Sargassum fusiforme fraction is a potent and specific inhibitor of HIV-1 fusion and reverse transcriptase.

Sargassum fusiforme (Harvey) Setchell has been shown to be a highly effective inhibitor of HIV-1 infection. To identify its mechanism of action, we performed bioactivity-guided fractionation on Sargassum fusiforme mixture. Here, we report isolation of a bioactive fraction SP4-2 (S. fusiforme), which at 8 mug/ml inhibited HIV-1 infection by 86.9%, with IC50 value of 3.7 mug. That represents 230-fold enhancement of antiretroviral potency as compared to the whole extract. Inhibition was mediated against both CXCR4 (X4) and CCR5 (R5) tropic HIV-1. Specifically, 10 mug/ml SP4-2 blocked HIV-1 fusion and entry by 53%. This effect was reversed by interaction of SP4-2 with sCD4, suggesting that S. fusiforme inhibits HIV-1 infection by blocking CD4 receptor, which also explained observed inhibition of both X4 and R5-tropic HIV-1. SP4-2 also inhibited HIV-1 replication after virus entry, by directly inhibiting HIV-1 reverse transcriptase (RT) in a dose dependent manner by up to 79%. We conclude that the SP4-2 fraction contains at least two distinct and biologically active molecules, one that inhibits HIV-1 fusion by interacting with CD4 receptor, and another that directly inhibits HIV-1 RT. We propose that S. fusiforme is a lead candidate for anti-HIV-1 drug development.

Inhibition of highly productive HIV-1 infection in T cells, primary human macrophages, microglia, and astrocytes by Sargassum fusiforme.

BACKGROUND: The high rate of HIV-1 mutation and increasing resistance to currently available antiretroviral (ART) therapies highlight the need for new antiviral agents. Products derived from natural sources have been shown to inhibit HIV-1 replication during various stages of the virus life cycle, and therefore represent a potential source of novel therapeutic agents. To expand our arsenal of therapeutics against HIV-1 infection, we investigated aqueous extract from Sargassum fusiforme (S. fusiforme) for ability to inhibit HIV-1 infection in the periphery, in T cells and human macrophages, and for ability to inhibit in the central nervous system (CNS), in microglia and astrocytes. RESULTS: S. fusiforme extract blocked HIV-1 infection and replication by over 90% in T cells, human macrophages and microglia, and it also inhibited pseudotyped HIV-1 (VSV/NL4-3) infection in human astrocytes by over 70%. Inhibition was mediated against both CXCR4 (X4) and CCR5 (R5)-tropic HIV-1, was dose dependant and long lasting, did not inhibit cell growth or viability, was not toxic to cells, and was comparable to inhibition by the nucleoside analogue 2', 3'-didoxycytidine (ddC). S. fusiforme treatment blocked direct cell-to-cell infection spread. To investigate at which point of the virus life cycle this inhibition occurs, we infected T cells and CD4-negative primary human astrocytes with HIV-1 pseudotyped with envelope glycoprotein of vesicular stomatitis virus (VSV), which bypasses the HIV receptor requirements. Infection by pseudotyped HIV-1 (VSV/NL4-3) was also inhibited in a dose dependant manner, although up to 57% less, as compared to inhibition of native NL4-3, indicating post-entry interferences. CONCLUSION: This is the first report demonstrating S. fusiforme to be a potent inhibitor of highly productive HIV-1 infection and replication in T cells, in primary human macrophages, microglia, and astrocytes. Results with VSV/NL4-3 infection, suggest inhibition of both entry and post-entry events of the virus life cycle. Absence of cytotoxicity and high viability of treated cells also suggest that S. fusiforme is a potential source of novel naturally occurring antiretroviral compounds that inhibit HIV-1 infection and replication at more than one site of the virus life cycle.

Chronic hypoxia alters vasoconstrictive responses of femoral artery in the fetal sheep.

The purpose of this study was to determine if mild hypoxia alters the responsiveness to vasoactive agents in the renal and the femoral arteries in the fetal sheep. Ten pregnant sheep were operated under halothane anesthesia at 116 to 124 days' gestation. A maternal tracheal catheter was placed for infusing compressed air (control group, n=5) or nitrogen (hypoxia group, n=5) starting on post operative day 6 and maintained for 5 days. Femoral and renal arteries were harvested from the fetus to study the constriction response to phenylephrine (PE 10(-9) to 10(-5)mol/L). To determine the involvement of nitric oxide as a modulator of vessel constriction, N-nitro-L-arginine methyl ester (L-NAME) was used at a concentration of 10 -4 mol/L in parallel chambers. In the hypoxia group, maternal PaO2 significantly decreased from a base-line of 110.4+/-1.4 to 80.5+/-1.6 (mmHg, p<0.01), fetal PaO2 significantly decreased from a baseline of 20.9+/-0.3 to 15.5+/-0.1 (mmHg, p<0.01). Hypoxia was associated with a significant increase in PE maximal response in the absence (184.5+/-6.6 vs. 146.2+/-4.3) and presence (166.9+/-6.3 vs. 145.0+/-4.5) of L-NAME, and a decrease in EC50 in the absence (6.0+/-1.1 vs. 27.0+/-4.1) of L-NAME of femoral arteries. However, there were no significant differences in PE maximal response and EC50 in the absence and presence of L-NAME of renal arteries. We concluded that mild chronic hypoxia seems to increase the fetal femoral artery response to PE, but not in the fetal renal artery. This observation is consistent with a redistribution of cardiac output away from the carcass.

The Ronald McDonald House as an alternative to antepartum hospitalization.

OBJECTIVE: We sought to evaluate the use of the Ronald McDonald House (RMH) for selected high-risk pregnant women. METHODS: Beginning in November of 1999, women on the Maternal Fetal Medicine service at Albany Medical Center Hospital (AMCH) were candidates for antepartum lodging at the Ronald McDonald House (RMH). Women whose only indication for antepartum hospitalization was to maintain proximity to a tertiary care center were offered stays at the RMH. Antenatal and neonatal outcomes were reviewed. RESULTS: A total of 41 antepartum subjects stayed at the RMH during the study period. No adverse perinatal outcomes were identified due to utilization of the RMH. Patients stayed at the RMH instead of staying at AMCH as inpatients for a total of 586 days during the study period. CONCLUSIONS: Outpatient management at the RMH is a cost-effective alternative for selected high-risk pregnancies. No adverse outcomes in the study population were attributable to the utilization of the RMH.

The timing of elective delivery in preterm premature rupture of the membranes: a survey of members of the Society of Maternal-Fetal Medicine.

OBJECTIVE: We sought to assess the gestational age at which elective delivery is considered in an otherwise uncomplicated patient with preterm premature rupture of the membranes (PROM) by members of the Society of Maternal Fetal-Medicine (SMFM). STUDY DESIGN: A 3-page survey was mailed to members of the SMFM for this observational study. Information solicited included demographic data and practice patterns for the timing of delivery in patients with preterm PROM. RESULTS: Seven hundred seventeen questionnaires (40%) were completed. The majority (81%) did not believe there is a consensus regarding the gestational age for elective delivery in patients with preterm PROM. With confirmed fetal lung maturity, the greatest number of respondents selected 32 and 34 weeks as the earliest gestational age for elective delivery. In the absence of fetal pulmonary maturity testing, the majority of respondents chose 34 weeks. CONCLUSION: Most SMFM respondents electively deliver uncomplicated patients with preterm PROM by 34 weeks' gestation.