The Regulatory Effect of the Paraventricular Nucleus on Hypertension.

Hypertension is among the most harmful factors of cardiovascular and cerebrovascular diseases and poses an urgent problem for the development of human society. In addition to previous studies on its pathogenesis focusing on the peripheral sympathetic nervous system, investigating the central causes of high blood pressure involving the neuroendocrine and neuroinflammatory mechanisms of the hypothalamic paraventricular nucleus (PVN) is paramount. This nucleus is considered to regulate the output of neurohormones and sympathetic nerve activity. In this article, we focussed on the neuroendocrine mechanism, primarily exploring the specific contributions and interactions of various neurons and neuroendocrine hormones, including GABAergic and glutamatergic neurons, nitric oxide, arginine vasopressin, oxytocin, and the renin-angiotensin system. Additionally, the neuroinflammatory mechanism in the PVN was discussed, encompassing microglia, reactive oxygen species, inflammatory factors, and pathways, as well as immune connections between the brain and extracerebral organs. Notably, the two central mechanisms involved in the PVN not only exist independently but also communicate with each other, jointly maintaining the hypertensive state of the body. Furthermore, we introduce well-known molecules and signal transduction pathways within the PVN that can play a regulatory role in the two mechanisms to provide a basis and inspire ideas for further research.

Crystal structure of mRNA cap (guanine-N7) methyltransferase E12 subunit from monkeypox virus and discovery of its inhibitors.

In July 2022, the World Health Organization announced monkeypox as a public health emergency of international concern (PHEIC), and over 85,000 global cases have been reported currently. However, preventive and therapeutic treatments for the monkeypox virus (MPXV) remain limited. MPXV mRNA cap N7 methyltransferase (MTase) is composed of two subunits (E1 C-terminal domain (E1CTD) and E12) which are essential for the replication of MPXV. Here, we solved a 2.16 Å crystal structure of E12. We also docked the D1CTD of the vaccinia virus (VACV) corresponding to the E1CTD in MPXV with E12 and found critical residues at their interface. These residues were further used for drug screening. After virtual screening, the top 347 compounds were screened out and a list of top 20 potential MPXV E12 inhibitors were discovered, including Rutin, Quercitrin, Epigallocatechin, Rosuvastatin, 5-hydroxy-L-Tryptophan, and Deferasirox, etc., which were potential E12 inhibitors. Taking the advantage of the previously unrecognized special structure of MPXV MTase composing of E1CTD and E12 heterodimer, we screened for inhibitors targeting MTase for the first time based on the interface between the heterodimer of MPXV MTase. Our study may provide insights into the development of anti-MPXV drugs.

Hypothalamic Paraventricular Nucleus Hydrogen Sulfide Exerts Antihypertensive Effects in Spontaneously Hypertensive Rats via the Nrf2 Pathway.

BACKGROUND: Hydrogen sulfide (H2S) is widely distributed throughout the nervous system with various antioxidant and anti-inflammatory properties. Hypertension involves an increase in reactive oxygen species (ROS) and inflammation in the hypothalamic paraventricular nucleus (PVN). However, it is unclear how H2S in PVN affects hypertension. METHODS: Our study used spontaneously hypertensive rats (SHR) and control Wistar Kyoto (WKY) rats, microinjected with adenovirus-associated virus (AAV)-CBS (cystathionine beta-synthase overexpression) or AAV-ZsGreen in bilateral PVN, or simultaneously injected with virus-carrying nuclear factor erythroid 2-related factor 2 (Nrf2)-shRNA for 4 weeks. Blood pressure (BP) and plasma noradrenaline level were detected, and the PVN was collected. Finally, levels of CBS, H2S, Nrf2, Fra-LI, ROS, gp91phox, p47phox, superoxide dismutase 1, interleukin (IL)-1ß, IL-6, IL-10, tumor necrosis factor-α, tyrosine hydroxylase, and glutamate decarboxylase 67 were measured. RESULTS: We found that AAV-CBS increased H2S in the PVN, and BP, neuronal activation, oxidative stress, and inflammation of PVN were substantially reduced. Furthermore, endogenous H2S in the PVN activated Nrf2 and corrected the PVN's imbalance of excitatory and inhibitory neurotransmitters. However, Nrf2 knockdown in the PVN was similarly observed to abolish the beneficial effect of H2S on hypertension. CONCLUSIONS: The findings imply that endogenous H2S in SHR PVN is reduced, and PVN endogenous H2S can alleviate hypertension via Nrf2-mediated antioxidant and anti-inflammatory effects.

Minocycline and Pyrrolidine Dithiocarbamate Attenuate Hypertension via Suppressing Activation of Microglia in the Hypothalamic Paraventricular Nucleus.

Proinflammatory cytokines, reactive oxygen species and imbalance of neurotransmitters are involved in the pathophysiology of angiotensin II-induced hypertension. The hypothalamic paraventricular nucleus (PVN) plays a vital role in hypertension. Evidences show that microglia are activated and release proinflammatory cytokines in angiocardiopathy. We hypothesized that angiotensin II induces PVN microglial activation, and the activated PVN microglia release proinflammatory cytokines and cause oxidative stress through nuclear factor-kappa B (NF-κB) pathway, which contributes to sympathetic overactivity and hypertension. Male Sprague-Dawley rats (weight 275-300 g) were infused with angiotensin II to induce hypertension. Then, rats were treated with bilateral PVN infusion of microglial activation inhibitor minocycline, NF-κB activation inhibitor pyrrolidine dithiocarbamate or vehicle for 4 weeks. When compared to control groups, angiotensin II-induced hypertensive rats had higher mean arterial pressure, PVN proinflammatory cytokines, and imbalance of neurotransmitters, accompanied with PVN activated microglia. These rats also had more PVN gp91phox (source of reactive oxygen species production), and NF-κB p65. Bilateral PVN infusion of minocycline or pyrrolidine dithiocarbamate partly or completely ameliorated these changes. This study indicates that angiotensin II-induced hypertensive rats have more activated microglia in PVN, and activated PVN microglia release proinflammatory cytokines and result in oxidative stress, which contributes to sympathoexcitation and hypertensive response. Suppression of activated PVN microglia by minocycline or pyrrolidine dithiocarbamate attenuates inflammation and oxidative stress, and improves angiotensin II-induced hypertension, which indicates that activated microglia promote hypertension through activated NF-κB. The findings may offer hypertension new strategies.

Values of OAS gene family in the expression signature, immune cell infiltration and prognosis of human bladder cancer.

BACKGROUND: Bladder cancer (BLCA) is one of the most common genitourinary malignancies in the world, but its pathogenic genes have not been fully identified and the treatment outcomes are still unsatisfactory. Although the members of 2', 5'-oligoadenylate synthetase (OAS) gene family are known involved in some tumorous biological processes, the roles of the OAS gene family in BLCA are still undetermined. METHODS: By combining vast bioinformatic datasets analyses of BLCA and the experimental verification on clinical BLCA specimen, we identified the expressions and biological functions of OAS gene family members in BLCA with comparison to normal bladder tissues. RESULTS: The expression levels of OAS gene family members were higher in BLCA than in normal bladder tissues. The expression levels of most OAS genes had correlations with genomic mutation and methylation, and with the infiltration levels of CD4 + T cells, CD8 + T cells, neutrophils, and dendritic cells in the microenvironment of BLCA. In addition, high expressions of OAS1, OAS2, OAS3, and OASL predicted better overall survival in BLCA patients. CONCLUSIONS: The highly expressed OAS genes in BLCA can reflect immune cells infiltration in the tumor microenvironment and predict the better overall survival of BLCA, and thus may be considered as a signature of BLCA. The study provides new insights into the diagnosis, treatment, and prognosis of BLCA.

cRGD peptide-conjugated polyethylenimine-based lipid nanoparticle for intracellular delivery of siRNA in hepatocarcinoma therapy.

The effective delivery system plays an important role in the application of siRNA in the antitumor study. However, until now, researches on the delivery systems targeting hepatocarcinoma cells are still being explored. Here we designed and prepared a novel siRNA delivery system, cRGD-PSH-NP, which was based on a modified polyethyleneimine (PSH) and DSPE-PEG2000-cRGD. cRGD-PSH-NP loaded with survivin siRNA (cRGD-PSH-NP/S) was composed of egg phosphatidylcholine, cationic PSH, PEGylated lipids, survivin siRNA, and cRGD peptide as a targeting ligand. The formulations of cRGD-PSH-NP/S were optimized and characterized. In vitro investigations showed excellent gene silencing and antitumor activity compared with the unmodified nanoparticles in HepG2 cells. In vivo antitumor efficacy of cRGD-PSH-NP/S exhibited potent tumor inhibition (74.71%) in HepG2-bearing nude mice without inducing toxicity. These data suggested further research of cRGD-PSH-NP/S in hepatocarcinoma therapy.

Paraventricular Nucleus Infusion of Oligomeric Proantho Cyanidins Improves Renovascular Hypertension.

Oxidative stress plays an important role in the pathogenesis of hypertension. Oligomeric proantho cyanidins (OPC) is the main polyphenol presents in grape seed and is known for its potent antioxidant and anti-inflammatory properties. In the present study, we hypothesize that OPC can attenuate oxidative stress in the paraventricular nucleus of hypothalamus (PVN), ameliorate neurotransmitter imbalance, decrease the blood pressure and sympathetic activity in renovascular hypertensive rats. After induction of renovascular hypertension by the two-kidney one-clip (2K-1C) method, male Sprague-Dawley rats received chronic bilateral PVN infusion of OPC (20 µg/h) or vehicle via osmotic minipump for 4 weeks. We found that hypertension induced by 2K-1C was associated with the production of reactive oxygen species (ROS) in the PVN. Infusion of OPC in the PVN significantly reduced the systolic blood pressure and norepinephrine in plasma of 2K-1C rats. In addition, PVN infusion of OPC decreased the level of ROS and the expression of stress-related nicotinamide adenine dinucleotide phosphate (NADPH) oxidases subunit NOX4, increased the levels of nuclear factor E2-related factor 2 (Nrf2) and antioxidant enzyme, balanced the content of cytokines, increased expression of glutamic acid decarboxylase and decreased the expression of tyrosine hydroxylase in the PVN of 2K-1C rats. Our findings provided strong evidence that PVN infusion of OPC inhibited the progression of renovascular hypertension through its potent anti-oxidative and anti-inflammatory function in the PVN.

Irisin lowers blood pressure by activating the Nrf2 signaling pathway in the hypothalamic paraventricular nucleus of spontaneously hypertensive rats.

Exercise training is one of the major non-pharmacological treatments for hypertension. However, the central mechanism by which exercise training attenuates the hypertensive responses remains unclear. Irisin is a muscle-secreted cytokine derived from fibronectin type III domain containing 5 (FNDC5) that will be released into the circulation during exercise. We hypothesized that irisin may play a role in the blood pressure regulation by exercise. To examine the hypothesis, our study investigated the effect of irisin on hypertension and its central mechanism. The study was performed in spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto rats. We found that intravenous injection of irisin effectively reduced blood pressure, plasma norepinephrine, paraventricular nucleus (PVN) levels of neuronal activation, oxidative stress and inflammation in SHRs. Moreover, irisin activated nuclear factor E2-related factor-2 (Nrf2) and restored the imbalance of neurotransmitters in the PVN. Our study also found PVN knockdown of Nrf2 abolished the protective effects of irisin on hypertension. These findings demonstrate irisin can improve hypertension via Nrf2-mediated antioxidant in the PVN.

Delivery of antisense oligonucleotide using polyethylenimine-based lipid nanoparticle modified with cell penetrating peptide.

Efficient and stable delivery system of antisense oligonucleotide (ASO) is important and urgently needed. Here, an ASO delivery system, Lp-PPRP, which contains a cationic polymer based on PEI (branched, 25 kDa), named PEI-PC and a palmitic acid modified R8 (R8-PA) was prepared to deliver a kind of ASO, LOR-2501. The characteristics of the nanoparticles and the cellular uptake of LOR-2501 in HeLa cells and A549 cells were studied. Lp-PPRP showed suitable particle size and zeta potential to combine with LOR-2501; the particle size and zeta potential of Lp-PPRP/LOR were 276.87 ± 5.63 nm and 18.03 ± 0.25 mV. In vitro experiments suggested that Lp-PPRP had lower cytotoxic and higher transfection efficiency for delivering LOR-2501 compared with PEI. The addition of PEI-PC and R8-PA contributed to enhance the transfection efficiency of the nanoparticles. In HeLa cells and A549 cells, Lp-PPRP could transport LOR-2501 and down-regulate the level of R1 protein efficiently, and the R1 down regulations were 64.56% and 66.34%, respectively. Results suggested potential utility of Lp-PPRP in the development of ASO in tumor therapy.

Effect of the changes of NMDA receptor in hypothalamic paraventricular nucleus on cardiac function and sympathetic nervous activity in rats with heart failure.

OBJECTIVE: To observe the effect of the changes of n-methyl-d-aspartate receptor 1 (NMDAR1), tyrosine hydroxylase (TH), and glutamic acid decarboxylase 67 (GAD67) in the hypothalamic paraventricular nucleus (PVN) on cardiac function and sympathetic nervous activity in rats with heart failure (HF). METHODS: Thirty-six adult male SD rats were randomly divided into the heart failure group (HF), the heart failure + NMDA receptors agonist AP5 intervention group (HF-AP5), and the Sham-operation group (SO) (n = 12). HF model in SD rats was induced by ligation of left coronary artery. AP5 (0.02 µg/h) was administrated by the paraventricular nucleus subsequently for 4 weeks. The cardiac function, renal sympathetic nerve activity (RSNA), lung/body weight ratio (L/BW), and right ventricle/body weight ratio (RV/BW), as well as the plasma noradrenaline (NE) and Angiotensin II (Ang II) level and the expressions of NMDAR1, GAD67, and TH in PVN, in different groups were recorded 4 weeks after the establishment of HF model. RESULTS: After the coronary artery was ligated, LVEDP was increased, ±dp/dt max and LVEF were decreased, lung/BW and RV/BW were raised. RSNA, Ang II and NE were raised. Expression of NMDAR1 and TH were increased, but GAD67 was decreased. The levels of LVEDP, lung/BW, and RV/BW in group HF-AP5 were reduced while ± dp/dtmax was increased after the treatment. The blood Ang II and NE content was decreased, RSNA was reduced, expression of NMDAR1 and TH were downregulated, but GAD67 was upregulated. CONCLUSIONS: NMDAR1 is significantly activated in PVN of HF rats, the activity of TH is increased, GAD67 is downregulated, RSNA is increased, and the heart function is decreased. NMDA receptor blockers can alleviate HF.

Excellent photocatalytic degradation activities of ordered mesoporous anatase TiO2-SiO2 nanocomposites to various organic contaminants.

Ordered 2-D hexagonal mesoporous TiO(2)-SiO(2) nanocomposites consisted of anatase TiO(2) nanocrystals and amorphous SiO(2) nanoparticles, with large mesochannels and high specific surface areas, have been extensively and detailedly evaluated using various cationic dyes (methylene blue, safranin O, crystal violet, brilliant green, basic fuchsin and rhodamine-6G), anionic dyes (acid fuchsin, orange II, reactive brilliant red X3B and acid red 1) and microcystin-LR. We use mesoporous 80TiO(2)-20SiO(2)-900 for the degradation of cationic dyes and MC-LR, due to the dominant adsorption of SiOH groups and synergistic role of coupled adsorption and photocatalytic oxidation. For anionic dyes, due to the adsorption results predominantly from TiOH groups, our strategy realizes the enhanced photocatalytic oxidation by strong surface acids and larger available specific surface area. Based on this, we prepared 90TiO(2)-10SiO(2)-700 to degrade them. The results show that our samples exhibit excellent degradation activities to all the contaminants, which are much higher than that of P25 photocatalyst. The dyes are not only decolorized promptly but degraded readily as well. It is strongly indicated that our mesoporous nanocomposites are considerably stable and reusable. These results demonstrate that our mesoporous TiO(2)-SiO(2) nanocomposites present extensive and promising application in the fast and highly efficient degradation of various organic pollutants.

Controllable and repeatable synthesis of thermally stable anatase nanocrystal-silica composites with highly ordered hexagonal mesostructures.

In this article, we report a controllable and reproducible approach to prepare highly ordered 2-D hexagonal mesoporous crystalline TiO2-SiO2 nanocomposites with variable Ti/Si ratios (0 to infinity). XRD, TEM, and N2 sorption techniques have been used to systematically investigate the pore wall structure, and thermal stability functioned with the synthetic conditions. The resultant materials are ultra highly stable (over 900 degrees C), have large uniform pore diameters (approximately 6.8 nm), and have high Brunauer-Emmett-Teller specific surface areas (approximately 290 m2/g). These mesostructured TiO2-SiO2 composites were obtained using titanium isopropoxide (TIPO) and tetraethyl orthosilicate (TEOS) as precursors and triblock copolymer P123 as a template based on the solvent evaporation-induced co-self-assembly process under a large amount of HCl. Our strategy was the synchronous assembly of titanate and silicate oligomers with triblock copolymer P123 by finely tuning the relative humidity of the surrounding atmosphere and evaporation temperature according to the Ti/Si ratio. We added a large amount of acidity to lower condensation and polymerization rates of TIPO and accelerate the rates for TEOS molecules. TEM and XRD measurements clearly show that the titania is made of highly crystalline anatase nanoparticles, which are uniformly embedded in the pore walls to form the "bricked-mortar" frameworks. The amorphous silica acts as a glue linking the TiO2 nanocrystals and improves the thermal stability. As the silica contents increase, the thermal stability of the resulting mesoporous TiO2-SiO2 nanocomposites increases and the size of anatase nanocrystals decreases. Our results show that the unique composite frameworks make the mesostructures overwhelmingly stable; even with high Ti/Si ratios (> or =80/20) the stability of the composites is higher than 900 degrees C. The mesoporous TiO2-SiO2 nanocomposites exhibit excellent photocatalytic activities (which are higher than that for commercial catalyst P25) for the degradation of rhodamine B in aqueous suspension. The excellent photocatalytic activities are ascribed to the bifunctional effect of highly crystallized anatase nanoparticles and high porosity.