Antimicrobial Peptide, LL-37, as a Potential Vaginal Contraceptive.
Notice bibliographique
Résumé
The increasing population growth and sexually transmitted diseases (STDs) call for new contraceptives that also exert anti-STD activities. Our objective is to search for antimicrobial peptides (AMPs) that are naturally present in the reproductive tract and can provide contraceptive actions. LL-37, a cathelicidin AMP found in the vagina, is likely a promising candidate for development into a vaginal contraceptive. Accumulated evidence indicates microbicidal and microstatic activities of LL-37 against STD-induced pathogens including HIV-1. LL-37 (2-10 μM) is produced in the vagina from its precursor present in the seminal plasma 2-6 h post-coitus. Therefore, motile sperm, which have already entered the uterus, are not exposed to LL-37. Like other cationic AMPs, LL-37 is known for its interaction with anionic molecules (e.g., lipopolysaccharide) on the microbial surface, which subsequently results in stasis or necrosis of the microbes. Among mammalian cells, sperm uniquely possess anionic sulfogalactosylglycerolipid (SGG) at 10 mole% of total lipids and our study indicates that LL-37 has a high affinity for SGG monolayers (immobilized in microtiter plate wells) (Kd = 455.7 ± 59.1 nM). We have previously shown that SGG is involved in egg binding via its direct affinity for the zona pellucida (ZP) as well as the formation of sperm lipid rafts, the sperm surface platforms for ZP interaction. These properties led us to investigate whether LL-37, if present together with sperm, could bind to the gametes and subsequently affect their fertilizing ability. Our study indicated that biotinylated LL-37 at a low concentration (0.36 μM) bound specifically to the convex ridge of the mouse sperm head, where SGG is localized, but at high concentrations (3.6 and 10.8 μM), it bound to the whole sperm. Significantly, treatment of capacitated mouse sperm with LL-37 dose-dependently inhibited their fertilizing ability in vitro and this parameter became zero at 3.6 μM LL-37. The decreases in sperm fertilizing ability are likely due to the loss of motility as well as the premature acrosome reaction induced by LL-37 in a dose dependent manner; at 3.6 μM LL-37, all sperm became immotile and 70% acrosome reacted. Interestingly, these inductions of LL-37 also occurred in non-capacitated sperm. Ability of LL-37-treated sperm to exclude a vital dye, Sytox Green, was further investigated. Our findings revealed that LL-37 induced Sytox Green entry to the treated sperm in a dose dependent manner, with 97-100% sperm positively stained, suggesting that LL-37 might perforate the sperm plasma membrane, and this possibility is being investigated by electron microscopy. The adverse effects of LL-37 on sperm motility, acrosome reaction induction and Sytox Green exclusion were similarly observed in non-capacitated and capacitated human sperm. In contrast, LL-37 at the same doses that induced sperm dysfunction did not cause toxicity to the human vaginal and ecto- and endocervical cell lines, as assessed by MTT reaction and Sytox Green exclusion. All of our results suggest that LL-37 can be potentially developed into a vaginal contraceptive, and we are currently assessing contraceptive effects of LL-37-included vaginal gel in vivo. Supported by Bill & Melinda Gates Foundation (Grand Challenges Exploration Program); CIHR; and scholarships from OGS and DPST (Thailand).
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».