Summary
The renin-angiotensin system (RAS), in addition to its endocrine functions, plays a role within individual tissues such as the brain. The brain RAS is thought to control blood pressure through effects on fluid intake, vasopressin release and sympathetic nerve activity (SNA), and may regulate metabolism through mechanisms which remain undefined. We used a double-transgenic mouse model that exhibits brain-specific RAS activity to examine mechanisms contributing to fluid and energy homeostasis. The mice exhibit high fluid turnover through increased adrenal steroids, which is corrected by adrenalectomy and attenuated by mineralocorticoid receptor blockade. They are also hyperphagic but lean because of a marked increase in body temperature and metabolic rate, mediated by increased SNA and suppression of the circulating RAS. β-adrenergic blockade or restoration of circulating angiotensin-II, but not adrenalectomy, normalized metabolic rate. Our data point to contrasting mechanisms by which the brain RAS regulates fluid intake and energy expenditure.
The renin-angiotensin system in the brain acts to regulate a number of physiological processes. Evidence suggests that angiotensin peptides may act as neurotransmitters, although their biosynthetic pathways are poorly understood. We review evidence for neuronal production of angiotensin peptides, and hypothesize that angiotensin may be synthesized intracellularly in neurons.
There is conflicting evidence regarding a possible association between the apolipoprotein E4 (APOE4) allele and the consequences of traumatic brain injury (TBI). Our aim was to carry out a meta-analysis of cohort studies of sufficient rigor to determine whether the presence of the APOE4 allele contributes to initial injury severity and/or poor outcome following TBI. MEDLINE, EMBase, CBMdisc, and CNKI databases were searched for literature published from January 1993 to October 2007. Of the 100 identified studies, 14 cohort studies were selected for analysis based on comprehensive quality assessment using a standardized scale. Data from the 14 eligible cohort studies included a total of 2527 participants, 736 with and 1791 without the APOE4 allele. The APOE4 allele was not associated with initial injury severity of TBI. The pooled RR were 1.11 (95% confidence interval [CI], 0.91 to 1.35) for severe injury, 1.06 (95% CI, 0.86-1.31) for moderate injury and 0.93 (95% CI, 0.81-1.06) for mild injury. However, the APOE4 allele was significantly associated with a poor outcome of TBI at 6 months after injury (RR = 1.36; 95% CI, 1.04-1.78). The association remained significant in sensitivity tests. This meta-analysis indicates that the presence of the APOE4 allele is not associated with the initial severity of brain injury following TBI but is associated with increased risk of poor long-term outcome at 6 months after injury.
Low-renin hypertension accounts for approximately 25% of essential hypertensive patients. It is modeled in animals by chronic delivery of deoxycorticosterone acetate and excess dietary sodium (the DOCA-salt model). Previous studies have demonstrated that DOCA-salt hypertension is mediated through activation of the brain renin-angiotensin system. Here, we demonstrate robust metabolic phenotypes of DOCA-salt treatment. Male C57BL/6J mice (6–8 weeks old) received a subcutaneous pellet of deoxycorticosterone acetate (50 mg, 21-day), and were offered a 0.15 mol/L NaCl drink solution in addition to regular chow and tap water. Treatment resulted in mild hypertension, a blunting of weight gain, gross polydipsia, polyuria, and sodium intake, alterations in urinary sodium and potassium turnover, and serum sodium retention. Most strikingly, DOCA-salt mice exhibited no difference in food intake, but a large elevation in basal metabolic rate. Normalization of blood pressure by hydralazine (500 mg/L in drink solutions) attenuated the hydromineral phenotypes and renal renin suppression effects of DOCA-salt, but had no effect on the elevated metabolic rate. In contrast, intracerebroventricular infusion of the angiotensin II type 1 receptor antagonist, losartan (5 μg/hr), attenuated the elevation in metabolic rate with DOCA-salt treatment. Together, these data illustrate the necessity of angiotensinergic signaling within the brain, independent of blood pressure alterations, in the metabolic consequences of DOCA-salt treatment.
Summary
Strategy of managing antibiotic‐resistant Vibrio alginolyticus, a bacterial pathogen that threatens human health and animal farming, is not available due to the lack of knowledge about the underlying mechanism of antibiotic resistance. Here, we showed that gentamicin‐resistant V. alginolyticus (VA‐RGEN) has four mutations on metabolism and one mutation on a two‐component system by whole‐genome and PCR‐based sequencing, indicating the metabolic shift in VA‐RGEN. Thus, metabolic profile was investigated by GC–MS based metabolomics. Glucose was identified as a crucial biomarker, whose abundance was decreased in VA‐RGEN. Further analysis with iPath, and gene expression and enzyme activity of the pyruvate cycle (the P cycle) demonstrated a global depressed metabolic pathway network in VA‐RGEN. Consistently, NADH, sodium‐pumping NADH:ubiquinone oxidoreductase (Na(+)‐NQR) system, membrane potential and intracellular gentamicin were decreased in VA‐RGEN. These findings indicate that the reduced redox state contributes to antibiotic resistance. Interestingly, exogenous glucose potentiated gentamicin to efficiently kill VA‐RGEN through the promotion of the P cycle, NADH, membrane potential and intracellular gentamicin. The potentiation was further confirmed in a zebrafish model. These results indicate that the gentamicin resistance reduces the P cycle and Na(+)‐NQR system and thereby decreases redox state, membrane potential and gentamicin uptake, which can be reversed by exogenous glucose.
Abstract-The primary product of the renin gene is preprorenin. A signal peptide sorts renin to the secretory pathway in juxtaglomerular cells where it is released into the circulation to initiate the renin-angiotensin system cascade. In the brain, transcription of renin occurs from an alternative promoter encoding an mRNA starting with a new first exon (exon 1b). Exon 1b initiating transcripts skip over the classical first exon (exon 1a) containing the initiation codon for preprorenin. Exon 1b transcripts are predicted to use a highly conserved initiation codon within exon 2, producing renin, which should remain intracellular, because it lacks the signal peptide. To evaluate the roles of secreted and intracellular renin, we took advantage of the organization of the renin locus to generate a secreted renin (sRen)-specific knockout, which preserves intracellular renin expression. Expression of sRen mRNA was ablated in the brain and kidney, whereas intracellular renin mRNA expression was preserved in fetal and adult brains. We noted a developmental shift from the expression of sRen mRNA in the fetal brain to intracellular renin mRNA in the adult brain. Homozygous sRen knockout mice exhibited very poor survival at weaning. The survivors exhibited renal lesions, low hematocrit, an inability to generate a concentrated urine, decreased arterial pressure, and impaired aortic contraction. These results suggest that preservation of intracellular renin expression in the brain is not sufficient to compensate for a loss of sRen, and sRen plays a pivotal role in renal development and function, survival, and the regulation of arterial pressure.
There was lots of information on anti-obesity and reduced risk of cardiovascular disease, to our best knowledge, little was known about the prevention of colitis by RPT. We firstly assessed effects of RPT on phenotypic improvements of DSS-induced colitis in mice.
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