Multimaterial Printing of Serpentine Microarchitectures with Synergistic Mechanical/Piezoelectric Stimulation for Enhanced Cardiac-Specific Functional Regeneration.

Recreating the natural heart's mechanical and electrical environment is crucial for engineering functional cardiac tissue and repairing infarcted myocardium in vivo. In this study, multimaterial-printed serpentine microarchitectures are presented with synergistic mechanical/piezoelectric stimulation, incorporating polycaprolactone (PCL) microfibers for mechanical support, polyvinylidene fluoride (PVDF) microfibers for piezoelectric stimulation, and magnetic PCL/Fe3O4 for controlled deformation via an external magnet. Rat cardiomyocytes in piezoelectric constructs, subjected to dynamic mechanical stimulation, exhibit advanced maturation, featuring superior sarcomeric structures, improved calcium transients, and upregulated maturation genes compared to non-piezoelectric constructs. Furthermore, these engineered piezoelectric cardiac constructs demonstrate significant structural and functional repair of infarcted myocardium, as evidenced by enhanced ejection and shortening fraction, reduced fibrosis and inflammation, and increased angiogenesis. The findings underscore the therapeutic potential of piezoelectric cardiac constructs for myocardial infarction therapy.

Identification and characterization of three monoclonal antibodies targeting the SFTSV glycoprotein and displaying a broad spectrum recognition of SFTSV-related viruses.

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a novel tick-borne viral pathogen that causes severe fever with thrombocytopenia syndrome (SFTS). The disease was initially reported in central and eastern China, then later in Japan and South Korea, with a mortality rate of 13-30%. Currently, no vaccines or effective therapeutics are available for SFTS treatment. In this study, three monoclonal antibodies (mAbs) targeting the SFTSV envelope glycoprotein Gn were obtained using the hybridoma technique. Two mAbs recognized linear epitopes and did not neutralize SFTSV, while the mAb 40C10 can effectively neutralized SFTSV of different genotypes and also the SFTSV-related Guertu virus (GTV) and Heartland virus (HRTV) by targeting a spatial epitope of Gn. Additionally, the mAb 40C10 showed therapeutic effect in mice infected with different genotypes of SFTSV strains against death by preventing the development of lesions and by promoting virus clearance in tissues. The therapeutic effect could still be observed in mice infected with SFTSV which were administered with mAb 40C10 after infection even up to 4 days. These findings enhance our understanding of SFTSV immunogenicity and provide valuable information for designing detection methods and strategies targeting SFTSV antigens. The neutralizing mAb 40C10 possesses the potential to be further developed as a therapeutic monoclonal antibody against SFTSV and SFTSV-related viruses.

Capsaicin pretreatment attenuates salt-sensitive hypertension by alleviating AMPK/Akt/Nrf2 pathway in hypothalamic paraventricular nucleus.

Background: Long term hypertension seriously promotes target organ damage in the brain and heart, and has increasingly become serious public health problem worldwide. The anti-hypertensive effects of capsaicin has been reported, however, the role and mechanism of capsaicin within the brain on salt-induced hypertension have yet to be elucidated. This study aimed to verify the hypothesis that capsaicin attenuates salt-induced hypertension via the AMPK/Akt/Nrf2 pathway in hypothalamic paraventricular nucleus (PVN). Methods: Dahl salt-sensitive (Dahl S) rats were used as animal model for the present study. Rats were randomly divided into four groups based on their dietary regimen (0.3% normal salt diet and 8% high salt diet) and treatment methods (infusion of vehicle or capsaicin in the PVN). Capsaicin was chronically administered in the PVN throughout the animal experiment phase of the study that lasted 6 weeks. Results: Our results demonstrated that PVN pretreatment with capsaicin can slow down raise of the blood pressure elevation and heart rate (HR) of Dahl S hypertensive rats given high salt diet. Interestingly, the cardiac hypertrophy was significantly improved. Furthermore, PVN pretreatment with capsaicin induced decrease in the expression of mRNA expression of NADPH oxidase-2 (NOX2), inducible nitric oxide synthase (iNOS), NOX4, p-IKKß and proinflammatory cytokines and increase in number of positive cell level for Nrf2 and HO-1 in the PVN of Dahl S hypertensive rats. Additionally, the protein expressions of phosphatidylinositol 3-kinase (p-PI3K) and phosphorylated protein kinase-B (p-AKT) were decreased, phosphorylated adenosine monophosphate-activated protein kinase (p-AMPK) were increased after the PVN pretreatment with capsaicin. Conclusion: Capsaicin pretreatment attenuates salt-sensitive hypertension by alleviating AMPK/Akt/iNOS pathway in the PVN.

TT-type resonator-based differential photoacoustic spectroscopy for trace gas detection.

A novel TT-type resonator was proposed for the first time, to our knowledge, to realize differential photoacoustic (PA) detection for trace gas measurement. The special design of the TT-type resonator allows us to install the microphone at the resonant center of the acoustic field to maximize the use of the absorption-induced PA signal. To meet the requirement of low gas consumption and easy integration, the TT-type resonator-based PA cell was fabricated as a fiber-coupled module with an inner volume of only 1.1 ml. For validation, the TT-type PA cell was integrated to a photoacoustic spectroscopy (PAS) system for acetylene detection. As a result, a linearity of 0.99999 was achieved in a concentration range from 0 to 5000 ppm with a noise equivalent sensitivity of 101 ppb. The proposed TT-type resonator contributes a new style of PA cell structure to the field of PAS gas detection, combining the advantages of easy integration, low gas consumption, differential detection, and photoacoustic enhancement together.

Central administration of AICAR attenuates hypertension via AMPK/Nrf2 pathway in the hypothalamic paraventricular nucleus of hypertensive rats.

BACKGROUND: Oxidative stress and inflammatory cytokines in the hypothalamus paraventricular nucleus (PVN) have been implicated in sympathetic nerve activity and the development of hypertension, but the specific mechanisms underlying their production in the PVN remains to be elucidated. Previous studies have demonstrated that activation of nuclear transcription related factor-2 (Nrf2) in the PVN reduced the production of reactive oxygen species (ROS) and inflammatory mediators. Moreover, AMP-activated protein kinase (AMPK), has been observed to decrease ROS and inflammatory cytokine production when activated in the periphery. 5-amino-1-ß-D-ribofuranosyl-imidazole-4-carboxamide (AICAR) is an AMPK agonist. However, little research has been conducted on the role of AMPK in the PVN during hypertension. Therefore, we hypothesized that AICAR in the PVN is involved in regulating AMPK/Nrf2 pathway, affecting ROS and inflammatory cytokine expression, influencing sympathetic nerve activity. METHODS: Adult male Sprague-Dawley rats were utilized to induce two-kidney, one-clip (2K1C) hypertension via constriction of the right renal artery. Bilateral PVN was microinjected with either artificial cerebrospinal fluid or AICAR once a day for 4 weeks. RESULTS: Compared to the SHAM group, the PVN of 2K1C hypertensive rats decreased p-AMPK and p-Nrf2 expression, increased Fra-Like, NAD(P)H oxidase (NOX)2, NOX4, tumor necrosis factor-α and interleukin (IL)-1ß expression, elevated ROS levels, decreased superoxide dismutase 1 and IL-10 expression, and elevated plasma norepinephrine levels. Bilateral PVN microinjection of AICAR significantly ameliorated these changes. CONCLUSION: These findings suggest that repeated injection of AICAR in the PVN suppresses ROS and inflammatory cytokine production through the AMPK/Nrf2 pathway, reducing sympathetic nerve activity and improving hypertension.

Cross-cultural adaptation and validation of the positive and negative social exchange scale in older adults with disabilities in China.

PURPOSE: This study translated the Positive and Negative Social Exchange (PANSE) scale into Chinese, examined its psychometric characteristics, and explored its feasibility for use among older adults with disabilities from China. MATERIALS AND METHODS: A two-stage study procedure was employed. In the first stage, the English version of the PANSE scale was translated and cross-culturally adapted. In the second stage, the reliability and validity of the scale were assessed based on item-total correlation, internal consistency, test-retest reliability, content validity, structural validity, concurrent criterion validity, and known group validity. RESULTS: A total of 357 older adults with disabilities participated in the survey. The Chinese version of the PANSE scale consisted of two parts, the Positive Social Exchange Scale and the Negative Social Exchange Scale. Exploratory factor analysis extracted six communal factors. The cumulative contribution of the two parts of the scale was 69.90% and 77.88%, respectively. The item-total correlation was 0.353 to 0.802, the internal consistency of the PANSE was 0.653 to 0.886. The PANSE demonstrated good content validity and it was correlated with the SSRS scale. CONCLUSION: The Chinese version of the PANSE is a valid and reliable instrument for assessing social exchange in Chinese older adults with disabilities.Implication for rehabilitationDespite the growing number of older adults with disabilities being a concern in China, the lack of tools to measure the type of social support limits research related to the health status of these people.This study cross-culturally adapted, translated into Chinese and validated the Positive and Negative Social Exchange (PANSE) scale as the measurement tool to be used in the cultural context of China.The two subscales of PANSE were validated in the Chinese population of older adults with disabilities.The PANSE scale measures social exchange among older adults with disabilities in China, which can guide the development of interventions to address issues in the social exchange of these people.

The Neutralizing Monoclonal Antibodies against SFTS Group Bandaviruses Suggest New Targets of Specific or Broad-Spectrum Antivirals.

Severe fever with thrombocytopenia syndrome virus (SFTSV), Heartland virus (HRTV) and Guertu virus (GTV) belong to the severe fever with thrombocytopenia syndrome/Heartland group of genus Bandavirus in the family Phenuiviridae of order Bunyavirales. Severe fever with thrombocytopenia syndrome virus and HRTV, identified from ticks from Asia and America, respectively, are important pathogens causing severe febrile diseases in humans. Guertu virus, closely related to these two viruses, is a potential pathogen, but no confirmed infection has been identified. So far, human-derived neutralizing monoclonal antibodies (mAbs) against SFTSV have been identified as having a great potential to be developed as antivirals; however, there is still a lack of neutralizing mAbs to GTV and HRTV. In this study, five neutralizing the mAbs against GTV and HRTV were obtained by hybridoma screening technology, four of which (14B4, 14D8, and 20D4 derived from GTV, and 27C8 derived from HRTV) showed cross reactivity and neutralization to all three viruses, and one derived from HRTV (10D6) neutralized HRTV specifically. The possible mechanisms of mAbs cross neutralization among the three viruses are discussed by analyzing their glycoprotein (GP) sequences and structures. Generating these neutralizing mAbs provides important antiviral candidates against GTV, HRTV, and SFTSV despite their differential activities, and their protective effect could be further evaluated in virus-infected mice. Their differential neutralizing efficiency and specificity further suggested that the three viruses share common mechanisms on the basis of GP functioning, and that HRTV poses a unique mechanism that differs from the other viruses. These findings shed light on developing broad-spectrum antiviral strategies against bandaviruses and promoting an understanding of the bandavirus infection process.

Simultaneous detection of greenhouse gases CH4 and CO2 based on a dual differential photoacoustic spectroscopy system.

In addition to the atmospheric measurement, detection of dissolved carbon oxides and hydrocarbons in a water region is also an important aspect of greenhouse gas monitoring, such as CH4 and CO2. The first step of measuring dissolved gases is the separation process of water and gases. However, slow degassing efficiency is a big challenge which requires the gas detection technology itself with low gas consumption. Photoacoustic spectroscopy (PAS) is a good choice with advantages of high sensitivity, low gas consumption, and zero background, which has been rapidly developed in recent years and is expected to be applied in the field of dissolved gas detection. In this study, a miniaturized differential photoacoustic cell with a volume of 7.9 mL is designed for CH4 and CO2 detection, and a dual differential method with four microphones is proposed to enhance the photoacoustic signal. What we believe to be a new method increases photoacoustic signal by 4 times and improves the signal to noise ratio (SNR) over 10 times compared with the conventional single-microphone mode. Two distributed feedback (DFB) lasers at 1651 nm and 2004nm are employed to construct the PAS system for CH4 and CO2 detection respectively. Wavelength modulation spectroscopy (WMS) and 2nd harmonic demodulation techniques are applied to further improve the SNR. As a result, sensitivity of 0.44 ppm and 7.39 ppm for CH4 and CO2 are achieved respectively with an integration time of 10 s. Allan deviation analysis indicates that the sensitivity can be further improved to 42 ppb (NNEA=4.7×10-10cm-1WHz-1/2) for CH4 and 0.86 ppm (NNEA=5.3×10-10cm-1WHz-1/2) for CO2 when the integration time is extended to 1000 s.

Enhancing Prognosis, Quality of Life, and Psychological Well-being in Cerebral Stroke Patients through Meticulous Risk Management: A Comprehensive Study.

Background: Cerebral stroke (CS) remains a leading cause of mortality worldwide. In addition to effective treatment, nursing intervention plays a pivotal role in the rehabilitation of CS patients. Objective: This study aims to assess the impact of meticulous care integrated with risk management on rehabilitating cerebral stroke patients. The objective is to provide valuable clinical insights for the management of CS patients. Methods: A comparative observational study was conducted, including a total of 180 CS patients admitted between February 2020 and February 2022 were selected for this study. Among them, 98 patients received meticulous care combined with risk management (research group), while 82 patients underwent routine nursing intervention (control group). We analyzed the changes in the Fugl-Meyer Motor Assessment scale, National Institute of Health Stroke Scale, Activities of Daily Living scale, and Barthel Index before and after the care interventions. Additionally, we documented nursing risk events during treatment, assessed nursing quality scores, and conducted a quality-of-life survey after a one-year follow-up. Results: The research group exhibited significantly higher post-care scores in the Fugl-Meyer Motor Assessment, Activities of Daily Living, and Barthel Index, along with lower National Institute of Health Stroke Scale scores, compared to the control group (P < .05). Furthermore, the research group experienced a lower incidence of nursing risk events and demonstrated higher nursing quality (P < .05). During the prognostic follow-up, the research group displayed a superior quality of life compared to the control group (P < .05). Conclusions: Meticulous care integrated with risk management enhances the recovery of CS patients and is strongly recommended for clinical implementation.

Capsaicin improves hypertension and cardiac hypertrophy via SIRT1/NF-κB/MAPKs pathway in the hypothalamic paraventricular nucleus.

BACKGROUND: Hypertension has seriously affected a large part of the adult and elderly population. The complications caused by hypertension are important risk factors for cardiovascular disease accidents. Capsaicin, a pungent component of chili pepper has been revealed to improve hypertension. However, its potential mechanism in improving hypertension remains to be explored. PURPOSE: In the present study, we aimed to investigate whether capsaicin could attenuate the SIRT1/NF-κB/MAPKs pathway in the paraventricular nucleus of hypothalamus (PVN). METHODS: We used spontaneous hypertensive rats (SHRs) as animal model rats. Micro osmotic pump was used to give capsaicin through PVN for 28 days, starting from age12-week-old. RESULTS: The results showed that capsaicin significantly reduced blood pressure from the 16th day of infusion onward. At the end of the experimental period, we measured cardiac hypertrophy index and the heart rate (HR), and the results showed that the cardiac hypertrophy and heart rate of rats was significantly improved upon capsaicin chronic infusion. Norepinephrine (NE) and epinephrine (EPI) in plasma of SHRs treated with capsaicin were also decreased. Additionally, capsaicin increased the protein expression and number of positive cells of SIRT1 and the 67-kDa isoform of glutamate decarboxylase (GAD67), decreased the production of reactive oxygen species (ROS), number of positive cells of NOX2, those of Angiotensin Converting Enzyme (ACE) and p-IKKß, tyrosine hydroxylase (TH), the gene expression levels of NOX4 and pro-inflammatory cytokines. Capsaicin also decreased the relative protein expressions of protein in MAPKs pathway. CONCLUSION: Current data indicated that capsaicin within the PVN improves hypertension and cardiac hypertrophy via SIRT1/NF-κB/MAPKs pathway in the PVN of SHRs, supporting its potential as candidate drug for preventing and improving hypertension.

Developing and characterizing monoclonal antibodies of Guertu bandavirus nucleoprotein for developing methods of Guertu bandavirus and severe fever with thrombocytopenia syndrome virus detection.

Belonging to genus Bandavirus in Phenuiviridae family, Guertu bandavirus (GTV) is a potential pathogen closely related to severe fever with thrombocytopenia syndrome virus (SFTSV) and heartland virus (HRTV) associated with human diseases. Although the medical significance of GTV is not clear, there was serological evidence suggesting past infection with this virus has occurred, indicating its potential threat to human health. So, it is important to prepare for detection of GTV infection so as to control virus transmission and promote disease diagnosis and treatment. This study is aimed at obtaining monoclonal antibodies (mAbs) against GTV nucleoprotein (NP) and evaluating their activities in recognizing viral antigens from genetic-related bandaviruses, SFTSV and HRTV. Eight mAbs were obtained and four of them (22G1, 25C2, 25E2, and 26F8) recognize linear epitopes of GTV NP. The four mAbs showed cross-reactivity to SFTSV but were unable to react with HRTV. Two fine epitopes were identified by the four mAbs, ENP1 (194YNSFRDPLHAAV205) and ENP2 (226GPDGLP231), which are highly conserved in the NPs of GTV and SFTSV but are distinct in HRTV NP. The features of epitopes, including their hydrophilicity, antibody accessibility, flexibility, antigenicity, and spatial locations, were predicted and analyzed, and their potential functional impacts on virus infection and replication and their use for virus detection were discussed. Our results promote the understanding of the molecular basis of GTV and SFTSV NP in inducing antibody responses. The NP-specific mAbs generated in this study are promising fundamental materials for developing viral antigen detection methods for GTV and SFTSV.

Luteolin Attenuates Hypertension via Inhibiting NF-κB-Mediated Inflammation and PI3K/Akt Signaling Pathway in the Hypothalamic Paraventricular Nucleus.

BACKGROUND: Luteolin is widely distributed among a number of vegetal species worldwide. The pharmacological effects of luteolin are diverse and amongst antioxidant, free radical scavenging, and anti-inflammatory activities. Preliminary study showed that luteolin can ameliorate hypertension. However, the precise mechanism needs further investigation. There is no evidence that luteolin affects the paraventricular nucleus of the hypothalamus (PVN), a brain nucleus associated with a critical neural regulator of blood pressure. Our main aim was to explore the effect of luteolin on the PI3K/Akt/NF-κB signaling pathway within the PVN of hypertensive rats. METHODS: spontaneously hypertensive rats (SHRs) and corresponding normotensive control rats, the Wistar Kyoto (WKY) rats were divided into four groups and subsequently treated for 4 weeks with bilateral PVN injections of either luteolin (20 µg/0.11 µL, volume: 0.11 µL/h) or vehicle (artificial cerebrospinal fluid). RESULTS: luteolin infusion to the PVN significantly decreased some hemodynamic parameters including the mean arterial pressure (MAP), heart rate (HR), circulating plasma norepinephrine (NE) and epinephrine (EPI). Additionally, there was a decrease in the expressions of the phosphatidylinositol 3-kinase (p-PI3K) and phosphorylated protein kinase-B (p-AKT), levels of reactive oxygen species (ROS), NAD(P)H oxidase subunit (NOX2, NOX4) in the PVN of SHRs. Meanwhile, the expression of inflammatory cytokines and the activity of nuclear factor κB (NF-κB) p65 in the PVN of SHRs were lowered. Furthermore, immunofluorescence results showed that injection of luteolin in the PVN reduced the expression of tyrosine hydroxylase (TH), and increased that of superoxide dismutase (SOD1) and the 67-kDa isoform of glutamate decarboxylase (GAD67) in the PVN of SHRs. CONCLUSION: Our novel findings revealed that luteolin lowered hypertension via inhibiting NF-κB-mediated inflammation and PI3K/Akt signaling pathway in the PVN.

The effectiveness of self-management programme based on multilevel social resources utilization in diabetes mellitus patients: A randomized controlled study.

AIMS: This study aimed to test the effects of a novel diabetes self-management education (DSME) programme focused on multilevel social resources utilization on improving self-management behaviour, social resources utilization and haemoglobin Alc (HbA1c ) in patients with type 2 diabetes mellitus (T2DM). METHODS: A randomized controlled design was used. A total of 118 participants with T2DM from two communities were recruited through randomized sampling, and randomly assigned to the novel DSME group or the traditional DSME group. DSME focusing on multilevel social resources utilization was implemented in the novel DSME group. Data were collected at baseline (T0 ), at the end of the intervention (T1 ) and 3 months after the end of intervention (T2 ) from 3 March to 16 November 2014. RESULTS: Comparing these two groups, the participants in the novel DSME group reported significantly better improvement in self-management behaviour and social resources utilization at T1 and T2 (all p < 0.01). A significant difference was found in the mean improvement of HbA1c level between the two groups at T2 (p < 0.05). CONCLUSIONS: The novel DSME programme focused on multilevel social resources utilization can effectively enhance T2DM patients' self-management behaviour and social resource utilization and lower HbA1c levels. More importantly, the effects could last longer.

Post-discharge care needs of the older people with hospital-associated disability: A longitudinal study.

AIMS: To investigate the change and associated factors of care needs within 6 months post-discharge in older people with hospital-associated disability, and the relationship between time-varying care needs and physical function. BACKGROUND: Older people with hospital-associated disability will have various care needs post-discharge. Understanding their care needs will help to improve their health. However, studies on this population are still limited. DESIGN: A longitudinal study. METHODS: The older people who met the inclusion and exclusion criteria were selected in 2 tertiary hospitals in Zhejiang Province, China. The questionnaire survey method was used to collect data about socio-demographic characteristics, physical function and care needs. The data of 375 older people who completed follow-up were analysed using logistic regression analysis, generalised estimating equations and generalised additive mixed model. We followed STROBE checklist for reporting the study. RESULTS: The care needs of the older people with hospital-associated disability declined unevenly, it decreased rapidly in the first three months, and then flattening out. The percentage of people with care needs in each dimension decreased over time, but daily care and rehabilitation needs were consistently more important. Socio-demographic factors and physical function had different effects on need at different time points, the physical function was the main factor among them. There were non-linear relationships between the physical function and different care needs with different inflection points. CONCLUSION: This research revealed change patterns of the care needs of older people with hospital-associated disability post-discharge and the non-linear relationship between physical function and care needs. These findings may help healthcare professionals and caregivers to provide accurate care. RELEVANCE TO CLINICAL PRACTICE: The findings can be used to identify effective approaches to address the care needs of older people with hospital-associated disability based on the time of discharge, in conjunction with age, education, and especially physical function, which will promote the justify allocation of nursing resources. What does this paper contribute to the wider global clinical community?

Resveratrol in the Hypothalamic Paraventricular Nucleus Attenuates Hypertension by Regulation of ROS and Neurotransmitters.

BACKGROUND: The hypothalamic paraventricular nucleus (PVN) is an important nucleus in the brain that plays a key role in regulating sympathetic nerve activity (SNA) and blood pressure. Silent mating-type information regulation 2 homolog-1 (sirtuin1, SIRT1) not only protects cardiovascular function but also reduces inflammation and oxidative stress in the periphery. However, its role in the central regulation of hypertension remains unknown. It is hypothesized that SIRT1 activation by resveratrol may reduce SNA and lower blood pressure through the regulation of intracellular reactive oxygen species (ROS) and neurotransmitters in the PVN. METHODS: The two-kidney one-clip (2K1C) method was used to induce renovascular hypertension in male Sprague-Dawley rats. Then, bilaterally injections of vehicle (artificial cerebrospinal fluid, aCSF, 0.4 µL) or resveratrol (a SIRT1 agonist, 160 µmol/L, 0.4 µL) into rat PVN were performed for four weeks. RESULTS: PVN SIRT1 expression was lower in the hypertension group than the sham surgery (SHAM) group. Activated SIRT1 within the PVN lowered systolic blood pressure and plasma norepinephrine (NE) levels. It was found that PVN of 2K1C animals injected with resveratrol exhibited increased expression of SIRT1, copper-zinc superoxide dismutase (SOD1), and glutamic acid decarboxylase (GAD67), as well as decreased activity of nuclear factor-kappa B (NF-κB) p65 and NAD(P)H oxidase (NOX), particularly NOX4. Treatment with resveratrol also decreased expression of ROS and tyrosine hydroxylase (TH). CONCLUSION: Resveratrol within the PVN attenuates hypertension via the SIRT1/NF-κB pathway to decrease ROS and restore the balance of excitatory and inhibitory neurotransmitters.

Exercise Training Attenuates Hypertension via Suppressing ROS/MAPK/NF-κB/AT-1R Pathway in the Hypothalamic Paraventricular Nucleus.

BACKGROUND: Aerobic exercise training (ExT) is beneficial for hypertension, however, its central mechanisms in improving hypertension remain unclear. Since the importance of the up-regulation of angiotensin II type 1 receptor (AT-1R) in the paraventricular nucleus (PVN) of the hypothalamic in sympathoexcitation and hypertension has been shown, we testified the hypothesis that aerobic ExT decreases blood pressure in hypertensive rats by down-regulating the AT-1R through reactive oxygen species (ROS)/mitogen-activated protein kinase (MAPK)/nuclear factors κB (NF-κB) pathway within the PVN. METHODS: Forty-eight male Sprague-Dawley (SD) rats were assigned to the following groups: sham operation (SHAM) + kept sedentary (Sed), SHAM + exercise training (ExT), two kidney-one clamp (2K1C) + Sed, and 2K1C + ExT groups. RESULTS: The 2K1C + Sed hypertensive rats showed higher systolic blood pressure (SBP), upregulated ROS, phosphorylated (p-) p44/42 MAPK, p-p38 MAPK, NF-κB p65 activity, and AT-1R expression in the PVN, and increased circulating norepinephrine (NE) than those of SHAM rats. After eight weeks of aerobic ExT, the 2K1C + ExT hypertensive rats showed attenuated NE and SBP levels, suppressed NF-κB p65 activity, and reduced expression of ROS, p-p44/42 MAPK, p-p38 MAPK, and AT-1R in the PVN, relatively to the 2K1C + Sed group. CONCLUSIONS: These data are suggestive of beneficial effects of aerobic ExT in decreasing SBP in hypertensive rats, via down-regulating the ROS/MAPK/NF-κB pathway that targets AT-1R in the PVN, and eventually ameliorating 2K1C-induced hypertension.

Engineering highly-aligned three-dimensional (3D) cardiac constructs for enhanced myocardial infarction repair.

Native myocardium exhibits well-organized cellular orientations and highly vascularized architectures, which is important for tissue survival and synchronic contraction activities. Mimicking such structural organizations to engineer functional cardiac constructs is a promising approach to treat myocardial infarctionin vivo. Here we propose a novel strategy to engineer highly-aligned three-dimensional (3D) cardiac constructs by co-culturing cardiomyocytes and rat aortic endothelial cells (RAECs) along with native extracellular matrix-derived fibrin within electrohydrodynamic-printed microfibrous architectures. Cell-laden fibrin with a relatively rapid gelation rate enables uniform cellular distribution in 3D and can re-organize to form multidirectionally aligned 3D cardiac bands with similar orientations to the printed microfibers. The resultant 3D cardiac constructs show enhanced cardiomyocyte-specific protein expression, synchronous contraction and low excitation threshold. The addition of RAECs significantly increases the width of cardiac bands and enhances their beating frequency. The engineered 3D cardiac constructs with layer-specific orientations were found to effectively reduce infracted area, enhance neovascularization and eventually realize functional repair of infarcted myocardiumin vivo. This exploration provides a promising strategy to engineer 3D cardiac constructs with tissue-specific cellular orientations for the functional repair of infarcted myocardium.

Genistein Alleviates Oxidative Stress and Inflammation in the Hypothalamic Paraventricular Nucleus by Activating the Sirt1/Nrf2 Pathway in High Salt-Induced Hypertension.

Hypertension caused by a high-salt (HS) diet is one of the major causes of cardiovascular diseases. Underlining pathology includes oxidative stress and inflammation in the hypothalamic paraventricular nucleus (PVN). This study investigates genistein's (Gen) role in HS-induced hypertension and the underlying molecular mechanism. We placed male Wistar rats on HS (8% NaCl) or normal salt diet (0.3% NaCl). Then, we injected bilateral PVN in rats with Gen, vehicle, or nicotinamide (NAM) for 4 weeks. Tail cuff was used weekly to assess the systolic pressure, diastolic pressure, and mean arterial pressure (MAP). Cardiac hypertrophy was analyzed by heart weight/body weight ratio and wheat germ agglutinin staining. ELISA kits, Western blot, or dihydroethidium staining determined the levels of inflammatory cytokines and oxidative stress markers. Western blot measured protein levels of Sirt1, Ac-FOXO1, Nrf2, NQO-1, HO-1, and gp91phox. Our result showed that PVN infusion of Gen significantly reduced the increase of systolic pressure, diastolic pressure, and MAP induced by an HS diet. Additionally, there was a decrease in cardiac hypertrophy and the levels of inflammatory cytokines in PVN and plasma. Meanwhile, PVN infusion of Gen notably inhibited the levels of oxidized glutathione and superoxide dismutase and improved the glutathione level and total antioxidant capacities and superoxide dismutase activities. It also decreased the level of reactive oxygen species and gp91phox expression in PVN. Furthermore, Gen infusion markedly increases the Sirt1, Nrf2, HO-1, and NQO-1 levels and decreases the Ac-FOXO1 level. However, PVN infusion of NAM could significantly block these changes induced by Gen in HS diet rats. Our results demonstrated that PVN infusion of Gen could inhibit the progression of hypertension induced by an HS diet by activating the Sirt1/Nrf2 pathway.

Blockade of Microglial Activation in Hypothalamic Paraventricular Nucleus Improves High Salt-Induced Hypertension.

BACKGROUND: It has been shown that activated microglia in brain releasing proinflammatory cytokines (PICs) contribute to the progression of cardiovascular diseases. In this study, we tested the hypothesis that microglial activation in hypothalamic paraventricular nucleus (PVN), induced by high-salt diet, increases the oxidative stress via releasing PICs and promotes sympathoexcitation and development of hypertension. METHODS: High-salt diet was given to male Dahl salt-sensitive rats to induce hypertension. Those rats were bilaterally implanted with cannula for PVN infusion of minocycline, a selective microglial activation blocker, or artificial cerebrospinal fluid for 4 weeks. RESULTS: High-salt diet elevated mean arterial pressure of Dahl salt-sensitive rats. Meanwhile, elevations of renal sympathetic nerve activity and central prostaglandin E2, as well as increase of plasma norepinephrine, were observed in those hypertensive rats. Tumor necrosis factor-α, interleukin-1ß (IL-1ß), and IL-6 increased in the PVN of those rats, associated with a significant activation of microglia and prominent disruption of redox balance, which was demonstrated by higher superoxide and NAD(P)H oxidase 2 (NOX-2) and NAD(P)H oxidase 4 (NOX-4), and lower Cu/Zn superoxide dismutase in PVN. PVN infusion of minocycline attenuated all hypertension-related alterations described above. CONCLUSION: This study indicates that high salt leads to microglial activation within PVN of hypertensive rats, and those activated PVN microglia release PICs and trigger the production of reactive oxygen species, which contributes to sympathoexcitation and development of hypertension. Blockade of PVN microglial activation inhibits inflammation and oxidative stress, therefore attenuating the development of hypertension induced by high-salt diet.

Na+/K+-ATPase Alpha 2 Isoform Elicits Rac1-Dependent Oxidative Stress and TLR4-Induced Inflammation in the Hypothalamic Paraventricular Nucleus in High Salt-Induced Hypertension.

BACKGROUND: Numerous studies have indicated that a high salt diet inhibits brain Na+/K+-ATPase (NKA) activity, and affects oxidative stress and inflammation in the paraventricular nucleus (PVN). Furthermore, Na+/K+-ATPase alpha 2-isoform (NKA α2) may be a target in the brain, taking part in the development of salt-dependent hypertension. Therefore, we hypothesized that NKA α2 regulates oxidative stress and inflammation in the PVN in the context of salt-induced hypertension. METHODS: Part I: We assessed NKA subunits (NKA α1, NKA α2, and NKA α3), Na+/K+-ATPase activity, oxidative stress, and inflammation in a high salt group (8% NaCl) and normal salt group (0.3% NaCl). Part II: NKA α2 short hairpin RNA (shRNA) was bilaterally microinjected into the PVN of salt-induced hypertensive rats to knockdown NKA α2, and we explored whether NKA α2 regulates downstream signaling pathways related to protein kinase C γ (PKC γ)-dependent oxidative stress and toll-like receptor 4 (TLR4)-induced inflammation in the PVN to promote the development of hypertension. RESULTS: High salt diet increased NKA α1 and NKA α2 protein expression in the PVN but had no effect on NKA α3 compared to the normal salt diet. Na+/K+-ATPase activity and ADP/ATP ratio was lower, but NAD(P)H activity and NF-κB activity in the PVN were higher after a high salt diet. Bilateral PVN microinjection of NKA α2 shRNA not only improved Na+/K+-ATPase activity and ADP/ATP ratio but also suppressed PKC γ-dependent oxidative stress and TLR4-dependent inflammation in the PVN, thus decreasing sympathetic activity in rats with salt-induced hypertension. CONCLUSIONS: NKA α2 in the PVN elicits PKC γ/Rac1/NAD (P)H-dependent oxidative stress and TLR4/MyD88/NF-κB-induced inflammation in the PVN, thus increasing MAP and sympathetic activity during the development of salt-induced hypertension.