions were performed using computational tools such as ProTox-II, CLC-Pred, and PASSOnline. The shortlisted drugs open a new class of allosteric Akt-1 inhibitors for the therapy of NSCLC. Primary bronchogenic carcinoma, widely recognized as lung cancer, is a deadly tumour originating from the respiratory mucosa or respiratory glands 1 . According to the latest GLOBOCAN estimates, globally, lung cancer is the leading cancer cause in terms of incidence and mortality, with roughly 1.8 million new deaths (11.4%) and 2.2 million new diagnoses (18%), representing a severe health hazard. The number of new cases and deaths tends to rise every year 2 . Lung malignancies are predominantly non-small cell lung cancer (NSCLC), with nearly 85% of patients falling into this subtype, scategorized as adenocarcinoma (LUAD), squamous cell carcinoma (LUSC), and large cell carcinoma 3 . Despite advances, there was no significant reduction in incidence and mortality rates. Cancer cells spreads and metastasize relatively faster in NSCLC; most diagnoses happen near the late stages. The average 5-year survival rate in NSCLC is ~ 15%, the lowest of all cancer types, and hence there is a need for finding novel robust therapies for the disease 4 . The serine/threonine kinase Akt, better known as protein kinase B, forms the phosphoinositide 3-kinase (PI3K) effector in the PI3K-Akt-mTOR signaling cascade 5 . This pathway intersects multiple signaling, and Akt forms a vital intermediary in cell survival mediated through growth factors 6 . Several oncologic proteins and tumour suppressor genes interconnect with the Akt pathway and contribute to cell size/growth, proliferation, and survival 7 . Three Akt isoforms are recognised, namely Akt-1/PKBα, Akt-2/PKBβ, and Akt-3/PKBγ, having a similar structure 8 . Dysregulation of this kinase plays a pivotal role in the onset and progression of several human cancers 9 . In NSCLC, the Akt-1 subtype plays a critical role in cell growth and migration and has been recognized widely as an anti-cancer target 10 . Akt isoforms have an N-terminal Pleckstrin homology (PH) ___domain, which is

ically active molecules is the ultimate destination in pharmaceutical research and development. Most drugs discovered are lipophilic and, hence, exhibit poor aqueous solubility, resulting in low bioavailability. Thus, there is a need to use various solubility enhancement techniques. Computational approaches enable the analysis of drug-carrier interactions or the numerous conformational changes in the carrier matrix that might establish an appropriate balance between cohesive and adhesive stability in a formulation. In this review, we discuss research approaches that provided molecular insight into drugs and their modifiers to unravel their solubility, stability, and bioavailability. Quantitative structure-activity relationship Quantitative structure-activity relationship (QSAR) models are important tools for drug discovery. Using QSAR, the physical and chemical properties of molecules can be quantitatively Reviews

The Akt pathway plays an important role in cell metabolism, growth, proliferation, and survival. Akt is the central protein whose phosphorylation controls many downstream pathways. In many diseases like Alzheimer's, Parkinson, and diabetes, there is downregulation of the Akt pathway. It is proven that the binding of small molecules to the PH ___domain of Akt facilitates its phosphorylation in the cytoplasm. In the current study, to identify Akt activators, ligand-based approaches like ngerprint-based 2D-QSAR, shape, and pharmacophore-based screening were used, followed by structure-based approaches like docking, MM-GBSA, ADME prediction, and MD simulation. Using the 2D-QSAR activity of the Asinex gold platinum database was predicted, and the top twenty-ve molecules found to be active using most models were selected for shapebased and pharmacophore-based screening. Later docking was performed using the PH ___domain of Akt1

Inflammation is a defensive response against invasion by foreign bodies, which need to be treated with safer molecules such as phytomolecules like caffeic acid (CA). This work aimed to formulate and evaluate topical cream with CA-loaded nanostructured lipid carriers (NLCs) for anti-inflammatory action. CA-loaded NLCs were formulated by solvent diffusion method followed by preparation of NLCs loaded cream which was evaluated and characterized for various parameters including in-vitro release behavior and in-vivo acute anti-inflammatory effect in carrageenaninduced rat paw edema wistar rats model. The CA-loaded NLCs showed good results for particle size, polydispersity index (PDI), zeta potential, and encapsulation efficiency, while 0.5% w/w cream had a significant anti-inflammatory effect when tested for the acute study. Furthermore, skin-irritation study was carried out on wistar rats and it was observed that the formulated creams did not produce any signs of irritation, edema, and erythema compared to the positive control group (0.9% v/v formalin group). Therefore, formulated NLCs loaded cream can be used as a safe and efficient acute anti-inflammatory agent and considered an alternative treatment strategy to existing formulations.

Background and significance-The A 2B adenosine receptor (A 2B AR) is the predominant adenosine receptor expressed in the colonic epithelia. We have previously shown that A 2B AR mRNA and protein levels are upregulated during colitis. In this study we addressed the role of the A 2B AR in the development of murine colitis and potential mechanism underlying its effects. Methods-Dextran sodium sulfate (DSS), 2,4,6-trinitrobenzene sulfonic acid (TNBS) and Salmonella typhimurium were used to induce colitis in A 2B AR null mice (A 2B AR -/-). Colitis was determined using established clinical and histological scoring. keratinocyte derived chemokine (KC) measurements were performed using ELISA. Results-Colonic inflammation induced by DSS, TNBS or S. typhimurium was attenuated in A 2B AR -/-compared to their WT counterparts. Clinical features, histological score, myeloperoxidase activity were significantly decreased in A 2B AR -/-mice. However, A 2B AR -/-showed increased susceptibility to systemic Salmonella infection. Tissue levels of the neutrophil chemokine, KC was decreased in colitic A 2B AR -/-mice. In addition, flagellin-induced KC levels were attenuated in A 2B AR -/-mice. Neutrophil chemotaxis in response to exogenous IL-8 was preserved in A 2B AR -/-mice, suggesting intact neutrophil migration in response to appropriate stimuli. Conclusions-These data demonstrate, for the first time, that the A 2B AR plays a pro-inflammatory role in colitis. A 2B receptor antagonism may be an effective treatment for acute inflammatory intestinal diseases such as acute flare of inflammatory bowel disease.

Karanda (Carissa carandas L.) is mostly eaten raw and contains numerous phytochemicals and high antioxidant capacity. The objective of this study was to investigate the effects of the Karanda fruit's developmental stages on its phytochemical contents, antioxidant capacity, and volatile compounds. The study herein examined three developmental stages; unripe, semi-ripe, and ripe, based on their stage of maturity as observed in their color and texture. Phytochemical properties; including pH, titratable acidity, vitamin C contents, total soluble solid, total phenolic contents, total flavonoid content, anthocyanin contents, and antioxidant capacity (determined through FRAP, DPPH, and ABTS) were measured. Our results found significant differences in the phytochemical properties in each stage of development. Ripe fruits had the highest pH, total soluble solid, anthocyanin content, and antioxidant capacity determined by FRAP. Thirteen volatile compounds were identified in the fruit samples: eight compounds within the unripe fruits, nine within the semi-ripe fruits, and seven compounds were present in the fully ripe fruits. Alanine ethyl amide and acetic acid were major volatile compounds found in unripe and semi-ripe fruits, whereas tartronic acid was present in the fully ripe fruit. We may conclude that the ripe stage of development, having the highest phytochemical contents and antioxidant activity, is most suitable for harvest and most beneficial for human health. The information obtained in this study will be useful for the efficient utilization of Karanda fruit.

Al 2 O 3 :Si,Ti is a sensitive thermoluminescent phosphor. ESR studies have been carried out in order to study the characteristics of the defect centers and the TL peaks observed in this phosphor. Two types of ESR centers (center I and center II) have been identified in Al 2 O 3 :Si,Ti. Center I is characteristic of a species exhibiting an isotropic g-value 2.0096 with a line width of 50 G. Center II is also characterized by an isotropic g-value 1.9526 with a line width of about 40 G. Thermal decay of center I shows three different annealing stages in the temperature ranges 125.225 • C, 430.525 • C and 600.680 • C, which indicates correlation between center I and TL peaks at 175, 475 and 625 • C, respectively. Decay of center II in the region 600.700 • C appears to relate with the TL peak around 625 • C.

BACKGROUND: Optically pure acetoin is an important potential pharmaceutical intermediate. It has also been widely used to synthesize novel optically active α-hydroxyketone derivatives and liquid crystal composites. Recombinant Escherichia coli was developed for efficient (3R)-acetoin production. Culture medium optimization and process control were carried out to improve (3R)-acetoin yield by the engineered strain. RESULTS: A synthetic pathway involved the budRAB genes from Serratia marcescens and NADH oxidase gene from Lactobacillus brevis in E. coli was developed for efficient (3R)-acetoin production. Batch culture showed that 23.4 g L -1 of (3R)-acetoin could be obtained from 60 g L -1 glucose by the engineered strain. Chiral-column GC analysis indicated that the stereoisomeric purity of (3R)-acetoin produced was 97.3%. Further, the medium composition was optimized in shake flasks by an orthogonal design method. Under optimal conditions, (3R)-acetoin concentration reached 38.3 g L -1 in flask fermentation. Fed-batch fermentation based on a suitable agitation speed was carried out in a 5 L bioreactor, and maximum (3R)-acetoin concentration of 60.3 g L -1 was achieved with a productivity of 1.55 g L -1 h -1 and yield 86.3%. CONCLUSION: An engineering E. coli for efficient (3R)-acetoin production was constructed. The optimization of fermentation variables and fed-batch culture resulted in a maximum (3R)-acetoin concentration of 60.3 g L -1 .

This report presents that Deferiprone, the only clinically used 3-hydroxypyridin-4-one (HPO), is able to penetrate the blood-brain barrier (BBB) in guinea pigs, whereas its glucosylated analogue is unable to do so. This finding is contrary to published information suggesting that the glucosylation of HPOs is a viable means of enhancing the brain uptake of this group of compounds.

Neurodegenerative disorders include a variety of pathological conditions, which share similar critical metabolic processes such as protein aggregation and oxidative stress, both of which are associated with the involvement of metal ions. Chelation therapy could provide a valuable therapeutic approach to such disease states, since metals, particularly iron, are realistic pharmacological targets for the rational design of new therapeutic agents.

The Trier social stress test (TSST) is one of the most reliable and widely used laboratory tests for evaluating the physiological stress response. We developed a virtual reality-based TSST (VR-TSST) and investigated the physiological responses to this test in patients with psychosis and healthy controls (HCs). Methods The participants comprised 60 patients with psychosis and 66 HCs. The VR-TSST consisted of three scenarios: a resting phase (baseline; 2 min), a job interview (5 min), and a mental arithmetic task (5 min). Blood cortisol levels were measured at baseline, during the test, and at 5-10 min and 30 min after the test. The skin conductance level, heart rate, and RR intervals were measured at baseline, during the job interview, and during the arithmetic task. The VR-TSST produced no discernible cortisol response in patients with psychosis compared to the HCs. However, a higher skin conductance level and heart rate and shorter RR intervals were found in the patients than in the HCs at baseline, during the job interview, and during the arithmetic task. Conclusion These findings suggest that the current version of the VR-TSST induces stronger autonomic and cardiovascular, but not endocrine, responses in patients with psychosis than in HCs. The VR-TSST could be a valuable tool to evaluate or train the stress response in patients with psychosis.

h i g h l i g h t s g r a p h i c a l a b s t r a c t Chloramine decaying Protein (CDP) existed in chloraminated system. Chloramine dosing in chloraminated reactor induced the production of CDP. Both bulk water and suspended biomass from chloraminated reactor contained CDP. Short term chloramine stress further induced CDP production in biomass. In the absence of chloramine, in ammoniated reactor, CDP gradually disappeared.

The interaction between an Al 2 O 3 colloid and c-sapphire surface (0 0 0 1) was investigated in an aqueous solution containing citrate ion, Cl -, NO 3 -or Br -using the colloidal probe method. The force curve measured in electrolyte solutions at pH = 4 showed a good agreement with the force curve predicted by the Derjaguin-Landau-Vervey-Overbeek theory at a long separation distance. The repulsive forces were observed at a shorter separation distance. The order of the strength of the repulsive force was citrate ion > Cl -> NO 3 -> Br -, corresponding to the Hofmeister series. All the force curves measured in aqueous solutions at pH = 10 were the same. This is caused by the cation (K + ) selectively affecting surface interaction because the Al 2 O 3 surface charged to negative at this pH. A particle size distribution measurement of the Al 2 O 3 colloids in the 0.001-0.1 mol/L Cl -and Br -aqueous solution was carried out. The agglomerates of the Al 2 O 3 colloids were observed in 0.1 mol/L Br -solutions. However, Al 2 O 3 colloids were well dispersed in the other aqueous solutions, which are reflected by the force curve results. Jump-in was observed only in the force curve measured in the 0.1 mol/L Br -solutions and not in any other solutions.

ObjectivesAlthough platelet‐rich plasma (PRP) has been proposed as a therapeutic tool to enhance wound repair, the cellular and molecular mechanisms stimulated by this agent are still not completely understood. The present study was designed to characterize the effects of PRP and platelet‐poor plasma (PPP) supernatants on cell responses involved in gingival tissue repair.MethodsWe studied the response of human gingival fibroblasts (HGF) to PRP and PPP fractions on: matrix contraction, cell migration, myofibroblastic differentiation, production of matrix components and proteolytic enzymes. PRP and PPP were obtained from donors using a commercial kit. Matrix contraction was evaluated by means of collagen lattices in the presence of matrix metalloproteinase (MMP) and actin polymerization inhibitors. The production of matrix molecules and proteinases was assessed through Western‐blot. RhoA activity was evaluated through a pull‐down assay. Actin distribution and focal adhesions were asse...

Adiponectin (APN) is a crucial regulator for many inflammatory processes, but its effect on Th cell-mediated responses has not been fully understood. Thus, we investigated the immune-modulatory effects of APN on dendritic cells (DCs) controlling Th cell polarization. APN induced maturation and activation of DCs, as demonstrated by the increased expression of MHC class II, costimulatory molecules in both mouse and human DCs, and it significantly enhanced production of proinflammatory cytokines. APN triggered degradation of IkB proteins, nuclear translocation of NF-kB p65 subunit, and phosphorylation of MAPKs in DCs. Pretreatment with a phospholipase C (PLC)g inhibitor and a JNK inhibitor suppressed IL-12 production and NF-kB binding activity. Additionally, PLCg inhibitor downregulated phosphorylation of JNK, indicating that PLCg and JNK may be upstream molecules of NF-kB. Importantly, APN-treated DCs significantly induced both Th1 and Th17 responses in allogeneic CD4 + T cells. The addition of a neutralizing anti-IL-12 mAb to the cocultures abolished the secretion of IFN-g, whereas the blockage of IL-23 and IL-1b suppressed APN-induced IL-17 production. Immunization of mice with OVA-pulsed, APN-treated DCs efficiently led to Ag-specific Th1 and Th17 cell responses. Taken together, these results demonstrated that APN effectively induced activation of DCs through PLCg/JNK/NF-kB-signaling pathways, leading to enhanced Th1 and Th17 responses.

Fibrosis is an intractable human disease for which no curative drugs have yet been developed. Recent work revealed that renal fibrosis is a manifestation of the epithelial mesenchymal transition (EMT). Chromones and chromone derivatives (CDs) are compounds based on a chemical scaffold found ubiquitously throughout the plant kingdom. We recently showed that eupatilin, a CD from an Artemisia species, efficiently shuts down osteoclastogenesis, concomitant with global downregulation of EMT associated genes. For this study, we established the mouse hepatic stellate cell (HSC) line ONGHEPA1.Real time imaging revealed that upon stimulation with TGFb, ONGHEPA1 cells uniformly differentiated into myofibroblasts, but fibrosis was completely inhibited by 50 uM eupatilin. Concomitant with these antifibrotic effects, multiple EMT inducible genes, such as Col11a1, periostin and Slit3, were significantly downregulated. Although pretreatment with eupatilin did not affect the antifibrotic effect by ...

Receptor activator of NF-κB ligand (RANKL) triggers the differentiation of bone marrow-derived monocyte/macrophage precursor cells (BMMs) of hematopoietic origin into osteoclasts through the activation of mitogen-activated protein (MAP) kinases and transcription factors. Recently, reactive oxygen species (ROS) and antioxidant enzymes were shown to be closely associated with RANKL-mediated osteoclast differentiation. Although glutaredoxin2 (Glrx2) plays a role in cellular redox homeostasis, its role in RANKL-mediated osteoclastogenesis is unclear. We found that Glrx2 isoform b (Glrx2b) expression is induced during RANKLmediated osteoclastogenesis. Over-expression of Glrx2b strongly enhanced RANKL- mediated osteoclastogenesis. In addition, Glrx2b-transduced BMMs enhanced the expression of key transcription factors c-Fos and NFATc1, but pre-treatment with SB203580, a p38-specific inhibitor, completely blocked this enhancement. Conversely, down-regulation of Glrx2b decreased RANKL- medi...

We developed an enzyme-linked antibody-ssDNA aptamer sandwich (ELAAS) method to detect three adipokines for diagnosing type 2 diabetes. For this application, three different aptamers for retinol-binding protein-4 (RBP4), visceral adipose tissue-derived serpin (Vaspin), and nicotinamide phosphoribosyltransferase (Nampt/visfatin) were used as capturing probes, and enzyme-linked polyclonal antibodies were used for signal generation. The sensitivities of this method for all three proteins were enhanced by at least 20-fold to up to 68-fold higher than that of the surface plasmon resonance (SPR) system, which only uses aptamers as capturing probes. In addition, this assay method exhibited equal sensitivity in the detection of each adipokine spiked in diluted human serum. In particular, the detection limit for RBP4 was similar to that obtained by western blotting, as reported previously. The simplicity, reproducibility, and high sensitivity of the ELAAS method could allow it to be extensively utilized in field.

Adiponectin (APN) is a crucial regulator for many inflammatory processes, but its effect on Th cell-mediated responses has not been fully understood. Thus, we investigated the immune-modulatory effects of APN on dendritic cells (DCs) controlling Th cell polarization. APN induced maturation and activation of DCs, as demonstrated by the increased expression of MHC class II, costimulatory molecules in both mouse and human DCs, and it significantly enhanced production of proinflammatory cytokines. APN triggered degradation of IκB proteins, nuclear translocation of NF-κB p65 subunit, and phosphorylation of MAPKs in DCs. Pretreatment with a phospholipase C (PLC)γ inhibitor and a JNK inhibitor suppressed IL-12 production and NF-κB binding activity. Additionally, PLCγ inhibitor downregulated phosphorylation of JNK, indicating that PLCγ and JNK may be upstream molecules of NF-κB. Importantly, APN-treated DCs significantly induced both Th1 and Th17 responses in allogeneic CD4+ T cells. The ad...

VapB has been shown to regulate calcium homeostasis in amyotrophic lateral sclerosis. Calcium signaling is also important in metabolic bone diseases, but the role of VapB in the generation of osteoclasts for bone resorption during osteoclastogenesis is not known. Therefore, we investigated the role of VapB in RANKL‐induced osteoclast differentiation. Interestingly, VapB is induced during osteoclastogenesis, and regulates osteoclast differentiation by modulating NFATc1. The results also suggest that VapB regulates osteoclastogenesis via PLCγ2‐Ca2+‐NFAT signaling. The involvement of PLCγ2‐Ca2+‐NFAT signaling in VapB‐regulated osteoclastogenesis was confirmed by a pharmacological study. Taken together, the results indicate that VapB positively regulates RANKL‐mediated osteoclastogenesis via PLCγ2‐Ca2+‐NFAT signaling.

Glutathione S-transferases (GSTs) play a pivotal role in the detoxi®cation of foreign chemicals and toxic metabolites. They were originally termed ligandins because of their ability to bind large molecules (molecular masses >400 Da), possibly for storage and transport roles. The ___location of the ligandin site in mammalian GSTs is still uncertain despite numerous studies in recent years. Here we show by X-ray crystallography that the ligandin binding site in human pi class GST P1-1 occupies part of one of the substrate binding sites. This work has been extended to the determination of a number of enzyme complex crystal structures which show that very large ligands are readily accommodated into this substrate binding site and in all, but one case, causes no signi®cant movement of protein side-chains. Some of these molecules make use of a hitherto undescribed binding site located in a surface pocket of the enzyme. This site is conserved in most, but not all, classes of GSTs suggesting it may play an important functional role.

Molecular dynamics (MD) simulations using empirical force fields are popular for the study of proteins. In this work, we compare anisotropic atomic fluctuations in nanosecond-timescale MD simulations with those observed in an ultra-high-resolution crystal structure of crambin. In order to make our comparisons, we have developed a compact graphical technique for assessing agreement between spatial atomic distributions determined by MD simulations and observed anisotropic temperature factors.

Biofilms are the habitat of 95% of bacteria successfully protecting bacteria from many antibiotics. However, inhibiting biofilm formation is difficult in that it is a complex system involving the physical and chemical interaction of both substrate and bacteria. Focusing on the substrate surface and potential interactions with bacteria, we examined both physical and chemical properties of substrates coated with a series of phenyl acrylate monomer derivatives. Atomic force microscopy (AFM) showed smooth surfaces often approximating surgical grade steel. Induced biofilm growth of five separate bacteria on copolymer samples comprising varying concentrations of phenyl acrylate monomer derivatives evidenced differing degrees of biofilm resistance via optical microscopy. Using goniometric surface analyses, the van Oss-Chaudhury-Good equation was solved linear algebraically to determine the surface energy profile of each polymerized phenyl acrylate monomer derivative, two bacteria, and collagen. Based on the microscopy and surface energy profiles, a thermodynamic explanation for biofilm resistance is posited.

Antigen-dependent engagement of germinal center (GC) B cell receptors (BCRs) promotes antigen internalization and presentation for follicular helper T cells. However, whether BCR signaling is critical or synergistic with T cell help for GC B cell selection or differentiation is unclear. Here, by adapting an experimental approach that enables independent delivery of BCRcrosslinking antigen or T cell help to GC B cells in vivo, we showed that T cell help was sufficient to induce GC B cell expansion and plasmablast formation. However, although BCR crosslinking could not by itself promote GC B cell selection or differentiation, it could synergize with T cell help to enhance the GC and plasmablast responses when T cell help was limiting. These findings indicate that GC B cells can integrate variable inputs from T cell help and BCR signaling in vivo for an optimal process of selection and differentiation, critical for potent long-term humoral immunity.

This study investigated the influence of air staging on combustion and NOx emission in a tangential-firing boiler at a 560 MWe capacity. For air staging, the stoichiometric ratio (SR) for the burner zone was varied from 0.995 to 0.94 while the overall value was fixed at 1.2. The temperature and heat flux in the burner zone and upper furnace corresponded to the distribution of SR, while the total boiler efficiency remained similar. The NOx emission at the furnace exit was reduced by up to 20% when the SR in the burner zone decreased to 0.94. However, the amount of unburned carbon and slagging propensity was not noticeably influenced by the changes in the SR of the burner zone. Therefore, it was favorable to lower the SR of the burner zone for reduction of NOx emission.

It analyzes the bibliographical references of the articles published by Revista Interamericana de Bibliotecología (Medellin, Colombia) from 1978 to 2001. The type of documents predominantly cited, the predominant languages, the countries of publication, the journals cited as well as age and rate of obsolescence is also analyzed. The citations showed a typical Bradfordian dispersion among five zones. Also Lotka's model

The three lowest ions in the K-like sequence, Ca II, Sc III and Ti IV have excited states 3p 5 3d 2 and 3p 5 3d 4s which lie above the 3p 6 ionization threshold. These excited (resonance or autoionizing) states increase greatly the cross sections for electron and photon ionization of the ground state of the ion. As the charge of the ion increases the number of resonance states of the form 3p 5 3d 2 or 3p 5 3d 4s which lie above the 3p 6 ionization threshold decreases. At present there is no experimental evidence for the existence of these resonances in V V, the next ion in the K-like sequence. Theoretical calculations (Tiwary et al 1983 J. Phys. B: At. Mol. Phys. 16 2457) suggest that there is a [3d 1 P4s] 2 P resonance in V V at an excitation energy of 2.81 au above the 3p 6 3d ground state. This paper presents an ab initio calculation of the transition energies and A-values between individual J levels of the ground 3p 6 3d state and the J levels of the 3p 6 np, 3p 6 nf and the 3p 5 3d 2 and 3p 5 3d 4s excited states of V V. These calculations indicate that there is a resonance multiplet [3d 1 P 4s] 2 P at an excitation energy of 2.73 au which is 0.33 au (9.0 eV) above the 3p 6 ionization threshold.

We investigated the suppressive effect of cocoa powder (cacao polyphenol content: 7.8%) on atherosclerosis in a spontaneous familial hypercholesterolemic model, Kurosawa and Kusanagi-hypercholesterolemic (KHC) rabbits. Six-month dietary administration of cocoa powder had no effects on body weight, hematology or blood chemistry parameters or a lipid profile in KHC rabbits. Antioxidative activity of lowdensity lipoprotein (LDL) was observed in the 2nd month and 3rd month of administration. Thiobarbituric acid reactive substances (TBARS), the marker of lipid peroxidation, in plasma were decreased in the cocoa powder treated group from the 2nd month of administration during the study period compared to that in the control group. The area of atherosclerotic lesions in th aorta was significantly smaller in the cocoa powder group (30.87%) than in the control (52.39%). Tissue cholesterol content also tended to decrease. Distensibility of the aortic wall was improved significantly in the cocoa powder treated group due to decreases in fatty streaks and intimal thickening compared to that in the control group. These results suggest that cocoa powder has suppressive effect on development of atherosclerotic lesions. We consider that antioxidative activity of polyphenols rich in cocoa powder may be a key factor for the anti-atherosclerotic effect.

We previously found increases in uncoupling protein (Ucp)-1 transcription in brown adipose tissue (BAT) of mice following a single oral dose of flavan 3-ol (FL)s, a fraction of catechins and procyanidins. It was confirmed that these changes were totally reduced by co-treatment of adrenaline blockers. According to these previous results, FLs possibly activate sympathetic nervous system (SNS). In this study, we confirmed the marked increase in urinary catecholamine (CA) s projecting SNS activity following a single dose of 50 mg/kg FLs. In addition, we examined the impact of the repeated administration of 50 mg/kg FLs for 14 days on adipose tissues in mice. In BAT, FLs tended to increase the level of Ucp-1 along with significant increase of thermogenic transcriptome factors expressions, such as peroxisome proliferator-activated receptor γ coactivator (PGC)-1α and PR ___domain-containing (PRDM)1. Expression of browning markers, CD137 and transmembrane protein (TMEM) 26, in addition to PGC-1α were increased in epididymal adipose (eWAT) by FLs. A multilocular morphology with cell size reduction was shown in the inguinal adipose (iWAT), together with increasing the level of Ucp-1 by FLs. These results exert that FLs induce browning in adipose, and this change is possibly produced by the activation of the SNS.

Cinnamtannin A2, an (-) epicatechin tetramer, was reported to have potent physiological activity. Cinnamtannin A2 is rarely absorbed from the gastrointestinal tract into the blood and the mechanisms of its beneficial activities are unknown. Cinnamtannin A2 reported to increase sympathetic nervous activity, which was induced by various stressors. In present study, we examined the stress response in the mouse paraventricular nucleus following a single oral dose of cinnamtannin A2 by monitoring mRNA expres sion of corticotropin releasing hormone (CRH) and c fos using in situ hybridization. Corticotropin releasing hormone mRNA showed a tendency to increase at 15 min and significantly increased at 60 min following a single oral administration of 100 µg/kg cinnamtannin A2. After a single dose of 10 µg/kg cinnamtannin A2, there was significant upregulation of CRH mRNA at 60 min. These results suggested that cinnamtannin A2 was recognized as a stressor in central nervous system and this may lead to its beneficial effects on circulation and metabolism.

The antioxidative substances contained in cacao liquor, which is one of the major ingredients of chocolate, were separated by column chromatography and high-performance liquid chromatography. Three major compounds were purified and two of them were identified by 'H, 13C NMR and mass spectra as (-)-epicatechin (EC) and (+) -catechin (CA). Their antioxidative activity was measured by monitoring the peroxide value of linoleic acid and the thiobarbituric acid-reactive substance values of erythrocyte ghost membranes and microsomes. EC and CA had strong antioxidative effects in all three methods, but one unidentified peak was found to be less effective. Additionally, we ana lyzed the polyphenol concentration of cacao liquor extractions produced in several countries. The total polyphenol concentration was 7.0 to 13.0%, catechin concentration was 0.31 to 0.49%, and epicatechin con centration was 0.35 to 1.68% in the extractions. It is believed that cho colate is stable against oxidative deterioration on account of the presence of these polyphenolic compounds, and it is also expected to have a pro tective role against lipid peroxidation in living systems.

, specifically catechin and its oligomer B-type procyanidins, are suggested to potently bind to bovine serum albumin (BSA). We examined the interaction between BSA and FLs by fluorescence quenching and found the following order of binding activities to BSA: cinnamtannin A2 (A2; tetramer) > procyanidin C1 (C1; trimer) ≈ procyanidin B2 (B2, dimer) > (-)epicatechin (EC, monomer). Docking simulations between BSA and each compound at the binding site showed that the calculated binding energies were consistent with the results of our experimental assay. FLs exerted cytotoxicity at 1000 µg/mL in F11 cell culture with fetal bovine serum containing BSA. In culture containing serum-free medium, FLs exhibited significant cell proliferation at 10 -4 µg/mL and cytotoxicity was observed at concentrations greater than 10 µg/mL. Results of this study suggest that interactions between polyphenols and BSA should be taken into account when evaluating procyanidin in an in vitro cell culture system.

Cacao liquor crude polyphenols (CLP) contained potent anti-oxidants, such as catechin, and their oligomers. An investigation was conducted on the effects of CLP on experimental arteriosclerosis with calcification in rats, induced by giving vitamin D 2 (2.5 × 10 5 I.U./kg) for the first 4 consecutive days with an atherogenic diet (2% cholesterol, 1.5% cholic acid, 0.1% methylthiouracil). The diet was prepared using a vitamin E deficient diet. CLP inhibited the increase of serum lipid peroxides, the increase of calcium (Ca) in the aorta, the increase of Ca and inorganic phosphorus (P) in the aortic elastin fraction, or in the renal Ca and P of the arteriosclerotic rats. Previously, vitamin E and vitamin K 2 showed anti-calcification and radical scavenging activities under the above experimental conditions without vitamin E deficiency. Moreover, CLP reduced lipid peroxides in plasma and in tissue induced by vitamin E deficiency, without maintaining vitamin E levels. It is suggested that the inhibitory effects of CLP on the accumulation of Ca and P in the aorta or kidney were partially due to an anti-oxidant activity.

We previously found increases in uncoupling protein (Ucp)-1 transcription in brown adipose tissue (BAT) of mice following a single oral dose of flavan 3-ol (FL)s, a fraction of catechins and procyanidins. It was confirmed that these changes were totally reduced by co-treatment of adrenaline blockers. According to these previous results, FLs possibly activate sympathetic nervous system (SNS). In this study, we confirmed the marked increase in urinary catecholamine (CA) s projecting SNS activity following a single dose of 50 mg/kg FLs. In addition, we examined the impact of the repeated administration of 50 mg/kg FLs for 14 days on adipose tissues in mice. In BAT, FLs tended to increase the level of Ucp-1 along with significant increase of thermogenic transcriptome factors expressions, such as peroxisome proliferator-activated receptor γ coactivator (PGC)-1α and PR ___domain-containing (PRDM)1. Expression of browning markers, CD137 and transmembrane protein (TMEM) 26, in addition to PGC-...

Flavan-3-ols (FLs), specifically catechin and its oligomer B-type procyanidins, are suggested to potently bind to bovine serum albumin (BSA). We examined the interaction between BSA and FLs by fluorescence quenching and found the following order of binding activities to BSA: cinnamtannin A2 (A2; tetramer) > procyanidin C1 (C1; trimer) ≈ procyanidin B2 (B2, dimer) > (−)epicatechin (EC, monomer). Docking simulations between BSA and each compound at the binding site showed that the calculated binding energies were consistent with the results of our experimental assay. FLs exerted cytotoxicity at 1000 μg/mL in F11 cell culture with fetal bovine serum containing BSA. In culture containing serum-free medium, FLs exhibited significant cell proliferation at 10−4 μg/mL and cytotoxicity was observed at concentrations greater than 10 μg/mL. Results of this study suggest that interactions between polyphenols and BSA should be taken into account when evaluating procyanidin in an in vitro c...

We previously found that elevated energy expenditure following a single oral dose of flavan 3-ols (FL), a mixture of catechins and B type procyanidins, is caused by sympathetic nerve activation. In the present study, we compared the activity of the FL components (-)-epicatechin (EC; monomer), procyanidin B2 (B2; dimer), procyanidin C1 (C1; trimer), cinnamtannin A2 (A2; tetramer), and more than pentamer fraction (P5). Male ICR mice were treated with a single oral dose of FL, EC, B2, C1, A2, or P5. The animals were sacrificed and blood and brown adipose tissue (BAT) sampled. The plasma catecholamine (CA) levels and BAT uncoupling protein (UCP)-1 mRNA expression were determined. A single dose of 10 mg/kg FL significantly increased plasma CA and UCP-1 mRNA levels. B2, C1, and A2, but not EC and P5 (all at 1 mg/kg), significantly increased plasma adrenaline levels. Plasma noradrenaline was significantly elevated by B2 and A2, but not by EC, C1, or P5. UCP-1 mRNA levels were significantly increased by C1 and P5. In the dose response study of A2, 10 -3 mg/kg A2 increased UCP-1 mRNA levels significantly, but not 10 -2 and 10 -1 mg/kg A2. In addition, combination treatment with 10 -1 mg/kg A2 and yohimbine, an α2 adrenalin blocker, remarkably increased UCP-1 mRNA levels.

The aims of the present study were to determine the level of (-)-epicatechin (EC) and its metabolites in rat plasma after oral administration of cocoa powder and to evaluate the protective effect of cocoa powder in terms of suppressing the oxidation of plasma components. Rats were orally administered 1 g cocoa powder/kg body weight, containing 7·80 mg EC, and their blood was collected before administration and at designated time intervals thereafter. The EC and its metabolites in plasma were treated with β-glucuronidase and/or sulfatase, then analysed by HPLC and by liquid chromatography–MS. Several EC-related compounds were detected in plasma such as free EC, and glucuronide, sulfate, and glucuronide–sulfate conjugates of non-methylated or methylated EC. All EC metabolites showed a maximum concentration in plasma at 30–60 min post-administration. Glucuronide conjugates of both non-methylated and methylated EC were found in high concentration in plasma. Moreover, administration of c...

Proanthocyanidins derived from cacao (CLP) have various antipathophysiological functions. We have tested whether dietary supplementation with CLP prevents cataract formation in rats with diabetes induced by streptozotocin (STZ), using histological, histochemical, and biochemical analyses. Starting at 7 days after the streptozotocin challenge, the animals were fed either a normal diet or a diet containing 0.5% w/w CLP over 10 weeks. There were no significant differences in plasma and urine glucose concentrations, plasma fructose amines, and plasma thiobarbituric reactive substances (TBARS) between the two dietary groups. Antioxidant status as assessed by measuring lipid peroxide production in plasma in response to azocompounds was lower in the STZ-rats fed control diet than in animals fed CLP. Opacity was first detected in the lenses of the control dietary group 5 weeks after STZ injection and cataracts had developed in the majority of these animals by 10 weeks. These changes were ra...

We evaluated the effect of cacao procyanidins (CP) on plasma lipid levels in high cholesterol-fed rats. Animals were divided into 4 groups, and each group was fed on either a normal diet, high cholesterol diet (HCD) containing 1% cholesterol (HCD without CP), HCD with 0.5% (HCD with 0.5% CP) or 1.0% CP (HCD with 1.0% CP) for 4 weeks. Plasma cholesterol level was significantly higher in the HCD without CP group than the normal diet group (p<0.01). Supplementation of CP significantly decreased plasma cholesterol (p<0.01) to levels similar to those of the normal diet group. The liver cholesterol and triglyceride levels in all HCD groups were significantly higher (p<0.01), but 1.0% CP feeding significantly reduced this increase. Fecal excretion of neutral sterol and triglyceride was significantly increased in all HCD groups (p<0.01), and the excreted amounts tended to be higher in the HCD with CP groups. The procyanidins dose-dependently reduced micellar solubility of choles...

Cocoa powder is rich in polyphenols such as catechins and procyanidins and has been shown in various models to inhibit LDL oxidation and atherogenesis. We examined whether long-term intake of cocoa powder alters plasma lipid profiles in normocholesterolemic and mildly hypercholesterolemic human subjects. Twenty-five subjects were randomly assigned to ingest either 12 g sugar/d (control group) or 26 g cocoa powder and 12 g sugar/d (cocoa group) for 12 wk. Blood samples were collected before the study and 12 wk after intake of the test drinks. Plasma lipids, LDL oxidative susceptibility, and urinary oxidative stress markers were measured. At 12 wk, we measured a 9% prolongation from baseline levels in the lag time of LDL oxidation in the cocoa group. This prolongation in the cocoa group was significantly greater than the reduction measured in the control group (-13%). A significantly greater increase in plasma HDL cholesterol (24%) was observed in the cocoa group than in the control g...

The antioxidative substances contained in cacao liquor, which is one of the major ingredients of chocolate, were separated by column chromatography and high-performance liquid chromatography. Three major compounds were purified and two of them were identified by 'H, 13C NMR and mass spectra as (-)-epicatechin (EC) and (+) -catechin (CA). Their antioxidative activity was measured by monitoring the peroxide value of linoleic acid and the thiobarbituric acid-reactive substance values of erythrocyte ghost membranes and microsomes. EC and CA had strong antioxidative effects in all three methods, but one unidentified peak was found to be less effective. Additionally, we ana lyzed the polyphenol concentration of cacao liquor extractions produced in several countries. The total polyphenol concentration was 7.0 to 13.0%, catechin concentration was 0.31 to 0.49%, and epicatechin con centration was 0.35 to 1.68% in the extractions. It is believed that cho colate is stable against oxidative deterioration on account of the presence of these polyphenolic compounds, and it is also expected to have a pro tective role against lipid peroxidation in living systems.

Cacao liquor crude polyphenols (CLP) contained potent anti-oxidants, such as catechin, and their oligomers. An investigation was conducted on the effects of CLP on experimental arteriosclerosis with calcification in rats, induced by giving vitamin D 2 (2.5 × 10 5 I.U./kg) for the first 4 consecutive days with an atherogenic diet (2% cholesterol, 1.5% cholic acid, 0.1% methylthiouracil). The diet was prepared using a vitamin E deficient diet. CLP inhibited the increase of serum lipid peroxides, the increase of calcium (Ca) in the aorta, the increase of Ca and inorganic phosphorus (P) in the aortic elastin fraction, or in the renal Ca and P of the arteriosclerotic rats. Previously, vitamin E and vitamin K 2 showed anti-calcification and radical scavenging activities under the above experimental conditions without vitamin E deficiency. Moreover, CLP reduced lipid peroxides in plasma and in tissue induced by vitamin E deficiency, without maintaining vitamin E levels. It is suggested that the inhibitory effects of CLP on the accumulation of Ca and P in the aorta or kidney were partially due to an anti-oxidant activity.

Dioxins enter the body through the diet and cause various toxicological effects through transformation of an aryl hydrocarbon receptor (AhR). Plant extracts and phytochemicals including flavonoids are reported to suppress this transformation. This paper investigates the suppression by a cacao polyphenol extract (CPE) of AhR transformation in vivo. The CPE was administered orally to C57BL/6 mice at 100 mg/kg of body weight, followed 1 h later by 3-methylcholanthrene (MC), an AhR agonist, injected intraperitoneally at 10 mg/kg of body weight. CPE suppressed the MC-induced transformation to the control level by inhibiting the formation of a heterodimer between AhR and an aryl hydrocarbon receptor nuclear translocator in the liver at 3 h postadministration. It also suppressed MC-induced cytochrome P4501A1 expression and NAD(P)H:quinone-oxidoreductase activity, whereas it increased glutathione S-transferase activity at 25 h. CPE constituents and their metabolites might contribute, at least in part, to the suppression of AhR transformation. The results indicate that the intake of CPE suppressed the toxicological effects of dioxins in the body.

The effect of 7 and 14 days water stress on yield and yield components of were studied. The water stress was given during flowering and fruiting phase to the muskmelon variety 'Kundan'. Three factors analysis indicated interactions of growth phase x moisture stress [GP x MS], growth phase x growth regulators [GP × GR], moisture stress x growth regulators [MS x GR] and growth phase x moisture stress x growth regulators [GP × MS × GR]. Water stress was significantly affected number of fruits plant -1 , fruit weight, yield plant -1 and WUE when irrigation was halted during fruiting phase. However, total soluble sugar was significantly higher in water stress treatment (maximum 13.82 brix). The WUE of control was 0.23 t ha -1 cm -1 and it was reduced 8.69 % in 7 days and 69.56% in 14 days water stress during flowering. The WUE were markedly reduced from 78.26 to 82.60 % in 7 to 14 days water stress in fruiting phase respectively. The impact of water stress at fruiting stage was more severe than that of flowering stage and also when given for longer period. Farmer can save 56 litres of water plant -1 and 7,20,720 litres of water if population is 12,870 plants ha -1 . By halting 7 days water during flowering stage, additional 816 plants or 0.06 ha area land may be irrigated that helps in muskmelon crop management. To combat water stress effect application of GA 3 @ 50 ppm mitigated water stress.

Without treamant at 30 DAP OSA treamant at 30 DAP Without treamant at 70 DAP OSA treamant at 70 DAP Effects of ortho-silicic acid on watermelon Without treatments (close view) Ortho-silicic acid treatment (close view) Farmer acknowledging the technology intervention Fruit size differences between treatments