Mediation of depressive symptoms in the association between blood urea nitrogen to creatinine ratio and cognition among middle-aged and elderly adults: evidence from a national longitudinal cohort study.

BACKGROUND: The relationships between BUNCr (blood urea nitrogen and creatinine ratio) and cognitive function, as well as depressive symptoms, remain unclear. We aim to investigate the association between BUNCr and cognition, as well as depressive symptoms, and to identify the mechanisms underlying these relationships. METHODS: We utilized data from the China Health and Retirement Longitudinal Study (CHARLS) from 2015 to 2020. Cognitive function was assessed using the Telephone Interview of Cognitive Status (TICS) scale, while depressive symptoms were assessed using the 10-item Center for Epidemiologic Studies Depression Scale (CES-D-10). We employed multivariate linear regression models to examine the association between BUNCr and cognitive function, as well as depressive symptoms. Additionally, causal mediation analysis was conducted to identify potential mediation effects of depressive symptoms between BUNCr and cognition. RESULTS: We observed a negative association between BUNCr and cognitive function (coefficient: -0.192; 95% confidence interval [CI]: -0.326 ∼ -0.059) and a positive relationship between BUNCr and depressive symptoms (coefficient: 0.145; 95% CI: 0.006 ∼ 0.285). In addition, the causal mediation analysis revealed that depressive symptoms (proportion mediated: 7.0%) significantly mediated the association between BUNCr and cognition. CONCLUSION: Our study has unveiled that BUNCr is inversely associated with cognitive function and positively linked to depressive symptoms. Moreover, we found that depressive symptoms significantly mediated the association between BUNCr and cognition. These findings provide new evidence and insights for the prevention and management of cognitive function and dementia.

Regional expression of NAD(P)H oxidase and superoxide dismutase in the brain of rats with neurogenic hypertension.

BACKGROUND: Single injection of small quantities of phenol into the kidney cortex causes hypertension which is mediated by renal afferent sympathetic pathway activation. This phenomenon can be prevented by superoxide dismutase (SOD) infusion in the lateral ventricle, suggesting the role of superoxide (O(2)(-).) in noradrenergic control of arterial pressure. Since NAD(P)H oxidase is a major source of O(2)(-)., we tested the hypothesis that hypertension in this model may be associated with upregulation of NAD(P)H oxidase in relevant regions of brain. METHODS: NAD(P)H oxidase subunits, mitochondrial (MnSOD) and cytoplasmic (CuZnSOD) SOD were measured in rats 4 weeks after injection of phenol or saline in the left kidney cortex. RESULTS: Phenol-injected rats exhibited hypertension, upregulation of gp91(phox), p22(phox), p47(phox) and p67(phox) in the medulla, gp91(phox) and p22(phox) in pons and gp91(phox) in hypothalamus. This was associated with upregulation of MnSOD with little change in CuZnSOD. CONCLUSIONS: Chronic hypertension in phenol-injected rats is associated with upregulation of NAD(P)H oxidase and hence increased O(2)(-). production capacity in the key regions of the brain involved in regulation of blood pressure. Since reactive oxygen species can intensify central noradrenergic activity, the observed maladaptive changes may contribute to the genesis and maintenance of the associated hypertension.

Regional expression of NO synthase, NAD(P)H oxidase and superoxide dismutase in the rat brain.

Nitric oxide (NO) derived from the endothelial NO synthase (eNOS) contributes to regulation of cerebral circulation, whereas that produced by neuronal NOS (nNOS) participates in the regulation of brain function. In particular, NO plays an important role in modulation of sympathetic activity and hence central regulation of arterial pressure. Superoxide derived from NAD(P)H oxidase avidly reacts with and inactivates NO and, thereby, modulates its bioavailability. Calmodulin (CM) is required for activation of NOS and soluble guanylate cyclase (sGC) serves as a NO receptor. Superoxide is dismutated to H2O2 by superoxide dismutase (SOD) and H2O2 is converted to H2O by catalase or glutathione peroxidase (GPX). Given the importance of NO in the regulation of brain perfusion and function, we undertook the present study to determine the relative expressions of immunodetectable nNOS, eNOS, CM, sGC, NAD(P)H oxidase and SOD by Western analysis in different regions of the normal rat brain. nNOS was abundantly expressed in the pons cerebellum and hypothalamus and less so in the cortex and medulla. sGC abundance was highest in the hypothalamus and pons, and lowest in the cerebellum and medulla. eNOS and calmodulin were equally abundant in all regions. NAD(P)H oxide was most abundant in the pons compared to other regions. Cytoplasmic SOD was equally distributed among different regions but catalase and GPX were more abundant in pons, hypothalamus and medulla and less so in the cortex and cerebellum. Thus, the study documented regional distributions of NOS, NAD(P)H oxidase, antioxidant enzymes, sGC and calmodulin which collectively regulate production and biological activities of NO and superoxide, the two important small molecular size signaling molecules.

A vitamin-E-fortified diet reduces oxidative stress, sympathetic nerve activity, and hypertension in the phenol-renal injury model in rats.

Renal injury caused by the injection of phenol in the lower pole of one kidney increases sympathetic nervous system (SNS) activity and blood pressure (BP), and these effects are mediated by increased reactive oxygen species (ROS) in brain nuclei involved in the noradrenergic control of BP. This suggests that therapy with antioxidants might be beneficial in this model. In this study, we tested the hypothesis that a vitamin (Vit)-E-enriched diet might decrease oxidative stress in the brain and result in reduced SNS activity and BP in animals with phenol-renal injury. To this end, we examined the effects of a Vit-E-fortified diet vs. a control diet on BP, norepinephrine (NE) secretion from the posterior hypothalamic nuclei (PH), and the abundance of several components of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) oxidase in the brain of rats with phenol-induced renal injury. A Vit-E-fortified diet mitigated the formation of ROS in the brain, and this was associated with reduced SNS activity and BP in rats with phenol-induced renal injury. In conclusion, antioxidants appear to be beneficial in the management of hypertension caused by renal injury and increased SNS activity.

Oxidative stress mediates the stimulation of sympathetic nerve activity in the phenol renal injury model of hypertension.

Renal injury caused by the injection of phenol in the lower pole of one kidney increases blood pressure (BP), norepinephrine secretion from the posterior hypothalamic nuclei (PH), and renal sympathetic nerve activity in the rat. Renal denervation prevents these effects of phenol. We have also demonstrated that noradrenergic traffic in the brain is modulated by NO and interleukin-1beta. In this study, we tested the hypothesis that the increase in sympathetic nervous system (SNS) activity in the phenol renal injury model is because of activation of reactive oxygen species. To this end, first we examined the abundance of several components of reduced nicotinamide-adenine dinucleotide phosphate oxidase (identified as the major source of reactive oxygen species), including gp91phox/Nox2, p22phox, p47phox, and Nox3 using real-time PCR. Second, we evaluated the effects of 2 superoxide dismutase mimetic, tempol (4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl), and superoxide dismutase-polyethylene glycol on central and peripheral SNS activation caused by intrarenal phenol injection. Intrarenal injection of phenol raised BP, NE secretion from the PH, renal sympathetic nerve activity, and the abundance of reduced nicotinamide-adenine dinucleotide phosphate and reduced the abundance of interleukin-1beta and neural-NO synthase mRNA in the PH, paraventricular nuclei, and locus coeruleus compared with control rats. When tempol or superoxide dismutase-polyethylene glycol were infused in the lateral ventricle before phenol, the effects of phenol on BP and SNS activity were abolished. The studies suggest that central activation of the SNS in the phenol-renal injury model is mediated by increased reactive oxygen species in brain nuclei involved in the noradrenergic control of BP.

Electrochemical study of lincomycin on a multi-wall carbon nanotubes modified glassy carbon electrode and its determination in tablets.

Multi-wall carbon nanotubes (MWNTs) were dispersed in dihexadecylphosphate (DHP), sodium dodecylbenzenesulfonate (SDBS), and Nafion to give a homogeneous and stable suspension, respectively. MWNTs film in different solvents was fabricated onto a glassy carbon electrode (GCE) with an easy and convenient method. It was found that on MWNTs-DHP film lincomycin exhibited a well-defined oxidation peak. The electrochemical behavior of lincomycin at coated GCE was investigated by cyclic voltammetry and chronocoulometry. The MWNTs-DHP film modified glassy carbon electrode shows obvious electrocatalytic activity to the oxidation of lincomycin, since it greatly enhances the oxidation peak current of lincomycin as well as lowers its oxidation overpotential. Based on this, a very sensitive and simple voltammetric method was developed for the measurement of lincomycin. A sensitive linear voltammetric response for lincomycin was obtained in the concentration range of 4.5x10(-7) to 1.5x10(-4) mol/l, and the detection limit is 2.0x10(-7) mol/l using linear sweep voltammetry. Compared with other methods, this proposed method possesses many advantages such as very low detection limit, fast response, low cost and simplicity. The practical application was demonstrated to determine lincomycin in tablets with good result.

Reactive oxygen species stimulate central and peripheral sympathetic nervous system activity.

Recent studies have implicated reactive oxygen species (ROS) in the pathogenesis of hypertension and activation of the sympathetic nervous system (SNS). Because nitric oxide (NO) exerts a tonic inhibition of central SNS activity, increased production of ROS could enhance inactivation of NO and result in activation of the SNS. To test the hypothesis that ROS may modulate SNS activity, we infused Tempol (4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl), a superoxide dismutase mimetic, or vehicle either intravenously (250 microg x kg(-1) x min(-1)) or in the lateral ventricle (50 microg x kg body wt(-1) x min(-1)), and we determined the effects on blood pressure (BP), norepinephrine (NE) secretion from the posterior hypothalamus (PH) measured by the microdialysis technique, renal sympathetic nerve activity (RSNA) measured by direct microneurography, the abundance of neuronal NO synthase (nNOS)-mRNA in the PH, paraventricular nuclei (PVN), and locus coeruleus (LC) measured by RT-PCR, and the secretion of nitrate/nitrite (NO(x)) in the dialysate collected from the PH of Sprague-Dawley rats. Tempol reduced BP whether infused intravenously or intracerebroventricularly. Tempol reduced NE secretion from the PH and RSNA when infused intracerebroventricularly but raised NE secretion from the PH and RSNA when infused intravenously. The effects of intravenous Tempol on SNS activity were blunted or abolished by sinoaortic denervation. Tempol increased the abundance of nNOS in the PH, PVN, and LC when infused intracerebroventricularly, but it decreased the abundance of nNOS when infused intravenously. When given intracerebroventricularly, Tempol also reduced the concentration of NO(x) in the dialysate collected from the PH. Pretreatment with N(omega)-nitro-l-arginine methyl ester did not abolish the effects of intracerebral Tempol on BP, heart rate, NE secretion from the PH, and RSNA suggesting that the effects of Tempol on SNS activity may be in part dependent and in part independent of NO. In all, these studies support the notion that ROS may raise BP via activation of the SNS. This activation may be mediated in part by downregulation of nNOS and NO production, in part by mechanisms independent of NO. The discrepancy in results between intracerebroventricular and intravenous infusion of Tempol can be best explained by direct inhibitory actions on SNS activity when given intracerebral. By contrast, Tempol may exert direct vasodilation of the peripheral circulation and reflex activation of the SNS when given intravenously.

Responses of proximal tubule sodium transporters to acute injury-induced hypertension.

Renal injury-induced by phenol injection activates renal sympathetic afferent pathways, increases norepinephrine release from the posterior hypothalamus, activates renal efferent pathways, and provokes a rapid and persistent hypertension. This study aimed to determine whether phenol injury provoked a redistribution of proximal Na(+) transporters from internal stores to the apical cell surface mediated by sympathetic activation, a response that could contribute to generation or maintenance of hypertension. Anesthetized rats were cannulated for arterial blood pressure tracing and saline infusion and then 50 microl 10% phenol or saline was injected into one renal cortex (n = 7 each). Fifty minutes after injection, kidneys were removed and renal cortex membranes from injected kidneys were fractionated on sorbitol gradients and pooled into three windows (WI-WIII) that contained enriched apical brush border (WI); mixed apical, intermicrovillar cleft and dense apical tubules (WII); and intracellular membranes (WIII). Na(+) transporter distributions were determined by immunoblot and expressed as percentage of total in gradient. Acute phenol injury increased blood pressure 20-30 mmHg and led to redistribution of Na(+)/H(+) exchanger type 3 (NHE3) out of WIII (from 22.79 +/- 4.75 to 10.79 +/- 2.01% of total) to WI (13.07 +/- 1.97 to 27.15 +/- 4.08%), Na(+)-P(i) cotransporter 2 out of WII (68.72 +/- 1.95 to 59.76 +/- 2.21%) into WI (9.5 +/- 1.62 to 18.7 +/- 1.45%), and a similar realignment of dipeptidyl-peptidase IV immunoreactivity and alkaline phosphatase activity to WI. Renal denervation before phenol injection prevented the NHE3 redistribution. By confocal microscopy, NHE3 localized to the brush border after phenol injection. The results indicate that phenol injury provokes redistribution of Na(+) transporters from intermicrovillar cleft/intracellular membrane pools to apical membranes associated with sympathetic nervous system activation, which may contribute to phenol injury-induced hypertension.

High salt intake inhibits nitric oxide synthase expression and aggravates hypertension in rats with chronic renal failure.

The pathophysiology of hypertension in chronic renal failure is complex, but sodium retention and volume expansion play an important role. High salt intake may aggravate hypertension in chronic renal failure, but the mechanisms of this action are not well established. In this study, we have tested the hypothesis that high salt intake aggravates hypertension in rats with chronic renal failure by decreasing nitric oxide synthase (NOS) expression and by increasing sympathetic nervous system activity. Sprague-Dawley rats were subjected to 5/6 nephrectomy (CRF) or sham-operation and fed a regular rat chow. Half of the rats were allowed to drink distilled water and half water containing 1% NaCl. Blood pressure was measured weekly by tail-cuff. Four weeks after nephrectomy or sham-surgery, animals were sacrificed and brains immediately separated and frozen. Norepinephrine (NE) content and NOS-mRNA gene expression were measured in the posterior hypothalamic (PH) nuclei, the locus coeruleus (LC), the paraventricular nuclei (PVN), and in the mesenteric vessels. The endogenous concentration of NE was greater in the PH, LC, and PVN of CRF rats than it was in control animals both during a normal and a high dietary salt intake. In control and CRF rats, the concentration of NE was greater (p < 0.01) during a high than during a normal salt intake in the PH, LC, PVN, and in the mesenteric vessels. A high salt intake reduced the nNOS-mRNA gene expression in the PH (from 100 +/- 2.4 to 46 +/- 1.0;p < 0.01), LC (from 92 +/- 1.9 to 69 +/- 1.2; p < 0.01) and PVN (from 63 +/- 0.8 to 46 +/- 1.3) of CRF rats. A similar reduction occurred in the PH (from 36 +/- 0.8 to 23.6 +/- 1.2), LC (from 33 +/- 1.4 to 24 +/- 1.1) and PVN (from 37 +/- 1. to 27 +/- 1.0) of control rats. High salt intake significantly reduced the nNOS-mRNA gene expression in the mesenteric arteries of control rats, but not in those of CRF rats. In conclusion, these studies provide evidence that in control and CRF rats, high salt intake inhibits nNOS-mRNA expression in the brain, resulting in activation of the sympathetic nervous system and higher blood pressure.

Renal injury caused by intrarenal injection of phenol increases afferent and efferent renal sympathetic nerve activity.

Intrarenal injection of phenol in rats causes a persistent elevation in blood pressure (BP) and in norepinephrine (NE) secretion from the posterior hypothalamus (PH), and downregulation of neuronal nitric oxide synthase (nNOS) and interleukin-1beta (IL-1beta) in the PH. These studies suggest that afferent impulses from the kidney to the brain may be responsible for hypertension associated with renal injury. Downregulation of nNOS and IL-1beta, two modulators of sympathetic nervous system (SNS) activity may mediate this activation. In this study we measured the effects of intrarenal phenol injection on peripheral SNS activity by direct renal nerve recording, plasma NE, nNOS, and IL-1beta abundance in the brain. We also determined whether renal denervation or administration of clonidine prevented these effects of phenol. Acutely, the phenol injection increased both afferent and efferent renal sympathetic nerve activity, decreased urinary sodium excretion, and increased plasma NE. Three weeks after the phenol injection, BP and plasma NE remained elevated. Renal denervation and pretreatment with clonidine prevented the increase in BP and plasma NE caused by phenol. Chronic renal injury caused by phenol was associated with decreased abundance of IL-1beta and nNOS in the PH. These studies have shown that a renal injury caused by phenol injection increases BP and central as well as peripheral SNS activity, which persist long after the injury. Renal denervation and antiadrenergic drugs abolish the effects of phenol on BP and plasma NE. Because NO and IL-1beta modulate SNS activity, the stimulatory action of phenol on the SNS could be mediated by downregulation of nNOS and IL-1beta in the brain.

Losartan reduces central and peripheral sympathetic nerve activity in a rat model of neurogenic hypertension.

We have developed a new model of neurogenic hypertension in the rat, in which hypertension is caused by injecting 50 microL of 10% phenol in the lower pole of one kidney. Administration of phenol in the kidney causes an immediate and persistent rise in blood pressure (BP), norepinephrine (NE) secretion from the posterior hypothalamic nuclei (PH), and renal sympathetic nerve activity (RSNA). Because angiotensin II (Ang II) is known to stimulate central and peripheral sympathetic nervous system (SNS) activity, we have tested the hypothesis that losartan, a specific Ang II AT1 receptor antagonist, may lower BP, at least in part, by SNS inhibition. To this end, we studied the effects of losartan on BP and SNS activity following intrarenal phenol injection. Central SNS activity was measured by NE secretion from the PH using a microdialysis technique, and peripheral SNS activity was measured by direct recording of renal nerve activity. At the end of the experiments, brains were isolated and interleukin (IL)-1beta and nitric oxide synthase (NOS) mRNA gene expression was measured by RT-PCR in the PH, paraventricular nuclei (PVN), and locus ceruleus (LC). The intrarenal injection of phenol raised BP, as well as central and renal SNS activity, but reduced the abundance of IL-1beta and neuronal NOS (nNOS) mRNA in the PH, PVN, and LC. Whether injected intravenously or in the lateral ventricle, losartan caused a significant (P<0.01) and dose-dependent inhibition of the effects of phenol on BP, NE secretion from the PH, and RSNA. Losartan also caused a significant (P<0.01) and dose-dependent rise in IL-1beta and nNOS-mRNA gene expression in the PH, PVN, and LC of phenol-injected rats. In conclusion, these studies have shown that the intrarenal injection of phenol causes a rise in central and renal SNS activity and a decrease in IL-1beta and nNOS-mRNA in the PH, PVN, and LC. Losartan prevented the rise in BP and SNS activity, as well as the decrease in IL-1beta and nNOS mRNA abundance caused by phenol. These studies have demonstrated that the antihypertensive action of losartan in the phenol renal injury model is largely mediated by inhibition of central and peripheral SNS activity and suggest that activation of IL-1beta and nNOS, 2 important modulators of central SNS activity, mediates the inhibitory action of losartan on SNS activity.

Downregulation of neuronal nitric oxide synthase and interleukin-1beta mediates angiotensin II-dependent stimulation of sympathetic nerve activity.

There is substantial evidence that angiotensin II (Ang II) enhances sympathetic nervous system (SNS) activity. We recently observed that nitric oxide and interleukin-1beta (IL-1beta) exert a tonic inhibitory action on central SNS activity. Moreover, in 2 rat models of neurogenic hypertension, one caused by intrarenal injection of phenol and the other by 5/6 nephrectomy, we observed that losartan, an Ang II type 1 receptor blocker, inhibits SNS activity and increases the abundance of IL-1beta and the neuronal isoform of nitric oxide synthase (nNOS) in the posterior hypothalamic nuclei (PH), paraventricular nuclei (PVN), and locus ceruleus (LC). This raises the possibility that the stimulatory effects of Ang II on central SNS activity may be mediated by inhibition of nNOS and IL-1beta. To test this hypothesis, we studied the effect of an intracerebroventricular (ICV) infusion of Ang II on blood pressure (BP), norepinephrine (NE) secretion from the PH, renal SNS activity (RSNA), and abundance of IL-1beta and nNOS mRNA in the PH, PVN, and LC of normal Sprague-Dawley rats. Finally, we measured the concentration of nitrite/nitrate in the dialysate collected from the PH after Ang II or vehicle. ICV infusion of Ang II (100 ng/kg body wt dissolved in 10 microL of artificial cerebrospinal fluid) raised BP, RSNA, and NE secretion from the PH compared with control rats. Ang II reduced the abundance of IL-1beta and nNOS mRNA in the PH, PVN, and LC. Pretreatment with losartan (10 microg/kg body wt dissolved in 10 microL of aCSF) given ICV 20 minutes before Ang II abolished the effects of Ang II on BP, RSNA, and NE secretion from the PH and IL-1beta and nNOS mRNA. Ang II also decreased the secretion of NO from the PH. In conclusion, these studies suggest that Ang II inhibits the expression of IL-1beta and nNOS in the brain. Because locally produced NO exerts a tonic inhibitory action on SNS activity, the decrease in NO expression caused by Ang II results in greater SNS activity.