Increased oxidative stress and mitochondrial impairments associated with increased expression of TNF-α and caspase-3 in palmitic acid-induced lipotoxicity in myoblasts.

Saturated fatty acids, whose circulating levels are markedly increased in the body, significantly affect the growth and functions of skeletal muscle. These fatty acids may exert a detrimental effect on the undifferentiated skeletal myoblasts that may adversely affect their differentiation. In the present study, the exposure of myoblasts to excess palmitic acid caused an elevation of tumor necrosis factor-α expression and an increase in reactive oxygen species levels consistent with the enhanced inflammation and oxidative stress. Various concentrations of palmitic acid significantly decreased the mitochondrial membrane potential, induced the programmed cell death by an increase in the caspase-3 expression, and DNA fragmentation in the myoblasts. These findings suggest that the increased concentrations of saturated fatty acid in the myoblasts increase lipotoxicity by increasing inflammation and oxidative stress, decreasing the mitochondrial function, and inducing apoptosis.

Flavonoid-based therapies in the early management of neurodegenerative diseases.

During the past several years, there has been enormous progress in the understanding of the causative factors that initiate neuronal damage in various neurodegenerative diseases, including Alzheimer disease, Parkinson disease, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington disease. Preventing neuronal damage and neuronal death will have a huge clinical benefit. However, despite major advances in causative factors that trigger these neurodegenerative diseases, to date there have been no therapies available that benefit patients who suffer from these diseases. Because most neurodegenerative diseases are late-onset and remain asymptomatic for most of the phases, the therapies initiated in advanced stages of the disease have limited value to patients. It may be possible to prevent or halt the disease progression to a great extent if therapies start at the initial stage of the disease. Such therapies may restore neuronal function by reducing or even eliminating the primary stressor. Flavonoids are key compounds for the development of a new generation of therapeutic agents that are clinically effective in treating neurodegenerative diseases. Regular consumption of flavonoids has been associated with a reduced risk of neurodegenerative diseases. In addition to their antioxidant properties, these polyphenolic compounds exhibit neuroprotective properties by their interaction with cellular signaling pathways followed by transcription and translation that mediate cell function under both normal and pathologic conditions. This review focuses on human intervention studies as well as animal studies on the role of various flavonoids in the prevention of neurodegenerative diseases.

Mitochondrial sirtuins: emerging roles in metabolic regulations, energy homeostasis and diseases.

The energy production and metabolic homeostasis are well-orchestrated networks of carbohydrate, lipid and protein metabolism. These metabolic pathways are integrated by a key cytoplasmic organelle, the mitochondria, leading to production of many metabolic intermediates and harvest cellular energy in the form of ATP. Sirtuins are a highly conserved family of proteins that mediate cellular physiology and energy demands in response to metabolic inputs. Mitochondria inhabit three main types of sirtuins classified as Sirt3, Sirt4 and Sirt5. These sirtuins regulate mitochondrial metabolic functions mainly through controlling post-translational modifications of mitochondrial protein. However, the biological mechanism involved in controlling mitochondrial metabolic functions is not well understood at this stage. In this review the current knowledge on how mitochondrial sirtuins govern mitochondrial functions including energy production, metabolism, biogenesis and their involvement in different metabolic pathways are discussed. The identifications of potential pharmacological targets of sirtuins in the mitochondria and the bioactive compounds that target mitochondrial sirtuins will increase our understanding on regulation of mitochondrial metabolism in normal and disease state.

Flavonoids in modulation of cell survival signalling pathways.

Flavonoids, a family of polyphenols, generally found in various fruits and vegetables, as well as in many plant beverages such as tea, pomegranate juice, raspberry, blueberries, and red wine. Recently, studies on flavonoids have attracted scientific attention as a potential nutritional strategy to prevent a broad range of chronic disorders. Many studies suggest that consumption of these flavonoids in sufficient amount plays neuroprotective, cardioprotective, anti-inflammatory, and chemopreventive roles. While there has been a major focus on the antioxidant properties, there is an emerging view that flavonoids and their in vivo metabolites do not act only as conventional antioxidants but may also exert modulatory actions on cellular system through direct action on various signalling pathways. These pathways include phosphoinositide 3-kinase, Akt/protein kinase B, mitogen-activated protein kinase, tyrosine kinases, and protein kinase C. Various inhibitory or stimulatory actions of flavonoids on these pathways greatly affect cellular functions by altering the phosphorylation state of targeted molecules. In addition, flavonoids also modulate various gene expressions through activation of various transcription factors. Thus, the present review will bestow a breathing overview regarding the prime role of flavonoids in modulation of survival signalling pathways at cellular system.