Palmitate induces integrated stress response and lipoapoptosis in trophoblasts.

Maternal obesity increases the risk of childhood obesity and programs the offspring to develop metabolic syndrome later in their life. Palmitate is the predominant saturated free fatty acid (FFA) that is transported across the placenta to the fetus. We have recently shown that saturated FFA in the maternal circulation as a result of increased adipose tissue lipolysis in third trimester of pregnancy induces trophoblast lipoapoptosis. Here, we hypothesized that palmitate induces integrated stress response by activating mitogen-activated protein kinases (MAPKs), endoplasmic reticulum (ER) stress and granular stress and lipoapoptosis in trophoblasts. Choriocarcinoma-derived third-trimester placental trophoblast-like cells (JEG-3 and JAR) referred as trophoblasts were exposed to various concentrations of palmitate (PA). Apoptosis was assessed by nuclear morphological changes and caspase 3/7 activity. Immunoblot and immunofluorescence analysis was performed to measure the activation of MAPKs, ER stress and granular stress response pathways. Trophoblasts exposed to pathophysiological concentrations of PA showed a concentration-dependent increase in trophoblast lipoapoptosis. PA induces a caspase-dependent trophoblast lipoapoptosis. Further, PA induces MAPK activation (JNK and ERK) via phosphorylation, and activation of ER stress as evidenced by an increased phosphorylation eIF2α & IRE1α. PA also induces the activation of stress granules formation. Two pro-apoptotic transcriptional mediators of PA-induced trophoblast lipoapoptosis, CHOP and FoxO3 have increased nuclear translocation. Mechanistically, PA-induced JNK is critical for trophoblast lipoapoptosis. However, PA-induced activation of ERK and stress granule formation were shown to be cell survival signals to combat subcellular stress due to PA exposure. In conclusion, PA induces the activation of integrated stress responses, among which small molecule inhibition of JNK demonstrated that activation of JNK is critical for PA-induced trophoblast lipoapoptosis and small molecule activation of stress granule formation significantly prevents PA-induced trophoblast lipoapoptosis.

Novel Therapeutic Nutrients Molecules That Protect against Zika Virus Infection with a Special Note on Palmitoleate.

Zika virus (ZIKV) is a Flavivirus from the Flaviviridae family and a positive-sense single strand RNA virus. ZIKV infection can cause a mild infection to the mother but can be vertically transmitted to the developing fetus, causing congenital anomalies. The prevalence of ZIKV infections was relatively insignificant with sporadic outbreaks in the Asian and African continents until 2006. However, recent epidemic in the Caribbean showed significant increased incidence of Congenital Zika Syndrome. ZIKV infection results in placental pathology which plays a crucial role in disease transmission from mother to fetus. Currently, there is no Food and Drug Administration (FDA) approved vaccine or therapeutic drug against ZIKV. This review article summarizes the recent advances on ZIKV transmission and diagnosis and reviews nutraceuticals which can protect against the ZIKV infection. Further, we have reviewed recent advances related to the novel therapeutic nutrient molecules that have been shown to possess activity against Zika virus infected cells. We also review the mechanism of ZIKV-induced endoplasmic reticulum and apoptosis and the protective role of palmitoleate (nutrient molecule) against ZIKV-induced ER stress and apoptosis in the placental trophoblasts.