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.

Positive, not negative, self-compassion mediates the relationship between self-esteem and well-being.

OBJECTIVES: The study examined the predictive strengths of self-esteem, and positive and negative self-compassion for hedonic and eudaimonic well-being as well as assessed the relative mediating roles of positive and negative self-compassion for the relationships among self-esteem, and hedonic and eudaimonic well-being. DESIGN: A correlational design was employed through which self-esteem, self-compassion, and hedonic and eudaimonic well-being were measured. METHODS: One hundred thirty-four male (M = 25.11, SD = 1.66) and 138 female (M = 21.89, SD = 1.87) participants were chosen by a convenient sampling. RESULTS: The findings evinced that there were significant positive correlations among self-esteem, positive self-compassion, and hedonic and eudaimonic well-being while negative self-compassion exhibited small positive correlations with both the well-being measures (criterion). The regression analyses showed that self-esteem and positive self-compassion reflected significant predictive strengths for hedonic as well as eudaimonic well-being while negative self-compassion did not. This was also true for the social and psychological aspects of well-being. The ß values reflected that positive self-compassion did show a higher contribution for both the well-being measures as compared to self-esteem. CONCLUSIONS: The findings evinced that positive, not negative, self-compassion mediated the relationship between self-esteem and hedonic well-being as well as self-esteem and eudaimonic well-being. Moreover, self-esteem and self-compassion have predictive strengths for both kinds of well-being. The findings showed the relevance of self-esteem and self-compassion to underscore well-being. The implications and directions for future researchers have been discussed. PRACTITIONER POINTS: Contrary to the earlier findings suggesting self-esteem and self-compassion carrying relevance to explicate performance and well-being of people with individualistic and collectivistic cultures, respectively, the findings of this study suggest both the constructs to be useful to understand the well-being of people with both the values belonging especially to the fast-changing societies like India. The study also suggests reconceptualization and empirical verification of self-compassion that will make it more effective for enhancing and promoting interventions for positive life outcomes.

Downregulation of sirtuin 3 by palmitic acid increases the oxidative stress, impairment of mitochondrial function, and apoptosis in liver cells.

Elevated levels of saturated fatty acids show a strong cytotoxic effect in liver cells. Sirtuin 3 (SIRT3), a mitochondrially localized member of NAD+ -dependent deacetylase has been shown to protect hepatocytes against the oxidative stress. The role of SIRT3 on the cytotoxicity caused by fatty acids in liver cells is not fully understood. The aim of this study was to evaluate the expression level of SIRT3, oxidative stress, and mitochondrial impairments in human hepatoma HepG2 cells exposed to palmitic acid (PA). Our results showed that PA treatment caused the deposition of lipid droplets and resulted in an increased expression of tumor necrosis factor-α in a dose-dependent manner. Excessive accumulation of PA induces the reactive oxygen species formation and apoptosis while dissipating the mitochondrial transmembrane potential. The level of SIRT3 expression in both nuclear and mitochondrial fractions in HepG2 cells was decreased with the increase in PA concentrations. However, in the cytosolic fraction, the SIRT3 was undetectable. In conclusion, our results showed that PA caused an increase in inflammation and oxidative stress in HepG2 cells. The exposure of PA also resulted in the decline in transmembrane potential and an increase in apoptosis. The underexpression of nuclear and mitochondrial SIRT3 by PA suggests that the PA target the process that regulates the stress-related gene expression and mitochondrial functions.

Metabolic enzymes dysregulation in heart failure: the prospective therapy.

The heart failure accounts for the highest mortality rate all over the world. The development of preventive therapeutic approaches is still in their infancy. Owing to the extremely high energy demand of the heart, the bioenergetics pathways need to respond efficiently based on substrate availability. The metabolic regulation of such heart bioenergetics is mediated by various rate limiting enzymes involved in energy metabolism. Although all the pertinent mechanisms are not clearly understood, the progressive decline in the activity of metabolic enzymes leading to diminished ATP production is known to cause progression of the heart failure. Therefore, metabolic therapy that can maintain the appropriate activities of metabolic enzymes can be a promising approach for the prevention and treatment of the heart failure. The flavonoids that constitute various human dietary ingredients also effectively offer a variety of health benefits. The flavonoids target a variety of metabolic enzymes and facilitate effective management of the equilibrium between production and utilization of energy in the heart. This review discusses the broad impact of metabolic enzymes in the heart functions and explains how the dysregulated enzyme activity causes the heart failure. In addition, the prospects of targeting dysregulated metabolic enzymes by developing flavonoid-based metabolic approaches are discussed.

Neurodegenerative diseases: From available treatments to prospective herbal therapy.

Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and many others represent a relevant health problem with age worldwide. Efforts have been made in recent years to discover the mechanism of neurodegenerative diseases and prospective therapy that can help to slow down the effects of the aging and prevent these diseases. Since pathogenesis of these diseases involves multiple factors therefore the important task for neuroscientists is to identify such multiple factors and prevent age-associated neurodegenerative diseases. For these neurodegenerative diseases yet we have only palliative therapies and none of them significantly capable to slow down or halt the underlying pathology. Polyphenolic compounds such as flavonoids present in vegetables and fruits are believed to have anti-aging properties and reduce the risk of neurodegenerative diseases. Despite their abundance, investigations into the benefits of these polyphenolic compounds in human health have only recently begun. Preclinical and clinical studies have demonstrated the potential beneficial effects of flavonoids in neurons. Although clinical trials on the effectiveness of dietary flavonoids to treat human diseases are limited but various animal models and cell culture studies have shown a great promise in developing these compounds as suitable therapeutic targets. In this review, we elaborate the neuroprotective properties of flavonoids especially their applications in prevention and intervention of different neurodegenerative diseases. Their multi-target properties may allow them to be potential dietary supplement in prevention and treatment of the age-associated neurodegenerative diseases.

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.