Hypothalamic Corticotropin-Releasing Hormone Contributes to Hypertension in Spontaneously Hypertensive Rats.

Corticotropin-releasing hormone (CRH) is a neuropeptide regulating neuroendocrine and autonomic function. CRH mRNA and protein levels in the hypothalamic paraventricular nucleus (PVN) are increased in primary hypertension. However, the role of CRH in elevated sympathetic outflow in primary hypertension remains unclear. CRHR1 proteins were distributed in retrogradely labeled PVN presympathetic neurons with an increased level in the PVN tissue in adult spontaneously hypertensive rats (SHRs) compared with age-matched male Wistar-Kyoto (WKY) rats. CRH induced a more significant increase in the firing rate of PVN-rostral ventrolateral medulla (RVLM) neurons and sympathoexcitatory response in SHRs than in WKY rats, an effect that was blocked by preapplication of NMDA receptors (NMDARs) antagonist AP5 and PSD-95 inhibitor, Tat-N-dimer. Blocking CRHRs with astressin or CRHR1 with NBI35965 significantly decreased the firing rate of PVN-RVLM output neurons and reduced arterial blood pressure (ABP) and renal sympathetic nerve activity (RSNA) in SHRs but not in WKY, whereas blocking CRHR2 with antisauvagine-30 did not. Furthermore, Immunocytochemistry staining revealed that CRHR1 colocalized with NMDARs in PVN presympathetic neurons. Blocking CRHRs significantly decreased the NMDA currents in labeled PVN neurons. PSD-95-bound CRHR1 and PSD-95-bound GluN2A in the PVN were increased in SHRs. These data suggested that the upregulation of CRHR1 in the PVN is critically involved in the hyperactivity of PVN presympathetic neurons and elevated sympathetic outflow in primary hypertension.SIGNIFICANCE STATEMENT Our study found that corticotropin-releasing hormone receptor (CRHR)1 protein levels were increased in the paraventricular nucleus (PVN), and CRHR1 interacts with NMDA receptors (NMDARs) through postsynaptic density protein (PSD)-95 in the PVN neurons in primary hypertension. The increased CRHR1 and CRHR1-NMDAR-PSD-95 complex in the PVN contribute to the hyperactivity of the PVN presympathetic neurons and elevated sympathetic vasomotor tone in hypertension in SHRs. Thus, the antagonism of CRHR1 decreases sympathetic outflow and blood pressure in hypertension. These findings determine a novel role of CRHR1 in elevated sympathetic vasomotor tone in hypertension, which is useful for developing novel therapeutics targeting CRHR1 to treat elevated sympathetic outflow in primary hypertension. The CRHR1 receptor antagonists, which are used to treat health consequences resulting from chronic stress, are candidates to treat primary hypertension.

Melatonin suppresses sympathetic vasomotor tone through enhancing GABAA receptor activity in the hypothalamus.

Introduction: Melatonin (5-methoxy-N-acetyl-tryptamine) is a circadian hormone synthesized and secreted by the pineal gland. In addition to regulating circadian rhythms of many physiological functions, melatonin is involved in regulating autonomic nervous function and blood pressure. Hypothalamus paraventricular nucleus (PVN), receiving melatonin projections from the superchiasmatic nucleus, is a critical brain region to regulate neuroendocrine and cardiovascular function. Here, we determined the synaptic mechanisms involved in the effect of melatonin on the sympathetic outflow and blood pressure. Methods and Results: Microinjection of melatonin into the PVN produced a depressor effect and decreased renal sympathetic nerve activity (RSNA). While microinjection of luzindole, a non-selective melatonin receptor antagonist, into the PVN did not change melatonin-induced sympathoinhibition, GABAA receptor antagonist bicuculline eliminated melatonin-induced sympathoinhibition. Furthermore, melatonin decreased firing rate of retrogradely labeled PVN neurons which project to the rostral ventrolateral medulla (RVLM), an effect was not altered by luzindole but eliminated by bicuculline. Melatonin significantly increased the amplitude of spontaneous and evoked GABAergic inhibitory synaptic currents, as well as GABA-induced currents. Conclusion: These data suggest that melatonin in the PVN suppresses sympathetic vasomotor tone through enhancing GABAA receptor activity. This study provides novel information for understanding the cellular mechanisms involved in the effect of melatonin on regulating blood pressure and sympathetic output.

Corticotropin-releasing hormone neurons in the central nucleus of amygdala are required for chronic stress-induced hypertension.

AIMS: Chronic stress is a well-known risk factor for the development of hypertension. However, the underlying mechanisms remain unclear. Corticotropin-releasing hormone (CRH) neurons in the central nucleus of the amygdala (CeA) are involved in the autonomic responses to chronic stress. Here, we determined the role of CeA-CRH neurons in chronic stress-induced hypertension. METHODS AND RESULTS: Borderline hypertensive rats (BHRs) and Wistar-Kyoto (WKY) rats were subjected to chronic unpredictable stress (CUS). Firing activity and M-currents of CeA-CRH neurons were assessed, and a CRH-Cre-directed chemogenetic approach was used to suppress CeA-CRH neurons. CUS induced a sustained elevation of arterial blood pressure (ABP) and heart rate (HR) in BHRs, while in WKY rats, CUS-induced increases in ABP and HR quickly returned to baseline levels after CUS ended. CeA-CRH neurons displayed significantly higher firing activities in CUS-treated BHRs than unstressed BHRs. Selectively suppressing CeA-CRH neurons by chemogenetic approach attenuated CUS-induced hypertension and decreased elevated sympathetic outflow in CUS-treated BHRs. Also, CUS significantly decreased protein and mRNA levels of Kv7.2 and Kv7.3 channels in the CeA of BHRs. M-currents in CeA-CRH neurons were significantly decreased in CUS-treated BHRs compared with unstressed BHRs. Blocking Kv7 channel with its blocker XE-991 increased the excitability of CeA-CRH neurons in unstressed BHRs but not in CUS-treated BHRs. Microinjection of XE-991 into the CeA increased sympathetic outflow and ABP in unstressed BHRs but not in CUS-treated BHRs. CONCLUSIONS: CeA-CRH neurons are required for chronic stress-induced sustained hypertension. The hyperactivity of CeA-CRH neurons may be due to impaired Kv7 channel activity, which represents a new mechanism involved in chronic stress-induced hypertension.

Parallel-Self-Assembling Stack, Center-Capture Effect, and Reactivity-Enhancing Effect of N-Layer (N = 1, 2, 3) Cyclo[18]carbon.

Cyclo[18]carbon (C18) is an captivating allotrope of carbon synthesized recently, which has drawn the attention among scientists. There are still few studies on the dynamic behaviors of C18. To gain knowledge in this area, we systematically explored the stacking behaviors and the oxidation kinetics of C18, as well the electronic transport behaviors of C18 oxides, by density functional theory and nonequilibrium Green's function calculations combined with reactive force field molecular dynamics simulations. The parallel-self-assembling behaviors were observed in the stack of two- or three-layer C18. During the oxidation process of C18, we found an evident center-capture effect in which the hollow rings would preferentially attract an O2 molecule into their centers. Moreover, the adsorption of O2 on the O2-doped rings was dramatically enhanced by the O2 at the center of the ring, showing the reactivity-enhancing effect. The excellent electron transport property of central-O2-doped C18 among 13 types of C18 oxides demonstrates the potential of C18 oxides as promising molecular devices for various applications. This study reveals the dynamic behaviors of C18 and provides theoretical guidance for use of C18 and C18 oxides in molecular devices.

Electron transport properties of PtSe2 nanoribbons with distinct edge reconstructions.

Edge reconstructions of two-dimensional (2D) materials play a central role in determining the electronic transport properties of nanodevices. However, it is not feasible to study the relationship between edge reconstruction and electronic properties using experimental methods because of the complexity of the experimental environment and the diversity of edge reconstruction. Herein, we have combined density functional theory (DFT) calculations and the nonequilibrium Green's function (NEGF) method to investigate the inner physical mechanism of platinum diselenide (PtSe2) nanoribbons, revealing distinctive negative differential resistance (NDR) behaviors in different nanoribbons with various edge reconstructions. The armchair PtSe2 nanoribbons with different edge reconstructions are all metallic, while the zigzag PtSe2 nanoribbons are semiconducting when the ratio of Pt to Se atoms at the edge is 1 : 2. These results reveal the internal source of the difference in the electron transport properties of PtSe2 nanoribbons with different edge reconstructions, providing new ideas for the design of novel multifunctional PtSe2 semiconducting and conducting electronic nanodevices with NDR properties.

Theoretical Study on the Aggregation and Adsorption Behaviors of Anticancer Drug Molecules on Graphene/Graphene Oxide Surface.

Graphene and its derivatives are frequently used in cancer therapy, and there has been widespread interest in improving the therapeutic efficiency of targeted drugs. In this paper, the geometrical structure and electronic effects of anastrozole(Anas), camptothecin(CPT), gefitinib (Gefi), and resveratrol (Res) on graphene and graphene oxide(GO) were investigated by density functional theory (DFT) calculations and molecular dynamics (MD) simulation. Meanwhile, we explored and compared the adsorption process between graphene/GO and four drug molecules, as well as the adsorption sites between carriers and payloads. In addition, we calculated the interaction forces between four drug molecules and graphene. We believe that this work will contribute to deepening the understanding of the loading behaviors of anticancer drugs onto nanomaterials and their interaction.

Signaling pathways involved in NMDA-induced suppression of M-channels in corticotropin-releasing hormone neurons in central amygdala.

Glutamate N-methyl-d-aspartate (NMDA) receptors (NMDARs) and Kv7/M channels are importantly involved in regulating neuronal activity involved in various physiological and pathological functions. Corticotropin-releasing hormone (CRH)-expressing neurons in the central nucleus of the amygdala (CeA) critically mediate autonomic response during stress. However, the interaction between NMDA receptors and Kv7/M channels in the CRHCeA neurons remains unclear. In this study, we identified rat CRHCeA neurons through the expression of an AAV viral vector-mediated enhanced green fluorescent protein (eGFP) driven by the rat CRH promoter. M-currents carried by Kv7/M channels were recorded using the whole-cell patch-clamp approach in eGFP-tagged CRHCeA neurons in brain slices. Acute exposure to NMDA significantly reduced M-currents recorded from the CRHCeA neurons. NMDA-induced suppression of M-currents was eliminated by chelating intracellular Ca2+ , supplying phosphatidylinositol 4,5-bisphosphate (PIP2) intracellularly, or blocking phosphoinositide3-kinase (PI3K). In contrast, inhibiting protein kinase C (PKC) or calmodulin did not alter NMDA-induced suppression of M-currents. Sustained exposure of NMDA decreased Kv7.3 membrane protein levels and suppressed M-currents, while the Kv7.2 expression levels remained unaltered. Pre-treatment of brain slices with PKC inhibitors alleviated the decreases in Kv7.3 and reduction of M-currents in CRHCeA neurons induced by NMDA. PKC inhibitors did not alter Kv7.2 and Kv7.3 membrane protein levels and M-currents in CRHCeA neurons. These data suggest that transient activation of NMDARs suppresses M-currents through the Ca2+ -dependent PI3K-PIP2 signaling pathway. In contrast, sustained activation of NMDARs reduces Kv7.3 protein expression and suppresses M-currents through a PKC-dependent pathway.

Near Room-Temperature Synthesis of Vertical Graphene Nanowalls on Dielectrics.

Vertical graphene nanowalls (VGNs) with excellent heat-transfer properties are promising to be applied in the thermal management of electronic devices. However, high growth temperature makes VGNs unable to be directly prepared on semiconductors and polymers, which limits the practical application of VGNs. In this work, the near room-temperature growth of VGNs was realized by utilizing the hot filament chemical vapor deposition method. Catalytic tantalum (Ta) filaments promote the decomposition of acetylene at ∼1600 °C. Density functional theory calculations proved that C2H* was the main active carbon cluster during VGN growth. The restricted diffusion of C2H* clusters induced the vertical growth of graphene nanoflakes on various substrates below 150 °C. The direct growth of VGNs successfully realized the excellent interfacial contact, and the thermal contact resistance could reach 3.39 × 10-9 m2·K·W-1. The temperature of electronic chips had a 6.7 °C reduction by utilizing directly prepared VGNs instead of thermal conductive tape as thermal-interface materials, indicating the great potential of VGNs to be directly prepared on electronic devices for thermal management.

Impaired Kv7 channel activity in the central amygdala contributes to elevated sympathetic outflow in hypertension.

AIMS: Elevated sympathetic outflow is associated with primary hypertension. However, the mechanisms involved in heightened sympathetic outflow in hypertension are unclear. The central amygdala (CeA) regulates autonomic components of emotions through projections to the brainstem. The neuronal Kv7 channel is a non-inactivating voltage-dependent K+ channel encoded by KCNQ2/3 genes involved in stabilizing the neuronal membrane potential and regulating neuronal excitability. In this study, we investigated if altered Kv7 channel activity in the CeA contributes to heightened sympathetic outflow in hypertension. METHODS AND RESULTS: The mRNA and protein expression levels of Kv7.2/Kv7.3 in the CeA were significantly reduced in spontaneously hypertensive rats (SHRs) compared with Wistar-Kyoto (WKY) rats. Lowering blood pressure with coeliac ganglionectomy in SHRs did not alter Kv7.2 and Kv7.3 channel expression levels in the CeA. Fluospheres were injected into the rostral ventrolateral medulla (RVLM) to retrogradely label CeA neurons projecting to the RVLM (CeA-RVLM neurons). Kv7 channel currents recorded from CeA-RVLM neurons in brain slices were much smaller in SHRs than in WKY rats. Furthermore, the basal firing activity of CeA-RVLM neurons was significantly greater in SHRs than in WKY rats. Bath application of specific Kv7 channel blocker 10, 10-bis (4-pyridinylmethyl)-9(10H)-anthracnose (XE-991) increased the excitability of CeA-RVLM neurons in WKY rats, but not in SHRs. Microinjection of XE-991 into the CeA increased arterial blood pressure (ABP) and renal sympathetic nerve activity (RSNA), while microinjection of Kv7 channel opener QO-58 decreased ABP and RSNA, in anaesthetized WKY rats but not SHRs. CONCLUSIONS: Our findings suggest that diminished Kv7 channel activity in the CeA contributes to elevated sympathetic outflow in primary hypertension. This novel information provides new mechanistic insight into the pathogenesis of neurogenic hypertension.

Pathways regulating nitrogen removal in constructed ditch wetlands: effects of different inflow ratios and artificial aeration.

Constructed ditch wetland (CDW) is a combination of idle ditch and constructed wetland, which is typically used in rural areas to remove pollutants from domestic wastewater. However, its low total nitrogen (TN) removal remains a pressing issue. To enhance total nitrogen removal, an approach of supplying water at two locations in the CDW at different influent flow ratios, combined with artificial aeration, was proposed to adjust carbon and oxygen distribution in the system. The highest average TN removal was achieved at low influent concentration (CDW4; influent flow ratio 1:2). The removal of TN in winter and spring were 58.93 and 83.26%, respectively. The distribution of carbon sources in the back zone enhanced denitrification. Of the high influent concentration treatments, CDW2 (2:1) achieved 16.97% more TN removal on average compared with CDW1 (3:0), after extra artificial aeration was applied in the front zone. However, nitrification was a limiting step in the system, which became the primary problem preventing pollutant purification. Moreover, nitrifying bacteria abundance was negatively correlated to the influent flow ratio and autotrophic denitrifying bacterial abundance was positively correlated to the influent flow ratios. Graphical abstract.

Oxidation of graphene with variable defects: alternately symmetrical escape and self-restructuring of carbon rings.

Variable defects such as vacancies and grain boundaries are unavoidable in the synthesis of graphene, but play a central role in the activation of oxidation. Here, we apply reactive molecular dynamics simulations to reveal the underpinning mechanisms of oxidation in graphene with or without defects at the atomic scale. There exist four oxidation modes generating CO2 or CO in different stages, beginning from a single-atom vacancy, and proceeding until the ordered structure broken down into carbon oxide chains. The oxidation process of the graphene sheets experiences four typical stages, in which alternately symmetrical escape phenomenon is observed. Importantly, disordered rings can self-restructure during the oxidation of grain boundaries. Of all defects, the oxidation of vacancy has the lowest energy barrier and is therefore the easiest point of nucleation. This study demonstrates the crucial role of defects in determining the oxidation kinetics, and provides theoretical guidance for the oxidation prevention of graphene and the production of functionalized graphene.

Iron scraps enhance simultaneous nitrogen and phosphorus removal in subsurface flow constructed wetlands.

In rural domestic wastewater treatment using subsurface constructed wetland system (SFCWs), the lack of a carbon source for denitrification and limited phosphorus uptake are responsible for low removal of nitrogen and phosphorus, and a suitable substrate is therefore, necessary. Iron is an important component in nitrogen and phosphorus biogeochemical cycles. Few studies have addressed the application of iron in SFCWs. Therefore, we constructed SFCWs that used iron scraps as a substrate. Enhanced nitrification, denitrification and removal of phosphorus were observed. The large proportion of nitrite-oxidising bacteria present in CWs with iron scraps (CW-T) compared to gravel beds indicated that iron may enhance ammonium (NH4+) oxidation. More nitrate-reducing bacteria related to Fe and autotrophic denitrifying bacteria were discovered in the back zone of CW-T and these enhanced denitrification process. Phosphate (PO43-) reacted with ferrous ion (Fe2+) and ferric ion (Fe3+) to generate the precipitant. Moreover, Fe3+ reacted with water to generate iron oxide (FeOOH) that had a large adsorption capacity for phosphorus. After six months of operation, average NH4+-N, total nitrogen and total phosphorus removal rates were 66.98 ±â€¯13.37 %, 71.26 ±â€¯13.57 % and 93.54 ±â€¯6.64 %, respectively. Iron scraps can potentially be utilised in SFCWs in rural domestic wastewater treatment.

Wetting state transition of a liquid gallium drop at the nanoscale.

Wetting state transition regulated by surface roughness has increasing importance for its wide applications. Molecular dynamics simulations have been performed to study the wetting state transition induced by surface roughness in the gallium-carbon system. There is a transition from the Wenzel state to the Cassie state when the roughness is changed. When the surface roughness is more than 1.8, the gallium droplet is in a Cassie state, but when it is less than 1.6, it is in the Wenzel state. The substrate composed of irregular pillars has a similar effect on the wetting state transition. Besides, distinctive variations occur in the interface tension, the mean-squared displacement, the wetted surface and the interaction energy as the wetting state changes, which are further explained by the proposed model. This study would provide significant guidance for designing superhydrophobic surfaces in the future.