Three new quassinoids isolated from the wood of Picrasma javanica and their anti-Vpr activities.

Three new quassinoids, javanicinols A and B (1 and 2) and 4-keto-(16S)-methoxyjavanicin B (3), together with three known quassinoids (4-6) were isolated from the chloroform-soluble fraction of the methanol extract of the Picrasma javanica wood. The structures of 1-3 were determined by spectroscopic analyses, including 1D and 2D NMR, HRESIMS, and CD. The anti-HIV-1 viral protein R (Vpr) assay revealed that 1 and 2 exhibited potent anti-Vpr activities at 1.25 µM. Furthermore, the assay also revealed the potent anti-Vpr activities of (16R)-methoxyjavanicin B (7) and (16S)-methoxyjavanicin B (8), which were previously isolated from the Picrasma javanica wood.

Bis-iridoid and iridoid glycosides: Viral protein R inhibitors from Picrorhiza kurroa collected in Myanmar.

Four new bis-iridoid glycosides, saungmaygaosides A-D (1-4), and six known iridoid glycosides (5-10) were isolated from the n-butanol extract of the stems of Picrorhiza kurroa collected in Myanmar. Their structures were elucidated by extensive spectroscopic techniques. All of the isolates were assayed for anti-Vpr activity, using TREx-HeLa-Vpr cells. Among the isolates, saungmaygaoside D (4), sylvestroside IV dimethyl acetal (7), and sweroside (8) were the most potent inhibitors with effective doses of 5 and 10 µM, respectively, without showing any notable cytotoxicities.

Preventive chemotherapy reverses covert, lymphatic-associated tissue change in young people with lymphatic filariasis in Myanmar.

OBJECTIVES: This longitudinal comparative study investigated the effect of preventive chemotherapy (PC) on covert tissue changes associated with lymphatic filariasis (LF) among young people living in an LF-endemic area in Myanmar. METHODS: Tissue compressibility and extracellular free fluid in the lower limbs of people aged 10-21 years were measured using indurometry and bioimpedance spectroscopy (BIS). Baseline measures were taken in October 2014, annual mass drug administration (MDA) of PC was delivered in December, and in March 2015 further PC was offered to LF-positive cases who had missed MDA. Follow-up measures were taken in February and June 2015. RESULTS: A total of 50 antigen-positive cases and 46 antigen-negative controls were included. Self-reported PC consumption was 60.1% during 2014 MDA and 66.2% overall. At second follow-up, 24 of 34 cases and 27 of 43 controls had consumed PC. Significant and clinically relevant between-group differences at baseline were not found post-PC. Bayesian linear mixed models showed a significant change in indurometer scores at both calves for antigen-positive cases who consumed any PC (dominant calf: -0.30 [95% CI -0.52, -0.07], P < 0.05 and non-dominant calf: -0.35 [95% CI -0.58, -0.12], P < 0.01). Changes in antigen-negative participants or those not consuming PC were not significant. CONCLUSION: This study is the first attempt to use simple field-friendly tools to track fluid and tissue changes after treatment of asymptomatic people infected with LF. Results suggested that PC alone is sufficient to reverse covert lymphatic disturbance. Longer follow-up of larger cohorts is required to confirm these improvements and whether they persist over time. These findings should prompt increased efforts to overcome low PC coverage, which misses many infected young people, particularly males, who are unaware of their infection status, unmotivated to take PC and at risk of developing lymphoedema. Indurometry and BIS should be considered in assessment of lymphatic filariasis-related lymphedema.

OBJECTIFS: Cette étude comparative longitudinale a investigué l'effet de la chimiothérapie préventive (CP) sur les modifications tissulaires cachées associées à la filariose lymphatique (FL) chez les jeunes vivant dans une zone d'endémie pour la FL au Myanmar. MÉTHODES: La compressibilité des tissus et le liquide libre extracellulaire dans les membres inférieurs des personnes âgées de 10 à 21 ans ont été mesurés par indurométrie et spectroscopie de bioimpédance (BIS). Les mesures de base ont été prises en octobre 2014, la distribution en masse de médicament (DMM) annuelle a été administrée en décembre et en mars 2015, et une CP additionnelle a été offerte aux cas positifs pour la FL qui avaient manqué la DMM. Des mesures de suivi ont été prises en février et juin 2015. RÉSULTATS: 50 cas positifs pour l'antigène et 46 témoins négatifs ont été inclus. L'administration de CP auto-déclarée était de 60,1% durant la DMM de 2014 et de 66,2% au total. Au deuxième suivi, 24 des 34 cas et 27 des 43 témoins avaient pris la CP. Des différences significatives et cliniquement pertinentes entre les groupes au départ n'ont pas été trouvées après la CP. Les modèles mixtes linéaires bayésiens ont montré un changement significatif des scores d'indurometrie aux deux mollets pour les cas positifs pour l'antigène qui prenaient une CP (mollet dominant: -0,30 [IC95%: -0,52, -0,07], p <0,05, mollet non dominant: - 0,35 [IC95%: -0,58, -0,12], p <0,01). Les changements chez les participants négatifs pour l'antigène ou ceux qui ne prenaient pas de CP n'étaient pas significatifs. CONCLUSION: Cette étude est la première tentative d'utilisation d'outils simples, conviviaux sur le terrain, pour suivre les modifications du tissu conjonctif après le traitement de personnes asymptomatiques infectées par la FL. Les résultats suggèrent que la CP seule est suffisante pour inverser les modifications lymphatiques cachées. Un suivi plus long de plus grandes cohortes est nécessaire pour confirmer ces améliorations et déterminer si elles persistent ou non. Ces résultats devraient inciter à redoubler d'efforts pour surmonter la faible couverture en CP, qui rate beaucoup de jeunes infectés, en particulier les hommes, qui ne sont pas au courant de leur statut d'infection, qui ne sont pas motivés pour prendre une CP et risquent de développer un lymphœdème. L'indurométrie et la BIS devraient être considérées dans l'évaluation du lymphoedème associé à la filariose lymphatique.

Two new quassinoids and other constituents from Picrasma javanica wood, and their biological activities.

Picrasma javanica Blume (Simaroubaceae) is a medium-sized tree that is distributed widely in tropical Asia. In our previous study, we isolated quassinoids from P. javanica bark collected in Myanmar, and reported their antiproliferative activities. In our ongoing research for the discovery of bioactive compounds from Myanmar medicinal plants, two new quassinoids, (16R)-methoxyjavanicin B (1) and (16S)-methoxyjavanicin B (2), along with seven known compounds (3-9), were isolated during the phytochemical investigation of the CHCl3 soluble portion of the MeOH extract of P. javanica wood. The structures of the new compounds were elucidated by analyses of their spectroscopic data (1D- and 2D-NMR, HRESIMS, and CD). A cytotoxicity assay revealed that compound 8 showed moderate activities against all tested cancer cell lines, the human lung (A549), breast (MCF7), and cervical (HeLa), and the normal fibroblast cell line, with IC50 values ranging from 48.6 to 65.9 µM. Furthermore, the antibacterial assay demonstrated that 1 and 2 had the highest activities (MIC value of 1.6 µM each), followed by 5 and 3 (MIC values of 3.1 and 6.3 µM, respectively) against the Gram-positive bacterium B. subtilis.

Labdane diterpenoids from Curcuma amada rhizomes collected in Myanmar and their antiproliferative activities.

Four new labdane diterpenoids, 12ß-hydroxy-15-norlabda-8(17),13(14)-dien-16-oic acid (1), (E)-15-ethoxy-15-methoxylabda-8(17),12-dien-16-al (2), (E)-15α-ethoxy-14α-hydroxylabda-8(17),12-dien-16-olide (3), and 15-ethoxy-12ß-hydroxylabda-8(17),13(14)-dien-16,15-olide (4) were isolated from the methanol extract of Curcuma amada rhizomes collected in Myanmar, together with 13 known analogs. Their structures were elucidated by extensive spectroscopic techniques. All of the isolates were evaluated for their antiproliferative activities against a small panel of five different human cancer cell lines (A549, human lung cancer; HeLa, human cervical cancer; MCF7, human breast cancer; PANC-1 and PSN-1, human pancreatic cancer). Among the isolates, compounds 2-4, 7, 8, 12, and 17 showed mild antiproliferative activities with IC50 values ranging from 19.7 to 96.1µM. (E)-14-Hydroxy-15-norlabda-8(17),12-dien-16-al (11) exhibited strong antiproliferative activities selectively against HeLa, PANC-1, and PSN-1 cells, with IC50 values of 5.88, 1.00, and 3.98µM, respectively. These potencies were comparable to those of the positive control, 5-fluorouracil.

Lymphatic Filariasis Increases Tissue Compressibility and Extracellular Fluid in Lower Limbs of Asymptomatic Young People in Central Myanmar.

When normal lymphatic function is hampered, imperceptible subcutaneous edema can develop and progress to overt lymphedema. Low-cost reliable devices for objective assessment of lymphedema are well accepted in clinical practice and research on breast-cancer related lymphedema but are untested in populations with lymphatic filariasis (LF). This is a cross-sectional analysis of baseline data in a longitudinal study on asymptomatic, LF antigen-positive and -negative young people in Myanmar. Rapid field screening was used to identify antigen-positive cases and a group of antigen-negative controls of similar age and gender were invited to continue in the study. Tissue compressibility was assessed with three tissue tonometers, and free fluids were assessed using bio-impedance spectroscopy (BIS). Infection status was confirmed by Og4C3 antigen assay. At baseline (n = 98), antigen-positive cases had clinically relevant increases in tissue compressibility at the calf using a digital Indurometer (11.1%, p = 0.021), and in whole-leg free fluid using BIS (9.2%, p = 0.053). Regression analysis for moderating factors (age, gender, hydration) reinforced the between-infection group differences. Results demonstrate that sub-clinical changes associated with infection can be detected in asymptomatic cases. Further exploration of these low-cost devices in clinical and research settings on filariasis-related lymphedema are warranted.

Quassinoids: Viral protein R inhibitors from Picrasma javanica bark collected in Myanmar for HIV infection.

Viral protein R (Vpr) is an accessory protein that plays important roles in the viral pathogenesis of Human Immunodeficiency Virus-1 (HIV-1). An assay for anti-Vpr activity, using TREx-HeLa-Vpr cells, is a promising strategy to discover Vpr inhibitors. The anti-Vpr assay revealed that the CHCl3-soluble extract of Picrasma javanica bark possesses potent anti-Vpr activity. Furthermore, studies of quassinoids (1-15) previously isolated from the extract demonstrated that all of the tested quassinoids exhibit anti-Vpr activity. Among the tested compounds, javanicin I (15) exhibited the most potent anti-Vpr activity ((***)p <0.001) in comparing with that of the positive control, damnacanthal. The structure-activity relationships of the active quassinoids suggested that the presence of a methyl group at C-13 in the 2,12,14-triene-1,11,16-trione-2,12-dimethoxy-18-norpicrasane quassinoids is the important factor for the potent inhibitory effect in TREx-HeLa-Vpr cells.

Picrajavanicins A-G, Quassinoids from Picrasma javanica Collected in Myanmar.

Seven new tetracyclic quassinoids, picrajavanicins A-G (1-7), along with three known analogues, were isolated from a CHCl3-soluble extract of the bark of Picrasma javanica collected in Myanmar. The structures of these compounds were elucidated using spectroscopic techniques, including 1D and 2D NMR. The absolute configuration at C-2 of 2 was determined to be S by the modified Mosher method. All the isolates were tested for their antiproliferative activities against a small panel of five human cancer cell lines. However, none of the isolated compounds exhibited inhibitory activity against any of the cancer cells used (IC50 values >10 µM).