No abstract

GRP78 is a positive modifier for sorafenib resistance acquisition in HCC and represents a prime target for overcoming sorafenib resistance.

It has been postulated that folic acid (folate) deficiency (FD) may be a risk factor for the pathogenesis of a variety of oxidative stress-triggered chronic degenerative diseases including diabetes, however, the direct evidence to lend support to this hypothesis is scanty. For this reason, we set out to study if FD can trigger the apoptotic events in an insulin-producing pancreatic RINm5F islet β cells. When these cells were cultivated under FD condition, a time-dependent growth impediment was observed and the demise of these cells was demonstrated to be apoptotic in nature proceeding through a mitochondria-dependent pathway. In addition to evoke oxidative stress, FD condition could also trigger nitrosative stress through a NF-κB-dependent iNOS-mediated overproduction of nitric oxide (NO). The latter compound could then trigger depletion of endoplasmic reticulum (ER) calcium (Ca2+) store leading to cytosolic Ca2+ overload and caused ER stress as evidence by the activation of CHOP expression. Furthermore, FD-induced apoptosis of RINm5F cells was found to be correlated with a time-dependent depletion of intracellular gluthathione (GSH) and a severe down-regulation of Bcl-2 expression. Along the same vein, we also demonstrated that FD could severely impede RINm5F cells to synthesize insulin and their abilities to secret insulin in response to glucose stimulation were appreciably hampered. Even more importantly, we found that folate replenishment could not restore the ability of RINm5F cells to resynthesize insulin. Taken together, our data provide strong evidence to support the hypothesis that FD is a legitimate risk factor for the pathogenesis of diabetes.

Photodynamic therapy (PDT) is a rapidly evolving treatment modality with diverse usages in the field of cancer therapy. Most of PDT is based on free radical-mediated photo-killing of cancer cells. This study aimed to elucidate the detailed cascade of events that lead to apoptotic cell death of HepG2 cells resulting from the photodynamic effect (PDE) of verteporfin. PDE of verteporfin could rapidly provoke hyper-oxidative stress and caspase activity. Glutathione (GSH) depletion and lipid peroxidation phenomena could simultaneously be evoked. The membrane integrity was decreased and permeability as reflected by the depolarization of the mitochondrial membrane potential (Deltapsi(m)) increased, resulting in a sudden influx of cytosolic calcium into the mitochondria. Altogether, it is suggested that these events serve as the final arbitrator to initiate the lethal apoptotic process of HepG2 cells under PDE. In addition, the data are consistent with the notion that GSH depletion is an effective strategy to sensitize cancer cells to undergo apoptosis.