Effect of general loss-cone distribution function on EIC waves in multi- component plasma-particle aspect approach

Electrostatic ion-cyclotron waves are investigated in multi-ion plasma (H+, He+ and O+) using particle aspect analysis. Variations with perpendicular wave number of wave frequency, resonant energy and growth rate with general loss-cone distribution function are studied. The whole plasma is considered to consist of resonant and non-resonant particles. The resonant particles participate in energy exchange while the non-resonant particles support the oscillatory motion of the wave. The wave is assumed to propagate obliquely to the static magnetic field. It is found that the frequency for the lighter ions increases then decreases by increasing the perpendicular wave number while the frequency for the heavier ions is constant. Perpendicular wave number decreases the growth rate of the wave and also decreases perpendicular resonant energy and increases parallel resonant energy. The effect of general loss-cone distribution is also discussed with multi-component plasma which increases the wave frequency, growth rate and parallel resonant energy while decreases the perpendicular resonant energy. The study may explain the EIC waves observed in auroral acceleration region. The results are interpreted for the space plasma parameters appropriate to the auroral acceleration region around the earth’s magnetosphere

Adenoviral Vectors Expressing Human Endostatin–Angiostatin and Soluble Tie2: Enhanced Suppression of Tumor Growth and Antiangiogenic Effects in a Prostate Tumor Model

Angiogenesis is essential for prostate cancer development and metastasis. Antiangiogenic therapy targeting tumor neovasculature, therefore, represents a promising approach for prostate cancer treatment. We hypothesized that adenoviral-mediated delivery of a combination of antiangiogenic factors might have an enhanced antitumor response. We developed the adenoviral vectors Ad-hEndo-angio, expressing a unique, chimeric human endostatin–angiostatin fusion protein, and Ad-sTie2, expressing a soluble form of endothelium-specific receptor tyrosine kinase Tie2. Matrigel angiogenesis assays using Ad-hEndo-angio revealed significant inhibition of tubular network formation and endothelial sprouting compared to Ad-sTie2. In vivo studies in a bilateral PC-3 tumor xenograft model following either intratumoral or systemic administration of Ad-hEndo-angio led to enhanced tumor growth suppression compared to Ad-sTie2. A novel finding is that an intratumoral, combination therapy employing one-half the dose of Ad-hEndo-angio as well as Ad-sTie2 led to a complete regression of the injected, as well as the contralateral uninjected, tumor and prolonged the tumor-free survival in 80% of the animals. In addition, a novel, real-time, intravital imaging modality was used to monitor antiangiogenic responses following adenoviral-mediated gene transfer. These results suggest that a combinatorial antiangiogenic gene therapy approach involving Ad-hEndo-angio and Ad-sTie2 could become a novel form of treatment for localized human prostate cancer

Selective targeting of activating and inhibitory Smads by distinct WWP2 ubiquitin ligase isoforms differentially modulates TGFβ signalling and EMT

Ubiquitin-dependent mechanisms have emerged as essential regulatory elements controlling cellular levels of Smads and TGFß-dependent biological outputs such as epithelial–mesenchymal transition (EMT). In this study, we identify a HECT E3 ubiquitin ligase known as WWP2 (Full-length WWP2-FL), together with two WWP2 isoforms (N-terminal, WWP2-N; C-terminal WWP2-C), as novel Smad-binding partners. We show that WWP2-FL interacts exclusively with Smad2, Smad3 and Smad7 in the TGFß pathway. Interestingly, the WWP2-N isoform interacts with Smad2 and Smad3, whereas WWP2-C interacts only with Smad7. In addition, WWP2-FL and WWP2-C have a preference for Smad7 based on protein turnover and ubiquitination studies. Unexpectedly, we also find that WWP2-N, which lacks the HECT ubiquitin ligase domain, can also interact with WWP2-FL in a TGFß-regulated manner and activate endogenous WWP2 ubiquitin ligase activity causing degradation of unstimulated Smad2 and Smad3. Consistent with our protein interaction data, overexpression and knockdown approaches reveal that WWP2 isoforms differentially modulate TGFß-dependent transcription and EMT. Finally, we show that selective disruption of WWP2 interactions with inhibitory Smad7 can stabilise Smad7 protein levels and prevent TGFß-induced EMT. Collectively, our data suggest that WWP2-N can stimulate WWP2-FL leading to increased activity against unstimulated Smad2 and Smad3, and that Smad7 is a preferred substrate for WWP2-FL and WWP2-C following prolonged TGFß stimulation. Significantly, this is the first report of an interdependent biological role for distinct HECT E3 ubiquitin ligase isoforms, and highlights an entirely novel regulatory paradigm that selectively limits the level of inhibitory and activating Smads

Mast Cells in Stress, Pain, Blood-Brain Barrier, Neuroinflammation and Alzheimer’s Disease

Mast cell activation plays an important role in stress-mediated disease pathogenesis. Chronic stress cause or exacerbate aging and age-dependent neurodegenerative diseases. The severity of inflammatory diseases is worsened by the stress. Mast cell activation-dependent inflammatory mediators augment stress associated pain and neuroinflammation. Stress is the second most common trigger of headache due to mast cell activation. Alzheimer’s disease (AD) is a progressive irreversible neurodegenerative disease that affects more women than men and woman’s increased susceptibility to chronic stress could increase the risk for AD. Modern life-related stress, social stress, isolation stress, restraint stress, early life stress are associated with an increased level of neurotoxic beta amyloid (Aβ) peptide. Stress increases cognitive dysfunction, generates amyloid precursor protein (APP), hyperphosphorylated tau, neurofibrillary tangles (NFTs), and amyloid plaques (APs) in the brain. Stress-induced Aβ persists for years and generates APs even several years after the stress exposure. Stress activates hypothalamic-pituitary adrenal (HPA) axis and releases corticotropin-releasing hormone (CRH) from hypothalamus and in peripheral system, which increases the formation of Aβ, tau hyperphosphorylation, and blood-brain barrier (BBB) disruption in the brain. Mast cells are implicated in nociception and pain. Mast cells are the source and target of CRH and other neuropeptides that mediate neuroinflammation. Microglia express receptor for CRH that mediate neurodegeneration in AD. However, the exact mechanisms of how stress-mediated mast cell activation contribute to the pathogenesis of AD remains elusive. This mini-review highlights the possible role of stress and mast cell activation in neuroinflammation, BBB, and tight junction disruption and AD pathogenesis

Alternate processing of Flt1 transcripts is directed by conserved cis-elements within an intronic region of FLT1 that reciprocally regulates splicing and polyadenylation

The vascular endothelial growth factor receptor, Flt1 is a transmembrane receptor co-expressed with an alternate transcript encoding a secreted form, sFlt1, that functions as a competitive inhibitor of Flt1. Despite shared transcription start sites and upstream regulatory elements, sFlt1 is in far greater excess of Flt1 in the human placenta. Phorbol myristic acid and dimethyloxalylglycine differentially stimulate sFlt1 compared to Flt1 expression in vascular endothelial cells and in cytotrophoblasts. An FLT1 minigene construct containing exon 13, 14 and the intervening region, recapitulates mRNA processing when transfected into COS-7, with chimeric intronic sFlt1 transcripts arising by intronic polyadenylation and other Flt1/sFlt1 transcripts by alternate splicing. Inclusion of exon 15 but not 14 had a modest stimulatory effect on the abundance of sFlt1. The intronic region containing the distal poly(A) signal sequences, when transferred to a heterologous minigene construct, inhibited splicing but only when cloned in sense orientation, consistent with the presence of a directional cis-element. Serial deletional and targeted mutational analysis of cis-elements within intron 13 identified intronic poly(A) signal sequences and adjacent cis-elements as the principal determinants of the relative ratio of intronic sFlt1 and spliced Flt1. We conclude that intronic signals reciprocally regulate splicing and polyadenylation and control sFlt1 expression

The PPAR-gamma agonist pioglitazone protects cortical neurons from inflammatory mediators via improvement in peroxisomal function

<p>Abstract</p> <p>Background</p> <p>Inflammation is known to play a pivotal role in mediating neuronal damage and axonal injury in a variety of neurodegenerative disorders. Among the range of inflammatory mediators, nitric oxide and hydrogen peroxide are potent neurotoxic agents. Recent evidence has suggested that oligodendrocyte peroxisomes may play an important role in protecting neurons from inflammatory damage.</p> <p>Methods</p> <p>To assess the influence of peroxisomal activation on nitric oxide mediated neurotoxicity, we investigated the effects of the peroxisomal proliferator activated receptor (PPAR) gamma agonist, pioglitazone in primary cortical neurons that were either exposed to a nitric oxide donor or co-cultured with activated microglia.</p> <p>Results</p> <p>Pioglitazone protected neurons and axons against both nitric-oxide donor-induced and microglia-derived nitric oxide-induced toxicity. Moreover, cortical neurons treated with this compound showed a significant increase in the protein and gene expression of PPAR-gamma, which was associated with a concomitant increase in the enzymatic activity of catalase. In addition, the protection of neurons and axons against hydrogen peroxide-induced toxicity afforded by pioglitazone appeared to be dependent on catalase.</p> <p>Conclusions</p> <p>Collectively, these observations provide evidence that modulation of PPAR-gamma activity and peroxisomal function by pioglitazone attenuates both NO and hydrogen peroxide-mediated neuronal and axonal damage suggesting a new therapeutic approach to protect against neurodegenerative changes associated with neuroinflammation.</p

Effect of general loss-cone distribution function on EIC waves in multi- component plasma-particle aspect approach

71-82Electrostatic ion-cyclotron waves are investigated in multi-ion plasma (H+, He+ and O+) using particle aspect analysis. Variations with perpendicular wave number of wave frequency, resonant energy and growth rate with general loss-cone distribution function are studied. The whole plasma is considered to consist of resonant and non-resonant particles. The resonant particles participate in energy exchange while the non-resonant particles support the oscillatory motion of the wave. The wave is assumed to propagate obliquely to the static magnetic field. It is found that the frequency for the lighter ions increases then decreases by increasing the perpendicular wave number while the frequency for the heavier ions is constant. Perpendicular wave number decreases the growth rate of the wave and also decreases perpendicular resonant energy and increases parallel resonant energy. The effect of general loss-cone distribution is also discussed with multi-component plasma which increases the wave frequency, growth rate and parallel resonant energy while decreases the perpendicular resonant energy. The study may explain the EIC waves observed in auroral acceleration region. The results are interpreted for the space plasma parameters appropriate to the auroral acceleration region around the earth’s magnetosphere

An evolutionarily conserved N-terminal Sgk1 variant with enhanced stability and improved function

Sgk1 is an aldosterone-induced kinase that regulates epithelial sodium channel (ENaC)-mediated Na+ transport in the collecting duct and connecting tubule of the kidney. The NH2 terminus of Sgk1 contains instability motifs that direct the ubiquitination of Sgk1 resulting in a rapidly degraded protein. By bioinformatic analysis, we identified a 5′ variant alternate transcript of human Sgk1 (Sgk1_v2) that is widely expressed, is conserved from rodent to humans, and is predicted to encode an Sgk1 isoform, Sgk1_i2, with a different NH2 terminus. When expressed in HEK293 cells, Sgk1_i2 was more abundant than Sgk1 because of an increased protein half-life and this correlated with reduced ubiquitination of Sgk1_i2 and enhanced surface expression of ENaC. Immunocytochemical studies demonstrated that in contrast to Sgk1, Sgk1_i2 is preferentially targeted to the plasma membrane. When coexpressed with ENaC subunits in FRT epithelia, Sgk1_i2 had a significantly greater effect on amiloride-sensitive Na+ transport compared with Sgk1. Together, the data demonstrate that a conserved NH2-terminal variant of Sgk1 shows improved stability, enhanced membrane association, and greater stimulation of epithelial Na+ transport in a heterologous expression system

An evolutionarily conserved N-terminal Sgk1 variant with enhanced stability and improved function

Sgk1 is an aldosterone-induced kinase that regulates epithelial sodium channel (ENaC)-mediated Na+ transport in the collecting duct and connecting tubule of the kidney. The NH2 terminus of Sgk1 contains instability motifs that direct the ubiquitination of Sgk1 resulting in a rapidly degraded protein. By bioinformatic analysis, we identified a 5′ variant alternate transcript of human Sgk1 (Sgk1_v2) that is widely expressed, is conserved from rodent to humans, and is predicted to encode an Sgk1 isoform, Sgk1_i2, with a different NH2 terminus. When expressed in HEK293 cells, Sgk1_i2 was more abundant than Sgk1 because of an increased protein half-life and this correlated with reduced ubiquitination of Sgk1_i2 and enhanced surface expression of ENaC. Immunocytochemical studies demonstrated that in contrast to Sgk1, Sgk1_i2 is preferentially targeted to the plasma membrane. When coexpressed with ENaC subunits in FRT epithelia, Sgk1_i2 had a significantly greater effect on amiloride-sensitive Na+ transport compared with Sgk1. Together, the data demonstrate that a conserved NH2-terminal variant of Sgk1 shows improved stability, enhanced membrane association, and greater stimulation of epithelial Na+ transport in a heterologous expression system