Infection by Japanese Encephalitis Virus (JEV) in humans is primarily characterized by signs and symptoms including non-specific febrile illness, arthralgia, myalgia etc. followed by its resolution due to joint action of host innate and adaptive immunity. However, in selective cases, complications arise owing to invasion of central nervous system (CNS) by JEV. Patients being unable to control peripheral viral replication owing to differences in host genetics and immunity experience JEV-associated neurological complications manifested in the form of headache, nausea, meningoencephalitis, coma and eventual death. Entry of JEV into CNS activates complex cascade of events resulting in loss of neuronal physiology and thus CNS tissue integrity. In present study, we have demonstrated role played by JEV in modulation of neuronal pyruvate dehydrogenase kinase 1 (PDK1) abundance and its effect upon neuronal health. Infection of neuron by JEV culminates into upregulation of PDK1 abundance. Albeit inhibition of JEV-induced PDK1-upregulation was accompanied by enhanced JEV propagation in neurons, abrogation of PDK1-upregulation was demonstrated to ameliorate neuronal apoptosis. PDK1 inhibition-associated reduction in neuronal death was observed to be associated with reduced generation of reactive oxygen species (ROS) in neurons. Our study hence provides a possible therapeutic target which upon modulation might help combat JEV infection-associated neuronal apoptosis via restoration of JEV-associated ROS generation.

Recent studies have revealed that cancer stem cells (CSCs) undergo metabolic alterations that differentiate them from non-CSCs. Inhibition of specific metabolic pathways in CSCs has been conducted to eliminate the CSC population in many types of cancer. However, there is conflicting evidence about whether CSCs depend on glycolysis or mitochondrial oxidative phosphorylation (OXPHOS) to maintain their stem cell properties. This review summarizes the latest knowledge regarding CSC-specific metabolic alterations and offers recent evidence that the surrounding microenvironments may play an important role in the maintenance of CSC properties.

Diabetes is a risk factor for breast cancer development and is associated with poor prognosis for breast cancer patients. However, the molecular and biochemical mechanisms underlying the association between diabetes and breast cancer have not been fully elucidated. Here, we investigated estradiol response in MCF-7 breast cancer cells with or without chronic exposure to insulin. We found that insulin priming is necessary and specific for estradiol-induced cancer cell growth, and induces anaplerotic shunting of glucose into macromolecule biosynthesis in the estradiol treated cells. Treatment with ERK or Akt specific inhibitors, U0126 or LY294002, respectively, suppressed estradiol-induced growth. Interestingly, molecular analysis revealed that estradiol treatment markedly increases expression of cyclin A and B, and decreases p21 and p27 in the insulin-primed cells. In addition, estradiol treatment activated metabolic genes in pentose phosphate (PPP) and serine biosynthesis pathways in the insulin-primed cells while insulin priming decreased metabolic gene expression associated with glucose catabolism in the breast cancer cells. Finally, we found that anti-diabetic drug metformin and AMPK ligand AICAR, but not thiazolidinediones (TZDs), specifically suppress the estradiol-induced cellular growth in the insulin-primed cells. These findings suggest that estrogen receptor (ER) activation under chronic hyperinsulinemic condition increases breast cancer growth through the modulation of cell cycle and apoptotic factors and nutrient metabolism, and further provide a mechanistic evidence for the clinical benefit of metformin use for ER-positive breast cancer patients with diabetes.