Nimbolide, a plant-derived limonoid has been shown to exert its antiproliferative effects in various cell lines. We demonstrate that nimbolide effectively inhibited proliferation of WiDr colon cancer cells through inhibition of cyclin A leading to S phase arrest. It also caused activation of caspase-mediated apoptosis through the inhibition of ERK1/2 and activation of p38 and JNK1/2. Further nimbolide effectively retarded tumor cell migration and invasion through inhibition of metalloproteinase-2/9 (MMP-2/9) expression, both at the mRNA and protein level. It was also a strong inhibitor of VEGF expression, promoter activity, and in vitro angiogenesis. Finally, nimbolide suppressed the nuclear translocation of p65/p50 and DNA binding of NF-κB, which is an important transcription factor for controlling MMP-2/9 and VEGF gene expression.

Heart diseases are common in the offspring of diabetic mother (ODM). Defects in mitochondrial metabolism and autophagy may, in part, be responsible for the adverse structural and functional alterations in the heart. The principal objective of this study was to investigate cardiac mitochondrial respiration and autophagy in male and female offspring of diabetic pregnancy at two different developmental stages of life, weaning and adult. Male and female offspring of rats with streptozotocin-induced gestational diabetes were used for the study and compared with offspring of control (non-diabetic) mother (OCM) rats. High-resolution respirometry was used to measure substrate-mediated respiration in mitochondria isolated from ventricular tissues of ODM and OCM. Expression of proteins associated with autophagy and oxidative stress was examined by western blot analysis. Mitochondrial complex I and complex II respiration was significantly reduced in adult male ODM while it was unaltered or less affected in weaning male, adult and weaning female ODM. Elevated autophagy was observed in adult male but not in adult female ODM. Expression of oxidative stress markers was observed to be similar in all the groups. Altered cardiac mitochondrial respiration and autophagy were observed in adult male ODM compared to OCM, while the male and female offspring at weaning stage were less affected. The results of the study show that maternal hyperglycemia affects mitochondrial respiration and autophagy in the ODM heart, which may potentially be responsible for the cardiovascular complications observed in adult life.

ObjectiveHeart diseases are common in offspring of gestational diabetic mother (ODM). Defects in mitochondrial metabolism and autophagy may be one of the basic reasons behind the abnormal structural and functional behaviour of offspring’s heart. So the main objective of the present study was to explore the cardiac mitochondrial respiration and autophagy in male and female offspring of diabetic pregnancy at two different developmental stages of life.MethodsHigh‐resolution respirometry was used to measure substrate‐mediated mitochondrial respiration in isolated mitochondria from ventricular tissues of offspring of streptozotocin‐induced diabetic mother rats. To find the expression of proteins involved in autophagic process and oxidative stress, western blotting and densitometric analysis were done.ResultsMitochondrial complex I and complex II respiration was found to be decreased in adult male offspring while it was unaltered or less affected in weaning male and female offspring. Elevated autophagy was shown by adult male, while there was no change observed in adult female. Also absence of elevated expression of oxidative stress markers was observed in all groups.ConcusionThe present study reports altered cardiac mitochondrial respiration and autophagy in male offspring of diabetic mothers than the control ones. The study also analysed the expression of various candidates of cardiac autophagic process in male and female offspring of diabetic pregnancy at two time points of development.