651 research outputs found
A novel DDAH-1 inhibitor improved cardiovascular function in a short-term anesthetized rat model of sepsis
A novel DDAH-1 inhibitor improved sepsis-induced impairment in vasoreactivity to noradrenaline in a rat endotoxaemia model
ORIGINAL COMMUNICATION Effects on health of fluid restriction during fasting in Ramadan
During the 9th month (Ramadan) of the Islamic calendar (Hijra) many millions of adult Muslims all over the world fast during the daylight hours. Since Hijra is a lunar calendar, Ramadan occurs at different times in the seasonal year over a 33-year cycle. Fasting during Ramadan is partial because the abstention from food, fluid, tobacco and caffeine is from sunrise to sunset. Several categories of people are exempt or can postpone the Ramadan fast. The effect on health and well being of the month-long intermittent fast and fluid restriction has been studied in various potentially vulnerable groups in addition to normal healthy individuals in many countries. The majority of the studies have found significant metabolic changes, but few health problems arising from the fast. A reduction in drug compliance was an inherent negative aspect of the fast. Common findings of the studies reviewed were increased irritability and incidences of headaches with sleep deprivation and lassitude prevalent. A small body mass loss is a frequent, but not universal, outcome of Ramadan. During the daylight hours of Ramadan fasting, practising Muslims are undoubtedly dehydrating, but it is not clear whether they are chronically hypohydrated during the month of Ramadan. No detrimental effects on health have as yet been directly attributed to negative water balance at the levels that may be produced during Ramadan
The ADMA/DDAH Pathway Regulates VEGF-Mediated Angiogenesis
Objectives— Asymmetrical dimethylarginine (ADMA) is a nitric oxide synthase (NOS) inhibitor and cardiovascular risk factor associated with angiogenic disorders. Enzymes metabolising ADMA, dimethylarginine dimethylaminohydrolases (DDAH) promote angiogenesis, but the mechanisms are not clear. We hypothesized that ADMA/DDAH modifies endothelial responses to vascular endothelial growth factor (VEGF) by affecting activity of Rho GTPases, regulators of actin polymerization, and focal adhesion dynamics.
Methods and Results— The effects of ADMA on VEGF-induced endothelial cell motility, focal adhesion turnover, and angiogenesis were studied in human umbilical vein endothelial cells (HUVECs) and DDAH I heterozygous knockout mice. ADMA inhibited VEGF-induced chemotaxis in vitro and angiogenesis in vitro and in vivo in an NO-dependent way. ADMA effects were prevented by overexpression of DDAH but were not associated with decreased proliferation, increased apoptosis, or changes in VEGFR-2 activity or expression. ADMA inhibited endothelial cell polarization, protrusion formation, and decreased focal adhesion dynamics, resulting from Rac1 inhibition after decrease in phosphorylation of vasodilator stimulated phosphoprotein (VASP). Constitutively active Rac1, and to a lesser extent dominant negative RhoA, abrogated ADMA effects in vitro and in vivo.
Conclusion— The ADMA/DDAH pathway regulates VEGF-induced angiogenesis in an NO- and Rac1-dependent manner
Regulation of fluid reabsorption in rat or mouse proximal renal tubules by asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase 1
Nitric oxide prevents hypertension yet enhances proximal tubule Na+ reabsorption. Nitric oxide synthase is inhibited by asymmetric dimethylarginine (ADMA) that is metabolized by dimethylarginine dimethylaminohydrolase (DDAH) whose type 1 isoform is expressed abundantly in the proximal tubule (PT). We hypothesize that ADMA metabolized by DDAH-1 inhibits fluid reabsorbtion (Jv) by the proximal tubule. S2 segments of the PT were microperfused between blocks in vivo to assess Jv in anesthetized rats. Compared with vehicle, microperfusion of ADMA or Nω-nitro-l-arginine methyl ester (l-NAME) in the proximal tubule reduced Jv dose dependently. At 10−4 mol/l both reduced Jv by ~40% (vehicle: 3.2 ± 0.7 vs. ADMA: 2.1 ± 0.5, P < 0.01 vs. l-NAME: 1.9 ± 0.4 nl·min−1·mm−1, P < 0.01; n = 10). Selective inhibition of DDAH-1 in rats with intravenous L-257 (60 mg/kg) given 2 h before and L-257 (10−5 mol/l) perfused in the proximal tubule for 5 min reduced Jv by 32 ± 4% (vehicle: 3.2 ± 0.5 vs. L-257: 2.2 ± 0.5 nl·min−1·mm−1; P < 0.01) and increased plasma ADMA by ≈50% (vehicle: 0.46 ± 0.03 vs. L-257: 0.67 ± 0.03 µmol/l, P < 0.0001) without changing plasma symmetric dimethylarginine. Compared with nontargeted control small-interference RNA, knock down of DDAH-1 in mice by 60% with targeted small-interference RNAs (siRNA) reduced Jv by 29 ± 5% (nontargeted siRNA: 2.8 ± 0.20 vs. DDAH-1 knockdown: 1.9 ± 0.31 nl·min−1·mm−1, P < 0.05). In conclusion, fluid reabsorption in the proximal tubule is reduced by tubular ADMA or by blocking its metabolism by DDAH-1. L-257 is a novel regulator of proximal tubule fluid reabsorption
Evaluation of low temperature waste heat as a low carbon heat resource in the UK
The capture and transport of waste heat represents a great opportunity for the decarbonisation of heat supply in buildings. To date, mostly high temperature waste heat has been reused and reported. However, with the recent advent of low and ambient temperature (4th and 5th generation) district energy networks, there is scope for the recovery and utilisation of heat from a range of novel, low temperature sources. The current study represents one of the first attempts to quantify the size of this opportunity, with particular focus in the UK, and complements the few previous attempts at estimating low temperature waste heat by focussing on a range of novel sources. The approach used was to evaluate a number of low temperature waste heat sources to determine: (a) the annual quantity of waste heat generated; and (b) the temperature(s) of the waste heat, for each heat source. In many cases, this was achieved using methodology and assumptions derived from the authors’ earlier investigations. The relative merits and potential of each heat source are also discussed, with respect to location, proximity to end users, need for upgrade using a heat pump, continuity of supply and distribution options for reuse, for example by using district energy networks with different operating temperatures. The total quantity of waste heat energy identified from the heat sources considered in this study, for England, Wales and Northern Ireland, was estimated to be 572 TWh.a−1, which would represent 132% of the total energy consumption for heat in these countries (432 TWh.a−1). Although this study focused on the UK potential for low temperature waste heat, the estimation methods developed and resulting analysis are generic and could also be applied in the context of other countries
The roles of calcium signaling and ERK1/2 phosphorylation in a Pax6(+/- )mouse model of epithelial wound-healing delay
BACKGROUND: Congenital aniridia caused by heterozygousity at the PAX6 locus is associated with ocular surface disease including keratopathy. It is not clear whether the keratopathy is a direct result of reduced PAX6 gene dosage in the cornea itself, or due to recurrent corneal trauma secondary to defects such as dry eye caused by loss of PAX6 in other tissues. We investigated the hypothesis that reducing Pax6 gene dosage leads to corneal wound-healing defects. and assayed the immediate molecular responses to wounding in wild-type and mutant corneal epithelial cells. RESULTS: Pax6(+/- )mouse corneal epithelia exhibited a 2-hour delay in their response to wounding, but subsequently the cells migrated normally to repair the wound. Both Pax6(+/+ )and Pax6(+/- )epithelia activated immediate wound-induced waves of intracellular calcium signaling. However, the intensity and speed of propagation of the calcium wave, mediated by release from intracellular stores, was reduced in Pax6(+/- )cells. Initiation and propagation of the calcium wave could be largely decoupled, and both phases of the calcium wave responses were required for wound healing. Wounded cells phosphorylated the extracellular signal-related kinases 1/2 (phospho-ERK1/2). ERK1/2 activation was shown to be required for rapid initiation of wound healing, but had only a minor effect on the rate of cell migration in a healing epithelial sheet. Addition of exogenous epidermal growth factor (EGF) to wounded Pax6(+/- )cells restored the calcium wave, increased ERK1/2 activation and restored the immediate healing response to wild-type levels. CONCLUSION: The study links Pax6 deficiency to a previously overlooked wound-healing delay. It demonstrates that defective calcium signaling in Pax6(+/- )cells underlies this delay, and shows that it can be pharmacologically corrected. ERK1/2 phosphorylation is required for the rapid initiation of wound healing. A model is presented whereby minor abrasions, which are quickly healed in normal corneas, transiently persist in aniridic patients, compromising the corneal stroma
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