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您现在的位置：首页>美国卫生研究院文献>American Journal of Physiology - Regulatory, Integrative and Comparative Physiology

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  • 刊频： Twice monthly, 2012-
  • NLM标题： Am J Physiol Regul Integr Comp Physiol
  • iso缩写： -
  • ISSN： -

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  • 1.

    【2hr】Altered expression of hepatic β-adrenergic receptors in aging rats: implications for age-related metabolic dysfunction in liver

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    机译 衰老大鼠肝β-肾上腺素能受体的表达变化：对肝脏年龄相关代谢功能障碍的影响
    摘要：Increased β-adrenergic receptor (β-AR)-mediated activation of adenylyl cyclase (AC) in rat liver during aging has been linked to age-related increases in hepatic glucose output and hepatosteatosis. In this study, we investigated the expression of β-ARs, individual receptor subtypes, and G protein-coupled receptor (GPCR) regulatory proteins in livers from aging rats. Radioligand-binding studies demonstrated that β-AR density increased by greater than threefold in hepatocyte membranes from senescent (24-mo-old) compared with young adult (7-mo-old) rats and that this phenomenon was blocked by food restriction, which is known to retard aging processes in rodents. Competition-binding studies revealed a mixed population of β1- and β2-AR subtypes in liver membranes over the adult life span, with a trend for greater β2-AR density with age. Expression of both β-AR subtype mRNAs in rat liver increased with age, whereas β2- but not β1-AR protein levels declined in livers of old animals. Immunoreactive β2- but not β1-ARs were preferentially distributed in pericentral hepatic regions. Levels of GRK2/3 and β-arrestin 2 proteins, which are involved in downregulation of agonist-activated GPCRs, including β-ARs, increased during aging. Insofar as sympathetic tone increases with age, our findings suggest that, despite enhanced agonist-mediated downregulation of hepatic β-ARs preferentially affecting the β2-AR subtype, increased generation of both receptor subtypes during aging augments the pool of plasma membrane-bound β-ARs coupled to AC in hepatocytes. This study thus identifies one or both β-AR subtypes as possible therapeutic targets involved in aberrant hepatic processes of glucose and lipid metabolism during aging.
  • 2.

    【2hr】Upregulation of fatty acid amide hydrolase in the dorsal periaqueductal gray is associated with neuropathic pain and reduced heart rate in rats

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    机译 导水管周围灰质中脂肪酸酰胺水解酶的上调与神经性疼痛和大鼠心率降低有关
    摘要：Nerve damage can induce a heightened pain response to noxious stimulation, which is termed hyperalgesia. Pain itself acts as a stressor, initiating autonomic and sensory effects through the dorsal periaqueductal gray (dPAG) to induce both sympathoexcitation and analgesia, which prior studies have shown to be affected by endocannabinoid signaling. The present study addressed the hypothesis that neuropathic pain disrupts autonomic and analgesic regulation by endocannabinoid signaling in the dPAG. Endocannabinoid contents, transcript levels of endocannabinoid signaling components, and catabolic enzyme activity were analyzed in the dPAG of rats at 21 days after painful nerve injury. The responses to two nerve injury models were similar, with two-thirds of animals developing hyperalgesia that was maintained throughout the postinjury period, whereas no sustained change in sensory function was observed in the remaining rats. Anandamide content was lower in the dPAG of rats that developed sustained hyperalgesia, and activity of the catabolic enzyme fatty acid amide hydrolase (FAAH) was higher. Intensity of hyperalgesia was correlated to transcript levels of FAAH and negatively correlated to heart rate and sympathovagal balance. These data suggest that maladaptive endocannabinoid signaling in the dPAG after nerve injury could contribute to chronic neuropathic pain and associated autonomic dysregulation. This study demonstrates that reduced anandamide content and upregulation of FAAH in the dPAG are associated with hyperalgesia and reduced heart rate sustained weeks after nerve injury. These data provide support for the evaluation of FAAH inhibitors for the treatment of chronic neuropathic pain.
  • 3.

    【2hr】Components of the cannabinoid system in the dorsal periaqueductal gray are related to resting heart rate

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    机译 导水管周围灰色的大麻素系统成分与静息心率有关
    摘要：The present study was undertaken to examine whether variations in endocannabinoid signaling in the dorsal periaqueductal gray (dPAG) are associated with baseline autonomic nerve activity, heart rate, and blood pressure. Blood pressure was recorded telemetrically in rats, and heart rate and power spectral analysis of heart rate variability were determined. Natural variations from animal to animal provided a range of baseline values for analysis. Transcript levels of endocannabinoid signaling components in the dPAG were analyzed, and endocannabinoid content and catabolic enzyme activity were measured. Higher baseline heart rate was associated with increased anandamide content and with decreased activity of the anandamide-hydrolyzing enzyme and fatty acid amide hydrolase (FAAH), and it was negatively correlated with transcript levels of both FAAH and monoacylglycerol lipase (MAGL), a catabolic enzyme for 2-arachidonoylglycerol (2-AG). Autonomic tone and heart rate, but not blood pressure, were correlated to levels of FAAH mRNA. In accordance with these data, exogenous anandamide in the dPAG of anesthetized rats increased heart rate. These data indicate that in the dPAG, anandamide, a FAAH-regulated lipid, contributes to regulation of baseline heart rate through influences on autonomic outflow.
  • 4.

    【2hr】The sleep-wake cycle and motor activity, but not temperature, are disrupted over the light-dark cycle in mice genetically depleted of serotonin

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    机译 在基因缺失了5-羟色胺的小鼠中，睡眠-觉醒周期和运动活动（而不是温度）在明暗周期中被破坏
    摘要：We examined the role that serotonin has in the modulation of sleep and wakefulness across a 12-h:12-h light-dark cycle and determined whether temperature and motor activity are directly responsible for potential disruptions to arousal state. Telemetry transmitters were implanted in 24 wild-type mice (Tph2+/+) and 24 mice with a null mutation for tryptophan hydroxylase 2 (Tph2−/−). After surgery, electroencephalography, core body temperature, and motor activity were recorded for 24 h. Temperature for a given arousal state (quiet and active wake, non-rapid eye movement, and paradoxical sleep) was similar in the Tph2+/+ and Tph2−/− mice across the light-dark cycle. The percentage of time spent in active wakefulness, along with motor activity, was decreased in the Tph2+/+ compared with the Tph2−/− mice at the start and end of the dark cycle. This difference persisted into the light cycle. In contrast, the time spent in a given arousal state was similar at the remaining time points. Despite this similarity, periods of non-rapid-eye-movement sleep and wakefulness were less consolidated in the Tph2+/+ compared with the Tph2−/− mice throughout the light-dark cycle. We conclude that the depletion of serotonin does not disrupt the diurnal variation in the sleep-wake cycle, motor activity, and temperature. However, serotonin may suppress photic and nonphotic inputs that manifest at light-dark transitions and serve to shorten the ultraradian duration of wakefulness and non-rapid-eye-movement sleep. Finally, alterations in the sleep-wake cycle following depletion of serotonin are unrelated to disruptions in the modulation of temperature.
  • 5.

    【2hr】Negative regulation of HIF in skeletal muscle of elite enduranceathletes: a tentative mechanism promoting oxidative metabolism

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    机译 精英耐力骨骼肌中HIF的负调控运动员：促进氧化代谢的初步机制
    摘要：The transcription factor hypoxia-inducible factor (HIF) has been suggested as a candidate for mediating training adaptation in skeletal muscle. However, recent evidence rather associates HIF attenuation with a trained phenotype. For example, a muscle-specific HIF deletion increases endurance performance, partly through decreased levels of pyruvate dehydrogenase kinase 1 (PDK-1). HIF activity is regulated on multiple levels: modulation of protein stability, transactivation capacity, and target gene availability. Prolyl hydroxylases (PHD1–3) induces HIF degradation, whereas factor-inhibiting HIF (FIH) and the histone deacetylase sirtuin-6 (SIRT6) repress its transcriptional activity. Together, these negative regulators introduce a mechanism for moderating HIF activity in vivo. We hypothesized that long-term training induces their expression. Negative regulators of HIF were explored by comparing skeletal muscle tissue from moderately active individuals (MA) with elite athletes (EA). In elite athletes, expression of the negative regulators PHD2 (MA 73.54 ± 9.54, EA 98.03 ± 6.58), FIH (MA 4.31 ± 0.25, EA 30.96 ± 7.99) and SIRT6 (MA 0.24 ± 0.07, EA 11.42 ± 2.22) were all significantly higher, whereas the response gene, PDK-1was lower (MA 0.12 ± 0.03, EA 0.04 ± 0.01). Similar results wereobserved in a separate 6-wk training study. In vitro, activation of HIF in humanprimary muscle cell culture by PHD inactivation strongly induced PDK-1 (0.84± 0.12 vs 4.70 ± 0.63), providing evidence of a regulatory linkbetween PHD activity and PDK-1 levels in a relevant model system. Citratesynthase activity, closely associated with aerobic exercise adaptation,increased upon PDK-1 silencing. We suggest that training-induced negativeregulation of HIF mediates the attenuation of PDK-1 and contributes to skeletalmuscle adaptation to exercise.
  • 6.

    【2hr】Heart rate variability and muscle sympathetic nerve activity response to acute stress: the effect of breathing

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    机译 心率变异性和肌肉交感神经活动对急性应激的反应：呼吸的影响
    摘要：Previous research has suggested a relationship between low-frequency power of heart rate variability (HRV; LF in normalized units, LFnu) and muscle sympathetic nerve activity (MSNA). However, investigations have not systematically controlled for breathing, which can modulate both HRV and MSNA. Accordingly, the aims of this experiment were to investigate the possibility of parallel responses in MSNA and HRV (LFnu) to selected acute stressors and the effect of controlled breathing. After data were obtained at rest, 12 healthy males (28 ± 5 yr) performed isometric handgrip exercise (30% maximal voluntary contraction) and the cold pressor test in random order, and were then exposed to hypoxia (inspired fraction of O2 = 0.105) for 7 min, during randomly assigned spontaneous and controlled breathing conditions (20 breaths/min, constant tidal volume, isocapnic). MSNA was recorded from the peroneal nerve, whereas HRV was calculated from ECG. At rest, controlled breathing did not alter MSNA but decreased LFnu (P < 0.05 for all) relative to spontaneous breathing. MSNA increased in response to all stressors regardless of breathing. LFnu increased with exercise during both breathing conditions. During cold pressor, LFnu decreased when breathing was spontaneous, whereas in the controlled breathing condition, LFnu was unchanged from baseline. Hypoxia elicited increases in LFnu when breathing was controlled, but not during spontaneous breathing. The parallel changes observed during exercise and controlled breathing during hypoxia suggest that LFnu may be an indication of sympathetic outflow in select conditions. However, since MSNA and LFnu did not change in parallel with all stressors, a cautious approach to the use of LFnu as a marker of sympathetic activity is warranted.
  • 7.

    【2hr】Working under pressure: coronary arteries and the endothelin system

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    机译 在压力下工作：冠状动脉和内皮素系统
    摘要：Endogenous endothelin-1-dependent (ET-1) tone in coronary arteries depends on the balance between ETA and ETB receptor-mediated effects and on parameters such as receptor distribution and endothelial integrity. Numerous studies highlight the striking functional interactions that exist between nitric oxide (NO) and ET-1 in the regulation of vascular tone. Many of the cardiovascular complications associated with cardiovascular risk factors and aging are initially attributable, at least in part, to endothelial dysfunction characterized by a dysregulation between NO and ET-1. The contribution of the imbalance between smooth muscle ETA/B and endothelial ETB receptors to this process is poorly understood. An increased contribution of ET-1 that is associated with a proportional decrease in that of NO accompanies the development of coronary endothelial dysfunction, coronary vasospasm, and atherosclerosis. These data form the basis for the rationale of testing therapeutic approaches counteracting ET-1-induced cardiovascular dysfunction. It remains to be determined whether the beneficial role of endothelial ETB receptors declines with age and risk factors for cardiovascular diseases, revealing smooth muscle ETB receptors with proconstricting and proinflammatory activities.
  • 8.

    【2hr】Activation and inhibition of the micturition reflex by penile afferents in the cat

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    机译 猫的阴茎传入激活和抑制排尿反射
    摘要：Coordination of the urinary bladder and the external urethral sphincter (EUS) is controlled by descending projections from the pons, and is also subject to modulation by segmental afferents. We quantified the effects on the micturition reflex of sensory inputs from genital afferents, traveling in the penile component of the somatic pudendal nerve, by electrical stimulation of the dorsal nerve of the penis (DNP) in α-chloralose anesthetized male cats. Depending on the frequency of stimulation (range 1–40 Hz), activation of penile afferents either inhibited contractions of the bladder and promoted urine storage or activated the bladder and produced micturition. Stimulation of the DNP at 5–10 Hz inhibited distension evoked contractions and increased the maximum bladder capacity before incontinence. Conversely, stimulation at 33 and 40 Hz augmented distension evoked contractions. When the bladder was filled above a threshold volume (70% of the volume necessary for distension evoked contractions), stimulation at 20–40 Hz activated de novo the micturition reflex and elicited detrusor contractions that increased voiding efficiency compared to distension evoked voiding. Electrical stimulation of the DNP with a cuff electrode or percutaneous wire electrode produced similar results. The ability to evoke detrusor contractions by activation of the DNP was preserved following acute spinal transection. These results demonstrate a clear role of genital afferents in modulating the micturition reflex and suggest the DNP as a potential target for functional restoration of bladder control using electrical stimulation.
  • 9.

    【2hr】Loss of prokineticin receptor 2 (Prokr2) signaling predisposes mice to torpor

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    机译 Prokineticin受体2（Prokr2）信号的丢失使小鼠容易患上Torpor
    摘要：The genes encoding prokineticin 2 polypeptide (Prok2) and its cognate receptor (Prokr2/Gpcr73l1) are widely expressed in both the suprachiasmatic nucleus (SCN) and its hypothalamic targets, and this signaling pathway has been implicated in the circadian regulation of behavior and physiology. We have previously observed that the targeted null mutation of Prokr2 disrupts circadian co-ordination of cycles of locomotor activity and thermoregulation. We have now observed spontaneous but sporadic bouts of torpor in the majority of these transgenic mice lacking Prokr2 signaling. During these torpor bouts, which lasted for up to 8h, body temperature and locomotor activity decreased markedly. Oxygen consumption and carbon dioxide production also decreased, and there was a decrease in RQ. These spontaneous torpor bouts generally began towards the end of the dark phase or in the early light phase when the mice were maintained on a 12:12 light-dark cycle, and persisted when mice were exposed to continuous darkness. Periods of food deprivation (16-24h) induced a substantial decrease in body temperature in all mice, but the duration and depth of hypothermia was significantly greater in mice lacking Prokr2 signaling compared to heterozygous and wild-type litter mates. Likewise, when tested in metabolic cages, food deprivation produced greater decreases in oxygen consumption and carbon dioxide production in the transgenic mice than the controls. We conclude that Prokr2 signaling plays a role in the hypothalamic regulation of energy balance, and loss of this pathway results in physiological and behavioral responses normally only detected when mice are in negative energy balance.
  • 10.

    【2hr】Small-conductance, Ca2• -activated K• channel 2 is the key functional component of SK channels in mouse urinary bladder

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    机译 Ca2•激活的小电导K•通道2是小鼠膀胱SK通道的关键功能组件
    摘要：Small-conductance Ca2• -activated K• (SK) channels play an important role in regulating the frequency and in shaping urinary bladder smooth muscle (UBSM) action potentials, thereby modulating contractility. Here we investigated a role for the SK2 member of the SK family (SK1−3) utilizing: 1) mice expressing • -galactosidase (• -gal) under the direction of the SK2 promoter (SK2 • -gal mice) to localize SK2 expression and 2) mice lacking SK2 gene expression (SK2• /• mice) to assess SK2 function. In SK2 • -gal mice, UBSM staining was observed, but staining was undetected in the urothelium. Consistent with this, urothelial SK2 mRNA was determined to be 4% of that in UBSM. Spontaneous phasic contractions in wild-type (SK2• /•) UBSM strips were potentiated (259% of control) by the selective SK channel blocker apamin (EC50 • 0.16 nM), whereas phasic contractions of SK2• /• strips were unaffected. Nerve-mediated contractions of SK2• /• UBSM strips were also increased by apamin, an effect absent in SK2• /• strips. Apamin increased the sensitivity of SK2• /• UBSM strips to electrical field stimulation, since pretreatment with apamin decreased the frequency required to reach a 50% maximal contraction (vehicle, 21 • 4 Hz, n • 6; apamin, 12 • 2 Hz, n • 7; P & 0.05). In contrast, the sensitivity of SK2• /• UBSM strips was unaffected by apamin. Here we provide novel insight into the molecular basis of SK channels in the urinary bladder, demonstrating that the SK2 gene is expressed in the bladder and that it is essential for the ability of SK channels to regulate UBSM contractility.
  • 11.

    【2hr】Slc39a1 to 3 (Subfamily II) Zip Genes in Mice have Unique Cell-Specific Functions during Adaptation to Zinc Deficiency

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    机译 小鼠中的Slc39a1至3（亚家族II）Zip基因在适应锌缺乏时具有独特的细胞特异性功能
    摘要：Subfamily II of the solute-carrier (Slc)39a family contains three highly conserved members (ZIPs 1 to 3) that share a twelve amino acid signature sequence present in the putative fourth transmembrane domain and function as zinc transporters in transfected cells. The physiological significance of this genetic redundancy is unknown. Herein, we report that the complete elimination of all three of these Zip genes, by targeted mutagenesis and cross-breeding mice, causes no overt phenotypic effect. When fed a zinc-adequate diet, several indicators of zinc status were indistinguishable between wild-type and triple-knockout mice; including embryonic morphogenesis and growth, alkaline phosphatase activity in the embryo, and ZIP4 protein in the visceral yolk sac and initial rates (30 min) of accumulation/retention of 67Zn in liver and pancreas. When fed a zinc-deficient diet, embryonic membrane-bound alkaline phosphatase activity was reduced to a much greater extent and 80% of the embryos in the triple-knock mice developed abnormally compared to 12% of the embryos in wild-type mice. During zinc deficiency, the accumulation/retention (3 hr) of 67Zn in the liver and pancreas of weanlings was significantly impaired in the triple-knockout mice compared to wild-type mice. Thus, none of these three mammalian Zip genes apparently plays a critical role in zinc homeostasis when zinc is replete, but they play important, non-compensatory roles when this metal is deficient.
  • 12.

    【2hr】TRPV1 mediated protection against endotoxin-induced hypotension and mortality in rats

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    机译 TRPV1介导的内毒素对大鼠低血压和死亡率的保护作用
    摘要：This study was designed to test the hypothesis that the transient receptor potential vanilloid type 1 (TRPV1) channel, expressed primarily in sensory nerves, and substance P (SP), released by sensory nerves, play a protective role against lipopolysaccharide (LPS)-induced hypotension. LPS (10 mg/kg, iv) elicited tachycardia and hypotension in anesthetized male Wistar rats, which peaked at 10 min and gradually recovered 1 hour after the injection. Blockade of TRPV1 with its selective antagonist, capsazepine (CAPZ, 3 mg/kg, iv), impaired recovery given that the fall in mean arterial pressure (MAP) was greater 1 hour after CAPZ plus LPS injections compared to LPS injection alone (45 ± 5 vs. 25 ± 4 mmHg, P < 0.05). Blockade of the neurokinin-1 (NK1) receptor with its selective antagonists, RP67580 (5 mg/kg, iv) or L-733,060 (4 mg/kg, iv), prevented recovery considering that falls in MAP were not different 1 hour after injections of NK1 antagonists plus LPS from their peak decreases (66 ± 9 vs. 74 ± 5 mmHg, or 60 ± 7 vs. 69 ± 3 mmHg, respectively, P>0.05). LPS increased plasma SP, norepinephrine (NE), and epinephrine (EPI) levels compared to vehicles, and the increases in plasma SP, NE, and EPI were significantly inhibited by CAPZ or RP67580, respectively. The survival rate at 24 or 48 hours after LPS injection (20 mg/kg, ip) was lower in conscious rats pretreated with CAPZ or RP67580 compared to rats treated with LPS alone (P<0.05). Thus, our results show that the TRPV1, possibly via triggering release of SP which activates the NK1 and stimulates the sympathetic axis, plays a protective role against endotoxin-induced hypotension and mortality, suggesting that TRPV1 receptors are essential in protecting vital organ perfusion and survival during the endotoxic condition.
  • 13.

    【2hr】Effect of exercise and calorie restriction on biomarkers of aging in mice

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    机译 运动和热量限制对小鼠衰老生物标志物的影响
    摘要：Unlike, calorie restriction, exercise fails to extend maximum life span, but the mechanisms that explain this disparate effect are unknown. We used a 24-wk protocol of treadmill running, weight matching, and pair feeding to compare the effects of exercise and calorie restriction on biomarkers related to aging. This study consisted of young controls, an ad libitum-fed sedentary group, two groups that were weight matched by exercise or 9% calorie restriction, and two groups that were weight matched by 9% calorie restriction + exercise or 18% calorie restriction. After 24 wk, ad libitum-fed sedentary mice were the heaviest and fattest. When weight-matched groups were compared, mice that exercised were leaner than calorie-restricted mice. Ad libitum-fed exercise mice tended to have lower serum IGF-1 than fully-fed controls, but no difference in fasting insulin. Mice that underwent 9% calorie restriction or 9% calorie restriction + exercise, had lower insulin levels; the lowest concentrations of serum insulin and IGF-1 were observed in 18% calorie-restricted mice. Exercise resulted in elevated levels of tissue heat shock proteins, but did not accelerate the accumulation of oxidative damage. Thus, failure of exercise to slow aging in previous studies is not likely the result of increased accrual of oxidative damage and may instead be due to an inability to fully mimic the hormonal and/or metabolic response to calorie restriction.
  • 14.

    【2hr】Regulation of Fto/Ftm gene expression in mice and humans

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    机译 小鼠和人类中Fto / Ftm基因表达的调控
    摘要：Two recent, large GWAS in European populations have associated a ∼47 Kb region that contains part of the FTO gene with high BMI. The functions of FTO and adjacent FTM in human biology are not clear. We examined expression of these genes in organs of mice segregating for monogenic obesity mutations, exposed to under/over feeding, and to 4 °C. Fto/Ftm expression was reduced in mesenteric adipose tissue of mice segregating for the Ay, Lepob, Leprdb, Cpefat or tub mutations and there was a similar trend in other tissues. These effects were not due to adiposity per se. Hypothalamic Fto and Ftm expression were decreased by fasting in lean and obese animals and by cold exposure in lean mice. The fact that responses of Fto and Ftm expression to these manipulations were almost indistinguishable suggested that the genes might be co-regulated. The putative overlapping regulatory region contains at least 2 canonical CUTL1 binding sites. One of these nominal CUTL1 sites includes rs8050136, a SNP associated with high body mass. The A allele of rs8050136 – associated with lower body mass than the C allele – preferentially bound CUTL1 in human fibroblast DNA. 70% knockdown of CUTL1 expression in human fibroblasts decreased FTO and FTM expression by 90 and 65 %, respectively. Animals and humans with various genetic interruptions of FTO or FTM have phenotypes reminiscent of aspects of the Bardet-Biedl obesity syndrome, a confirmed “ciliopathy”. FTM has recently been shown to be a ciliary basal body protein.
  • 15.

    【2hr】Detectable serum flagellin and lipopolysaccharide and upregulated anti-flagellin and lipopolysaccharide immunoglobulins in human short bowel syndrome

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    机译 人短肠综合征中可检测的血清鞭毛蛋白和脂多糖以及抗鞭毛蛋白和脂多糖免疫球蛋白上调
    摘要：Gut barrier dysfunction may occur in short bowel syndrome (SBS). We hypothesized that systemic exposure to flagellin and lipopolysaccharide (LPS) in SBS might regulate specific immune responses. We analyzed serial serum samples obtained from parenteral nutrition (PN)-dependent patients with SBS versus non-SBS control serum. Serum from 23 adult SBS patients was obtained at baseline and 4, 8, 12, 16, 20, and 24 wk in a trial of modified diet with or without growth hormone. Control serum was obtained from 48 healthy adults and 37 adults requiring PN during critical illness. Serum flagellin was detected by an ELISA recognizing an array of gram-negative flagellins, and LPS was detected by limulus assay. Serum flagellin- and LPS-specific immunoglobulin levels (IgM, IgA, and IgG) were determined by ELISA. Serum flagellin and LPS were undetectable in control subjects. In contrast, serum flagellin, LPS, or both were detected in 14 SBS patients (61%) during one or more time points [flagellin alone, 5/23 (22%); LPS alone, 6/23 (26%); or flagellin + LPS, 3/23 (13%)]. Flagellin-specific serum IgM, IgA, and IgG levels were markedly increased in SBS patients compared with both control populations and remained elevated during the 6-mo study period. LPS-specific IgA was significantly higher in SBS patients compared with healthy controls; LPS-specific IgM, IgA, and IgG levels each decreased over time in association with PN weaning. We conclude that adults with PN-dependent SBS are systemically exposed to flagellin and LPS, presumably from the gut lumen. This likely regulates innate and adaptive immune responses to these specific bacterial products.
  • 16.

    【2hr】TNF-alpha inhibition reduces renal injury in DOCA-salt hypertensive rats

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    机译 TNF-α抑制作用减轻DOCA-盐高血压大鼠的肾脏损伤
    摘要：Studies suggest that the inflammatory cytokine, TNF-α plays a role in the prognosis of end-stage renal diseases. We have previously shown that TNF-α inhibition slowed the progression of hypertension and renal damage in angiotensin II salt-sensitive hypertension. Thus, we hypothesize that TNF-α contributes to renal inflammation in a model of mineralocorticoid-induced hypertension. Four groups of rats (n=5-6) were studied for 3 weeks with the following treatments 1) placebo, 2) placebo + TNF-α inhibitor, etanercept (1.25 mg/kg/day, sc), 3) deoxycorticosterone acetate plus 0.9 % NaCl to drink (DOCA-salt), or 4) DOCA-salt + etanercept. Mean arterial blood pressure (MAP) measured by telemetry increased in DOCA-salt rats compared to baseline (177±4 vs. 107±3 mmHg, P<0.05) and TNF-α inhibition had no effect in the elevation of MAP in these rats (177±8 mmHg). Urinary protein excretion significantly increased in DOCA-salt rats compared to placebo (703±76 vs. 198±5 mg/day, respectively); etanercept lowered the proteinuria (514±64 mg/day, P < 0.05 vs. DOCA-salt alone). Urinary albumin excretion followed a similar pattern in each group. Urinary MCP-1 and ET-1 excretion were also increased in DOCA-salt rats compared to placebo (MCP-1: 939±104 vs. 43±7 ng/day, and ET-1: 3.30±0.29 vs. 1.07±0.03 fmol/day, respectively, both P<0.05); TNF-α inhibition significantly decreased both MCP-1 and ET-1 excretion (409±138 ng/day and 2.42±0.22 fmol/day, respectively, both P < 0.05 vs. DOCA-salt alone). Renal cortical NFκB activity also increased in DOCA-salt hypertensive rats and etanercept treatment significantly reduced this effect. These data support the hypothesis that TNF-α contributes to the increase in renal inflammation in DOCA-salt rats.
  • 17.

    【2hr】Amiloride-sensitive NaCl taste responses are associated with genetic variation of ENaC α-subunit in mice

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    机译 阿米洛利敏感的NaCl味觉反应与小鼠ENaCα亚基的遗传变异有关
    摘要：An epithelial Na+ channel (ENaC) is expressed in taste cells and may be involved in the salt taste transduction. ENaC activity is blocked by amiloride, which in several mammalian species also inhibits taste responses to NaCl. In mice, lingual application of amiloride inhibits NaCl responses in the chorda tympani (CT) gustatory nerve much stronger in the C57BL/6 (B6) strain than in the 129P3/J (129) strain. We examined whether this strain difference is related to gene sequence variation or mRNA expression of three ENaC subunits (α, β, γ). Real-time RT-PCR and in situ hybridization detected no significant strain differences in expression of all three ENaC subunits in fungiform papillae. Sequences of the β- and γENaC subunit genes were also similar in the B6 and 129 strains, but αENaC gene had three single nucleotide polymorphisms (SNPs). One of these SNPs resulted in a substitution of arginine in the B6 strain to tryptophan in the 129 strain (R616W) in the αENaC protein. To examine association of this SNP with amiloride sensitivity of CT responses to NaCl, we produced F2 hybrids between B6 and 129 strains. Amiloride inhibited CT responses to NaCl in F2 hybrids with B6/129 and B6/B6 αEnaC R616W genotypes stronger than in F2 hybrids with 129/129 genotype. This suggests that the R616W variation in the αENaC subunit affects amiloride sensitivity of the ENaC channel and provides evidence that ENaC is involved in amiloride-sensitive salt taste responses in mice.
  • 18.

    【2hr】Connexin 40 and ATP-dependent intercellular calcium wave in renal glomerular endothelial cells

    包量

    机译 肾小球内皮细胞中连接蛋白40和ATP依赖性细胞间钙波
    摘要：Endothelial intracellular calcium ([Ca2+]i) plays an important role in the function of the juxtaglomerular vasculature. The present studies aimed to identify the existence and molecular elements of an endothelial calcium wave in cultured glomerular endothelial cells (GENC). GENCs on glass coverslips were loaded with Fluo-4/Fura red, and ratiometric [Ca2+]i imaging was performed using fluorescence confocal microscopy. Mechanical stimulation of a single GENC caused a nine-fold increase in [Ca2+]i, which propagated from cell to cell throughout the monolayer (7.9 ± 0.3 μm/s) in a regenerative manner (without decrement of amplitude, kinetics, and speed) over distances >400 μm. Inhibition of voltage-dependent calcium channels with nifedipine had no effect on the above parameters, but the removal of extracellular calcium reduced Δ[Ca2+]i by 50%. Importantly, the gap junction uncoupler α-glycyrrhetinic acid or knockdown of connexin 40 (Cx40) by transfecting GENCs with Cx40 short interfering RNA (siRNA) almost completely eliminated Δ [Ca2+]i and the calcium wave. Breakdown of extracellular ATP using a scavenger cocktail (apyrase and hexokinase) or nonselective inhibition of purinergic P2 receptors with suramin, had similar blocking effects. Scraping cells off along a line eliminated physical contact between cells but did not effect calcium wave propagation. Using an ATP biosensor technique, we detected a significant elevation in extracellular ATP (Δ = 76 ± 2 μM) during calcium wave propagation, which was abolished by Cx40 siRNA treatment (Δ = 6 ± 1 μM). These studies suggest that connexin 40 hemichannels and extracellular ATP are key molecular elements of the glomerular endothelial calcium wave, which may serve important juxtaglomerular functions.
  • 19.

    【2hr】Exercise training normalizes enhanced glutamate-mediated sympathetic activation from the PVN in heart failure

    包量

    机译 运动训练可使心力衰竭中由PVN引起的谷氨酸介导的交感神经激活增强
    摘要：Exercise training (ExT) normalizes the increased sympathetic outflow in heart failure (HF), but the mechanisms are not known. We hypothesized ExT would normalize the augmented glutamatergic mechanisms mediated by NMDA receptors within the PVN that occurs with HF. Four groups of rats were used: 1) Sham Sedentary (Sed); 2) Sham ExT; 3) HF Sed; and 4) HF ExT. HF was induced by left coronary artery ligation, and ExT consisted of three weeks of treadmill running. In α-chloralose-urethane-anesthetized rats, the increase in renal sympathetic nerve activity (RSNA) in response to the highest dose of NMDA (200 pmol) injected into the PVN in the HF Sed group was approximately twice that of the Sham Sed group. In the HF ExT group the response was not different from the Sham Sed or Sham ExT groups. Relative NMDA receptor subunit NR1 mRNA expression was 63% higher in the HF Sed group compared to the Sham Sed group, but in the HF ExT group was not different from the Sham Sed or Sham ExT groups. NR1 receptor subunit protein expression was increased 87% in the HF Sed group compared to the Sham Sed group but in the HF ExT group was not significantly different from the Sham Sed or Sham ExT groups. Thus, one mechanism by which ExT alleviates elevated sympathetic outflow in HF may be through normalization of glutamatergic mechanisms within the PVN.
  • 20.

    【2hr】Gene expression profiling in human skeletal muscle during recovery from eccentric exercise

    包量

    机译 离心运动恢复过程中人体骨骼肌的基因表达谱
    摘要：We used cDNA microarrays to screen for differentially expressed genes during recovery from exercise-induced muscle damage in humans. Male subjects (n = 4) performed 300 maximal eccentric contractions, and skeletal muscle biopsy samples were analyzed at 3 h and 48 h after exercise. In total, 113 genes increased 3 h postexercise, and 34 decreased. At 48 h postexercise, 59 genes increased and 29 decreased. On the basis of these data, we chose 19 gene changes and conducted secondary analyses using real-time RT-PCR from muscle biopsy samples taken from 11 additional subjects who performed an identical bout of exercise. Real-time RT-PCR analyses confirmed that exercise-induced muscle damage led to a rapid (3 h) increase in sterol response element binding protein 2 (SREBP-2), followed by a delayed (48 h) increase in the SREBP-2 gene targets Acyl CoA:cholesterol acyltransferase (ACAT)-2 and insulin-induced gene 1 (insig-1). The expression of the IL-1 receptor, a known regulator of SREBP-2, was also elevated after exercise. Taken together, these expression changes suggest a transcriptional program for increasing cholesterol and lipid synthesis and/or modification. Additionally, damaging exercise induced the expression of protein kinase H11, capping protein Z alpha (capZα), and modulatory calcineurin-interacting protein 1 (MCIP1), as well as cardiac ankryin repeat protein 1 (CARP1), DNAJB2, c-myc, and junD, each of which are likely involved in skeletal muscle growth, remodeling, and stress management. In summary, using DNA microarrays and RT-PCR, we have identified novel genes that respond to skeletal muscle damage, which, given the known biological functions, are likely involved in recovery from and/or adaptation to damaging exercise.
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