Placoisoflavones A and B, two new cytotoxic isoflavonoids from Placolobium vietnamense N.D.Khôi & Yakovlev.

Two previously unreported isoflavonoids, placoisoflavones A and B (1 and 2), along with five known compounds, calopogonium isoflavone B (3), jamaicin (4), 6-methoxycalopogonium isoflavone A (5), vestitol (6), and caviunin (7) have been isolated from the stems of Placolobium vietnamense N.D.Khôi & Yakovlev. The structures of all isolated compounds were fully characterized using spectroscopic data and comparison with the previous literature. The cytotoxicity of all isolated compounds was evaluated against HepG2 cell line, and compound 1 showed the most potent cytotoxicity with an IC50 value of 8.0 µM.

New prenyl flavanone and diarylbutanol from Uvaria siamensis stem bark and their α-glucosidase inhibitory activity.

One new prenyl flavanone (1), (2S)-8-prenyl-5,6-dihydroxy-7-methoxyflavanone, and one new diarylbutanol (2), (7'S)-3'-hydroxy-linderagatin-A, were isolated from the stem bark of Uvaria siamensis (Annonaceae), along with five known compounds, eriodictyol (3), quercetin (4), paprazine (5), N-trans-caffeoyltyramine (6), and N-trans-feruloyltyramine (7). Their structures were determined through extensive spectroscopic analyses and comparison with the literature. The α-glucosidase inhibitory potential of 1-7 was evaluated. Compound 6 showed the highest inhibitory activity against α-glucosidase and exhibited superior potency compared to the positive control, with an IC50 value of 0.12 µM.

Opportunities and challenges for the development of M1 muscarinic receptor positive allosteric modulators in the treatment for neurocognitive deficits.

Targeting allosteric sites of M1 muscarinic acetylcholine receptors (M1 receptors) is a promising strategy to treat neurocognitive disorders, such as Alzheimer's disease and schizophrenia. Indeed, the last two decades have seen an impressive body of work focussing on the design and development of positive allosteric modulators (PAMs) for the M1 receptor. This has led to the identification of a structurally diverse range of highly selective M1 PAMs. In preclinical models, M1 PAMs have shown rescue of cognitive deficits and improvement of endpoints predictive of symptom domains of schizophrenia. Yet, to date only a few M1 PAMs have reached early-stage clinical trials, with many of them failing to progress further due to on-target mediated cholinergic adverse effects that have plagued the development of this class of ligand. This review covers the recent preclinical and clinical studies in the field of M1 receptor drug discovery for the treatment of Alzheimer's disease and schizophrenia, with a specific focus on M1 PAM, highlighting both the undoubted potential but also key challenges for the successful translation of M1 PAMs from bench-side to bedside.

Two new dimethylpyranoflavanones from the roots of Melodorum fruticosum.

Two previously unreported dimethylpyranoflavanones, pyronomelodorones A and B (1 and 2), along with five known compounds, 7-O-methyldihydrowogonin (3), 5,6,7-trimethoxyflavanone (4), 5,6-dihydroxy-7-methoxy-dihydroflavone (5), 5,7,8-trimethoxydihydroflavone (6), and pinostrobin (7), were isolated from the roots of Melodorum fruticosum. The structures of all isolates were fully characterized using spectroscopic data and comparison with the previous literature. All isolates were evaluated for their in vitro α-glucosidase inhibition and their cytotoxicity against KB, HepG2, and MCF7 cell lines. Among the isolates, compound 1 exhibited the most inhibitory activity against α-glucosidase and was superior to the positive control with an IC50 value of 1.32 µM. Compounds 1 and 2 showed weak cytotoxicity against the three human cancer cell lines, with IC50 values in the range of 53.3-79.0 µM.

The metabolic effects of mirabegron are mediated primarily by ß3 -adrenoceptors.

The ß3 -adrenoceptor agonist mirabegron is approved for use for overactive bladder and has been purported to be useful in the treatment of obesity-related metabolic diseases in humans, including those involving disturbances of glucose homeostasis. We investigated the effect of mirabegron on glucose homeostasis with in vitro and in vivo models, focusing on its selectivity at ß-adrenoceptors, ability to cause browning of white adipocytes, and the role of UCP1 in glucose homeostasis. In mouse brown, white, and brite adipocytes, mirabegron-mediated effects were examined on cyclic AMP, UCP1 mRNA, [3 H]-2-deoxyglucose uptake, cellular glycolysis, and O2 consumption. Mirabegron increased cyclic AMP levels, UCP1 mRNA content, glucose uptake, and cellular glycolysis in brown adipocytes, and these effects were either absent or reduced in white adipocytes. In brite adipocytes, mirabegron increased cyclic AMP levels and UCP1 mRNA content resulting in increased UCP1-mediated oxygen consumption, glucose uptake, and cellular glycolysis. The metabolic effects of mirabegron in both brown and brite adipocytes were primarily due to actions at ß3 -adrenoceptors as they were largely absent in adipocytes derived from ß3 -adrenoceptor knockout mice. In vivo, mirabegron increased whole body oxygen consumption, glucose uptake into brown and inguinal white adipose tissue, and improved glucose tolerance, all effects that required the presence of the ß3 -adrenoceptor. Furthermore, in UCP1 knockout mice, the effects of mirabegron on glucose tolerance were attenuated. Thus, mirabegron had effects on cellular metabolism in adipocytes that improved glucose handling in vivo, and were primarily due to actions at the ß3 -adrenoceptor.

A sesquiterpenoid tropolone and 1,2,3,4-tetrahydronaphthalene derivatives from Olax imbricata roots.

The methanol extract of Olax imbricata roots afforded one new sesquiterpenoid tropolone and three new 1,2,3,4-tetrahydronaphthalene derivatives, olaximbrisides A-D (1-4). Their structures were determined by 1D and 2D NMR experiments in combination of HRESIMS. The relative configurations were assigned by the NOESY experiments. The absolute configurations were established by a combination of X-ray diffraction analysis and electronic circular dichroism (ECD) experiments. All isolated compounds were evaluated for their cytotoxic effects against some cancer cell lines. Among them, compound 1 exhibited the cytotoxicities against MCF-7, HepG2 and LU cell lines with IC50 values of 16.3, 34.3 and 8.0 µM, respectively.

Homosexuality-related stigma and sexual risk behaviors among men who have sex with men in Hanoi, Vietnam.

This article examined the associations between three forms of homosexuality-related stigma (enacted, perceived, and internalized homosexual stigmas) with risky sexual behaviors, and to describe the mechanisms of these associations, among men who have sex with men (MSM) in Hanoi, Vietnam. We used respondent-driven sampling (RDS) to recruit 451 MSM into a cross-sectional study conducted from August 2010 to January 2011. Data were adjusted for recruitment patterns due to the RDS approach; logistic regression and path analyses were performed. Participants were young and single; most had attended at least some college. Nine out of ten participants engaged in sexual behaviors at moderate to high risk levels. Compared to those who had no enacted homosexual stigma, men having low and high levels of enacted homosexual stigma, respectively, were 2.23 times (95 % CI 1.35-3.69) and 2.20 times (95 % CI 1.04-4.76) more likely to engage in high levels of sexual risk behaviors. In addition, there was an indirect effect of perceived homosexual stigma and internalized homosexual stigma on sexual risk behaviors through depression and drug and alcohol use. Our study provides valuable information to our understanding of homosexual stigma in Vietnam, highlighting the need for provision of coping skills against stigma to the gay community and addressing drinking and drug use among MSM, to improve the current HIV prevention interventions in Vietnam.

Measurement of Stigma in Men Who Have Sex with Men in Hanoi, Vietnam: Assessment of a Homosexuality-Related Stigma Scale.

Objective. To develop and assess a homosexuality-related stigma scale among men who have sex with men (MSM) in Hanoi, Vietnam. Methods. We conducted a cross-sectional study using respondent-driven sampling in Hanoi, Vietnam, in 2011. We used a cross-validation approach. Factor analysis was performed, and interitem correlation matrices were constructed to identify the latent factor structures, examine the goodness of fit, and assess convergent and discriminant validity of the determined scales. Internal consistency checks were performed in split samples and whole sample, and separately for each determined factor. Results. The findings were consistent in split samples. Three homosexuality-related stigma factors were identified: enacted homosexual stigma, perceived homosexual stigma, and internalized homosexual stigma. The fit indices of the confirmatory factor analysis in both split samples supported the hypothesized three-factor structures (in subsamples A and B: χ (2)/degrees of freedom ratio = 1.77 and 1.59, nonnormed fit index = 0.92 and 0.94, comparative fit index = 0.93 and 0.95, and the root mean square of approximation = 0.06 and 0.05, resp.). The interitem correlation supported the convergent and discriminant validity of the scales. The reliability of the three scales indicated good consistency (Cronbach's alpha: 0.79-0.84) across split samples and for the whole data. Conclusion. Our scales have good psychometric properties for measuring homosexuality-related stigma. These comprehensive and practical tools are crucial not only to assess stigma against MSM and its consequence, but also to guide the development of interventions targeting MSM, as well as to evaluate the efficacy of existing stigma reduction efforts in Vietnam and other countries with similar settings.

Development and characterization of candidate rotavirus vaccine strains derived from children with diarrhoea in Vietnam.

In Vietnam, rotavirus infection accounts for more than one-half of all hospitalizations for diarrhoea among children less than 5 years of age. While new vaccines to prevent rotavirus diarrhoea have been developed and introduced into some countries by multinational manufacturers, the ability for developing countries such as Vietnam to introduce several new and important vaccines into the routine infant immunization schedule may be challenging. In order to be partially self-sufficient in vaccine production, Vietnam has pursued the development of several rotavirus strains as candidate vaccines using isolates obtained from Vietnamese children with diarrhoea. This paper describes the origin, isolation and characterization of 3 human rotavirus strains being considered for further vaccine development in Vietnam. The goal is to prepare a monovalent G1P [8] rotavirus vaccine using one of these strains obtained in Vietnam and naturally attenuated by multiple passages in cell culture. While this is an ambitious project that will require several years' work, we are using the lessons learned to improve the overall quality of vaccine production including the use of Vero cell techniques for the manufacture of other vaccines in Vietnam.