Scott and Roy showed that a-synuclein plays a role in maintaining the overall size of the recycling pool of vesicles. We observed expression and synaptic localization of a-synuclein in excitatory neurons, but not in inhibitory neurons, although there were no obvious differences between the two types of Rapamycin neurons in expression of the synaptic markers synaptotagmin and synapsin. We also observed that activity-dependent presynaptic membrane recycling occurred independently of the presence of a-synuclein. While there have been many studies investigating the properties of postsynaptic channels including kinetics and the signaling molecules involved in synaptic transduction, less is known about the presynaptic differences between excitatory and inhibitory neurons. Recent work revealed that the sizes of both the recycling pool and total vesicular pool are more variable at glutamatergic synapses than gamma-aminobutyric acid synapses. This heterogeneity of the size of the recycling pool at glutamatergic synapses may provide a dynamic range of synaptic strength that is not present at GABAergic synapses. a-Synuclein might act as a modulator of the size of the recycling pool at excitatory synapses. a-Synuclein is also suggested to be involved in mobilization of glutamate from the reserve pool using electrophysiology of hippocampal slices. There is a possibility that the differential expression of asynuclein is due to a difference in protein turnover between excitatory and inhibitory neurons. However, treatment with inhibitors of proteasomes or lysosomes did not alter the immunostaining patterns of a-synuclein, suggesting that differential synthesis rather than degradation of a-synuclein is responsible for the distinct expression patterns in neurons. Recently, it was reported that a-synuclein promotes early neurite outgrowth in cultured primary neurons. It has also been suggested that a-synuclein plays important roles in the early development of synapses. The expression ratio of asynuclein/synaptophysin is higher during early development than in adult and aged rat brain. We demonstrated that cultured neurons exhibit differential expression of a-synuclein by 30 h after cell dissemination. At this stage, there were no synaptic connections established between neurons. In addition, expression of GAD was very weak and not strong enough to distinguish inhibitory neurons. These results suggest that a-synuclein is involved in the differentiation of neurons. Concerning the pathogenicity of a-synuclein, we observed that inhibitory neurons did not exhibit aggregate formation after treatment with preformed fibrils. This result was due to the low expression level of a-synuclein, because the expression of exogenous human a-synuclein in GAD neurons enabled them to form a-synuclein aggregates.

We showed that sympathetic hyperactivity does not change VEGF and Akt, which is a key intracellular mediator of this pathway. However, our findings are in accordance with lines of evidence showing that exercise induces a local angiogenic phenotype characterized by overexpression of VEGF in the heart. Moreover, we observed high expression of active Akt form and Bcl-2 protein as well as a SCH772984 reduction of pro-apoptotic Bad. These findings have been previously shown in myocardial injury by ischemia/reperfusion, hypertension, and diabetes. Thus, as a novel finding, we show that the kallikrein-kinin system/VEGF/Akt pathway may be involved in exercise-induced cardioprotection against sympathetic hyperactivity. In the current study, one cardioprotective pathway elicited for kinin and VEGF action could be NO release. NO is a short-lived free radical gas involved in several physiological and pathological processes. When synthesized by eNOS, NO plays an important role in endothelial function and cardioprotection. In fact, findings have emphasized that NO may antagonize sympathetic stimulation. Therefore, our findings showed an increase of eNOS in exercise rats, suggesting that this molecule may participate in cytoprotection from the cardiotoxic effects of catecholamines. Preterm birth, respiratory distress syndrome, and bronchopulmonary dysplasia, the chronic lung disease of prematurity, continue to be important causes of morbidity and mortality in the neonatal intensive care unit. Despite improvements in perinatal care, the incidence of BPD remains unchanged. Preterm birth before 28 weeks of gestation interrupts the normal sequence of lung growth leading to impaired alveolar and lung vascular development. Emerging evidence suggests that BPD may have long-term respiratory complications that reach beyond childhood. Follow-up studies indicate that children and young adults who were born very preterm are at an increased risk of respiratory symptoms, poor lung function, lower exercise capacity and pulmonary hypertension. Currently, there is no effective treatment for BPD. Hydrogen sulfide has long been considered a noxious and toxic gas. Newly acquired evidence indicates potential biomedical applications for H2S. H2S is now recognized – along with carbon monoxide and nitric oxide – as an endogenous gaseous mediator exerting important physiological actions. The role of H2S in the developing lung is unknown. The discovery that H2S is an endogenously produced gaseous second messenger capable of modulating many physiological processes including vasodilation and cytoprotection, much like NO, prompted us to investigate the potential of H2S as a lung-protective agent. Thus, we hypothesized that H2S would preserve alveolar development and prevents PHT in experimental oxygen-induced lung injury in newborn rats. Our findings demonstrate the protective effect of H2S on chronic hyperoxia-induced injury in the developing lung: In vitro, treatment with H2S protects HPAECs from O2 toxicity and promotes HPAECs network formation. In vivo, H2S administration preserves and restores alveolar growth and alleviates echographic and structural signs of PHT.

We report here the efficacy of radioembolization followed by sorafenib in unresectable HCC in the Phase II study. This study represents the first prospective Phase II evaluation of sequential radioembolization-sorafenib therapy in patients from Asia-Pacific region. The majority of patients included in this trial had advanced HCC and a high tumor burden in the liver, and were not ideal candidates for TACE. The combination of radioembolization-sorafenib appears to be manageable and consistent with previously published experience with each treatment. Excluding hand-foot syndrome, 23% of events were grade 3 or above. Most events were transient and managed with sorafenib dose adjustments or WZ8040 discontinuation. By comparison, treatment-emergent adverse events were reported in 98% of patients in the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol study. The evaluation of the combination of doxorubicin-eluting beads with sorafenib found that most patients experienced at least one grade 3 to 4 toxicity, the most common being grade 3–4 fatigue in 36% of patients, and required dose reductions in 73% of patients. By comparison, the most commonly reported adverse event with radioembolization was fatigue occurring in 54% of patients, including 2% with grade 3 events, with an increase in total bilirubin reported as the most commonly reported grade 3+ event in 6% of patients at 3 months post-treatment. The incentive for therapeutic intervention to palliate symptoms or extend survival of HCC must be balanced against the degree of hepatic functional reserve and the ability of the patient to tolerate the procedure. Compromised hepatic function as manifested by thrombocytopenia, excessive elevations in transaminases and bilirubin, jaundice and ascites were reported in 14% of patients following radioembolization-sorafenib in this study. These cases resolved upon withdrawal of sorafenib and the administration of steroid therapy. Liver dysfunction with sorafenib is a rare event. The risk of radioembolization-induced liver disease reported by Sangro et al 2008 increased significantly with high total bilirubin, jaundice and ascites in the absence of overt tumor progression and/or bile duct dilatation. As advised by Lau et al 2012, the dose for uninvolved, normal parenchyma should never be.70 Gy and should preferably remain,50 Gy with some institutions, especially in Asia, having set even lower thresholds of 40–43 Gy. Further study by Sangro et al 2013 has shown that the frequency and severity of this complication can be significantly reduced through modifications to the activity calculations, combined with lowering the threshold for radioembolization from a total bilirubin of 3 to 2 mg/dL and the routine use of ursodeoxycholic acid and low-dose steroid over the two months post-radioembolization. There was one case of thrombocytopenia which was a modest event at 3.5 months post-treatment followed by patient death due to progressive disease 2 months later. Thrombocytopenia has been commonly observed in HCC patients following sorafenib administration and has been rarely reported following radioembolization.

Both FGF21and irisin/FNDC5 have been mechanistically linked to the conversion of white to beige adipose tissue. In light of the potential clinical significance of FGF21 and irisin/FNDC5 for the treatment of obesity, an understanding of their regulation is of obvious importance. In this regard, we have considered two potential regulators/perturbations that are not necessarily mutually exclusive: the sympathetic nervous system and sprint interval exercise training. Stimulation of sympathetic activity via cold exposure is a well-known activator of beige fat in humans. There is some evidence from experimental animals suggesting that the sympathetic nervous system may also have a direct regulatory role pertaining to FGF21, and indirectly to irisin/FNDC5 via stimulation of peroxisome R428 proliferator-activated receptor gamma co-activator 1-alpha. Further, exercise, perhaps via intermittent increased sympathetic activation, may also stimulate FGF21 and/or irisin/ FNDC5, although the evidence is somewhat contradictory depending on species and type of exercise. In the current manuscript we present two studies. Study 1 is a retrospective analysis of plasma collected during a previously published study ; we address the new hypothesis that the sympathetic nervous system is an important physiological regulator of FGF21 and irisin in adult males. In Study 2 we performed a prospective investigation in which we examined the hypothesis that short-term sprint interval training would increase skeletal muscle FNDC5 protein content, and increase circulating concentrations of irisin and FGF21 in adult males and females. FGF21 and irisin/FNDC5 have been mechanistically linked to the conversion of white adipose to thermogenic beige adipose tissue, however the physiological control of these regulators is both important to clarify and, at the moment, poorly understood. The novel findings of this manuscript are: 1) basal sympathetic activity does not influence circulating FGF21 or irisin; 2) FGF21 is increased in response to acute sympathetic activation; 3) sprint interval training decreases FGF21, does not affect skeletal muscle FNDC5, and results in a sexual dimorphic response in systemic irisin. The sympathetic nervous system is a well-known activator of beige adipose in adult humans. Combined use of positron emission tomography and computed tomography scanning during administration of fluorodeoxyglucose is currently the gold standard non-invasive method of quantifying beige fat activation ; b-adrenergic receptor blockade decreases the metabolic activity of beige fat, thus rendering its detection extremely difficult. It seems plausible that the sympathetic nervous system may also contribute to the regulation of FGF21 and/or irisin/FNDC5 as part of the coordinated control of the “browning” of adipocytes. Data from cell and animal studies support this notion. Administration of a non-selective b-adrenergic receptor agonist increases FGF21 mRNA and secretion in rodents, and b3-adrenergic receptor stimulation increases FGF21 gene expression in the white and brown adipose tissue of mice.

In mammalian cells, H2S is produced from L-cysteine, catalyzed by one of two pyridoxal-59-phosphate-dependent enzymes, cystathionine b-synthase and/or cystathionine c-lyase. H2S is considered a toxic gas. Its smell of rotten eggs can be perceived at concentrations as low as 0.0047 ppm. In serious cases, it causes cough, headache, pulmonary edema, or even coma. However, recent reports show that H2S is endogenously generated in the mammalian body and plays important physiological roles. Growing evidence implicates H2S in the pathogenesis of pulmonary diseases. In the present study we show, both in vitro and in vivo, that H2S treatment displays lung-protective properties in the developing lung. Because angiogenesis contributes to alveolar growth, we examined the protective effect of H2S on HPAECs. In vitro, H2S preserved HPAECs viability and maintained HPAECs network formation in hyperoxia. Furthermore, H2S reduced HPAEC ROS levels in hyperoxia. This is consistent with reports showing that H2S protects cells and proteins from oxidative stress induced by peroxynitrite and hypochlorous acid. In endothelial cells, hydrogen peroxide and organic hydroperoxides such as lipid hydroperoxides are responsible for the activation of heme oxygenase-1, one of the ROS responders that trigger extensive oxidative damage in endothelial cells. H2S is capable of destroying hydrogen peroxide and LOOHs. Consistent with these in vitro data, we show through vWF staining and CD31 lung protein expression that H2S preserved lung vascular growth in rats pups exposed to chronic hyperoxia. Inhaled NO is a potent pulmonary vasodilator and promotes distal lung growth. Inhaled NO shows promise as a prophylactic therapy to decrease the incidence of BPD in experimental models, while results in preterm infants remain inconclusive. Thus, we hypothesized that H2S would have similar beneficial effects on distal lung growth and PHT. In vivo, H2S indeed ONX-0914 attenuated the arrested alveolar growth in the chronic oxygen induced arrested alveolar growth in rat model. While we demonstrate for the first time the protective effect of H2S on the developing lung, recent reports indicated a therapeutic potential of H2S in various acute adult lung injury models. Inhalation of 80 ppm H2S ameliorates lung pathology in LPS and in ventilator induced lung injury. Interestingly, Francis et al observed that 1 or 5 ppm H2S did not alter ventilation-induced lung injury, while 60 ppm H2S worsened ventilator-induced lung injury. In contrast, intravenous pretreatment with sodium sulfide attenuated reduced pulmonary edema, enhanced the pulmonary expression of Nrf2-dependent antioxidant genes and prevented oxidative stress-induced depletion of glutathione in lung tissue. This is consistent with the protective effect observed in the neonatal chronic hyperoxia-induced lung injury model, in which Nrf2 preserves alveolar growth while Nrf2 deficiency worsens lung injury,. PHT often complicates chronic lung diseases including BPD and significantly worsens the prognosis. H2S induces vasodilatation and inhibits vascular smooth muscle cell proliferation.