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.

Cognitive impairments in type 2 diabetes, risk factors and preventive strategies.

Mild cognitive impairment (MCI) is a modifiable risk factor in progression of several diseases including dementia and type 2 diabetes. If cognitive impairments are not reversed at an early stage of appearance of symptoms, then the prolonged pathogenesis can lead to dementia and Alzheimer's disease (AD). Therefore, it is necessary to detect the risk factors and mechanism of prevention of cognitive dysfunction at an early stage of disease.

Dietary Flavonoids for Immunoregulation and Cancer: Food Design for Targeting Disease.

Flavonoids, one of the most abundant phytochemicals in a diet rich in fruits and vegetables, have been recognized as possessing anti-proliferative, antioxidant, anti-inflammatory, and estrogenic activities. Numerous cellular and animal-based studies show that flavonoids can function as antioxidants by preventing DNA damage and scavenging reactive oxygen radicals, inhibiting formation of DNA adducts, enhancing DNA repair, interfering with chemical damage by induction of Phase II enzymes, and modifying signaling pathways. Recent evidence also shows their ability to regulate the immune system.

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.

Distinct contribution of protein kinase Cδ and protein kinase Cε in the lifespan and immune response of human blood monocyte subpopulations.

Monocytes, key components of the immune system, are a heterogeneous population comprised of classical monocytes (CD16(-) ) and non-classical monocytes (CD16(+) ). Monocytes are short lived and undergo spontaneous apoptosis, unless stimulated. Dysregulation of monocyte numbers contribute to the pathophysiology of inflammatory diseases, yet the contribution of each subset remains poorly characterized.

Apigenin protects endothelial cells from lipopolysaccharide (LPS)-induced inflammation by decreasing caspase-3 activation and modulating mitochondrial function.

Acute and chronic inflammation is characterized by increased reactive oxygen species (ROS) production, dysregulation of mitochondrial metabolism and abnormal immune function contributing to cardiovascular diseases and sepsis. Clinical and epidemiological studies suggest potential beneficial effects of dietary interventions in inflammatory diseases but understanding of how nutrients work remains insufficient. In the present study, we evaluated the effects of apigenin, an anti-inflammatory flavonoid abundantly found in our diet, in endothelial cells during inflammation.

Molecular basis for the action of a dietary flavonoid revealed by the comprehensive identification of apigenin human targets.

Flavonoids constitute the largest class of dietary phytochemicals, adding essential health value to our diet, and are emerging as key nutraceuticals. Cellular targets for dietary phytochemicals remain largely unknown, posing significant challenges for the regulation of dietary supplements and the understanding of how nutraceuticals provide health value. Here, we describe the identification of human cellular targets of apigenin, a flavonoid abundantly present in fruits and vegetables, using an innovative high-throughput approach that combines phage display with second generation sequencing.

Apigenin induces DNA damage through the PKCδ-dependent activation of ATM and H2AX causing down-regulation of genes involved in cell cycle control and DNA repair.

Apigenin, an abundant plant flavonoid, exhibits anti-proliferative and anti-carcinogenic activities through mechanisms yet not fully defined. In the present study, we show that the treatment of leukemia cells with apigenin resulted in the induction of DNA damage preceding the activation of the apoptotic program. Apigenin-induced DNA damage was mediated by p38 and protein kinase C-delta (PKCδ), yet was independent of reactive oxygen species or caspase activity.

The small heat shock protein 27 is a key regulator of CD8+ CD57+ lymphocyte survival.

Differences in CD8(+)CD57(-) and CD8(+)CD57(+) lymphocyte lifespan have been documented. Lower numbers and shorter lifespan are characteristic of CD8(+)CD57(+) in normal individuals. However, CD8(+)CD57(+) are expanded in certain disease states including T cell large granular leukemia and other hematologic malignancies.

Importance of cytochrome c redox state for ceramide-induced apoptosis of human mammary adenocarcinoma cells.

Background: Ceramides are intracellular lipid mediator implicated in various cellular responses, including oxidative stress and programmed cell death. Studies demonstrated strong links between ceramide and the mitochondria in the regulation of apoptosis. However, the mechanism of apoptosis induced by ceramides is not fully understood.

Monocytes and macrophages regulate immunity through dynamic networks of survival and cell death.

Monocytes and macrophages are central cells of the innate immune system, responsible for defending against diverse pathogens. While they originate from a common myeloid precursor and share functions in innate immunity, each has a very distinct life span finely tuned by the apoptotic caspases. Normally, circulating monocytes are short-lived and undergo spontaneous apoptosis on a daily basis.

Selective targeting of TRPV1 expressing sensory nerve terminals in the spinal cord for long lasting analgesia.

Chronic pain is a major clinical problem and opiates are often the only treatment, but they cause significant problems ranging from sedation to deadly respiratory depression. Resiniferatoxin (RTX), a potent agonist of Transient Receptor Potential Vanilloid 1 (TRPV1), causes a slow, sustained and irreversible activation of TRPV1 and increases the frequency of spontaneous excitatory postsynaptic currents, but causes significant depression of evoked EPSCs due to nerve terminal depolarization block. Intrathecal administration of RTX to rats in the short-term inhibits nociceptive synaptic transmission, and in the long-term causes a localized, selective ablation of TRPV1-expressing central sensory nerve terminals leading to long lasting analgesia in behavioral models.

Alpha-synuclein overexpression and aggregation exacerbates impairment of mitochondrial functions by augmenting oxidative stress in human neuroblastoma cells.

Overexpression of alpha-synuclein and oxidative stress has been implicated in the neuronal cell death in Parkinson's disease. Alpha-synuclein associates with mitochondria and excessive accumulation of alpha-synuclein causes impairment of mitochondrial functions. However, the mechanism of mitochondrial impairment caused by alpha-synuclein is not fully understood.

mAtNOS1 induces apoptosis of human mammary adenocarcinoma cells.

mAtNOS1 is a novel gene recently reported in mammalian genome with functions that are not fully understood. The present study shows that in human mammary adenocarcinoma MCF-7 cells, mAtNOS1 expression increases mitochondrial nitric oxide and calcium. Our study further shows that overexpression of mAtNOS1 induces apoptosis in MCF-7 cells by increasing mitochondrial protein tyrosine nitration and cytochrome c release.

Detection assays for determination of mitochondrial nitric oxide synthase activity; advantages and limitations.

Nitric oxide (NO) is a reactive radical synthesized by members of the NO synthase (NOS) family, including mitochondrial-specific NOS (mtNOS). Some of the assays used for the determination of cytoplasmic NOS activity have been utilized to detect mtNOS activity. However, it seems that many of those assays need to be adjusted and optimized to detect NO in the unique environment of mitochondria.

Nitric oxide irreversibly inhibits cytochrome oxidase at low oxygen concentrations: evidence for inverse oxygen concentration-dependent peroxynitrite formation.

The present study shows that nitric oxide (NO) irreversibly inhibits purified cytochrome oxidase in a reverse oxygen concentration-dependent manner. The inhibition is dramatically protected by a peroxynitrite scavenger, suggesting that peroxynitrite is formed from the reaction of NO with cytochrome oxidase at low oxygen concentration, and that peroxynitrite is involved in irreversible cytochrome oxidase inactivation. Production of nitroxyl anion or superoxide was tested as potential mechanisms underlying the conversion of NO to peroxynitrite.

mAtNOS1 regulates mitochondrial functions and apoptosis of human neuroblastoma cells.

mAtNOS1 is a novel gene recently reported in mammalian cells with functions that are not fully understood. The present study generated human neuroblastoma SHSY cells over- and underexpressing mAtNOS1 and shows that mAtNOS1 is involved in regulating mitochondrial nitric oxide, mitochondrial transmembrane potential, protein tyrosine nitration, cytochrome c release, and apoptosis of those cells.

Significance of mitochondrial calcium and nitric oxide for apoptosis of human breast cancer cells induced by tamoxifen and etoposide.

In the present study, we tested the significance of mitochondria for apoptosis upon exposure to tamoxifen and etoposide using two human breast cancer cell lines, MCF-7 and MDA-MB-231. We showed that both tamoxifen and etoposide induced apoptosis, increased intramitochondrial calcium and nitric oxide, and decreased mitochondrial transmembrane potential in both cell lines. Both drugs increased mitochondrial protein tyrosine nitration and caused release of cytochrome c from the mitochondria of both cell lines.

Inactivation of mitochondrial respiratory chain complex I leads mitochondrial nitric oxide synthase to become pro-oxidative.

We recently demonstrated that mitochondrial nitric oxide synthase (mtNOS) functionally couples with mitochondrial respiratory chain complex I to produce nitric oxide [M.S. Parihar, R.

Direct role of streptozotocin in inducing thermal hyperalgesia by enhanced expression of transient receptor potential vanilloid 1 in sensory neurons.

Streptozotocin (STZ) is a diabetogenic agent extensively used to induce diabetes and to study complications including diabetic peripheral neuropathy (DPN). While studying the influence of transient receptor potential vanilloid 1 (TRPV1) on DPN in the STZ-induced diabetic mouse model, we found that a proportion of STZ-treated mice was nondiabetic but still exhibited hyperalgesia. To understand the mechanism underlying this phenomenon, dorsal root ganglion (DRG) neurons and stably TRPV1 expressing human embryonic kidney (HEK) 293T cells were used to study the expression and function of TRPV1.

Mitochondria in multiple sclerosis.

Multiple sclerosis (MS) is a neurological disorder of the central nervous system characterized by demyelination and neurodegeneration. Although the pathogenesis of MS is not completely understood, various studies suggest that immune-mediated loss of myelin and mitochondrial dysfunction are associated with the disease. Mitochondria are one of the main cellular sources of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and play a pivotal role in many neuro-pathological conditions.

12(S)-hydroperoxyeicosatetraenoic acid (12-HETE) increases mitochondrial nitric oxide by increasing intramitochondrial calcium.

12(S)-hydroxyeicosatetraenoic acid (12-HETE) is one of the metabolites of arachidonic acid involved in pathological conditions associated with mitochondria and oxidative stress. The present study tested effects of 12-HETE on mitochondrial functions. In isolated rat heart mitochondria, 12-HETE increases intramitochondrial ionized calcium concentration that stimulates mitochondrial nitric oxide (NO) synthase (mtNOS) activity.

Oxidative stress and anti-oxidative mobilization in burn injury.

A severe burn is associated with release of inflammatory mediators which ultimately cause local and distant pathophysiological effects. Mediators including Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS) are increased in affected tissue, which are implicated in pathophysiological events observed in burn patients. The purpose of this article is to understand the role of oxidative stress in burns, in order to develop therapeutic strategies.

Tamoxifen induces oxidative stress and mitochondrial apoptosis via stimulating mitochondrial nitric oxide synthase.

Tamoxifen is an anticancer drug that induces oxidative stress and apoptosis via mitochondria-dependent and nitric oxide (NO)-dependent pathways. The present report shows that tamoxifen increases intramitochondrial ionized Ca(2+) concentration and stimulates mitochondrial NO synthase (mtNOS) activity in the mitochondria from rat liver and human breast cancer MCF-7 cells. By stimulating mtNOS, tamoxifen hampers mitochondrial respiration, releases cytochrome c, elevates mitochondrial lipid peroxidation, increases protein tyrosine nitration of certain mitochondrial proteins, decreases the catalytic activity of succinyl-CoA:3-oxoacid CoA-transferase, and induces aggregation of mitochondria.