GLP-1 in the Hypothalamic Paraventricular Nucleus Promotes Sympathetic Activation and Hypertension.

Glucagon-like peptide-1 (GLP-1) and its analogs are widely used for diabetes treatment. The paraventricular nucleus (PVN) is crucial for regulating cardiovascular activity. This study aims to determine the roles of GLP-1 and its receptors (GLP-1R) in the PVN in regulating sympathetic outflow and blood pressure. Experiments were carried out in male normotensive rats and spontaneously hypertensive rats (SHR). Renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were recorded. GLP-1 and GLP-1R expressions were present in the PVN. PVN microinjection of GLP-1R agonist recombinant human GLP-1 (rhGLP-1) or EX-4 increased RSNA and MAP, which were prevented by GLP-1R antagonist exendin 9-39 (EX9-39) or GLP-1R antagonist 1, superoxide scavenger tempol, antioxidant N-acetylcysteine, NADPH oxidase (NOX) inhibitor apocynin, adenylyl cyclase (AC) inhibitor SQ22536 or protein kinase A (PKA) inhibitor H89. PVN microinjection of rhGLP-1 increased superoxide production, NADPH oxidase activity, cAMP level, AC, and PKA activity, which were prevented by SQ22536 or H89. GLP-1 and GLP-1R were upregulated in the PVN of SHR. PVN microinjection of GLP-1 agonist increased RSNA and MAP in both WKY and SHR, but GLP-1 antagonists caused greater effects in reducing RSNA and MAP in SHR than in WKY. The increased superoxide production and NADPH oxidase activity in the PVN of SHR were augmented by GLP-1R agonists but attenuated by GLP-1R antagonists. These results indicate that activation of GLP-1R in the PVN increased sympathetic outflow and blood pressure via cAMP-PKA-mediated NADPH oxidase activation and subsequent superoxide production. GLP-1 and GLP-1R upregulation in the PVN partially contributes to sympathetic overactivity and hypertension.

Chemerin in caudal division of nucleus tractus solitarius increases sympathetic activity and blood pressure.

Chemerin is an adipokine that contributes to metabolism regulation. Nucleus tractus solitarius (NTS) is the first relay station in the brain for accepting various visceral afferent activities for regulating cardiovascular activity. However, the roles of chemerin in the NTS in regulating sympathetic activity and blood pressure are almost unknown. This study aimed to determine the role and potential mechanism of chemerin in the NTS in modulating sympathetic outflow and blood pressure. Bilateral NTS microinjections were performed in anaesthetized adult male Sprague-Dawley rats. Renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP) and heart rate (HR) were continuously recorded. Chemerin and its receptor chemokine-like receptor 1 (CMKLR1) were highly expressed in caudal NTS (cNTS). Microinjection of chemerin-9 to the cNTS increased RSNA, MAP and HR, which were prevented by CMKLR1 antagonist α-NETA, superoxide scavenger tempol or N-acetyl cysteine, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors diphenyleneiodonium or apocynin. Chemerin-9 increased superoxide production and NADPH oxidase activity in the cNTS. The increased superoxide production induced by chemerin-9 was inhibited by α-NETA. The effects of cNTS microinjection of chemerin-9 on the RSNA, MAP and HR were attenuated by the pretreatment with paraventricular nucleus (PVN) microinjection of NMDA receptor antagonist MK-801 rather than AMPA/kainate receptor antagonist CNQX. These results indicate that chemerin-9 in the NTS increases sympathetic outflow, blood pressure and HR via CMKLR1-mediated NADPH oxidase activation and subsequent superoxide production in anaesthetized normotensive rats. Glutamatergic inputs in the PVN are needed for the chemerin-9-induced responses.

Understanding Variations in Ferrate Detection through the ABTS Method in the Presence of Electron-Rich Organic Compounds.

The chromogenic reaction between 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonate) (ABTS) and ferrate [Fe(VI)] has long been utilized for Fe(VI) content measurement. However, the presence of electron-rich organic compounds has been found to significantly impact Fe(VI) detection using the ABTS method, leading to relative errors ranging from ∼88 to 100%. Reducing substances consumed ABTS•+ and resulted in underestimated Fe(VI) levels. Moreover, the oxidation of electron-rich organics containing hydroxyl groups by Fe(VI) could generate a phenoxyl radical (Ph•), promoting the transformation of Fe(VI) → Fe(V) → Fe(IV). The in situ formation of Fe(IV) can then contribute to ABTS oxidation, altering the ABTS•+:Fe(VI) stoichiometry from 1:1 to 2:1. To overcome these challenges, we introduced Mn(II) as an activator and 3,3',5,5'-tetramethylbenzidine (TMB) as a chromogenic agent for Fe(VI) detection. This Mn(II)/TMB method enables rapid completion of the chromogenic reaction within 2 s, with a low detection limit of approximately 4 nM and a wide detection range (0.01-10 µM). Importantly, the Mn(II)/TMB method exhibits superior resistance to reductive interference and effectively eliminates the impact of phenoxyl-radical-mediated intermediate valence iron transfer processes associated with electron-rich organic compounds. Furthermore, this method is resilient to particle interference and demonstrates practical applicability in authentic waters.

Construction and Biological Evaluation of Biomimetic Coatings on Titanium Surfaces Using Naringin-7-O-Neohesperidoside at Different Concentrations.

Objective: The biomimetic coating on titanium surface affects the adhesion, proliferation, and differentiation of bone cells on the surface of implants. Naringin-7-O-Neohesperidoside (NRG) positively affects the proliferation and differentiation of bone cells, while inhibiting the formation of osteoclasts, thereby affecting the osteogenic effect. This study aimed to construct biomimetic coatings on pure titanium surfaces using layer by layer (LBL) self-assembly of NRGat different concentrations. The effects of the assembled NRG biomimetic coatings on the proliferation and differentiation of mouse preosteoblast cells (MC3T3-E1) in vitro were investigated. The influence of NRG concentration and culture time on MC3T3-E1 cells was also explored. Methods: LBL is a technology that allows for the creation of thin membranes made of polyelectrolytes through electrostatic attraction between polyanions and polycations, which effectively incorporates charged polyelectrolytes onto solid surfaces while preserving their biological activity. Alkaline phosphatase (ALP) plays a crucial role in biomineralization, and its activity is considered as a marker for osteoblast differentiation. Real-time quantitative PCR accurately and quantitatively measures gene expression levels, which reflect the transcriptional activity of genes and thus reflect the proliferation and differentiation of osteoblasts. The research different concentrations of NRG biomimetic coatings (1×10-4 mol/L, 1×10-5 mol/L, 1×10-6 mol/L, and 1×10-7 mol/L) were constructed on titanium surfaces using the LBL self-assembly technique. The control groups included the blank group and the group without drugs. The effects of the coatings on the proliferation of MC3T3-E1 cells were evaluated by ALP activity assay. The differentiation of MC3T3-E1 cells was evaluated by ALP activity assay. Real-time quantitative PCR was performed to detect the gene expressions of OC mRNA, Runx2 mRNA, and Col1a1 mRNA in MC3T3-E1 cells grown on the titanium samples of different experimental groups. Results: The proliferation indices of all NRG concentration groups were higher than those of the groups without drug and blank groups. The highest ALP value was detected at a concentration of 10-4 mol/L. All NRG concentrations upregulated the expression of Col1al mRNA compared to the group without the drug, and the concentrations of 10-5 mol/L and 10-6 mol/L showed statistically significant differences (P < .01). NRG at a concentration of 10-6 mol/L significantly upregulated the expression of Runx2 mRNA (P < .05), while all NRG concentration groups upregulated the expression of OC mRNA. NRG at a concentration of 10-6 mol/L demonstrated a 4 times increase in Runx2 mRNA expression, indicating a significant impact on osteogenic differentiation. Conclusions: NRG biomimetic coatings on titanium surfaces were successfully constructed using the LBL technique. NRG at different concentrations had stronger effects on the proliferation and differentiation of MC3T3-E1 cells compared to the groups without drug and blank groups, with the concentration of 10-6 mol/L demonstrating the best effect. These findings suggest that NRG-loaded biomimetic coatings may enhance the osseointegration of titanium implants, offering promising prospects for dental and orthopedic applications.

Yu-Ping-Feng-San alleviates inflammation in atopic dermatitis mice by TLR4/MyD88/NF-κB pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Yu-Ping-Feng-San (YPF) is a traditional Chinese medicine formula that has therapeutic effects on allergic diseases such as allergic rhinitis and asthma. However, its potential efficacy and mechanism in the treatment of atopic dermatitis (AD) has not been extensively illustrated. AIM OF THE STUDY: The purpose of this study was to investigate the efficacy and possible mechanisms of YPF in AD pathogenesis. METHODS: Network pharmacology and GEO data mining were adopted to firstly identify the potential mechanisms of YPF on AD. Then DNCB induced-AD murine model was established to test the efficacy of YPF and verify its effects on inflammatory cytokines and NF-κB pathway. In addition, molecular docking was performed to detect the binding affinity of YPF's active components with NF-κB pathway related molecules. RESULTS: Network pharmacology and human data mining suggested that YPF may act on the NF-κB pathway in AD pathogenesis. With DNCB mice model, we found that YPF significantly improved AD symptoms, reduced SCORAD scores, and alleviated skin tissue inflammation in mice. At the same time, the expression of inflammatory cytokines, TNF-α, sPLA2-IIA and IL-6, was down-regulated. Moreover, YPF suppressed TLR4/MyD88/NF-κB pathway in situ in a dose-dependent manner. Molecular docking further confirmed that seven compounds in YPF had exceptional binding properties with TNF-α, IL-6 and TLR4. CONCLUSION: YPF may help the recovery of AD by inhibiting the TLR4/MyD88/NF-κB pathway, which provides novel insights for the treatment of AD by YPF.

Displacement-pressure biparametrically regulated softness sensory system for intraocular pressure monitoring.

High intraocular pressure (IOP) is one of the high-risk pathogenic factors of glaucoma. Existing methods of IOP measurement are based on the direct interaction with the cornea. Commercial ophthalmic tonometers based on snapshot measurements are expensive, bulky, and their operation requires trained personnel. Theranostic contact lenses are easy to use, but they may block vision and cause infection. Here, we report a sensory system for IOP assessment that uses a soft indentor with two asymmetrically deployed iontronic flexible pressure sensors to interact with the eyelid-eyeball in an eye-closed situation. Inspired by human fingertip assessment of softness, the sensory system extracts displacement-pressure information for soft evaluation, achieving high accuracy IOP monitoring (>96%). We further design and custom-make a portable and wearable ophthalmic tonometer based on the sensory system and demonstrate its high efficacy in IOP screening. This sensory system paves a way towards cost-effective, robust, and reliable IOP monitoring.

High-resolution flexible iontronic skins for both negative and positive pressure measurement in room temperature wind tunnel applications.

Flexible skins that can be laminated on curved surfaces are a desired form for wind pressure measurement. Sensors for such applications need to detect both negative and positive wind pressure with ultrahigh pressure resolution over a wide range up to 600 kPa, whereas existing flexible sensors are unsatisfactory to such demands. Here, we report a flexible skin containing two iontronic pressure sensors for negative pressure and positive pressure sensing, respectively, and show the potential of the skin for pressure measurement in room temperature wind tunnels. We control the contact state of iontronic interface of a sensor to introduce a pre-pressure that enables negative pressure sensing, exhibiting a pressure resolution of -20 Pa (0.025%) within a broad pressure regime (from -100 kPa to -10 Pa). The other sensor for positive pressure sensing exhibits a pressure-resolution of 100 Pa (0.025%) over 600 kPa, in addition to a wide frequency bandwidth up to 400 Hz. The skin with the two types of sensors can be attached on curved surfaces of wing surface for pressure measurement at various free stream velocities and angles of attack. This study provides a promising technology of using flexible skins for pressure measurement in aviation applications.

An orexin-receptor-2-mediated heart-brain axis in cardiac pain.

Orexin is a neuropeptide released from hypothalamus regulating feeding, sleeping, arousal, and cardiovascular activity. Past research has demonstrated that orexin receptor 2 (OX2R) agonist infusion in the brain results in sympathoexcitatory responses. Here, we found that epicardial administration of OX2R agonism leads to opposite responses. We proved that OX2R is expressed mainly in DRG neurons and transported to sensory nerve endings innervating the heart. In a capsaicin-induced cardiac sympathetic afferent reflex (CSAR) model, we recorded the calcium influx in DRG neurons, measured heart rate variability, and examined the PVN c-Fos activity to prove that epicardial OX2R agonism administration could attenuate capsaicin-induced CSAR. We further showed that OX2R agonism could partially rescue acute myocardial infarction by reducing sympathetic overactivation. Our data indicate that epicardial application of OX2R agonist exerts a cardioprotective effect by attenuating CSAR. This OX2R-mediated heart-brain axis may provide therapeutic targets for acute cardiovascular diseases.