High-grade serous ovarian cancer (HGSOC) is a lethal gynecological malignancy with a need for new therapeutics. Many of the most widely used chemotherapeutic drugs are derived from natural products or their semi-synthetic derivatives. We have developed potent synthetic analogues of a class of compounds known as phyllanthusmins, inspired by natural products isolated from Beille. The most potent analogue, PHY34, had the highest potency in HGSOC cell lines and displayed cytotoxic activity through activation of apoptosis. PHY34 exerts its cytotoxic effects by inhibiting autophagy at a late stage in the pathway, involving the disruption of lysosomal function. The autophagy activator, rapamycin, combined with PHY34 eliminated apoptosis, suggesting that autophagy inhibition may be required for apoptosis. PHY34 was readily bioavailable through intraperitoneal administration where it significantly inhibited the growth of cancer cell lines in hollow fibers, as well as reduced tumor burden in a xenograft model. We demonstrate that PHY34 acts as a late-stage autophagy inhibitor with nanomolar potency and significant antitumor efficacy as a single agent against HGSOC This class of compounds holds promise as a potential, novel chemotherapeutic and demonstrates the effectiveness of targeting the autophagic pathway as a viable strategy for combating ovarian cancer. .
A series of arylnaphthalene lignan lactones based on the structure of the phyllanthusmins, a class of potent natural products possessing diphyllin as the aglycone, has been synthesized and screened for activity against multiple cancer cell lines. SAR exploration was performed on both the carbohydrate and lactone moieties of this structural class. These studies have revealed the importance of functionalization of the carbohydrate hydroxy groups with both acetylated and methylated analogues showing increased potency relative to those with unsubstituted sugar moieties. In addition, the requirement for the presence and position of the C-ring lactone has been demonstrated through reduction and selective re-oxidation of the lactone ring. The most potent compound in this study displayed an IC value of 18 nM in an HT-29 assay with several others ranging from 50 to 200 nM. In an effort to elucidate their potential mechanism(s) of action, the DNA topoisomerase IIa inhibitory activity of the most potent compounds was examined based on previous reports of structurally similar compounds, but does not appear to contribute significantly to their antiproliferative effects.
Dietary supplementation with concentrates is regarded as an effective strategy to decrease the intensity of methane (CH4) emissions, although it has rarely been evaluated in late lactation dairy cows. The aim of the present study was to investigate the effects of two levels of dietary concentrate supplementation on CH4 emissions and milk production and composition of dairy cows in late lactation. The study was conducted using 24 multiparous Holstein Friesian cows in late lactation (253 ± 18 d in milk), and had a duration of 3 wk, including 2 wk of adaptation to the diet and 1 wk of measurements. Treatments consisted of two levels of concentrate supplementation (4 vs. 8 kg d-1 cow-1 ; as-fed) offered daily in two equal rations during milking. In addition, diets included 2 kg DM grazed grass and 8 kg as-fed of grass hay. In week 3 of the study, CH4 emissions were measured for 7 consecutive days using the sulfur hexafluoride tracer technique. Average total DM intakes for the cows fed the 4 and 8 kg concentrate treatments were 12.3 and 15.6 kg DM, respectively. Treatments had no effect on milk yield, milk fat, or milk lactose concentrations. Milk protein concentration tended to increase in cows offered 8 kg of concentrate. Higher concentrate intake tended to increase cow body mass gain, but not condition score change. The 8 kg treatment increased total CH4 emissions (g d-1) by 10.7%, whereas CH4 yield (g kg-1 DM intake) was decreased by 12.7%. Methane intensity (g kg-1 milk yield) was unaffected by treatments. Dietary concentrate supplementation for late lactation cows is ineffective in mitigating CH4 emission intensity, because animals do not respond with an increase in milk production.
<p>SF1: Synthesis & characterization of PHYs, SF2: Purity of PHYs, SF3: PHY34 cytotoxicity in various cancer types, SF4: Additional in vivo data, SF5: PHY25 & 30 cytotoxicity time course.</p>
El dengue es una enfermedad vírica febril aguda que se caracteriza por comienzo repentino de fiebre, cefaleo, mialgia, autralgia, dolor retroocular y anorexia. Este es transmitido a los humanos por picadura de la mosquita del género Aedes aegypti cuya propagación está asociado a las temperaturas tropicales, la alta humedad y bajas alturas. Además de esto, los altos índices de densidad, urbanización mal planificada y la disponibilidad de servicios públicos inadecuados hacen que la incidencia de ésta enfermedad vaya en aumento. Estas son condiciones suficientes para que en el país se detecten cuatro (4) manifestaciones del virus del dengue Durante el período comprendido entre enero de 1997 y octubre de 1998, se registraron 274 casos de fiebre dengue en un centro de salud privado de Santo Domingo, donde sólo se tomaron casos pediátricos. El tipo de dengue con más incidencia entre los niños fue el hemorrágico, con un 56% de los casos. El estudio de tipo retrospectivo, demostró al comparar estos resultados con otros previos, que el dengue ha aumentado en un 51% en un período de un (1) año y nuevo (9) meses Las medidas preventivas llevadas a cabo actualmente en el país son insuficientes y no llegan a la población más afectada: la clase obrera y dentro de ella los niños. La falta de educación de estas personas y la poca información que reciben, hacen que sean los más vulnerables de todo el universo estudiado.
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