The roundworm C. elegans reversibly arrests larval development during starvation 1, but extended early-life starvation reduces reproductive success 2, 3. Maternal dietary restriction (DR) buffers ...progeny from starvation as young larvae, preserving reproductive success 4. However, the developmental basis of reduced fertility following early-life starvation is unknown, and it is unclear how maternal diet modifies developmental physiology in progeny. We show here that extended starvation in first-stage (L1) larvae followed by unrestricted feeding results in a variety of developmental abnormalities in the reproductive system, including proliferative germ-cell tumors and uterine masses that express neuronal and epidermal cell fate markers. We found that maternal DR and reduced maternal insulin/insulin-like growth factor (IGF) signaling (IIS) increase oocyte provisioning of vitellogenin lipoprotein, reducing penetrance of starvation-induced abnormalities in progeny, including tumors. Furthermore, we show that maternal DR and reduced maternal IIS reduce IIS in progeny. daf-16/FoxO and skn-1/Nrf, transcriptional effectors of IIS, are required in progeny for maternal DR and increased vitellogenin provisioning to suppress starvation-induced abnormalities. daf-16/FoxO activity in somatic tissues is sufficient to suppress starvation-induced abnormalities, suggesting cell-nonautonomous regulation of reproductive system development. This work reveals that early-life starvation compromises reproductive development and that vitellogenin-mediated intergenerational insulin/IGF-to-insulin/IGF signaling mediates adaptation to nutrient availability.
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•Early-life starvation and unrestricted feeding result in reproductive abnormalities•Maternal dietary restriction protects progeny from starvation-induced abnormalities•Maternal diet and insulin/IGF signaling affect vitellogenin oocyte provisioning•Vitellogenin oocyte provisioning affects progeny insulin/IGF signaling
Jordan et al. show that early-life starvation causes reproductive abnormalities in C. elegans but that maternal dietary restriction increases progeny starvation resistance. Dietary restriction and reduced insulin/IGF signaling increase maternal vitellogenin provisioning, which activates daf-16/FoxO in progeny to confer protection from starvation.
•BP-1,6-Q stimulated the production of reactive oxygen species (ROS) in intact endothelial cells and isolated mitochondria.•Mitochondrial complex I and III are the sites for the overproduction of ROS ...by BP-1,6-Q.•BP-1,6-Q stimulated expression of vascular adhesion molecule and triggered endothelial-monocyte interaction.
Strong epidemiological evidence supports the association between increased air pollution and the risk of developing atherosclerotic cardiovascular diseases (CVDs). However, the mechanism remains unclear. As an environmental air pollutant and benzo-a-pyrene (BP) metabolite, BP-1,6-quinone (BP-1,6-Q) is present in the particulate phase of air pollution. This study was undertaken to examine the redox activity of BP-1,6-Q and mechanisms associated with it using EA.hy926 endothelial cells. BP-1,6-Q at 0.01–1 μM significantly stimulated the production of reactive oxygen species (ROS)·in intact cells and isolated mitochondria. Furthermore, BP-1,6-Q-induced ROS was altered by mitochondrial electron transport chain (METC) inhibitors of complex I (rotenone) and complex III (antimycin A), denoting the involvement of mitochondrial electron transport chain (METC) in BP-1,6-Q mediated ROS production. In METC deficient cells, interestingly, BP-1,6-Q-mediated ROS production was enhanced, suggesting that overproduction of ROS by BP-1,6-Q is not only produced from mitochondria but can also be from the cell outside of mitochondria (extramitochondrial). BP-1,6-Q also triggered endothelial-monocyte interaction and stimulated expression of vascular adhesion molecule-1 (VCAM-1). In conclusion, these results demonstrate that BP-1,6-Q can generate ROS within both mitochondria and outside of mitochondria, resulting in stimulation of adhesion of monocytes to endothelial cells, a key event in the pathogenesis of atherosclerosis.
Environmental pollutant exposure has gained considerable attention as a potential risk factor contributing towards cardiovascular diseases (CVDs). Acrolein is a highly reactive electrophilic aldehyde ...known for its ubiquitous presence in the atmosphere. It is generated during the burning of organic matter and fuels and gets released into the atmosphere through smoke. Acrolein has been studied in the pathology of various respiratory and neurodegenerative disorders. However, the mechanisms regulating the cardiovascular risk implications of acrolein have not been understood completely. The goal of this project was to investigate acrolein-induced cell injury and endothelial dysfunction. Acrolein, at lower concentrations of 20 and 40 µM, was shown to cause no effect in cellular viability. However, these concentrations of acrolein significantly increased monocyte-endothelial binding through increased expression of monocyte chemotactic protein-1 (MCP-1), E-selectin, and Interleukin (IL)-8. In addition, acrolein also depleted cellular and mitochondrial glutathione (GSH) and increased the levels of reactive oxygen species (ROS) in endothelial cells. Furthermore, acrolein also induced nuclear factor-kappa B (Nf-kB) transcriptional activity, degradation of inhibitor of kappa B (IkB-?), and nuclear translocation of p65 subunit. In contrast, acrolein, at higher concentrations of 80 and 120 µM, was shown to promote EA.hy926 endothelial cell death. In addition, acrolein-incurred cell death at those concentrations was classified to be necrosis, as evidenced by the increased release of lactose dehydrogenase (LDH) and increased staining of DNA-binding propidium iodide (PI). Acrolein also rapidly depleted cellular antioxidant glutathione (GSH) and phase II detoxification enzymes, glutathione-S-transferase (GST) and NAD(P)H Quinone Oxireductase-1 (NQO1), in a dose-dependent manner. To further determine the role of GSH in acrolein-mediated cytotoxicity, we pretreated the cells with buthionine sulfoximine (BSO), an inhibitor for cellular GSH biosynthesis. It was observed that depleted GSH levels significantly potentiated acrolein toxicity. Next, induction of cellular GSH levels, achieved through pre-treatment of EA.hy926 cells with CDDO-Im (1-2-cyano-3,12 dioxooleana -1,9(11)- dien-28-oyl imidazolide), was shown to offer cytoprotection against acrolein toxicity. It was also found that the upregulation of GSH by CDDO-Im involved the activation of the Nrf2/ARE signaling and increased expression of the modifier-subunit of ?-glumatylcysteine ligase (GCLM). In conclusion, acrolein at low concentrations induces monocyte-endothelial interactions, a key step in early atherosclerosis, through depletion of intracellular GSH and activation of Nf-kB pathway. Acrolein at high concentrations induces necrosis in endothelial cells, which can enhance the inflammatory response and increase the susceptibility of developing atherosclerosis. Upregulation of GSH can provide protection against acrolein-mediated cell death. The results, taken together, provide evidence for the cardiovascular risk posed by acrolein and the importance of GSH and Nf-kB in acrolein toxicity.
Vascular inflammation plays a significant role in the pathogenesis of atherosclerosis. Luteolin, a naturally occurring flavonoid present in many medicinal plants and some commonly consumed fruits and ...vegetables, has received wide attention for its potential to improve vascular function in vitro. However, its effect in vivo and the molecular mechanism of luteolin at physiological concentrations remain unclear. Here, we report that luteolin as low as 0.5μM significantly inhibited tumor necrosis factor (TNF)-α-induced adhesion of monocytes to human EA.hy 926 endothelial cells, a key event in triggering vascular inflammation. Luteolin potently suppressed TNF-α-induced expression of the chemokine monocyte chemotactic protein-1 (MCP-1) and adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), key mediators involved in enhancing endothelial cell–monocyte interaction. Furthermore, luteolin inhibited TNF-α-induced nuclear factor (NF)-κB transcriptional activity, IκBα degradation, expression of IκB kinase β and subsequent NF-κB p65 nuclear translocation in endothelial cells, suggesting that luteolin can inhibit inflammation by suppressing NF-κB signaling. In an animal study, C57BL/6 mice were fed a diet containing 0% or 0.6% luteolin for 3 weeks, and luteolin supplementation greatly suppressed TNF-α-induced increase in circulating levels of MCP-1/JE, CXCL1/KC and sICAM-1 in C57BL/6 mice. Consistently, dietary intake of luteolin significantly reduced TNF-α-stimulated adhesion of monocytes to aortic endothelial cells ex vivo. Histology shows that luteolin treatment prevented the eruption of endothelial lining in the intima layer of the aorta and preserved elastin fibers' delicate organization as shown by Verhoeff–Van Gieson staining. Immunohistochemistry studies further show that luteolin treatment also reduced VCAM-1 and monocyte-derived F4/80-positive macrophages in the aorta of TNF-α-treated mice. In conclusion, luteolin protects against TNF-α-induced vascular inflammation in both in vitro and in vivo models. This anti-inflammatory effect of luteolin may be mediated via inhibition of the NF-κB-mediated pathway.
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