Targeted delivery of MerTK protein via cell membrane engineered nanoparticle enhances efferocytosis and attenuates atherosclerosis in diabetic ApoE-/- Mice.

BACKGROUND: Clearance of apoptotic cells by efferocytosis is crucial for prevention of atherosclerosis progress, and impaired efferocytosis contributes to the aggravated atherosclerosis. RESULTS: In this study, we found that diabetic ApoE-/- mice showed aggravated atherosclerosis as hyperglycemia damaged the efferocytosis capacity at least partially due to decreased expression of Mer tyrosine kinase (MerTK) on macrophages. To locally restore MerTK in the macrophages in the plaque, hybrid membrane nanovesicles (HMNVs) were thus developed. Briefly, cell membrane from MerTK overexpressing RAW264.7 cell and transferrin receptor (TfR) overexpressing HEK293T cell were mixed with DOPE polymers to produce nanovesicles designated as HMNVs. HMNVs could fuse with the recipient cell membrane and thus increased MerTK in diabetic macrophages, which in turn restored the efferocytosis capacity. Upon intravenous administration into diabetic ApoE-/- mice, superparamagnetic iron oxide nanoparticles (SMN) decorated HMNVs accumulated at the aorta site significantly under magnetic navigation, where the recipient macrophages cleared the apoptotic cells efficiently and thus decreased the inflammation. CONCLUSIONS:  Our study indicates that MerTK decrease in macrophages contributes to the aggravated atherosclerosis in diabetic ApoE-/- mice and regional restoration of MerTK in macrophages of the plaque via HMNVs could be a promising therapeutic approach.

Supplementation of Clostridium butyricum Alleviates Vascular Inflammation in Diabetic Mice.

Background: Gut microbiota is closely related to the occurrence and development of diabetes and affects the prognosis of diabetic complications, and the underlying mechanisms are only partially understood. We aimed to explore the possible link between the gut microbiota and vascular inflammation of diabetic mice. Methods: The db/db diabetic and wild-type (WT) mice were used in this study. We profiled gut microbiota and examined the and vascular function in both db/db group and WT group. Gut microbiota was analyzed by 16s rRNA sequencing. Vascular function was examined by ultrasonographic hemodynamics and histological staining. Clostridium butyricum (CB) was orally administered to diabetic mice by intragastric gavage every 2 days for 2 consecutive months. Reactive oxygen species (ROS) and expression of nuclear factor erythroid-derived 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) were detected by fluorescence microscopy. The mRNA expression of inflammatory cytokines was tested by quantitative polymerase chain reaction. Results: Compared with WT mice, CB abundance was significantly decreased in the gut of db/db mice, together with compromised vascular function and activated inflammation in the arterial tissue. Meanwhile, ROS in the vascular tissue of db/db mice was also significantly increased. Oral administration of CB restored the protective microbiota, and protected the vascular function in the db/db mice via activating the Nrf2/HO-1 pathway. Conclusion: This study identified the potential link between decreased CB abundance in gut microbiota and vascular inflammation in diabetes. Therapeutic delivery of CB by gut transplantation alleviates the vascular lesions of diabetes mellitus by activating the Nrf2/HO-1 pathway.

Ultra-processed food consumption and risk of cardiovascular events: a systematic review and dose-response meta-analysis.

Background: Ultra-processed food (UPF) consumption continues to increase worldwide. However, evidences from meta-analyses are limited regarding the effects on cardiovascular events (CVEs). Methods: A meta-analysis was performed to assess the dose-response relationship of UPF consumption and CVEs risk (including the morbidity and mortality of cardiovascular causes, and myocardial infarction, stroke, transient ischemic attack, coronary intervention). Databases (PubMed, EMBASE, Cochrane Library, and Web of Science) were searched for observational studies published in English language up to October 24, 2023. Generalized least squares regression and restricted cubic splines were used to estimate the linear/nonlinear relationship. PROSPERO CRD 42023391122. Findings: Twenty studies with 1,101,073 participants and 58,201 CVEs cases with a median follow-up of 12.2 years were included. A positive linear relationship between UPF intake and CVEs risk was identified. In addition, positive correlation between coronary heart disease and UPF consumption in terms of daily serving and daily energy proportion. No significant association of UPF consumption with the risk of cerebrovascular disease was observed. Briefly, 10% increase of UPF by daily weight proportion was associated with a 1.9% increase of CVEs risk (RR = 1.019; 95% CI, 1.007-1.031; P = 0.002), an additional daily serving corresponding to 2.2% CVEs risk increase (RR = 1.022; 95% CI, 1.013-1.031; P < 0.001), and 10% increase by daily energy proportion corresponding to 1.6% CVEs risk increase (RR = 1.016; 95% CI, 1.002-1.030; P = 0.022). Interpretation: UPF consumption were associated with a higher risk of CVEs in the positive linear relationship. Our findings highlight the importance of minimizing UPF consumption for cardiovascular health and might be help to pursue public health policies in control of UPF consumption. Funding: This work was supported by the Key Research and Development Program of Shaanxi Province (2023-ZDLSF-22), the Innovative Talent Support Program of Shaanxi Province (2022KJXX-106), and the Key Research and Development Program of Shaanxi Province (2023-YBSF-424).

Ultrasound Imaging of Tumor Vascular CD93 with MMRN2 Modified Microbubbles for Immune Microenvironment Prediction.

Vascular microenvironment is found to be closely related to immunotherapy efficacy. Identification and ultrasound imaging of the unique vascular characteristics, able to predict immune microenvironment, is important for immunotherapy decision-making. Herein, it is proved that high CD93 expression in the tumor vessels is closely related to the poor immune response of prostate cancer. For ultrasound molecular imaging of CD93, CD93-targeted microbubbles (MBs) consist a gaseous core and the MMRN2 (Multimerin-2) containing cell membrane (CM) /lipid hybrid membrane is then synthesized. In vitro and in vivo assays demonstrate that these MBs can recognize CD93 efficiently and then accumulate within tumor regions highly expressing CD93. Contrast-enhanced ultrasound (CEUS) imaging with CD93-targeted MBs demonstrates that targeted ultrasound intensity is negatively related to inflammatory tumor immune microenvironment (TIME) and cytotoxic T cell infiltration. Together, endothelial expression of CD93 in tumor is a unique predictor of immunosuppressive microenvironment and CD93-targeted MBs have a great potential to evaluate tumor immune status.

Long-term simulated microgravity fosters carotid aging-like changes via Piezo1.

AIMS: Elucidating the impacts of long-term spaceflight on cardiovascular health is urgently needed in face of the rapid development of human space exploration. Recent reports including the NASA Twins Study on vascular deconditioning and aging of astronauts in spaceflight are controversial. The aims of this study were to elucidate whether long-term microgravity promotes vascular aging and the underlying mechanisms. METHODS AND RESULTS: Hindlimb unloading (HU) by tail suspension was used to simulate microgravity in rats and mice. The dynamic changes of carotid stiffness in rats during 8 weeks of HU were determined. Simulated microgravity led to carotid artery aging-like changes as evidenced by increased stiffness, thickness, fibrosis and elevated senescence biomarkers in the HU rats. Specific deletion of the mechanotransducer Piezo1 in vascular smooth muscles significantly blunted these aging-like changes in mice. Mechanistically, mechanical stretch-induced activation of Piezo1 elevated microRNA-582-5p in vascular smooth muscle cells, with resultant enhanced synthetic cell phenotype and increased collagen deposition via PTEN/PI3K/Akt signaling. Importantly, inhibition of miRNA-582-5p alleviated carotid fibrosis and stiffness not only in HU rats but also in aged rats. CONCLUSIONS: Long-term simulated microgravity induces carotid aging-like changes via the mechanotransducer Piezo1-initiated and miRNA-mediated mechanism.

Echocardiographic evaluation of cardiac reserve to detect subtle cardiac dysfunction in mice.

AIMS: Cardiac reserve is a sensitive tool for early detection of cardiac dysfunction. However, cardiac reserve assessment by catecholamine stress echocardiography in mice varied in the doses of ß-adrenergic agonists and the time point for measurements, which may lead to inaccurate readouts. This study aims to establish a standardized protocol for assessing cardiac reserve in mice. MAIN METHODS: C57BL/6J mice under isoflurane anesthesia were intraperitoneally injected with varying doses of isoproterenol (Iso), and subjected to echocardiographic measurements. KEY FINDINGS: Heart rate (HR), ejection fraction (EF), fractional shortening (FS), global longitudinal strain (GLS) and strain rate all reached peak values within 1-3 min after Iso injection at doses higher than 0.2 mg/kg. Compared with 0.1 mg/kg Iso, 0.2 mg/kg Iso resulted in higher HR, EF, FS and GLS, whereas doses higher than 0.2 mg/kg did not yield further increase. Cardiac response of female mice recapitulated main characteristics of those of male mice except that female mice displayed higher maximum HR and were more sensitive to higher doses of Iso. Furthermore, the advantages of present stress protocol over conventional baseline echocardiographic measurements were verified in comparisons of exercised vs. sedentary and aged vs. young mice for cardiac function evaluation. SIGNIFICANCE: We developed a reproducible and sensitive approach to evaluate cardiac reserve by continuously monitoring cardiac function every minute for 3 min after 0.2 mg/kg Iso injection. This approach will enable detection of subtle cardiac dysfunction and accelerate innovative research in cardiac pathophysiology.

Exercise Improves Metabolism and Alleviates Atherosclerosis via Muscle-Derived Extracellular Vesicles.

Regular exercise maintains a healthy metabolic profile, while the underlying mechanisms have not been fully elucidated. Extracellular vesicles serve as an important mediator in intercellular communication. In this study, we aimed to explore whether exercise-induced extracellular vesicles (EVs) of skeletal muscle origins contribute to exercise-related protective effects on metabolism. We found that the twelve weeks of swimming training improved glucose tolerance, reduced visceral lipid accumulation, alleviated liver damage, and inhibited atherosclerosis progression in both obese WT mice and ApoE-/- mice, which could be partially blocked by EV biogenesis repression. Injection of skeletal muscle-derived EVs from exercised C57BL/6J mice (twice a week for 12 weeks) had similar protective effects on both obese WT mice and ApoE-/- mice as exercise itself. Mechanistically, these exe-EVs could be endocytosed by major metabolic organs, especially the liver and adipose tissue. With the protein cargos rich in mitochondrial and fatty acid oxidation-related components, exe-EVs remodeled metabolism towards beneficial cardiovascular outcomes. Our study here has shown that exercise remodels metabolism towards beneficial cardiovascular outcomes at least partially via the skeletal muscle secreted EVs. Therapeutic delivery of exe-EVs or the analogues could be promising for prevention of certain cardiovascular and metabolic diseases.

Ultrasound Responsive Nanovaccine Armed with Engineered Cancer Cell Membrane and RNA to Prevent Foreseeable Metastasis.

Cancer vaccine has been considered as a promising immunotherapy by inducing specific anti-tumor immune response. Rational vaccination at suitable time to efficiently present tumor associated antigen will boost tumor immunity and is badly needed. Here, a poly (lactic-co-glycolic acid) (PLGA)-based cancer vaccine of nanoscale is designed, in which engineered tumor cell membrane proteins, mRNAs, and sonosensitizer chlorin e6 (Ce6) are encapsulated at high efficiency. The nanosized vaccine can be efficiently delivered into antigen presentation cells (APCs) in lymph nodes after subcutaneous injection. In the APCs, the encapsulated cell membrane and RNA from engineered cells, which have disturbed splicing resembling the metastatic cells, provide neoantigens of metastatic cancer in advance. Moreover, the sonosensitizer Ce6 together with ultrasound irradiation promotes mRNA escape from endosome, and augments antigen presentation. Through 4T1 syngeneic mouse model, it has been proved that the proposed nanovaccine is efficient to elicit antitumor immunity and thus prevent cancer metastasis.

Canonical transient receptor potential channel 1 aggravates myocardial ischemia-and-reperfusion injury by upregulating reactive oxygen species.

The canonical transient receptor potential channel (TRPC) proteins form Ca2+-permeable cation channels that are involved in various heart diseases. However, the roles of specific TRPC proteins in myocardial ischemia/reperfusion (I/R) injury remain poorly understood. We observed that TRPC1 and TRPC6 were highly expressed in the area at risk (AAR) in a coronary artery ligation induced I/R model. Trpc1-/- mice exhibited improved cardiac function, lower serum Troponin T and serum creatine kinase level, smaller infarct volume, less fibrotic scars, and fewer apoptotic cells after myocardial-I/R than wild-type or Trpc6-/- mice. Cardiomyocyte-specific knockdown of Trpc1 using adeno-associated virus 9 mitigated myocardial I/R injury. Furthermore, Trpc1 deficiency protected adult mouse ventricular myocytes (AMVMs) and HL-1 cells from death during hypoxia/reoxygenation (H/R) injury. RNA-sequencing-based transcriptome analysis revealed differential expression of genes related to reactive oxygen species (ROS) generation in Trpc1-/- cardiomyocytes. Among these genes, oxoglutarate dehydrogenase-like (Ogdhl) was markedly downregulated. Moreover, Trpc1 deficiency impaired the calcineurin (CaN)/nuclear factor-kappa B (NF-κB) signaling pathway in AMVMs. Suppression of this pathway inhibited Ogdhl upregulation and ROS generation in HL-1 cells under H/R conditions. Chromatin immunoprecipitation assays confirmed NF-κB binding to the Ogdhl promoter. The cardioprotective effect of Trpc1 deficiency was canceled out by overexpression of NF-κB and Ogdhl in cardiomyocytes. In conclusion, our findings reveal that TRPC1 is upregulated in the AAR following myocardial I/R, leading to increased Ca2+ influx into associated cardiomyocytes. Subsequently, this upregulates Ogdhl expression through the CaN/NF-κB signaling pathway, ultimately exacerbating ROS production and aggravating myocardial I/R injury.

AHNAK-modified microbubbles for the intracranial delivery of triptolide: In-vitro and in-vivo investigations.

Autophagic dysfunction related cascade events might induce the accumulation of α-synuclein (αSyn) in Parkinson's disease (PD). Triptolide (T10) has been reported as a potential autophagy inducer but limited by hepatotoxicity, low solubility and rapid metabolism. In this study, a novel AHNAK-targeted microbubbles integrated with T10 (T10-AHNAK-MBs) was developed to alleviate motor deficit in rAAV2/5-wild type and A53T mutant αSyn transfected PD mouse model. AHNAK facilitated the accumulation of microbubbles (MBs) near the cerebral vessel wall. Furthermore, bubble cavitation caused by focused-ultrasound (FUS) exposure could simultaneously induce drug release and blood-brain-barrier opening in the area of interest. The results of western blotting, thioflavin S staining, immunofluorescence, ELISA and behavior test demonstrated that T10-AHNAK-MBs with FUS exposure (T10-AHNAK-MBs-FUS) could significantly delivery more T10 into substantia nigra, promote clearance of various forms of αSyn, reduce tyrosine hydroxylase positive neuron loss, restore dopamine secretion, and eventually alleviate motor deficits, along with largely reduced adverse effects. The analyses of autophagic markers suggested that autophagy lysosome pathway (ALP) might dominate the T10-induced αSyn degeneration, including the oligomers and pre-formed fibrils. Thus, T10-AHNAK-MBs-FUS constitutes a promising strategy against the motor deficits in PD by promoting clearance of pathogenic αSyn aggregates via inducing ALP.

Aerobic exercise training reduces cerebrovascular impedance in older adults: a 1-year randomized controlled trial.

Older adults have higher cerebrovascular impedance than young individuals which may contribute to chronic brain hypoperfusion. Besides, middle-aged athletes exhibit lower cerebrovascular impedance than their sedentary peers. We examined whether aerobic exercise training (AET) reduces cerebrovascular impedance in sedentary older adults. We conducted a proof-of-concept trial that randomized 73 older adults to 1 yr of AET (n = 36) or stretching and toning (SAT, n = 37) interventions. Cerebrovascular impedance was estimated from simultaneous recordings of carotid artery pressure (CAP) via applanation tonometry and cerebral blood flow velocity (CBFV) in the middle cerebral artery via transcranial Doppler using transfer function analysis. Fifty-six participants completed 1-yr interventions, and 41 of those completed cerebrovascular impedance measurements. AET group showed a significant increase in V̇o2peak after the intervention [estimated marginal mean (95% confidence interval); from 22.8 (21.6 to 24.1) to 24.9 (23.6 to 26.2) mL·kg-1·cm-1, P < 0.001], but not SAT [from 21.7 (20.5 to 22.9) to 22.3 (21.1 to 23.7) mL·kg-1·cm-1, P = 0.114]. Coherence between changes in CBFV and CAP was >0.90 in the frequency range of 0.78-3.12 Hz. The averaged cerebrovascular impedance modulus (Z) in this frequency range decreased after 1-yr AET [from 1.05 (0.96 to 1.14) to 0.95 (0.92 to 1.06) mmHg·s·cm-1, P = 0.023], but not SAT [from 0.96 (0.87 to 1.04) to 1.01 (0.92 to 1.10) mmHg·s·cm-1, P = 0.138]. Reductions in Z were correlated positively with reductions in carotid pulse pressure (r = 0.628, P = 0.004) and inversely with mean CBFV (r = -0.563, P = 0.012) in the AET group. One-year AET reduces cerebrovascular impedance in older adults, which may benefit brain perfusion.NEW & NOTEWORTHY Estimation of cerebrovascular impedance is essential for understanding dynamic cerebral blood flow regulation. This randomized controlled trial demonstrated that aerobic exercise training reduced cerebrovascular impedance in older adults, which may benefit brain perfusion.

Colon specific delivery of miR-155 inhibitor alleviates estrogen deficiency related phenotype via microbiota remodeling.

Compelling data have indicated menopause-associated increase in cardiovascular disease in women, while the underlying mechanisms remain largely unknown. It is established that changes of intestinal microbiota affect cardiovascular function in the context of metabolic syndrome. We here aimed to explore the possible link between host intestinal function, microbiota, and cardiac function in the ovariectomy (OVX) mouse model. Mice were ovariectomized to induce estrogen-related metabolic syndrome and cardiovascular defect. Microbiota was analyzed by 16s rRNA sequencing. miRNA and mRNA candidates expression were tested by qPCR. Cardiac function was examined by echocardiography. Colon specific delivery of miRNA candidates was achieved by oral gavage of Eudragit S100 functionalized microspheres. In comparison with the sham-operated group, OVX mice showed compromised cardiac function, together with activated inflammation in the visceral adipose tissue and heart. Lactobacillus abundance was significantly decreased in the gut of OVX mice. Meanwhile, miR-155 was mostly upregulated in the intestinal epithelium and thus the feces over other candidates, which in turn decreased Lactobacillus abundance in the intestine when endocytosed. Oral delivery of miR-155 antagonist restored the protective microbiota and thus protected the cardiac function in the OVX mice. This study has established a possible regulatory axis of intestinal miRNAs-microbiota-estrogen deficiency related phenotype in the OVX model. Colon specific delivery of therapeutic miRNAs would possibly restore the microbiota toward protective phenotype in the context of metabolic syndrome.

Clinical Value of TCCD for Evaluating the Prognosis of Patients with Severe Traumatic Brain Injury After Large Decompressive Craniectomy: A Retrospective Study.

INTRODUCTION: It is challenging to assess the prognosis of patients with severe traumatic brain injury (sTBI) after large decompressive craniectomy (DC). The aim of this study was to evaluate the clinical value of transcranial color-coded duplex sonography (TCCD) for assessing the prognosis of sTBI patients 6 months after large DC. METHODS: This was a retrospective observational study that consecutively enrolled 84 patients with sTBI who were followed up for prognosis until 6 months after large DC. The primary endpoint was the Glasgow Outcome Score (GOS). According to the GOS, patients were divided into an unfavorable prognosis group (GOS 1-3, n = 47) and a favorable prognosis group (GOS 4-5, n = 37). RESULTS: Significant between-group differences were found in age and hemodynamic parameters (systolic peak blood flow velocity, end-diastolic blood flow velocity, mean blood flow velocity, pulsatility index and resistance index) of the middle cerebral artery detected by TCCD (P < 0.05 for all). Subsequently, ridge regression was used to build a prognostic model for patients with large DC. Based on the cerebral hemodynamic parameters measured by TCCD and age, the mean (± standard deviation) area under the curve of the prognostic model in patients with sTBI after large DC was 0.76 ± 0.22. The sensitivity and specificity were 82.08% and 74.17%, respectively. CONCLUSIONS: The cerebral hemodynamic parameters detected by TCCD, combined with age, may be used to predict the outcomes of patients with sTBI at 6 months after large DC. As a noninvasive method, TCCD has the potential to assess the prognosis of these patients. TRIAL REGISTRATION: ChiCTR: ChiCTR1800019758. Registered 27 November 2018-retrospectively registered ( http://www.chictr.org.cn/index.aspx ).

Bioinspired therapeutic platform based on extracellular vesicles for prevention of arterial wall remodeling in hypertension.

Arterial stiffness due to the vessel remodeling is closely linked to raised blood pressure, and its physiopathologic mechanism is still not fully understood. We here aimed to explore whether extracellular vesicle (EV) mediated intercellular communication between endothelium and smooth muscle cell contribute to the blood vessel remodeling under hypertension. We here revealed that the arterial endothelial cells robustly secreted EV, which in turn could be circulated and/or directly taken up by the subendothelial smooth muscle cells (SMC). Under hypertension, the EV secretion increased and the miRNA profile changed significantly mainly due to the raised mechanical force and subsequent enhanced reactive oxygen species generation. Among the miRNA cargos in the EV, miR-320d/423-5p were found increased most significantly. In vivo delivery of miR-320d/423-5p mimics via engineered EV increased their expression in arterial vessels, recapitulating the phenotype in hypertension. In contrast, therapeutic delivery of miR-320d/423-5p inhibitors via engineered EV alleviated the phenotype in spontaneous hypertension rat model. Together, we have found that the injured endothelium due to the raised mechanical force in hypertension contributes to the arterial wall remodeling via the secreted EV. Our study has not only provided novel insights on the mechanism of hypertension associated blood vessel wall remodeling, but also shed light on therapeutic intervention of hypertension associated vascular diseases.

Risk Factors for Anthracycline-Induced Cardiotoxicity.

Background: Several cardiovascular risk factors have been suggested to be associated with anthracycline-induced cardiotoxicity, but their quantitative effects have not reached a consensus. Methods: We searched PubMed, EMBASE, and Cochrane Library databases for manuscripts published from inception to February 2021, which reported the results of cardiotoxicity due to anthracycline chemotherapy without trastuzumab. Cardiotoxicity defined by any reduction of left ventricular eject fraction (LVEF) to below 50% or a >10% reduction from baseline was defined as the primary endpoint. Odd ratios (OR) with 95% confidence intervals (CI) were calculated using a random-effects model meta-analysis. Results: A total of 7,488 patients receiving anthracycline chemotherapy without trastuzumab were included, who had at least one risk factor at baseline. Hypertension (OR: 1.99; 95% CI: 1.43-2.76), diabetes mellitus (OR: 1.74; 95% CI: 1.11-2.74), and obesity (OR: 1.72; 95% CI: 1.13-2.61) were associated with increased risk of cardiotoxicity. In addition, the relative reduction of global longitudinal strain (GLS) from baseline after anthracycline treatment could significantly improve the detection ability of cardiotoxicity (28.5%, 95% CI: 22.1-35.8% vs. 16.4%, 95% CI: 13.4-19.9%) compared with LVEF. The early detection rate of anthracycline-induced cardiotoxicity (3 months after chemotherapy) by GLS was 30.2% (95% CI: 24.9-36.1%), which is similar with the overall result of GLS. Conclusions: Hypertension, diabetes mellitus, and obesity are associated with increased risk of anthracycline-induced cardiotoxicity, which indicates that corresponding protective strategies should be used during and after anthracycline treatment. The findings of higher detection rate and better early detection ability for cardiotoxicity than LVEF added new proofs for the advantages of GLS in detection of AIC.

Cuff-Method Thigh Arterial Occlusion Counteracts Cerebral Hypoperfusion Against the Push-Pull Effect in Humans.

Exposure to acute transition from negative (-Gz) to positive (+ Gz) gravity significantly impairs cerebral perfusion in pilots of high-performance aircraft during push-pull maneuver. This push-pull effect may raise the risk for loss of vision or consciousness. The aim of the present study was to explore effective countermeasures against cerebral hypoperfusion induced by the push-pull effect. Twenty healthy young volunteers (male, 21 ± 1 year old) were tested during the simulated push-pull maneuver by tilting. A thigh cuff (TC) pressure of 200 mmHg was applied before and during simulated push-pull maneuver (-0.87 to + 1.00 Gz). Beat-to-beat cerebral and systemic hemodynamics were measured continuously. During rapid -Gz to + Gz transition, mean cerebral blood flow velocity (CBFV) was decreased, but to a lesser extent, in the TC bout compared with the control bout (-3.1 ± 4.9 vs. -7.8 ± 4.4 cm/s, P < 0.001). Similarly, brain-level mean blood pressure showed smaller reduction in the TC bout than in the control bout (-46 ± 12 vs. -61 ± 13 mmHg, P < 0.001). The systolic CBFV was lower but diastolic CBFV was higher in the TC bout. The systemic blood pressure response was blunted in the TC bout, along with similar heart rate increase, smaller decrease, and earlier recovery of total peripheral resistance index than control during the gravitational transition. These data demonstrated that restricting thigh blood flow can effectively mitigate the transient cerebral hypoperfusion induced by rapid shift from -Gz to + Gz, characterized by remarkable improvement of cerebral diastolic flow.

Older age and male sex are associated with higher cerebrovascular impedance.

Cerebral blood flow (CBF) becomes pulsatile in response to the pulsatile change in perfusion pressure that is regulated by cerebrovascular impedance. In this study, we aimed to characterize age-related differences in cerebrovascular impedance across the adult lifespan. Carotid artery pressure [(CAP), via applanation tonometry] and CBF velocity (CBFV) in the middle cerebral artery (via transcranial Doppler) were measured in 148 healthy adults (21-79 yr, 62% women). Cerebrovascular impedance was quantified using transfer function analysis. Coherence between changes in CBFV and CAP was >0.90 in the frequency range of 0.78-2.73 Hz, suggesting a linear dynamic relationship between these two variables. Impedance modulus at the first harmonics (0.78-1.56 Hz) of CBFV and CAP oscillations (Z1), reflecting mainly heart rate frequency, was 20% higher in the old (>64 yr, P = 0.002) and 13% higher in the middle-aged (45-64 yr, P = 0.08) than in young individuals (<45 yr). In addition, Z1 was 24% higher in men than in women (P < 0.001). Multiple linear regression analysis revealed that Z1 is negatively associated with systolic (ß = -0.470), diastolic (ß = -0.418), pulsatile (ß = -0.374), and mean CBFV (ß = -0.473; P < 0.001 for all) after adjustment for age, sex, and body mass index (BMI). These results suggest that older age and male sex are associated with higher cerebrovascular impedance than young individuals, which may contribute to brain hypoperfusion.NEW & NOTEWORTHY Impedance modulus at the first harmonics of cerebral blood flow velocity (CBFV) and carotid artery pressure oscillations (Z1) was higher in the old (>64 yr) than in the young individuals (<45 yr), and it was higher in men than in women. Z1 is negatively associated with CBFV after adjustment for age, sex, and body mass index. Increases in cerebrovascular impedance with age may buffer systemic arterial pressure fluctuations at the cost of increased brain hypoperfusion risk.

Effective inhibition of miR-330/SHIP1/NF-κB signaling pathway via miR-330 sponge repolarizes microglia differentiation.

Neuroinflammation mediated by microglia has been identified as vital pathogenesis in Parkinson's disease (PD). This study aimed to investigate the role and potential regulatory mechanism of microRNA-330 in the lipopolysaccharide (LPS)-induced chronic neuroinflammatory model. Primary microglia chronic inflammation model and PD animal model were established by LPS treatment. Bulged microRNA-330 sponges containing six microRNA binding sites were constructed and delivered by plasmid or recombinant adeno-associated virus (rAAV2)/5-green fluorescent protein (GFP) vector. The expression levels of microRNA-330 were assessed by a quantitative real-time polymerase chain reaction. Primary microglia polarization was determined by flow cytometry; meanwhile, dopamine and pro-(anti-)inflammatory cytokines were measured by enzyme-linked immunosorbent assay. Expression levels of GFAP, lba1, inducible nitric oxide synthase (iNOS), Arg1, SHIP1, cytoplasmic, and nuclear factor-κB (NF-κB) were analyzed by Western blot. The behavioral deficit was determined by the rotarod test. The expression of microRNA-330 increased in the first 4 days and reached a plateau subsequently after LPS treatment. The sponges-mediated repression effect on M1 polarization was gradually enhanced with time. Treatment of miR-330 sponges increased the SHIP1 and Arg1 expression, and decreased the translocation of NF-κB and iNOS expression, suggesting the repression of inflammation. In the LPS-induced PD mice, administration of rAAV-sponge-GFP suppressed activation of microglia, downregulated proinflammatory cytokines, resumed the secretion of dopamine, rescued the dopaminergic neurons, and alleviated motor dysfunction. Our results demonstrated that microRNA-330 sponges could sustainably suppress LPS-induced polarization of microglia both in vivo and in vitro probably by negatively regulating NF-κB activity via target SHIP1 in microglia, which might be a promising neuroprotective strategy in neurological diseases, such as PD.

Time-restricted feeding alleviates cardiac dysfunction induced by simulated microgravity via restoring cardiac FGF21 signaling.

Dietary restriction has been well-described to improve health metrics, but whether it could benefit pathophysiological adaptation to extreme environment, for example, microgravity, remains unknown. Here, we investigated the effects of a daily rhythm of fasting and feeding without reducing caloric intake on cardiac function and metabolism against simulated microgravity. Male rats under ad libitum feeding or time-restricted feeding (TRF; food access limited to 8 hours every day) were subjected to hindlimb unloading (HU) to simulate microgravity. HU for 6 weeks led to left ventricular dyssynchrony and declined cardiac function. HU also lowered pyruvate dehydrogenase (PDH) activity and impaired glucose utilization in the heart. All these were largely preserved by TRF. TRF showed no effects on HU-induced loss of cardiac mass, but significantly improved contractile function of cardiomyocytes. Interestingly, TRF raised liver-derived fibroblast growth factor 21 (FGF21) level and enhanced cardiac FGF21 signaling as manifested by upregulation of FGF receptor-1 (FGFR1) expression and its downstream markers in HU rats. In isolated cardiomyocytes, FGF21 treatment improved PDH activity and glucose utilization, consequently enhancing cell contractile function. Finally, both liver-specific knockdown (KD) of FGF21 and cardiac-specific FGFR1 KD abrogated the cardioprotective effects of TRF in HU rats. These data demonstrate that TRF improves cardiac glucose utilization and ameliorates cardiac dysfunction induced by simulated microgravity, at least partially, through restoring cardiac FGF21 signaling, suggesting TRF as a potential countermeasure for cardioprotection in long-term spaceflight.

Ultrasound targeted microbubble destruction assisted exosomal delivery of miR-21 protects the heart from chemotherapy associated cardiotoxicity.

Chemotherapy related cardiotoxicity is now becoming one of the biggest hurdles for the prognosis of cancer patients. Therapeutically delivering protective small RNAs holds promise for the cardiotoxicity prevention and therapy. However, heart is intrinsically refractory to the nanoparticle-mediated drug delivery. In this study, we found that the exosome-mediated miRNA delivery into the heart could be significantly augmented with the aid of ultrasound targeted microbubble destruction (UTMD). Moreover, we found that UTMD assisted exosomal miR-21 delivery into the heart significantly decreased the cell death, and restored the cardiac function in a doxorubicin induced cardiotoxicity mouse model. Our study here not only provides a promising strategy to protect the heart from the chemotherapy related cardiotoxicity, but also sheds light on gene therapy of other heart diseases.