The ability and optimal cutoff value of serum cell division cycle 42 in estimating major adverse cardiac event in STEMI patients treated with percutaneous coronary intervention.

Cell division cycle 42 (CDC42) regulates cholesterol efflux, chronic inflammation, and reendothelialization in various atherosclerotic diseases. This study aimed to investigate the correlation of serum CDC42 with myocardial injury indicators and major adverse cardiac event (MACE) in ST-elevation myocardial infarction (STEMI) patients who were treated with percutaneous coronary intervention (PCI). In 250 STEMI patients about to receive PCI, serum samples were collected at enrollment before PCI treatment, and the serum samples were also obtained from 100 healthy controls (HCs) at enrollment. Serum CDC42 was detected by enzyme-linked immunosorbent assay. Serum CDC42 was decreased (versus HCs, P < 0.001) and negatively correlated with diabetes mellitus (P = 0.017), multivessel disease (P = 0.016), cardiac troponin I (P < 0.001), creatine kinase MB (P = 0.012), stent diameter ≥ 3.5 mm (P = 0.039), white blood cell (P < 0.001), low-density lipoprotein cholesterol (P = 0.049), and C-reactive protein (P < 0.001) in STEMI patients. Besides, 29 (11.6%) STEMI patients experienced MACE. The 1-year, 2-year, and 3-year accumulating MACE rates were 7.5%, 17.3%, and 19.3%, accordingly. Serum CDC42 was reduced in STEMI patients who experienced MACE compared to those who did not (P = 0.001). Serum CDC42 ≥ 250 pg/mL, ≥ 400 pg/mL, ≥ 700 pg/mL (cut by near integer value of 1/4th quartile, median, and 3/4th quartile) were associated with decreased accumulating MACE rates in STEMI patients (all P < 0.050). Notably, serum CDC42 ≥ 250 pg/mL (hazard ratio = 0.435, P = 0.031) was independently related to reduced accumulating MACE risk in STEMI patients. A serum CDC42 level of ≥ 250 pg/mL well predicts decreased MACE risk in STEMI patients who are treated with PCI.

Giant Energy Storage Density with Antiferroelectric-Like Properties in BNT-Based Ceramics via Phase Structure Engineering.

Driven by the information industry, advanced electronic devices require dielectric materials which combine both excellent energy storage properties and high temperature stability. These requirements hold the most promise for ceramic capacitors. Among these, the modulated Bi0.5 Na0.5 TiO3 (BNT)-based ceramics can demonstrate favorable energy storage properties with antiferroelectric-like properties, simultaneously, attaching superior temperature stability resulted from the high Curie temperature. Inspired by the above properties, a strategy is proposed to modulate antiferroelectric-like properties via introducing Ca0.7 La0.2 TiO3 (CLT) into Bi0.395 Na0.325 Sr0.245 TiO3 (BNST) ((1-x)BNST-xCLT, x = 0.10, 0.15, 0.20, 0.25). Combining both orthorhombic phase and defect dipole designs successfully achieve antiferroelectric-like properties in BNST-CLT ceramics. The results illustrate that 0.8BNST-0.2CLT presents superior recoverable energy storage density ≈8.3 J cm-3 with the ideal η ≈ 80% at 660 kV cm-1 . Structural characterizations demonstrate that there is the intermediate modulated phase with the coexistence of the antiferroelectric and ferroelectric phases. In addition, in situ temperature measurements prove that BNST-CLT ceramics exhibit favorable temperature stability over a wide temperature range. The present work illustrates that BNT-based ceramics with antiferroelectric-like properties can effectively enhance the energy storage performance, which provides novel perspectives for the subsequent development of advanced pulsed capacitors.

Delayed Polarization Saturation Induced Superior Energy Storage Capability of BiFeO3 -Based Ceramics Via Introduction of Non-Isovalent Ions.

Electrostatic capacitors are emerging as a highly promising technology for large-scale energy storage applications. However, it remains a significant challenge to improve their energy densities. Here, an effective strategy of introducing non-isovalent ions into the BiFeO3 -based (BFO) ceramic to improve energy storage capability via delaying polarization saturation is demonstrated. Accordingly, an ultra-high energy density of up to 7.4 J cm-3 and high efficiency ≈ 81% at 680 kV m-1 are realized, which is one of the best energy storage performances recorded for BFO-based ceramics. The outstanding comprehensive energy storage performance is attributed to inhibiting the polarization hysteresis resulting from generation ergodic relaxor zone and random field, and generating highly-delayed polarization saturation with continuously-increased polarization magnitudes with the electric field of supercritical evolution. The contributions demonstrate that delaying the polarization saturation is a consideration for designing the next generation of lead-free dielectric materials with ultra-high energy storage performance.

Calculated and Empirical Values of Vibronic Transition Dipole Moments of Reactive Chemical Intermediates for Determination of Concentrations.

Absorption spectroscopy has long been known as a technique for making molecular concentration measurements and has received enhanced visibility in recent years with the advent of new techniques, like cavity ring-down spectroscopy, that have increased its sensitivity. To apply the method, it is necessary to have a known molecular absorption cross section for the species of interest, which typically is obtained by measurements of a standard sample of known concentration. However, this method fails if the species is highly reactive, and indirect means for attaining the cross section must be employed. The HO2 and alkyl peroxy radicals are examples of reactive species for which absorption cross sections have been reported. This work explores and describes for these peroxy radicals the details of an alternative approach for obtaining these cross sections using quantum chemistry methods for the calculation of the transition dipole moment upon whose square the cross section depends. Likewise, details are given for obtaining the transition moment from the experimentally measured cross sections of individual rovibronic lines in the near-IR Ã-X̃ electronic spectrum of HO2 and the peaks of the rotational contours in the corresponding electronic transitions for the alkyl (methyl, ethyl, and acetyl) peroxy radicals. In the case of the alkyl peroxy radicals, good agreement for the transition moments, ≈20%, is found between the two methods. However, rather surprisingly, the agreement is significantly poorer, ≈40%, for the HO2 radical. Possible reasons for this disagreement are discussed.

A combined experimental and computational study on the transition of the calcium isopropoxide radical as a candidate for direct laser cooling.

Vibronically resolved laser-induced fluorescence/dispersed fluorescence (LIF/DF) and cavity ring-down (CRD) spectra of the electronic transition of the calcium isopropoxide [CaOCH(CH3)2] radical have been obtained under jet-cooled conditions. An essentially constant energy separation of 68 cm-1 has been observed for the vibrational ground levels and all fundamental vibrational levels accessed in the LIF measurement. To simulate the experimental spectra and assign the recorded vibronic bands, Franck-Condon (FC) factors and vibrational branching ratios (VBRs) are predicted from vibrational modes and their frequencies calculated using the complete-active-space self-consistent field (CASSCF) and equation-of-motion coupled-cluster singles and doubles (EOM-CCSD) methods. Combined with the calculated electronic transition energy, the computational results, especially those from the EOM-CCSD calculations, reproduced the experimental spectra with considerable accuracy. The experimental and computational results suggest that the FC matrix for the studied electronic transition is largely diagonal, but transitions from the vibrationless levels of the à state to the X̃-state levels of the CCC bending (ν14 and ν15), CaO stretch (ν13), and CaOC asymmetric stretch (ν9 and ν11) modes also have considerable intensities. Transitions to low-frequency in-plane [ν17(a')] and out-of-plane [ν30(a'')] CaOC bending modes were observed in the experimental LIF/DF spectra, the latter being FC-forbidden but induced by the pseudo-Jahn-Teller (pJT) effect. Both bending modes are coupled to the CaOC asymmetric stretch mode via the Duschinsky rotation, as demonstrated in the DF spectra obtained by pumping non-origin vibronic transitions. The pJT interaction also induces transitions to the ground-state vibrational level of the ν10(a') mode, which has the CaOC bending character. Our combined experimental and computational results provide critical information for future direct laser cooling of the target molecule and other alkaline earth monoalkoxide radicals.

Fine and hyperfine interactions of PbF studied by laser-induced fluorescence spectroscopy.

The fine and hyperfine interactions in PbF have been studied using the laser-induced fluorescence (LIF) spectroscopy method. Cold PbF molecular beam was produced by laser-ablating a Pb rod under jet-cooled conditions, followed by the reaction with SF6. The LIF excitation spectrum of the (0, 0) band in the B2Σ+-X2Π1/2 system of the 208PbF, 207PbF, and 206PbF isotopologues has been recorded with rotational, fine structure, and hyperfine-structure resolution. Transitions in the LIF spectrum were assigned and combined with the previous X2Π3/2-X2Π1/2 emission spectrum in the near-infrared region [Ziebarth et al., J. Mol. Spectrosc. 191, 108-116 (1998)] and the X2Π1/2 state pure rotational spectrum of PbF [Mawhorter et al., Phys. Rev. A 84, 022508 (2011)] in a global fit to derive the rotational, spin-orbit, spin-rotation, and hyperfine interaction parameters of the ground (X2Π1/2) and the excited (B2Σ+) electronic states. Molecular constants determined in the present work are compared with previously reported values. Particularly, the significance of the hyperfine parameters, A⊥ and A‖, of 207Pb is discussed.

Research on a Bearing Fault Enhancement Diagnosis Method with Convolutional Neural Network Based on Adaptive Stochastic Resonance.

As a powerful feature extraction tool, a convolutional neural network (CNN) has strong adaptability for big data applications such as bearing fault diagnosis, whereas the classification performance is limited when the quality of raw signals is poor. In this paper, stochastic resonance (SR), which provides an advanced feature enhancement approach for weak signals with strong background noise, is introduced as a data pre-processing method for the CNN to improve its classification performance. First, a multiparameter adjusting bistable Duffing system that can achieve SR under large-parameter weak signals is introduced. A hybrid optimization algorithm (HOA) combining the genetic algorithm (GA) and the simulated annealing (SA) is proposed to adaptively obtain the optimized parameters and output signal-to-noise ratio (SNR) of the Duffing system. Therefore, the data optimization based on the multiparameter-adjusting SR of Duffing system can be realized. An SR-based mapping method is further proposed to convert the outputs of the Duffing system into grey images, which can be further processed by a normal CNN with batch normalization (BN) layers and dropout layers. After verifying the feasibility of the HOA in multiparameter optimization of the Duffing system, the bearing fault data set from the CWRU bearing data center was processed by the proposed fault enhancement classification and identification method. The research showed that the weak features of the bearing signals could be enhanced significantly through the adaptive multiparameter optimization of SR, and classification accuracies for 10 categories of bearing signals could achieve 100% and those for 20 categories could achieve more than 96.9%, which is better than other methods. The influences of the population number on the classification accuracies and calculation time were further studied, and the feature map and network visualization are presented. It was demonstrated that the proposed method can realize high-performance fault enhancement classification and identification.

Overview of extracellular vesicles in the pathogenesis of preeclampsia†.

Preeclampsia (PE) is a leading cause of maternal and fetal-neonatal deaths, and its pathogenesis has been linked to the involvement of extracellular vesicles (EVs). EVs are a heterogeneous group of cell-originated membranous vesicles including exosomes, microvesicles, and apoptotic bodies. EVs transport various bioactive cargos such as lipids, proteins, or nucleic acids, and thus mediate cellular communication and contribute to the proper functioning of cells, organs and processes, including normal pregnancy. Numerous studies have reported that EVs are associated with abnormal levels of soluble fms-like tyrosine kinase-1 (sFlt-1), soluble endoglin (sEng), and placental growth factor (PlGF) in PE. EVs isolated from preeclamptic women have been implicated in trophoblast dysfunction and have been reported to activate endothelium, monocytes, and platelets, and to be involved in defective placentation, imbalanced angiogenesis, and intravascular inflammation. When injected into pregnant rodents, these EVs induced hypertension, proteinuria, and adverse fetal outcomes. Deciphering the contribution of EVs to PE will advance our current understanding of this disorder and may lead to more clinical strategies for the management of PE. Of note, the composition of EV cargos may be characteristic of the status and stages of gestation, providing researchers the possibility of one day using EVs as novel, noninvasive, biomarkers for early screening of PE. Herein, we reviewed the latest research into EVs with emphasis on their role in the pathogenesis of PE and their applications as biomarkers in the early screening of this pregnancy-specific disorder.

Acetylcholine ameliorated hypoxia-induced oxidative stress and apoptosis in trophoblast cells via p38 MAPK/NF-κB pathway.

Hypoxia-induced oxidative stress and apoptosis of trophoblast are involved in the pathogenesis of preeclampsia (PE). Extensive research reports that the principal vagal neurotransmitter acetylcholine (ACh) shows anti-oxidative and anti-apoptotic effects in various diseases models. However, the role of ACh in hypoxic trophoblast remains unknown. Here, we examined the apoptotic levels of human placenta and explored the role(s) of ACh on cobalt chloride (CoCl2)-treated (trophoblast-derived) HTR-8/SVneo cells for mimicking hypoxic injuries. Cell counting kit-8 (CCK-8), dihydroethidium (DHE) probe, western blotting, immunofluorescence staining, migration and invasion assay were employed in the current study. Our data showed that placentas from PE women exhibited increased level of reactive oxygen species (ROS) and apoptotic index than those in normal pregnancy. Our in vitro study showed that CoCl2 enhanced ROS generation and apoptosis in HTR-8/SVneo cells through the activation of the p38 mitogen-activated protein kinase (p38 MAPK)/nuclear factor-κB (NF-κB) pathway. ACh significantly decreased hypoxia-induced ROS generation and the resulting apoptosis, accompanied by lowered phosphorylation of p38 MAPK and NF-κB. Western blotting analysis further confirmed that ACh decreased the ratio of pp38 MAPK/p38 MAPK, p-NF-κB/NF-κB, Bax/Bcl-2 and cleaved Caspase-3/Caspase-3. Besides, ACh promoted cell invasion and migration ability under hypoxic conditions. Atropine, the muscarinic receptor antagonist, abolished ACh's effects mentioned above. Overall, our data showed that ACh exerted protective effects on hypoxia-induced oxidative stress and apoptosis in trophoblast cells via muscarinic receptors, indicating that improved vagal activity may be of therapeutic value in PE management.

Chronic Infusion of Astaxanthin Into Hypothalamic Paraventricular Nucleus Modulates Cytokines and Attenuates the Renin-Angiotensin System in Spontaneously Hypertensive Rats.

ABSTRACT: Oxidative stress, the renin-angiotensin system (RAS), and inflammation are some of the mechanisms involved in the pathogenesis of hypertension. The aim of this study is to examine the protective effect of the chronic administration of astaxanthin, which is extracted from the shell of crabs and shrimps, into hypothalamic paraventricular nucleus (PVN) in spontaneously hypertensive rats. Animals were randomly assigned to 2 groups and treated with bilateral PVN infusion of astaxanthin or vehicle (artificial cerebrospinal fluid) through osmotic minipumps (Alzet Osmotic Pumps, Model 2004, 0.25 µL/h) for 4 weeks. Spontaneously hypertensive rats had higher mean arterial pressure and plasma level of norepinephrine and proinflammatory cytokine; higher PVN levels of reactive oxygen species, NOX2, NOX4, IL-1ß, IL-6, ACE, and AT1-R; and lower PVN levels of IL-10 and Cu/Zn SOD, Mn SOD, ACE2, and Mas receptors than Wistar-Kyoto rats. Our data showed that chronic administration of astaxanthin into PVN attenuated the overexpression of reactive oxygen species, NOX2, NOX4, inflammatory cytokines, and components of RAS within the PVN and suppressed hypertension. The present results revealed that astaxanthin played a role in the brain. Our findings demonstrated that astaxanthin had protective effect on hypertension by improving the balance between inflammatory cytokines and components of RAS.

Laser-Induced Fluorescence Spectroscopy of Large Secondary Alkoxy Radicals: Part I. Spectral Overviews and Vibronic Analysis.

We report vibronically resolved laser-induced fluorescence (LIF) spectra of jet-cooled C5-C10 secondary alkoxy radicals. The LIF spectra demonstrate vibronic structures similar to smaller (C3-C4) secondary alkoxies. For 2-pentoxy and 2-hexoxy, rotationally resolved LIF spectra have also been recorded. Two types of rotational structures have been observed in vibronic bands of each molecule. Extensive quantum chemistry calculations have been performed on 2-pentoxy and 2-hexoxy. The computed results include the relative energies of conformers, their geometries, and the energy separations between the nearly degenerate à and X̃ electronic states (ΔEÃ-X̃). Based on the similarity between the vibronic structures of different secondary alkoxies and calculated molecular parameters, including the relative energies of conformers, the B̃ ← X̃ transition frequencies, and the vibrational frequencies, strong vibronic bands in the LIF spectra are assigned to the origin bands and CO stretch bands of the two lowest-energy conformers of each secondary alkoxy radical. The distinct rotational structures of the two different conformations of 2-pentoxy and 2-hexoxy will be simulated and analyzed in Part II of this series ( J. Phys. Chem. A 2021, DOI: 10.1021/acs.jpca.0c10663).

Laser-Induced Fluorescence Spectroscopy of Large Secondary Alkoxy Radicals: Part II. Rotational and Fine Structure.

Selected vibronic bands of the B̃ ← X̃ laser-induced fluorescence (LIF) spectra of jet-cooled 2-pentoxy and 2-hexoxy, including the origin and CO-stretch bands, have been measured with rotational resolution and analyzed using (1) an effective Hamiltonian that comprises a rotational part and a spin-rotation (SR) part (the "isolated-states model") and (2) a recently developed Hamiltonian in which the nearly degenerate à and X̃ states are treated together (the "coupled-states model") (see Liu, J., J. Chem. Phys. 2018, 148, 124112). The observed rotational and fine structures of the strongest vibronic bands have first been simulated using a genetic algorithm with the isolated-states model. The parameters for the simulation include rotational constants for both the X̃ and B̃ states, which can be calculated from the electronic structure theory, as well as the electronic SR constants of the X̃ state and the transition dipole moments (TDMs), both of which are predicted based on their transferability in an "orbital-fixed coordinate system" using iso-propoxy as the reference molecule. Quantum chemistry calculations suggest that the lowest two electronic (X̃ and Ã) states of secondary alkoxy radicals have small energy separations on the order of 100 cm-1 (see Part I of this series: J. Phys. Chem. A 2021, DOI: 10.1021/acs.jpca.0c10662). The electron configurations of these two nearly degenerate states have been determined by comparing the experimentally determined rotational constants and the TDMs to the ones predicted for the X̃ and à states. The experimental LIF spectra were also simulated with the coupled-states model, in which the effective spin-orbit (SO) constants (aζed) and the SO-free separation between the à and the X̃ states (ΔE0) have been determined. Molecular constants derived from fitting the rotational and fine structures of the experimental LIF spectra enabled unambiguous assignment of the observed vibronic bands to specific conformers of 2-pentoxy and 2-hexoxy as reported in Part I.

Electronic spectroscopy of the A1̃2A''/A2̃2A'-X̃2A' transitions of jet-cooled calcium ethoxide radicals: Vibronic structure of alkaline earth monoalkoxide radicals of Cs symmetry.

Laser-induced fluorescence/dispersed fluorescence (LIF/DF) and cavity ring-down spectra of the A1̃2A''/A2̃2A'-X̃2A' electronic transition of the calcium ethoxide (CaOC2H5) radical have been obtained under jet-cooled conditions. An essentially constant Ã2-Ã1 energy separation for different vibronic levels is observed in the LIF spectrum, which is attributed to both the spin-orbit (SO) interaction and non-relativistic effects. Electronic transition energies, vibrational frequencies, and spin-vibrational eigenfunctions calculated using the coupled-cluster method, along with results from previous complete active space self-consistent field calculations, have been used to predict the vibronic energy level structure and simulate the recorded LIF/DF spectra. Although the vibrational frequencies and Franck-Condon (FC) factors calculated under the Born-Oppenheimer approximation and the harmonic oscillator approximation reproduce the dominant spectral features well, the inclusion of the pseudo-Jahn-Teller (pJT) and SO interactions, especially those between the A1̃2A″/A2̃2A' and the B̃2A' states, induces additional vibronic transitions and significantly improves the accuracy of the spectral simulations. Notably, the spin-vibronic interactions couple vibronic levels and alter transition intensities. The calculated FC matrix for the A1̃2A''/A2̃2A'-X̃2A' transition contains a number of off-diagonal matrix elements that connect the vibrational ground levels to the levels of the ν8 (CO stretch), ν11 (OCC bending), ν12 (CaO stretch), ν13 (in-plane CaOC bending), and ν21 (out-of-plane CaOC bending) modes, which are used for vibrational assignments. Transitions to the ν21(a″) levels are allowed due to the pJT effect. Furthermore, when LIF transitions to the Ã-state levels of the CaOC-bending modes, ν13 and ν21, are pumped, A1̃2A''/A2̃2A'→X̃2A' transitions to the combination levels of these two modes with the ν8, ν11, and ν12 modes are also observed in the DF spectra due to the Duschinsky mixing. Implications of the present spectroscopic investigation to laser cooling of asymmetric-top molecules are discussed.

Electroactive Interface for Enabling Spectroelectrochemical Investigations in Evanescent-Wave Cavity-Ring-Down Spectroscopy.

In this study, we report the development of an electrically active solid-liquid interface for the evanescent-wave cavity-ring-down spectroscopic (EW-CRDS) technique to enable spectroelectrochemical investigations of redox events. Because of a high-quality transparent conductive electrode film of indium tin oxide (ITO) coated on the interface of total internal reflection of the EW-CRDS platform, a cavity ring-down time of about 900 ns was obtained allowing spectroelectrochemical studies at solid-liquid interfaces. As a proof-of-concept on the capabilities of the developed platform, measurements were performed to address the effects of an applied electric potential to the adsorption behavior of the redox protein cytochrome c (Cyt-C) onto different interfaces, namely, bare-ITO, 3-aminopropyl triethoxysilane (APTES), and Cyt-C antibody. For each interface, the adsorption and desorption constants, the surface equilibrium constant, the Gibbs free energy of adsorption, and the surface coverage were optically measured by our electrically active EW-CRDS tool. Optical measurements at a set of constant discrete values of the applied electric potential were acquired for kinetic adsorption analysis. Cyclic voltammetry (CV) scans under synchronous optical readout were performed to study the effects of each molecular interface on the redox process of surface-adsorbed protein species. Overall, the experimental results demonstrate the ability of the electro-active EW-CRDS platform to unambiguously measure electrode-driven redox events of surface-confined molecular species at low submonolayer coverages and at a single diffraction-limited spot. Such capability is expected to open several opportunities for the EW-CRDS technique to investigate a variety of electrochemical phenomena at solid-liquid interfaces.

MSCs attenuate hypoxia induced pulmonary hypertension by activating P53 and NF-kB signaling pathway through TNFα secretion.

Hypoxia could cause vascular smooth muscle hypertrophy, leading to high pulmonary circulation resistance, pulmonary artery (PA) pressure, even pulmonary arterial hypertension (PAH). Recent studies have demonstrated the ability of mesenchymal stem cell (MSC) to ameliorate PAH but the mechanism was controversial. In this study, we revealed that the growth rate of pulmonary artery smooth muscle cells (PASMCs) treated with hypoxia was significantly increased than normal and showed lower expression of potassium channels. However, cells co-cultured with MSC showed decreased proliferation capability and down-regulated expression of ion channel of PAMSCs. The protein array data showed that the changes of PAMSCs was substantially associated with a high level of tumor necrosis factor alpha (TNFα) secretion from MSC. We further demonstrated that TNFα rescued the cell behavior of PAMSCs through activating the expression of P53 and NF-kB and inducing cell cycle arrest by P21/CDK2/CDK4 downregulation. These findings suggested that MSCs could attenuate abnormal function of PAMSCs by TNFα secretion, which was more or less associated with the beneficial effects of MSC on improving PAH.

IL-22 hinders antiviral T cell responses and exacerbates ZIKV encephalitis in immunocompetent neonatal mice.

BACKGROUND: The Zika virus (ZIKV) outbreak that occurred in multiple countries was linked to increased risk of nervous system injuries and congenital defects. However, host immunity- and immune-mediated pathogenesis in ZIKV infection are not well understood. Interleukin-22 (IL-22) is a crucial cytokine for regulating host immunity in infectious diseases. Whether IL-22 plays, a role in ZIKV infection is unknown. METHODS: The cellular source of IL-22 was identified in IFNAR-/- mice and wild-type (WT) neonatal mice during ZIKV infection. To determine the role of IL-22, we challenged 1-day-old WT and IL-22-/- mice with ZIKV and monitored clinical manifestations. Glial cell activation in the brain was assessed by confocal imaging. ZIKV-specific CD8+ T cell responses in both the spleen and brain were analyzed by flow cytometry. In addition, glial cells were cultured in vitro and infected with ZIKV in the presence of IL-22, followed by the evaluation of cell proliferation, cytokine expression, and viral loads. RESULTS: We found that γδ T cells were the main source of IL-22 during ZIKV infection in both the spleen and brain. WT mice began to exhibit weight loss, staggered steps, bilateral hind limb paralysis, and weakness at 10 days post-infection (dpi) and ultimately succumbed to infection at 16-19 dpi. IL-22 deficiency lessened weight loss, moderated the systemic inflammatory response, and greatly improved clinical signs of neurological disease and mortality. ZIKV infection also induced the activation of microglia and astrocytes in vitro. Additional analysis demonstrated that the absence of IL-22 resulted in reduced activation of microglia and astrocytes in the cortex. Although IL-22 displayed a negligible effect on glial cells in vitro, IL-22-/- mice mounted more vigorous ZIKV-specific CD8+ T cell responses, which led to a more effective control of ZIKV in the brain. CONCLUSIONS: Our data revealed a pathogenic role of IL-22 in ZIKV encephalitis.

Acetylcholine ameliorated TNF-α-induced primary trophoblast malfunction via muscarinic receptors†.

Oxidative stress and apoptosis of trophoblasts are involved in preeclampsia (PE). Numerous studies have shown that acetylcholine (ACh), the principal vagal neurotransmitter, plays a crucial role in attenuating oxidative stress, inflammation, and apoptosis in a variety of human diseases. However, the role of ACh in PE management remains unclear. Here, we aimed to determine the effects of ACh on TNF-α-treated human primary trophoblast cells. Western blotting, CCK-8, DHE, TUNEL immunofluorescence staining, transwell assays, and wound-healing assays were performed to evaluate the role of ACh in vitro. We found that both TNF-α expression and the apoptotic index were higher in placentas from preeclamptic women than in normal placentas. TNF-α enhanced oxidative stress and increased the number of TUNEL-positive nuclei, Bax/Bcl-2 ratio, and the cleaved caspase-3/caspase-3 ratio while decreasing cell viability in primary human trophoblast cells. TNF-α promoted cell migration and invasion. PDTC, a selective NF-κB inhibitor, significantly blunted TNF-α-induced effects. ACh treatment attenuated oxidative stress and apoptosis while further promoting migration and invasion of TNF-α-treated primary trophoblast cells. The effects of ACh could be reversed by the muscarinic receptor antagonist atropine. Overall, our findings indicate that ACh significantly ameliorates TNF-α-induced oxidative stress and apoptosis of human primary trophoblast cells via muscarinic receptors. This is the first time that the improvement of vagal activity served as a therapeutic strategy for PE-like trophoblasts, suggesting its potential value in clinical practice.

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.

Docosahexaenoic acid inhibits Ca2+ influx and downregulates CaSR by upregulating microRNA-16 in pulmonary artery smooth muscle cells.

Docosahexaenoic acid (DHA) is reported to have the potential to ameliorate pulmonary arterial hypertension (PAH), while the specific mechanism is still obscure. This study aims to investigate the function of DHA in pulmonary artery smooth muscle cells (PASMCs) and explore the underlying mechanism. In our study, DHA was used to incubate PASMCs. Cytosolic-free Ca2+ concentration ([Ca2+ ]cyt) was measured using Fluo-3 AM method. Real-time polymerase chain reaction was used to detect microRNA-16 (miR-16) and calcium-sensing receptor (CaSR) messenger RNA expression levels. CCK-8 assay, BrdU assay, and Transwell assay were employed to detect the effects of DHA on proliferation and migration of PASMCs. CaSR was confirmed as a direct target of miR-16 using dual-luciferase assay, polymerase chain reaction, and Western blot analysis. It was found that DHA significantly inhibited PASMC proliferation and migration and decreased [Ca2+ ]cyt. After transfection of miR-16 mimics, proliferation and migration ability of PASMCs were significantly inhibited, whereas opposite effects were observed after miR-16 inhibition. [Ca2+ ]cyt was also inhibited by miR-16 transfection. DHA then promoted the expression of miR-16, and the effects of DHA on PASMCs were annulled when miR-16 was inhibited. CaSR was identified as a direct target of miR-16. CaSR was inhibited directly by miR-16 and indirectly by DHA. In conclusion, DHA inhibits the proliferation and migration of PASMCs, and probably ameliorates PAH via regulating miR-16/CaSR axis.

Hydrogen-rich water alleviates cyclosporine A-induced nephrotoxicity via the Keap1/Nrf2 signaling pathway.

Oxidative stress induced by long-term cyclosporine A (CsA) administration is a major cause of chronic nephrotoxicity, which is characterized by tubular atrophy, tubular cell apoptosis, and interstitial fibrosis in the progression of organ transplantation. Although hydrogen-rich water (HRW) has been used to prevent various oxidative stress-related diseases, its underlying mechanisms remain unclear. This study investigated the effects of HRW on CsA-induced nephrotoxicity and its potential mechanisms. After administration of CsA (25 mg/kg/day), rats were treated with or without HRW (12 mL/kg) for 4 weeks. Renal function and vascular activity were investigated. Histological changes in kidney tissues were analyzed using Masson's trichrome and terminal deoxynucleotidyl transferase dUTP nick-end labeling stains. Oxidative stress markers and the activation of the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway were also measured. We found that CsA increased the levels of reactive oxygen species (ROS) and malonaldehyde (MDA), but it reduced glutathione (GSH) and superoxide dismutase (SOD) levels. Such alterations induced vascular dysfunction, tubular atrophy, interstitial fibrosis, and tubular apoptosis. This was evident secondary to an increase in urinary protein, serum creatinine, and blood urea nitrogen, ultimately leading to renal dysfunction. Conversely, HRW decreased levels of ROS and MDA while increasing the activity of GSH and SOD. This was accompanied by an improvement in vascular and renal function. Moreover, HRW significantly decreased the level of Keap1 and increased the expression of Nrf2, NADPH dehydrogenase quinone 1, and heme oxygenase 1. In conclusion, HRW restored the balance of redox status, suppressed oxidative stress damage, and improved kidney function induced by CsA via activation of the Keap1/Nrf2 signaling pathway.