Synthesis of substituted 3-amino-N-phenyl-1H-indazole-1-carboxamides endowed with antiproliferative activity

Several new N-phenyl-1H-indazole-1-carboxamides 1c-h and 4l,m were prepared by reacting phenyl isocyanate derivatives 3a,b with 3-amino-1H-indazole derivatives 2c,e,g or 1H-indazole 2l respectively. Chemical transformations of compounds 1a,b and 1g,h gave 3-acetamido-N-phenyl-1H-indazole-1-carboxamide derivatives 5a,b, and 3,5-diamino-N-phenyl-1H-indazole-1-carboxamide derivatives 4i, j respectively. Finally, 3,5-diacetamido-N-phenyl-1H-indazole-1-carboxamide derivatives 6a,b were prepared by acetylation of 4i, j. Some of synthesized compounds were evaluated for their in vitro antiproliferative activity against the full NCI tumor cell lines panel derived from nine clinically isolated cancer types (leukemia, non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate and breast). Compound 1c, the most active of the series, was able to inhibit cell growth showing GI₅₀ values in the 0.041-33.6 μM range, mean GI₅₀ 1.90 μM, being very effective against colon and melanoma cell lines. Cell cycle analysis in K562 cells showed that 1c causes a marked increase of cells in G0-G1 phase. Moreover, it increases the ratio between hypophosphorylated pRb and total pRb.     

Synthesis and anticoagulant activity of a new series of 1,4-dihydropyridine derivatives

A series of 1,4-dihydropyridine derivatives (1a-g) were prepared from three compounds condensation reaction of ethylacetoacetate, aromatic aldehyde and ammonium hydroxide. A new series of compounds (2a-g) were prepared from compounds (1a-g) via reaction with thiosemicarbazide using the condensation method. The synthesized compounds were confirmed by IR, ¹H NMR, ¹³C NMR, mass spectral and elemental analyses. The synthesized compounds (1a-g) and (2a-g) were also screened for anticoagulant properties.     

Design, synthesis and biological evaluation of brain-specific glucosyl thiamine disulfide prodrugs of naproxen

Glucosyl derivates exhibited favorable distribution to the brain. However, bidirectional transport of glucose transporter 1 might decrease concentrations of the prodrugs in brain before the release of parent drugs. To overcome this defect, glucosyl thiamine disulfide prodrugs 1a-1c incorporating naproxen were designed and synthesized. Furthermore, prodrug 2 and 3 were also prepared as control. The favorable physicochemical properties of these prodrugs were verified by stability and metabolism studies. Results from the in vivo distribution study indicated that 1a-1c, and 1b in particular, significantly increased the level of naproxen in brain when compared to 2 and 3. The study suggested glucosyl thiamine disulfide was a promising carrier to enhance the brain bioavailability of central nervous system active drugs.     

Healthcare quality improvement programme improves monitoring of people with diabetes

QuestionDoes a healthcare quality improvement programme, incorporating education and claims-based feedback about practice-specific models of monitoring diabetes care, increase the regularity with which primary care physicians assess people with diabetes mellitus receiving Medicare benefits?Study designCluster randomised controlled trial.Main results22, 971 Medicare recipients with diabetes who could be linked with one of 477 study physicians in 123 non-urban counties were identified. The health care quality improvement programme significantly improved monitoring of circulating glycosylated haemoglobin (HbA1c) levels in people with diabetes compared with a no-intervention comparison group (see Table 1). There was no significant difference in number of eye exams or monitoring of urine protein levels between groups.     

6.

Synthesis and anti-inflammatory activity of ent-kaurene derivatives     

Hueso-Falcón I  Cuadrado I  Cidre F  Amaro-Luis JM  Ravelo AG  Estevez-Braun A  de Las Heras B  Hortelano S 《European journal of medicinal chemistry》2011,46(4):1291-1305

A series of kaurene derivatives (1-63) were prepared and evaluated for anti-inflammatory activity. Thirteen of the tested compounds were able to inhibit NO production with an IC₅₀ between 2 and 10 μM. Compounds 11, 12, 14 and 23 showed low percentage of cell viability, whereas compounds 9, 10, 17, 28, 37, 48, 55, 61 and 62 were non-cytotoxic at the concentration up to 25 μM. Some structure-activity relationships were outlined. Compounds 28, 55 and 62, were selected as representative compounds and they potently inhibited the protein expression of NOS-2. We also determined that inhibition of NF-κB activation might be the mechanism involved in anti-inflammatory effects of these kaurene derivatives. As expected, cytokines IL-6, IL-1α, TNF-α and IFN-γ were downregulated in the presence of compound 28, 55 and 62 after stimulation with LPS. These results indicate that kaurene derivatives might be used for the design of new anti-inflammatory agents.     

7.

Relationships of alcohol dehydrogenase 1B (<Emphasis Type="Italic">ADH1B</Emphasis>) and aldehyde dehydrogenase 2 (<Emphasis Type="Italic">ALDH2</Emphasis>) genotypes with alcohol sensitivity,drinking behavior and problem drinking in Japanese older men     

Marowa Hashimoto  Masutaka Watanabe  Yuji Uematsu  Sonomi Hattori  Nobuyuki Miyai  Miyoko Utsumi  Mayumi Oka  Mariko Hayashida  Kenji Kinoshita  Mikio Arita  Tatsuya Takeshita 《Environmental health and preventive medicine》2016,21(3):138-148

Objectives

Many East Asians have the genetic polymorphisms rs1229984 in alcohol dehydrogenase 1B (ADH1B) and rs671 in aldehyde dehydrogenase 2 (ALDH2). Here we analyzed the relationships of the two genotypes with alcohol sensitivity, drinking behavior and problem drinking among older and younger men living in rural areas of Japan.

Methods

The subjects were 718 Japanese men aged 63.3 ± 10.8 (mean ± SD), categorized into the older (≥65 years, n = 357) and younger (<65 years, n = 361) groups. Facial flushing frequency, drinking behavior and positive CAGE results were compared among the genotypes using Bonferroni-corrected χ² test and a multivariate logistic regression analysis adjusting for age, BMI and lifestyle factors.

Results

The frequency of ‘always’ facial flushing among the ADH1B*1/*2 carriers was significantly lower than that among the ADH1B*2/*2 carriers in the older group (P < 0.01). The alcohol consumption (unit/day) in the ADH1B*1/*2 carriers tended to be higher compared with that in the ADH1B*2/*2 carriers among the older group (P = 0.050). In the younger group, no significant differences in alcohol sensitivity and drinking habits were generally found among the ADH1B genotypes. The ADH1B*1/*1 genotype tended to be positively associated with problem drinking in the older group (P = 0.080) but not in the younger group. The ALDH2 genotypes consistently and strongly affected the alcohol sensitivity, drinking behavior and problem drinking in both the younger and older group.

Conclusions

We for the first time observed a significant difference in alcohol sensitivity between ADH1B*1/*2 and ADH1B*2/*2 in older men aged 65 and above.

     

8.

Ultrastructural differences of Hartmannella culbertsoni Singh and Das, 1970, in mouse brain and under different cultural conditions     

S C Maitra  B N Krishna Prasad  S R Das  S C Agarwala 《Transactions of the Royal Society of Tropical Medicine and Hygiene》1974,68(3):229-235

     

9.

Low hemoglobin A1C increases the risk of disability in community-dwelling older non-diabetics adults     

K.-I. Kim  S. Kim  K.-W. Kim  H.-C. Jang  C.-H. Kim  Ho Jun Chin 《The journal of nutrition, health & aging》2016,20(3):341-346

Objective

To describe the health characteristics of individuals with low HbA1c levels and evaluate the association between HbA1c level and disability or all-cause mortality in non-diabetic older adults.

Design

Prospective observational cohort study.

Setting

Seongnam, Gyeongi Province, Korea.

Participants

Among the 1,000 community-dwelling Koreans ≥ 65 years of age who were followed for 5 years, 760 non-diabetic individuals were analyzed.

Measurements

Activities of Daily Living (ADL) and Instrumental ADL (IADL) were evaluated and mortality data were obtained from the National Statistics Office of Korea.

Results

The mean age was 76.3 (SD 9.0) years, and 319 subjects (42.0%) were male. Lower level of HbA1c was associated with less frequent hypertension and less frequent use of aspirin or statin, and lower values of body mass index, hematocrit, total iron-binding capacity, albumin, and cholesterol level. The participants were categorized into 3 groups according to their HbA1c (group I, < 5.5%; group II, 5.5～5.9%; and group III, 6.0 ～ 6.4%). Although, there was no significant difference in functional status according to baseline HbA1c level, disability was more frequently observed as the HbA1c level decrease (18.3% in group I, 12.5% in group II, and 5.3% in group III, p=0.029) at the 5-year follow-up evaluation. There were 172 deaths (22.6%) during the follow-up period. There was no significant difference in mortality among the groups, however, group I had a 2.071-fold higher risk for the incident disability or mortality over group III after adjusting age, gender, and possible confounder (95% CI: 1.040 ～ 4.124, p=0.038).

Conclusions

Lower level of HbA1c was associated with an increased risk of disability in non-diabetic older adults.

     

10.

Synthesis and anti-microbial activity of some 1- substituted amino-4,6-dimethyl-2-oxo-pyridine-3-carbonitrile derivatives     

Khidre RE  Abu-Hashem AA  El-Shazly M 《European journal of medicinal chemistry》2011,46(10):5057-5064

A new series of 1- substituted amino-4,6-dimethyl-2-oxo-pyridine-3-carbonitrile such as hydrazide hydrazones 3a-h; ethane-1,2-diaminopyridine 6; phthalimidopyridines 8a,b; hydrazides 10a,b; urea 11a and thiourea 11b were synthesized in a good to excellent yield in step efficient process, using 1-amino-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (1) as a key intermediate. The antibacterial and antifungal activities of the synthesized compounds were evaluated. The obtained data indicated that the majority of the tested compounds exhibited both antibacterial and antifungal activities, particularly compounds 8a and 8b showed a comparable effect to a well known antibacterial and antifungal agents.     

11.

Synthesis, characterization and antimicrobial studies of some new pyrazole incorporated imidazole derivatives     

Vijesh AM  Isloor AM  Telkar S  Peethambar SK  Rai S  Isloor N 《European journal of medicinal chemistry》2011,46(8):3531-3536

In the present study two series of novel imidazole derivatives containing substituted pyrazole moiety (3a-d and 5a-j) were synthesized. The first series were synthesized by the reaction of 3-aryl-1H-pyrazole-4-carbaldehyde thiosemicarbazones (2a-d) with DMAD and the second series by the reaction of 3-aryl-1H-pyrazole-4-carbaldehydes (1a-e) with 1,2-diketones (4a,b) in the presence of ammonium acetate. Structures of newly synthesized compounds were characterized by spectral studies. New compounds were screened for antifungal and antibacterial activities. Among the synthesized compounds, compound 3c was found to be potent antimicrobial agent. The acute oral toxicity study for the compound 3c was carried out and the experimental studies revealed that compound 3c is safe up to 3000 mg/kg and no death of animals were recorded.     

12.

Synthesis, evaluation and application of polycyclic fluorescent analogues as N-methyl-D-aspartate receptor and voltage gated calcium channel ligands     

Joubert J  van Dyk S  Green IR  Malan SF 《European journal of medicinal chemistry》2011,46(10):5010-5020

A series of polycyclic fluorescent ligands were synthesised and evaluated in murine striatal synaptoneurosomes for N-methyl-d-aspartate receptor (NMDAR) mediated calcium flux inhibition and inhibition of calcium influx through voltage gated calcium channels (VGCC). Amantadine (a) and N-(1-adamantyl)-1,3-propanediamine (c) substituted with 1-cyanoisoindole (3), indazole (5), dinitrobenzene (7, 8), dansyl (9, 10) and coumarin (11) moieties showed moderate to high inhibition of the NMDAR. A high degree of VGCC inhibition was observed for the cyanoisoindole compounds (3, 4) the dansyl compounds (9, 10) and the coumarin compound (12). Fluorophores conjugated to hydroxy-4-aza-8-oxoheptacyclotetradecane (13, 14) did not exhibit any significant VGCC inhibition, but the indazole conjugate (14) showed promising NMDAR activity. Dose response curves were calculated for selected NMDAR inhibitors (8-11) and N-[3-(1-adamantylamino)propyl]-5-dimethylaminonaphthalene-1-sulfonamide (10) exhibited the highest activity of the novel compounds. Compound 10 was further used as a fluorescent NMDAR ligand in a fluorescent competition assay utilizing MK-801, NGP1-01 and amantadine as known NMDAR inhibitors to demonstrate the possible applications of the novel fluorescent compounds. These small molecule fluorescent ligands can be considered as possible pharmacological tools in assay development and/or other investigations in the study of neurodegeneration.     

13.

Green tea consumption and glutathione S-transferases genetic polymorphisms on the risk of adult leukemia     

Ping?LiuEmail author  Min?Zhang  Xing?Xie  Jie?Jin  C.?D’Arcy?J.?Holman 《European journal of nutrition》2017,56(2):603-612

Purpose

Green tea may have a beneficial role of inhibiting leukemia. Glutathione S-transferases (GSTs) are known to detoxify certain carcinogens. We investigated the roles of green tea consumption and polymorphisms of GSTM1, GSTT1 and GSTP1 on the risk of adult leukemia, and to determine whether the associations varied within GSTs genotypes.

Methods

A multicenter case–control study was conducted in China, 2008–2013. It comprised 442 incident, hematologically confirmed adult leukemia cases and 442 outpatient controls, individually matched to cases by gender, birth quinquennium and study site. Data were collected by face-to-face interview using a validated questionnaire. Genetic polymorphisms were assayed by PCR.

Results

An inverse association between green tea consumption and adult leukemia risk was observed. Compared with non-tea drinkers, the adjusted odds ratios (95 % confidence intervals) were 0.50 (0.27–0.93), 0.31 (0.17–0.55) and 0.53 (0.29–0.99) for those who, respectively, consumed green tea >20 years, ≥2 cups daily and dried tea leaves >1000 g annually. In assessing the associations by GSTs genotypes, risk reduction associated with green tea consumption was stronger in individuals with the GSTT1-null genotype (OR 0.24; 95 % CI 0.11–0.53) than GSTT1-normal carriers (OR 0.67; 95 % CI 0.42–1.05; P interaction = 0.02). GSTM1 and GSTP1 did not significantly modify the inverse association of leukemia with green tea.

Conclusions

The results suggest that regular daily green tea consumption may reduce leukemia risk in Chinese adults regardless of GSTM1 and GSTP1 polymorphic status. The association between green tea and adult leukemia risk varied with GSTT1 genotype and highlights further study.

     

14.

Applications of 2-arylhydrazononitriles in synthesis: preparation of new indole containing 1,2,3-triazole, pyrazole and pyrazolo[1,5-a]pyrimidine derivatives and evaluation of their antimicrobial activities     

Behbehani H  Ibrahim HM  Makhseed S  Mahmoud H 《European journal of medicinal chemistry》2011,46(5):1813-1820

In this effort, 2-arylhdrazononitriles were used as key synthons for the preparation of wide variety of new, uniquely substituted heterocyclic substances. In addition, the results of biological evaluations demonstrate that members of the group prepared have promising antimicrobial activities against Gram negative bacteria, Gram positive bacteria and Yeast. In the synthetic sequences, 3-(1-methyl-1H-indol-3-yl)-3-oxo-2-(phenylhydrazono)propanenitrile 2a and its 2-methyl derivative 2b were found to react with hydroxylamine hydrochloride to yield the corresponding indolyl-5-amino-2-phenyl-1,2,3-triazoles 4a,b. These amines react with cyanoacetic acid in presence of acetic anhydride either thermally or under microwave irradiation conditions to yield the corresponding cyanoacetamides 5a,b, which condensed readily with dimethylformamide dimethylacetal to yield the enaminonitriles 6a,b. Whereas heating of 6a,b with hydrazine hydrate affords compound 8, compound 12 is produced when these reactants are subjected to microwave irradiation. We observed that the aminopyrazole 9 reacts with enaminal 13 to yield 14 and that its reactions with enaminones 15 afford 17. Finally, compound 5 reacts with cinnamaldehyde to yield the corresponding Schiff’s base 18 that does not undergo cyclization to form the pyridine derivative 19. The activities of all new substances synthesized in this investigation were evaluated against a panel of microbial organisms. The results show that 4a, 4b, 5b and 9b display strong antimicrobial activities against all of the tested organisms.     

15.

Correlation of emotional labor and cortisol concentration in hair among female kindergarten teachers     

Xingliang?QiEmail author  Shuang?Ji  Jing?Zhang  Wanyong?Lu  Judith?K.?Sluiter  Huihua?Deng 《International archives of occupational and environmental health》2017,90(1):117-122

Objectives

The purpose of this study was to explore whether two types of emotional labor, surface acting and deep acting, are related to hair cortisol concentration among kindergarten teachers.

Methods

Surface acting and deep acting over the last month were measured with the Chinese version of the emotional labor scale in 43 kindergarten teachers. Hair samples with 1 cm in length were cut from their posterior vertex region to represent cortisol excretion over one month. Cortisol concentrations were analyzed with high-performance liquid chromatography–tandem mass spectrometry.

Results

Positive association of emotion labor with hair cortisol concentration was significant for surface acting (r = 0.34, p < 0.05) and not significant for deep acting (r = 0.14, p > 0.05).

Conclusions

More surface acting showed to be associated stronger with stress responses or higher HPA axis activity.

     

16.

Cocoa polyphenols and fiber modify colonic gene expression in rats     

Malen?Massot-Cladera  àngels?Franch  Margarida?Castell  Francisco?J.?Pérez-CanoEmail author 《European journal of nutrition》2017,56(5):1871-1885

Purpose

Cocoa intake has been associated with health benefits, improving cardiovascular function and metabolism, as well as modulating intestinal immune function. The aim of this study was to take an in-depth look into the mechanisms affected by the cocoa intake by evaluating the colonic gene expression after nutritional intervention, and to ascertain the role of the fiber of cocoa in these effects.

Methods

To achieve this, Wistar rats were fed for 3 weeks with either a reference diet, a diet containing 10 % cocoa (C10), a diet based on cocoa fiber (CF) or a diet containing inulin (I). At the end of the study, colon was excised to obtain the RNA to evaluate the differential gene expression by microarray. Results were validated by RT-PCR.

Results

The C10 group was the group with most changes in colonic gene expression, most of them down-regulated but a few in common with the CF diet. The C10 diet significantly up-regulated the expression of Scgb1a1 and Scnn1 g and down-regulated Tac4, Mcpt2, Fcer1a and Fabp1 by twofold, most of them related to lipid metabolism and immune function. The CF and I diets down-regulated the expression of Serpina10 and Apoa4 by twofold. Similar patterns of expression were found by PCR.

Conclusion

Most of the effects attributed to cocoa consumption on genes related to the immune system (B cell and mast cell functionality) and lipid metabolism in the colon tissue were due not only to its fiber content, but also to the possible contribution of polyphenols and other compounds.

     

17.

Synthesis of 4H-chromene, coumarin, 12H-chromeno[2,3-d]pyrimidine derivatives and some of their antimicrobial and cytotoxicity activities     

Sabry NM  Mohamed HM  Khattab ES  Motlaq SS  El-Agrody AM 《European journal of medicinal chemistry》2011,46(2):765-772

Condensation of 3-N,N-diethylaminophenol (1) with α-cyanocinnamonitriles (2a-c) and ethyl α-cyanocinnamates (2d-f) provided compounds 3a-f and 4a-c. 12H-Chromeno[2,3-d]pyrimidine derivatives 6, 11-13 and 16 were obtained by treatment of 4H-chromene compounds (3) with different electrophiles followed by nucleophilic reagents. Structures of these compounds were established on the basis of IR, UV, ¹H NMR, ¹³C NMR and MS data. Some of the new compounds were evaluated for antimicrobial and cytotoxicity activities.     

18.

A Communication Matrix Intervention to Increase Adoption of Federal Government Safety Recommendations     

Steve Booth-Butterfield  Sybil Ott  Tara Hartley  Kimberly Clough Thomas  Nicholas J. Lawryk 《Health communication》2013,28(4):307-312

A 3-year, multichannel intervention project assessed adoption of federal government workplace safety testing methods among 3 randomly drawn samples of industrial hygienists. A communication matrix (McGuire, 1985 McGuire, W. 1985. “Attitudes and attitude change”. In The handbook of social psychology, 3rd Edited by: Lindzey, G. and Aronson, E. Vol. 1, 233–346.  [Google Scholar], 1989 McGuire, W. 1989. “Theoretical foundations of campaigns”. In Public communication campaigns, 2nd Edited by: Rice, R. and Atkin, C. 43–66.  [Google Scholar]) framework focusing on stages of reception, processing, and response was used to create, implement, and evaluate the intervention. Participants were interviewed by phone during 3 waves: baseline, immediately following year 1 of the intervention, and immediately following year 2 of the intervention. Results indicate a gain in reception over the course of the intervention. Increases in attitudes, control beliefs, intentions, and self-reported behavior were found between baseline and the 1st year of the intervention, and were maintained (although not increased) during the 2nd year of the intervention. Strengths and weaknesses of the intervention are viewed through the scope of the communication matrix.     

19.

The dietary form of choline during lactation affects maternal immune function in rats     

N.?S.?Dellschaft  C.?Richard  E.?D.?Lewis  S.?Goruk  R.?L.?Jacobs  J.?M.?Curtis  C.?J.?FieldEmail author 《European journal of nutrition》2018,57(6):2189-2199

Purpose

The present study was designed to determine the effects of both choline form and availability on maternal immune function during lactation.

Methods

Sprague–Dawley rats were randomized to one of the three diets 24–48 h before parturition and fed ad libitum until 21 days postnatal: 1 g/kg choline as free choline (C, n = 11), the current form, and amount of choline in commercial diets; 1 g/kg choline as phosphatidylcholine (PC1, n = 11); or 2.5 g/kg choline as PC (PC2.5, n = 8). Choline metabolites in offspring stomach contents were quantified. At 21 days, lymphocytes from mothers’ mesenteric lymph nodes and spleens were isolated and phenotypes and ex vivo cytokine production after mitogen exposure were determined.

Results

There was a higher proportion of choline and a lower proportion of lyso-PC in stomach contents (representing dam’s milk) of C pups compared to PC1. In the mesenteric lymph nodes, feeding PC1 compared to C led to a higher IL-2 production after Concanavalin A (ConA) stimulation and a higher proportion of T cells (CD3+) and a lower proportion of B cells [immunoglobulin (Ig)κ, CD45RA+, and IgM+; P < 0.05]. Splenocytes from the PC1 group produced more IL-6 and TNF-α after lipopolysaccharides stimulation compared to C (P < 0.05). Splenocytes from the PC2.5 group produced more IL-2 and IL-6 after ConA stimulation compared to PC1 (P < 0.05).

Conclusions

Feeding choline as PC in the maternal diet improved the ability of immune cells to respond ex vivo to mitogens and increasing the amount of PC in the diet further improved T cell proliferation.

     

20.

Quality of life and stability of tooth color change at three months after dental bleaching     

Cristian Bersezio  Javier Martín  Carla Mayer  Oriana Rivera  Juan Estay  Rolando Vernal  Ziyad S. Haidar  Pablo Angel  Osmir B. OliveiraJr.  Eduardo Fernández 《Quality of life research》2018,27(12):3199-3207

Purpose

Intracoronary bleaching is a minimally invasive, alternative treatment that addresses aesthetic concerns related to non-vital teeth discoloration. However, to the best of our knowledge, no studies have assessed the psychosocial impacts of such procedures on patients’ aesthetic perceptions. The aim of this study was to evaluate aesthetic perceptions and the psychosocial impact of patients up to 3 months after their teeth had been bleached with hydrogen peroxide (35%) and carbamide peroxide (37%) using the walking bleach technique.

Methods

The patients were randomly divided into two groups according to the bleaching agent used: G1?=?hydrogen peroxide 35% (n?=?25) and G2?=?carbamide peroxide 37% (n?=?25). Non-vital bleaching was performed in four sessions. Color was objectively (ΔE) and subjectively (ΔSGU) evaluated. Aesthetic perception and psychosocial factors were evaluated before, 1 week and 1 month after the bleaching using the Oral Health Impact Profile (OHIP) and Psychosocial Impact of Dental Aesthetics Questionnaire (PIDAQ) questionnaires.

Results

The color change (ΔE) values at 1 month were G1?=?16.80?±?6.07 and G2?=?14.09?±?4.83. These values remained stable until the third month after treatment (p?>?0.05). There was a decrease in the values of OHIP-aesthetics and PIDAQ after treatment versus baseline (p?<?0.05). This status was maintained through the third month after treatment.

Conclusions

Both agents were highly effective and had a positive impact on the aesthetic perception and psychosocial impact of patients, values that also remained stable over time. Non-vital bleaching yields positive and stable impacts on aesthetic perception and psychosocial factors. ClinicalTrials.gov identifier NCT02718183.

     

Synthesis and anti-inflammatory activity of ent-kaurene derivatives

A series of kaurene derivatives (1-63) were prepared and evaluated for anti-inflammatory activity. Thirteen of the tested compounds were able to inhibit NO production with an IC₅₀ between 2 and 10 μM. Compounds 11, 12, 14 and 23 showed low percentage of cell viability, whereas compounds 9, 10, 17, 28, 37, 48, 55, 61 and 62 were non-cytotoxic at the concentration up to 25 μM. Some structure-activity relationships were outlined. Compounds 28, 55 and 62, were selected as representative compounds and they potently inhibited the protein expression of NOS-2. We also determined that inhibition of NF-κB activation might be the mechanism involved in anti-inflammatory effects of these kaurene derivatives. As expected, cytokines IL-6, IL-1α, TNF-α and IFN-γ were downregulated in the presence of compound 28, 55 and 62 after stimulation with LPS. These results indicate that kaurene derivatives might be used for the design of new anti-inflammatory agents.     

Relationships of alcohol dehydrogenase 1B (<Emphasis Type="Italic">ADH1B</Emphasis>) and aldehyde dehydrogenase 2 (<Emphasis Type="Italic">ALDH2</Emphasis>) genotypes with alcohol sensitivity,drinking behavior and problem drinking in Japanese older men

Objectives

Many East Asians have the genetic polymorphisms rs1229984 in alcohol dehydrogenase 1B (ADH1B) and rs671 in aldehyde dehydrogenase 2 (ALDH2). Here we analyzed the relationships of the two genotypes with alcohol sensitivity, drinking behavior and problem drinking among older and younger men living in rural areas of Japan.

Methods

The subjects were 718 Japanese men aged 63.3 ± 10.8 (mean ± SD), categorized into the older (≥65 years, n = 357) and younger (<65 years, n = 361) groups. Facial flushing frequency, drinking behavior and positive CAGE results were compared among the genotypes using Bonferroni-corrected χ² test and a multivariate logistic regression analysis adjusting for age, BMI and lifestyle factors.

Results

The frequency of ‘always’ facial flushing among the ADH1B*1/*2 carriers was significantly lower than that among the ADH1B*2/*2 carriers in the older group (P < 0.01). The alcohol consumption (unit/day) in the ADH1B*1/*2 carriers tended to be higher compared with that in the ADH1B*2/*2 carriers among the older group (P = 0.050). In the younger group, no significant differences in alcohol sensitivity and drinking habits were generally found among the ADH1B genotypes. The ADH1B*1/*1 genotype tended to be positively associated with problem drinking in the older group (P = 0.080) but not in the younger group. The ALDH2 genotypes consistently and strongly affected the alcohol sensitivity, drinking behavior and problem drinking in both the younger and older group.

Conclusions

We for the first time observed a significant difference in alcohol sensitivity between ADH1B*1/*2 and ADH1B*2/*2 in older men aged 65 and above.

     

Low hemoglobin A1C increases the risk of disability in community-dwelling older non-diabetics adults

Objective

To describe the health characteristics of individuals with low HbA1c levels and evaluate the association between HbA1c level and disability or all-cause mortality in non-diabetic older adults.

Design

Prospective observational cohort study.

Setting

Seongnam, Gyeongi Province, Korea.

Participants

Among the 1,000 community-dwelling Koreans ≥ 65 years of age who were followed for 5 years, 760 non-diabetic individuals were analyzed.

Measurements

Activities of Daily Living (ADL) and Instrumental ADL (IADL) were evaluated and mortality data were obtained from the National Statistics Office of Korea.

Results

The mean age was 76.3 (SD 9.0) years, and 319 subjects (42.0%) were male. Lower level of HbA1c was associated with less frequent hypertension and less frequent use of aspirin or statin, and lower values of body mass index, hematocrit, total iron-binding capacity, albumin, and cholesterol level. The participants were categorized into 3 groups according to their HbA1c (group I, < 5.5%; group II, 5.5～5.9%; and group III, 6.0 ～ 6.4%). Although, there was no significant difference in functional status according to baseline HbA1c level, disability was more frequently observed as the HbA1c level decrease (18.3% in group I, 12.5% in group II, and 5.3% in group III, p=0.029) at the 5-year follow-up evaluation. There were 172 deaths (22.6%) during the follow-up period. There was no significant difference in mortality among the groups, however, group I had a 2.071-fold higher risk for the incident disability or mortality over group III after adjusting age, gender, and possible confounder (95% CI: 1.040 ～ 4.124, p=0.038).

Conclusions

Lower level of HbA1c was associated with an increased risk of disability in non-diabetic older adults.

     

Synthesis and anti-microbial activity of some 1- substituted amino-4,6-dimethyl-2-oxo-pyridine-3-carbonitrile derivatives

A new series of 1- substituted amino-4,6-dimethyl-2-oxo-pyridine-3-carbonitrile such as hydrazide hydrazones 3a-h; ethane-1,2-diaminopyridine 6; phthalimidopyridines 8a,b; hydrazides 10a,b; urea 11a and thiourea 11b were synthesized in a good to excellent yield in step efficient process, using 1-amino-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (1) as a key intermediate. The antibacterial and antifungal activities of the synthesized compounds were evaluated. The obtained data indicated that the majority of the tested compounds exhibited both antibacterial and antifungal activities, particularly compounds 8a and 8b showed a comparable effect to a well known antibacterial and antifungal agents.     

Synthesis, characterization and antimicrobial studies of some new pyrazole incorporated imidazole derivatives

In the present study two series of novel imidazole derivatives containing substituted pyrazole moiety (3a-d and 5a-j) were synthesized. The first series were synthesized by the reaction of 3-aryl-1H-pyrazole-4-carbaldehyde thiosemicarbazones (2a-d) with DMAD and the second series by the reaction of 3-aryl-1H-pyrazole-4-carbaldehydes (1a-e) with 1,2-diketones (4a,b) in the presence of ammonium acetate. Structures of newly synthesized compounds were characterized by spectral studies. New compounds were screened for antifungal and antibacterial activities. Among the synthesized compounds, compound 3c was found to be potent antimicrobial agent. The acute oral toxicity study for the compound 3c was carried out and the experimental studies revealed that compound 3c is safe up to 3000 mg/kg and no death of animals were recorded.     

Synthesis, evaluation and application of polycyclic fluorescent analogues as N-methyl-D-aspartate receptor and voltage gated calcium channel ligands

A series of polycyclic fluorescent ligands were synthesised and evaluated in murine striatal synaptoneurosomes for N-methyl-d-aspartate receptor (NMDAR) mediated calcium flux inhibition and inhibition of calcium influx through voltage gated calcium channels (VGCC). Amantadine (a) and N-(1-adamantyl)-1,3-propanediamine (c) substituted with 1-cyanoisoindole (3), indazole (5), dinitrobenzene (7, 8), dansyl (9, 10) and coumarin (11) moieties showed moderate to high inhibition of the NMDAR. A high degree of VGCC inhibition was observed for the cyanoisoindole compounds (3, 4) the dansyl compounds (9, 10) and the coumarin compound (12). Fluorophores conjugated to hydroxy-4-aza-8-oxoheptacyclotetradecane (13, 14) did not exhibit any significant VGCC inhibition, but the indazole conjugate (14) showed promising NMDAR activity. Dose response curves were calculated for selected NMDAR inhibitors (8-11) and N-[3-(1-adamantylamino)propyl]-5-dimethylaminonaphthalene-1-sulfonamide (10) exhibited the highest activity of the novel compounds. Compound 10 was further used as a fluorescent NMDAR ligand in a fluorescent competition assay utilizing MK-801, NGP1-01 and amantadine as known NMDAR inhibitors to demonstrate the possible applications of the novel fluorescent compounds. These small molecule fluorescent ligands can be considered as possible pharmacological tools in assay development and/or other investigations in the study of neurodegeneration.     

Green tea consumption and glutathione S-transferases genetic polymorphisms on the risk of adult leukemia

Purpose

Green tea may have a beneficial role of inhibiting leukemia. Glutathione S-transferases (GSTs) are known to detoxify certain carcinogens. We investigated the roles of green tea consumption and polymorphisms of GSTM1, GSTT1 and GSTP1 on the risk of adult leukemia, and to determine whether the associations varied within GSTs genotypes.

Methods

A multicenter case–control study was conducted in China, 2008–2013. It comprised 442 incident, hematologically confirmed adult leukemia cases and 442 outpatient controls, individually matched to cases by gender, birth quinquennium and study site. Data were collected by face-to-face interview using a validated questionnaire. Genetic polymorphisms were assayed by PCR.

Results

An inverse association between green tea consumption and adult leukemia risk was observed. Compared with non-tea drinkers, the adjusted odds ratios (95 % confidence intervals) were 0.50 (0.27–0.93), 0.31 (0.17–0.55) and 0.53 (0.29–0.99) for those who, respectively, consumed green tea >20 years, ≥2 cups daily and dried tea leaves >1000 g annually. In assessing the associations by GSTs genotypes, risk reduction associated with green tea consumption was stronger in individuals with the GSTT1-null genotype (OR 0.24; 95 % CI 0.11–0.53) than GSTT1-normal carriers (OR 0.67; 95 % CI 0.42–1.05; P interaction = 0.02). GSTM1 and GSTP1 did not significantly modify the inverse association of leukemia with green tea.

Conclusions

The results suggest that regular daily green tea consumption may reduce leukemia risk in Chinese adults regardless of GSTM1 and GSTP1 polymorphic status. The association between green tea and adult leukemia risk varied with GSTT1 genotype and highlights further study.

     

Applications of 2-arylhydrazononitriles in synthesis: preparation of new indole containing 1,2,3-triazole, pyrazole and pyrazolo[1,5-a]pyrimidine derivatives and evaluation of their antimicrobial activities

In this effort, 2-arylhdrazononitriles were used as key synthons for the preparation of wide variety of new, uniquely substituted heterocyclic substances. In addition, the results of biological evaluations demonstrate that members of the group prepared have promising antimicrobial activities against Gram negative bacteria, Gram positive bacteria and Yeast. In the synthetic sequences, 3-(1-methyl-1H-indol-3-yl)-3-oxo-2-(phenylhydrazono)propanenitrile 2a and its 2-methyl derivative 2b were found to react with hydroxylamine hydrochloride to yield the corresponding indolyl-5-amino-2-phenyl-1,2,3-triazoles 4a,b. These amines react with cyanoacetic acid in presence of acetic anhydride either thermally or under microwave irradiation conditions to yield the corresponding cyanoacetamides 5a,b, which condensed readily with dimethylformamide dimethylacetal to yield the enaminonitriles 6a,b. Whereas heating of 6a,b with hydrazine hydrate affords compound 8, compound 12 is produced when these reactants are subjected to microwave irradiation. We observed that the aminopyrazole 9 reacts with enaminal 13 to yield 14 and that its reactions with enaminones 15 afford 17. Finally, compound 5 reacts with cinnamaldehyde to yield the corresponding Schiff’s base 18 that does not undergo cyclization to form the pyridine derivative 19. The activities of all new substances synthesized in this investigation were evaluated against a panel of microbial organisms. The results show that 4a, 4b, 5b and 9b display strong antimicrobial activities against all of the tested organisms.     

Correlation of emotional labor and cortisol concentration in hair among female kindergarten teachers

Objectives

The purpose of this study was to explore whether two types of emotional labor, surface acting and deep acting, are related to hair cortisol concentration among kindergarten teachers.

Methods

Surface acting and deep acting over the last month were measured with the Chinese version of the emotional labor scale in 43 kindergarten teachers. Hair samples with 1 cm in length were cut from their posterior vertex region to represent cortisol excretion over one month. Cortisol concentrations were analyzed with high-performance liquid chromatography–tandem mass spectrometry.

Results

Positive association of emotion labor with hair cortisol concentration was significant for surface acting (r = 0.34, p < 0.05) and not significant for deep acting (r = 0.14, p > 0.05).

Conclusions

More surface acting showed to be associated stronger with stress responses or higher HPA axis activity.

     

Cocoa polyphenols and fiber modify colonic gene expression in rats

Purpose

Cocoa intake has been associated with health benefits, improving cardiovascular function and metabolism, as well as modulating intestinal immune function. The aim of this study was to take an in-depth look into the mechanisms affected by the cocoa intake by evaluating the colonic gene expression after nutritional intervention, and to ascertain the role of the fiber of cocoa in these effects.

Methods

To achieve this, Wistar rats were fed for 3 weeks with either a reference diet, a diet containing 10 % cocoa (C10), a diet based on cocoa fiber (CF) or a diet containing inulin (I). At the end of the study, colon was excised to obtain the RNA to evaluate the differential gene expression by microarray. Results were validated by RT-PCR.

Results

The C10 group was the group with most changes in colonic gene expression, most of them down-regulated but a few in common with the CF diet. The C10 diet significantly up-regulated the expression of Scgb1a1 and Scnn1 g and down-regulated Tac4, Mcpt2, Fcer1a and Fabp1 by twofold, most of them related to lipid metabolism and immune function. The CF and I diets down-regulated the expression of Serpina10 and Apoa4 by twofold. Similar patterns of expression were found by PCR.

Conclusion

Most of the effects attributed to cocoa consumption on genes related to the immune system (B cell and mast cell functionality) and lipid metabolism in the colon tissue were due not only to its fiber content, but also to the possible contribution of polyphenols and other compounds.

     

Synthesis of 4H-chromene, coumarin, 12H-chromeno[2,3-d]pyrimidine derivatives and some of their antimicrobial and cytotoxicity activities

Condensation of 3-N,N-diethylaminophenol (1) with α-cyanocinnamonitriles (2a-c) and ethyl α-cyanocinnamates (2d-f) provided compounds 3a-f and 4a-c. 12H-Chromeno[2,3-d]pyrimidine derivatives 6, 11-13 and 16 were obtained by treatment of 4H-chromene compounds (3) with different electrophiles followed by nucleophilic reagents. Structures of these compounds were established on the basis of IR, UV, ¹H NMR, ¹³C NMR and MS data. Some of the new compounds were evaluated for antimicrobial and cytotoxicity activities.     

A Communication Matrix Intervention to Increase Adoption of Federal Government Safety Recommendations

A 3-year, multichannel intervention project assessed adoption of federal government workplace safety testing methods among 3 randomly drawn samples of industrial hygienists. A communication matrix (McGuire, 1985 McGuire, W. 1985. “Attitudes and attitude change”. In The handbook of social psychology, 3rd Edited by: Lindzey, G. and Aronson, E. Vol. 1, 233–346.  [Google Scholar], 1989 McGuire, W. 1989. “Theoretical foundations of campaigns”. In Public communication campaigns, 2nd Edited by: Rice, R. and Atkin, C. 43–66.  [Google Scholar]) framework focusing on stages of reception, processing, and response was used to create, implement, and evaluate the intervention. Participants were interviewed by phone during 3 waves: baseline, immediately following year 1 of the intervention, and immediately following year 2 of the intervention. Results indicate a gain in reception over the course of the intervention. Increases in attitudes, control beliefs, intentions, and self-reported behavior were found between baseline and the 1st year of the intervention, and were maintained (although not increased) during the 2nd year of the intervention. Strengths and weaknesses of the intervention are viewed through the scope of the communication matrix.     

The dietary form of choline during lactation affects maternal immune function in rats

Purpose

The present study was designed to determine the effects of both choline form and availability on maternal immune function during lactation.

Methods

Sprague–Dawley rats were randomized to one of the three diets 24–48 h before parturition and fed ad libitum until 21 days postnatal: 1 g/kg choline as free choline (C, n = 11), the current form, and amount of choline in commercial diets; 1 g/kg choline as phosphatidylcholine (PC1, n = 11); or 2.5 g/kg choline as PC (PC2.5, n = 8). Choline metabolites in offspring stomach contents were quantified. At 21 days, lymphocytes from mothers’ mesenteric lymph nodes and spleens were isolated and phenotypes and ex vivo cytokine production after mitogen exposure were determined.

Results

There was a higher proportion of choline and a lower proportion of lyso-PC in stomach contents (representing dam’s milk) of C pups compared to PC1. In the mesenteric lymph nodes, feeding PC1 compared to C led to a higher IL-2 production after Concanavalin A (ConA) stimulation and a higher proportion of T cells (CD3+) and a lower proportion of B cells [immunoglobulin (Ig)κ, CD45RA+, and IgM+; P < 0.05]. Splenocytes from the PC1 group produced more IL-6 and TNF-α after lipopolysaccharides stimulation compared to C (P < 0.05). Splenocytes from the PC2.5 group produced more IL-2 and IL-6 after ConA stimulation compared to PC1 (P < 0.05).

Conclusions

Feeding choline as PC in the maternal diet improved the ability of immune cells to respond ex vivo to mitogens and increasing the amount of PC in the diet further improved T cell proliferation.

     

Quality of life and stability of tooth color change at three months after dental bleaching

Purpose

Intracoronary bleaching is a minimally invasive, alternative treatment that addresses aesthetic concerns related to non-vital teeth discoloration. However, to the best of our knowledge, no studies have assessed the psychosocial impacts of such procedures on patients’ aesthetic perceptions. The aim of this study was to evaluate aesthetic perceptions and the psychosocial impact of patients up to 3 months after their teeth had been bleached with hydrogen peroxide (35%) and carbamide peroxide (37%) using the walking bleach technique.

Methods

The patients were randomly divided into two groups according to the bleaching agent used: G1?=?hydrogen peroxide 35% (n?=?25) and G2?=?carbamide peroxide 37% (n?=?25). Non-vital bleaching was performed in four sessions. Color was objectively (ΔE) and subjectively (ΔSGU) evaluated. Aesthetic perception and psychosocial factors were evaluated before, 1 week and 1 month after the bleaching using the Oral Health Impact Profile (OHIP) and Psychosocial Impact of Dental Aesthetics Questionnaire (PIDAQ) questionnaires.

Results

The color change (ΔE) values at 1 month were G1?=?16.80?±?6.07 and G2?=?14.09?±?4.83. These values remained stable until the third month after treatment (p?>?0.05). There was a decrease in the values of OHIP-aesthetics and PIDAQ after treatment versus baseline (p?<?0.05). This status was maintained through the third month after treatment.

Conclusions

Both agents were highly effective and had a positive impact on the aesthetic perception and psychosocial impact of patients, values that also remained stable over time. Non-vital bleaching yields positive and stable impacts on aesthetic perception and psychosocial factors. ClinicalTrials.gov identifier NCT02718183.