Theoretical design of D-π-A system new dyes candidate for DSSC application.

Currently, dye-sensitized solar cells (DSSCs) are one of the energy technologies that has piqued the interest of researchers, due to their distinct characteristics such as excellent air stability, ease of synthesis and photovoltaic properties interesting. This work aims to study the optoelectronic properties and photovoltaic of six organic dyes based on phenothiazine (PTZ). The effects of bridging core modifications of recently synthesized PSB-4(R) molecule on structural, photovoltaic, electronic, and optical properties of D1-D6 are studied. Using the method Density Functional Theory (DFT) level of the B3LYP (Becke three-parameter Lee-Yang-Parr) exchange correlation functional with 6-31G (d, p) and time-dependent DFT (TD-DFT). According to the obtained results, optoelectronic properties and photovoltaic of the dyes, we can suggest that these designed molecules are better sensitizers as a candidate for the production of dye solar cells (DSSCs). This theoretical study paves the way for chemists to synthesize more efficient sensitizers for applications in dye solar cells.

Hypoxia differentially regulates stress proteins in cultured cardiomyocytes: role of the p38 stress-activated kinase signaling cascade, and relation to cytoprotection.

OBJECTIVE: Stress proteins (heat shock proteins, HSPs) are molecular chaperones that have been shown to enhance the survival of cells exposed to environmental stress. We sought to investigate the effects of hypoxia on the levels of HSP27 and heme oxygenase-1 (HO-1 or HSP32) in an established model of rat neonatal cardiac myocytes in culture. METHODS: Myocytes were subjected to hypoxia (<0.5% O(2) for 16 h). Studies of cell viability and nuclear morphology showed no evidence of cell death under these conditions. RESULTS: Messenger RNA analysis demonstrated constitutive expression of HSP27 and low levels of HO-1. Hypoxia strongly induced HO-1 mRNA without affecting HSP27 mRNA. In parallel to mRNA levels, hypoxia increased HO-1 protein level without affecting HSP27. To further assess the signaling pathways implicated in HO-1 induction, we used inhibition experiments. The tyrosine kinase inhibitor tyrphostin and the mitogen-activated protein kinase inhibitor PD98059 did not prevent HO-1 induction, while the protein kinase C inhibitor chelerythrine partially blocked this response. The p38 stress-activated kinase inhibitor SB203580 was the most potent in suppressing hypoxia-induced HO-1. In vitro kinase assays, cell labeling and immunoprecipitation showed activation of signaling pathways downstream of p38 stress-activated kinase as revealed by an increase in phosphorylation of MAPKAPK-2/3 kinases and HSP27. CONCLUSIONS: These data show a differential pattern of hypoxia-induced HSP expression and implicate the stress kinase in HO-1 induction. Thus, selective regulation of HSP levels may play a role in the cardioprotective mechanisms that participate in the adaptive response to hypoxia-induced stress.

Inter and intra-species-related differences in the regulation of the cardiac autonomic system.

The heart rate response to isoproterenol (HR-Iso), density and affinity (kd) of beta-adrenergic (beta-AR) and muscarinic (M2) receptors were compared among three rodents with different generation-life histories of confinement and of high altitude exposure. The European guinea pig (Cavia porcellus) (EGp), a laboratory animal that arrived in Europe after the Spanish Conquest of South America and the Peruvian guinea pig (C. porcellus) (PGp), a semi-wild animal that came from the altiplano to sea level at least 25 generations ago, were used for intra-species comparison. Wistar rats (WR) were used for inter-species comparison as representative of a typical sea level laboratory animal. The HR-Iso was lower in EGp than in the PGp. The PGp showed the highest beta-AR density (P < 0.0005) and the highest beta-AR kd values (P < 0.0005) when compared to both EGp and WR groups (beta-AR Bmax (fmol mg-1 prot), WR, 19 +/- 4; Egp, 34 +/- 10; PGp, 74 +/- 15. beta-AR kd (pM), WR, 24 +/- 10; Egp, 17 +/- 7; PGp, 39 +/- 14). In contrast, PGp showed lower M2 receptor density values than the EGp (P < 0.0005). The WR had the highest M2 receptor densities (M2 Bmax (fmol mg-1 prot), WR, 188 +/- 15; Egp, 147 +/- 9; PGp, 118 +/- 6 and M2 kd (pM), WR, 65 +/- 12; Egp, 67 +/- 6; PGp, 92 +/- 2). The inter and intra-species differences found may be related to their respective history of confinement rather than to their history of exposure to high altitude.

Expression and regulation of adhesion molecules in cardiac cells by cytokines: response to acute hypoxia.

Adhesion molecules mediate inflammatory myocardial injury after ischemia/reperfusion. Cytokine release and hypoxia are features of acute ischemia that may influence expression of these molecules. Accordingly, we studied intercellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM) responses to cytokines and acute hypoxia in cultured myocardial cells. Northern blot analysis and immunoassay showed that the proinflammatory cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha stimulated concentration-dependent increases in ICAM and VCAM mRNA and protein. In both cardiac myocytes and fibroblasts, pretreatment with a specific inhibitor of nuclear transcription factor-kappaB (NF-kappaB) prevented cytokine induction of both molecules. We also found that inhibition of tyrosine kinase and p38/RK (stress-activated protein kinase) pathways prevented IL-1beta-induced ICAM and VCAM protein synthesis, whereas extracellular signal-regulated protein kinase (ERK1/ERK2) inhibition did not. Neither hypoxia (0% O2 for 6 hours) alone nor hypoxia/reoxygenation had any significant effect on ICAM and VCAM mRNA. However, hypoxia did enhance IL-1beta-induced ICAM mRNA expression in myocytes. As a possible mechanism of this synergistic action on CAM expression, hypoxia induced a time-dependent increase in the DNA binding activity of both NF-kappaB and activator protein-1 (AP-1), two transcription factors important for cell adhesion molecule expression. In contrast to the enhanced ICAM mRNA induced by IL-1beta during hypoxia, however, protein levels for this adhesion molecule were unchanged beyond IL-1beta-stimulated levels, suggesting posttranscriptional and/or posttranslational control mechanisms. We conclude that cytokines regulate ICAM and VCAM mRNA and protein in both cardiac myocytes and fibroblasts. Furthermore, adhesion molecule induction requires translocation of at least two transcription factors, NF-kappaB and AP-1.

Chronic hypoxia modulates the interleukin-1beta-stimulated inducible nitric oxide synthase pathway in cardiac myocytes.

BACKGROUND: We wished to determine whether the cytokine-inducible nitric oxide synthase (iNOS) pathway is modulated by chronic hypoxia in vitro. METHODS AND RESULTS: We investigated the effects of the proinflammatory cytokine interleukin (IL)-1beta on expression of iNOS mRNA, iNOS protein, and NO production in cultured neonatal rat cardiomyocytes subjected to 1% O2 for 48 hours. Among several cytokines tested, IL-1beta was the most effective in stimulating NO production, which was maximum at 48 hours. In parallel, IL-1beta induced expression of both iNOS mRNA and protein. Hypoxia alone had no effect on NO production, iNOS gene expression, or protein induction. However, chronic hypoxia decreased IL-1beta-stimulated NO production, mRNA expression, and protein level in cardiac myocytes. Radioligand binding and electrophoretic mobility shift assays showed that during chronic hypoxia, IL-1 receptor density and activity of the transcription factor NF-kappaB induced by IL-1beta were decreased, which may account at least in part for the decrease in iNOS expression. CONCLUSIONS: These data indicate that IL-1beta induces iNOS gene expression, de novo synthesis of iNOS protein, and NO generation in neonatal rat cardiomyocytes and that chronic hypoxia appears to be a potent negative regulator of iNOS expression in these cells.

Hypoxia- and normoxia-induced reversibility of autonomic control in Andean guinea pig heart.

We herein describe the regulation of cardiac receptors in a typical high-altitude native animal. Heart rate response to isoproterenol (HRIso) (beats.min-1.mg Iso.kg-1) and atropine, the density of beta-adrenergic (beta AR) and muscarinic (M2) receptors, and the ventricular content of norepinephrine (NE) and dopamine (DA) were studied in guinea pigs (Cavia porcellus). Animals native to Lima, Peru (150 m) were studied at sea level (SL) and after 5 wk at 4,300-m altitude (SL-HA). Animals native to Rancas [Pasco, Peru (4,300 m)] were studied at high altitude (HA) and after 5 wk at SL (HA-SL). HA animals had a lower HRIso, maximum number of beta AR binding sites (Bmax), beta AR dissociation constant (Kd), NE, and DA (P < 0.05) and a higher M2 Bmax (P < 0.001) when compared with the SL group. HA-SL showed an increase of the HRIso, beta Ar Kd, and NE (P < 0.05) and a decrease of the M2 Bmax and Kd (P < 0.0001) when compared with the HA group. The present study demonstrates the differential regulation and reversibility of the autonomic control in the guinea pig heart.

Differential regulation of G protein expression in rat hearts exposed to chronic hypoxia.

Chronic hypoxia impairs adrenergic responsiveness. A modulation of Gs and/or G1 protein alpha-subunits may be associated with the downregulation of the beta-adrenergic receptors previously found in chronic hypoxia. G protein gene expression and protein level and function in rat hearts exposed to a 30-day hypobaric chronic hypoxia were compared with control rat hearts. No change was observed in G alpha s mRNA levels in either right or left ventricles. In right ventricles, mRNA levels of G alpha i-2 increased by 40% (P < 0.05), but not in left ventricles. In both left and right ventricles, chronic hypoxia did not modify G alpha i-2 and G alpha s protein amounts, but significantly decreased functional activity of G alpha s. In conclusion, gene expression, protein levels of G alpha s and G alpha i-2, and activity of G alpha s do not change in parallel fashion with chronic hypoxia. In chronic hypoxic right ventricles, although the mRNA level of G alpha i-2 is increased, the protein level is unchanged. One potential mechanism of desensitization to catecholamines in chronic hypoxia appears to involve a decreased functional activity of G alpha s in spite of normal mRNA and protein levels.

Adrenergic status of humans during prolonged exposure to the altitude of 6,542 m.

Plasma norepinephrine (NE) concentration increases with altitude exposure while maximal heart rate (HR) and chronotropic response to isoproterenol (IP) are blunted. Downregulation of cardiac beta-adrenergic receptors (beta-AR) has been evoked to explain this phenomenon. Chronotropic response was studied at extreme altitude in 10 subjects (4 women, 6 men; aged 35 +/- 6 yr). Observations were made in normoxia (N) and after 1 (H1) and 3 (H3) wk at 6,542 m. Acclimatization was accomplished by gradual climbing from 4,000 to 6,542 m over 10 days. Plasma NE was obtained at rest and during submaximal exercise. Successive doses of IP (0.02, 0.04, and 0.06 microgram/kg-1.min-1) were infused for 5 min each. Density and affinity of lymphocyte beta 2-AR were also measured. Increase in HR for maximal dose of IP decreased from 57 +/- 12 to 34 +/- 7 and 37 +/- 10 min-1 in H1 and H3, respectively (P < 0.001 for both). IP dose for which HR rises by 25 min-1 (I25) increased from 27 +/- 5 in N to 42 +/- 10 and 43 +/- 17 ng.kg-1.min-1 in H1 and H3, respectively (P < 0.001 for both). Arterial O2 saturation at rest was 98 +/- 2% in N, 72 +/- 6% in H1 (P < 0.001), and 79 +/- 5% in H3 (P < 0.001). The chronotropic response was neither restored nor further attenuated after 3 wk at 6,542 m. Plasma NE levels at rest and during exercise were higher at 6,542 m than values obtained in previous studies at 4,350 and 4,800 m.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypoxia-induced differential modulation of adenosinergic and muscarinic receptors in rat heart.

To better understand the decreased chronotropic response to catecholamines in chronic hypoxia, we compared the inhibitory pathways regulating adenylate cyclase in rats exposed for 30 days to hypobaric hypoxia (380 Torr; HX) with those in control rats (CT) by the analysis of adenosinergic A1-receptors (8-cyclopentyl-1,3-[3H]dipropylxanthine) and muscarinic M2-receptors ([3H]quinuclidinyl benzilate). A1-receptor density was decreased by 46% in sarcolemmal preparations without a change in the affinity for agonist [(R)-phenylisopropyladenosine]. M2-receptor density was increased (HX: 280 +/- 16 fmol/mg, CT: 188 +/- 15 fmol/mg; n = 7; P < 0.001) without a change in dissociation constant. Displacement of [3H]quinuclidinyl benzilate by carbachol indicated significant decreases in the dissociation constants of both superhigh- (HX: 73 +/- 19 nM, CT: 182 +/- 42 nM; P < 0.001) and high-affinity binding sites (HX: 4 +/- 1 microM, CT: 12 +/- 3 microM; P < 0.001). Our data show that chronic hypoxia leads to differential modulation of cardiac receptors with a downregulation of adenosine receptors and increases in muscarinic receptor affinity and density, which may contribute to the blunted responsiveness of the heart to catecholamines.

[Altitude and pregnancy. Apropos of an experimental study on the pregnant rat]. / Altitude et grossesse. A propos d'un travail expérimental sur la rate gestante.

Pregnancies that occur at high altitude are bedevilled by many complications and particularly those due to pressure disorders. Although there are many maternal and placental mechanisms that are brought to bear to "blunt" the effects of hypoxia in the fetus, these pregnancies are characterised by low birth weights. This work has been carried out to find out the effects of hypoxia during part only of the pregnancy. The study was carried out on three groups of ten pregnant Wistar Rats: a control group with normal oxygenation (N); a group exposed to hypobaric hypoxia during the 4th to the 12th day of pregnancy (480 mmHg, equivalent to altitude of 5200 m) (HP); and a group exposed to the same levels of hypoxia between the 12th and 20th days of pregnancy (HT). The litters were the same size in each group. Mortality of the little rats respectively were 0%, 8.1% and 30.6% in groups N, HP and HT (p < 0.001). With hypoxia the rats eat less at whichever stage of pregnancy. Weight gain in pregnancy overall was less in the groups exposed to hypoxia. The weight gain in the compression chamber was particularly low in the early exposed group (HP). The mean weight of the small rats was lowered most in group HT (p 0.001). In conclusion, exposure to hypoxia is particularly damaging if it occurs in the second half of pregnancy but if hypoxia occurs only in the first half of pregnancy there are disturbances. Exposure to hypoxia goes up mainly as an increase in neonatal mortality with low birth weights.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypoxia-induced downregulation of beta-adrenergic receptors in rat heart.

To test the desensitization hypothesis of cardiac beta-adrenergic receptors (beta-AR) in chronic hypoxia, the effect of 1, 3, 7, 15, and 21 days of exposure to hypobaric hypoxia (380 Torr) was evaluated in Wistar rats. Exposure to hypoxia for 1-15 days did not induce any change in right and left ventricular beta-AR density (Bmax) determined with [125I]iodocyanopindolol or in antagonist affinity. After 21 days, Bmax decreased by 24% in the left ventricle. In contrast, no change in beta-AR was shown in the right hypertrophied ventricle. Agonist affinity in the left ventricle was not altered, as shown by the analysis of displacement curves of isoproterenol (normoxia 185 +/- 26 nM, hypoxia 170 +/- 11 nM). Moreover, there was no significant decrease in adenylate cyclase activity (pmol.mg-1.min-1) in the left ventricle. In the right ventricle, a 21-day exposure to hypoxia led to a decrease in basal and maximal activity when stimulated by isoproterenol. A decrease in tissue norepinephrine content was observed after 7 days of hypoxia. In conclusion, these data support the beta-AR downregulation hypothesis as one of the mechanisms of myocardial adaptation to high altitude occurring after 2-3 wk of exposure to hypoxia. The regulation pathways of beta-AR may differ between left nonhypertrophied and right hypertrophied ventricles. No evidence of profound abnormality of signal transduction was shown.

The control of cardiac chronotropic function in hypobaric hypoxia.

Altitude hypoxia induces an increase in adrenergic activity in humans. However, a decrease in maximal heart rate is observed after a few days of exposure to altitudes above 3500 m, as well as a decrease in chronotropic response to isoproterenol infusion. This phenomenon has been linked to a desensitization of beta-adrenoceptors (beta AR), and/or an increase in parasympathetic activity. A decrease in the density of beta AR in chronic hypoxia has been found in rat left ventricle and in human lymphocytes, without modification of the affinity of beta AR for an agonist or antagonist, and a decreased adenylate cyclase activity in the right ventricle. In the same conditions, the density of adenosine A1 receptors is decreased by 46% in rat myocardium, without alteration in the coupling between hormone, receptor and Gi protein. The density of muscarinic receptors is increased by 40%, with an increase in the affinity for an agonist, suggesting an augmented parasympathetic effect. Hypoxia probably acts on all the receptors involved in the modulation of cardiac chronotropic activity; the combined effects of chronic hypoxia on these receptors tend to a beneficial limitation of myocardial oxygen consumption, especially during heavy exercise.

Adrenergic system in high altitude residents.

Heart rate (HR) response to isoproterenol (ISO) infusion (IP) is decreased in normal sea level (SL) natives exposed to high altitude (HA). Since norepinephrine plasma concentration is higher in HA hypoxia, a downregulation of beta-adrenoceptors (beta AR) was evoked. We explored this phenomenon at 3600 m in a HA normal population (HAN) and in polycythemic subjects (HAP). Results are compared to SL natives in normoxia (SLN), and during chronic hypoxia at 4800 m (SLH) (J Appl Physiol 65:1957-1961, 1988). ISO dose required to raise HR by 25 min-1 (I 25) is not different in HAN or HAP group when compared to SLN. Density of beta AR on lymphocytes was 39% and 25% lower in HAN and HAP than in SLN group, respectively. Chronotropic response to IP is similar in SL and HA subjects under their usual environmental conditions, while SL natives show a blunted response under hypoxia, probably due to a decrease in beta AR density. No adrenergic desensitization was found in highlanders. Lower beta AR density in HA groups could be an adaptive mechanism to chronic hypoxia. Polycythemia does not affect this responsiveness.