Esculetin inhibits the pyroptosis of microvascular endothelial cells through NF-κB /NLRP3 signaling pathway.

The effect of Esculetin on pyroptosis and its possible mechanism in endothelium were explored. 10 µg/mL LPS and 0.5 mM ATP were used to stimulate the rat intestinal microvascular endothelial cells. Then add different concentrations of Esculetin (20µM, 40 µM) to the culture medium containing LPS and ATP culturing for 24 h. The expression of p-NF-κB p65, NF-κB p65, I-κB, p-I-κB, NLRP3, ASC, caspase-1, and gasdermin-D were detected by Western blot, and the release level of IL-18 and IL-1ß were measured by ELISA. The NLRP3 inhibitor MCC950 was used at the concentration of 10 µM for 4 h to disentangle the potential mechanism of the influence of Esculetin on pyroptosis. In our experiments, the expression of gasdermin-d and important proteins of NF-κB and NLRP3 signaling pathways were inhibited by Esculetin. Besides, Esculetin also attenuated the morphological changes like swelling rupture and pores on the membrane caused by pyroptosis thereby protecting cells from being damaged by pyroptosis. Combining with the effect of Esculetin on proteins above and its protective effect on cell morphology, we believe that Esculetin has an anti-pyroptosis effect. The inhibiting pyroptosis effects mentioned above are similar to MCC950, which means the anti-pyroptosis effects of Esculetin are associated with the NLRP3 signaling pathway. In conclusion, Esculetin inhibits the pyroptosis of microvascular endothelial cells through the NF-κB/NLFP3 signaling pathway and is expected to be conducive in treating pyroptosis-related diseases.

The vasculature: a therapeutic target in heart failure?

It is well established that the vasculature plays a crucial role in maintaining oxygen and nutrients supply to the heart. Increasing evidence further suggests that the microcirculation has additional roles in supporting a healthy microenvironment. Heart failure is well known to be associated with changes and functional impairment of the microvasculature. The specific ablation of protective signals in endothelial cells in experimental models is sufficient to induce heart failure. Therefore, restoring a healthy endothelium and microcirculation may be a valuable therapeutic strategy to treat heart failure. This review article will summarize the current understanding of the vascular contribution to heart failure with reduced or preserved ejection fraction. Novel therapeutic approaches including next generation pro-angiogenic therapies and non-coding RNA therapeutics, as well as the targeting of metabolites or metabolic signalling, vascular inflammation and senescence will be discussed.

The palliative effects of folic acid on retinal microvessels in diabetic retinopathy via regulating the metabolism of DNA methylation and hydroxymethylation.

Diabetic retinopathy (DR) is one of the severe microvascular complications of diabetes. The protective effects of FA on retinal vascular endothelial cells against high glucose levels involve in multiple aspects in DR; however, the underlying mechanism is not fully elucidated. In present study, we investigated the transcriptome as well as genome-wide DNA methylation and hydroxymethylation signature in human retinal microvascular endothelial ACBRI 181 cells cultured within high glucose (HG) medium supplemented with or without FA by RNA-seq, MeDIP-seq, and hMeDIP-seq. Total 3308 differential expressed genes (DEGs) were involved in multiple biological processes and molecular functions containing angiogenesis, inflammation, S-adenosyl methionine metabolism, and hypoxia response. Moreover, the global DNA methylation and hydroxymethylation in ACBRI 181 cells with FA treatment were both compromised compared to HG. Combined with transcriptome data, four subclusters of DEGs with hyper- or hypomethylated promoters were further verified. Unexpectedly, promoters of these 487 genes all displayed a pattern of increased DNA hydroxymethylation. Furthermore, hyperglycemia rat model was established and administered with FA. The DNA methylation and hydroxymethylation changes of selected target genes COL1A1, ITGA7, MMP-14, and VEGFB confirmed by MeDIP-qPCR were consistent with the results in human ACBRI 181 cells. Finally, the presence of activated DNMT1 and TET2 induced by FA was determined in ACBRI 181 cells and hyperglycemia rat. Taken together, this research provided a resource of expression and epigenetic profiles in retinal microvascular endothelial cell, emphasizing a pharmacological mechanism of FA on DNA methylation and hydroxymethylation regulation in retinal microvessel cells of DR.

ß-Caryophyllene Induces Apoptosis and Inhibits Angiogenesis in Colorectal Cancer Models.

Beta-Caryophyllene (BCP), a naturally occurring sesquiterpene abundantly found in cloves, hops, and cannabis, is the active candidate of a relatively new group of vascular-inhibiting compounds that aim to block existing tumor blood vessels. Previously, we have reported the anti-cancer properties of BCP by utilizing a series of in-vitro anti-tumor-related assays using human colorectal carcinoma cells. The present study aimed to investigate the effects of BCP on in-vitro, ex-vivo, and in-vivo models of anti-angiogenic assays and evaluate its anti-cancer activity in xenograft tumor (both ectopic and orthotopic) mice models of human colorectal cancer. Computational structural analysis and an apoptosis antibody array were also performed to understand the molecular players underlying this effect. BCP exhibited strong anti-angiogenic activity by blocking the migration of endothelial cells, tube-like network formation, suppression of vascular endothelial growth factor (VEGF) secretion from human umbilical vein endothelial cells and sprouting of rat aorta microvessels. BCP has a probable binding at Site#0 on the surface of VEGFR2. Moreover, BCP significantly deformed the vascularization architecture compared to the negative control in a chick embryo chorioallantoic membrane assay. BCP showed a remarkable reduction in tumor size and fluorescence molecular tomography signal intensity in all the mice treated with BCP, in a dose-dependent relationship, in ectopic and orthotopic tumor xenograft models, respectively. The histological analysis of the tumor from BCP-treated mice revealed a clear reduction of the density of vascularization. In addition, BCP induced apoptosis through downregulation of HSP60, HTRA, survivin, and XIAP, along with the upregulation of p21 expressions. These results suggest that BCP acts at multiple stages of angiogenesis and could be used as a promising therapeutic candidate to halt the growth of colorectal tumor cells.

CaMK4 is a downstream effector of the α1G T-type calcium channel to determine the angiogenic potential of pulmonary microvascular endothelial cells.

Pulmonary microvascular endothelial cells (PMVECs) uniquely express an α1G-subtype of voltage-gated T-type Ca2+ channel. We have previously revealed that the α1G channel functions as a background Ca2+ entry pathway that is critical for the cell proliferation, migration, and angiogenic potential of PMVECs, a novel function attributed to the coupling between α1G-mediated Ca2+ entry and constitutive Akt phosphorylation and activation. Despite this significance, mechanism(s) that link the α1G-mediated Ca2+ entry to Akt phosphorylation remain incompletely understood. In this study, we demonstrate that Ca2+/calmodulin-dependent protein kinase (CaMK) 4 serves as a downstream effector of the α1G-mediated Ca2+ entry to promote the angiogenic potential of PMVECs. Notably, CaMK2 and CaMK4 are both expressed in PMVECs. Pharmacological blockade or genetic knockdown of the α1G channel led to a significant reduction in the phosphorylation level of CaMK4 but not the phosphorylation level of CaMK2. Pharmacological inhibition as well as genetic knockdown of CaMK4 significantly decreased cell proliferation, migration, and network formation capacity in PMVECs. However, CaMK4 inhibition or knockdown did not alter Akt phosphorylation status in PMVECs, indicating that α1G/Ca2+/CaMK4 is independent of the α1G/Ca2+/Akt pathway in sustaining the cells' angiogenic potential. Altogether, these findings suggest a novel α1G-CaMK4 signaling complex that regulates the Ca2+-dominated angiogenic potential in PMVECs.

Danhong injection enhances the therapeutic effect of mannitol on hemispheric ischemic stroke by ameliorating blood-brain barrier disruption.

Mannitol, a representative of hyperosmolar therapy, is indispensable for the treatment of malignant cerebral infarction, but its therapeutic effect is limited by its exacerbation of blood-brain barrier (BBB) disruption. This study was to explore whether Danhong injection (DHI), a standardized product extracted from Salvia miltiorrhiza Bunge and Carthamus tinctorius L., inhibits the destructive effect of mannitol on BBB and thus enhancing the treatment of hemispheric ischemic stroke. SD rats were subjected to pMCAO followed by intravenous bolus injections of mannitol with/without DHI intervention. Neurological deficit score, brain edema, infarct volume at 24 h after MCAO and histopathology, microvascular ultrastructure, immunohistochemistry and immunofluorescence staining of endothelial cell junctions, energy metabolism in the ischemic penumbra were assessed. Intravenous mannitol after MCAO resulted in a decrease in 24 h mortality and cerebral edema, whereas no significant benefit on neurological deficits, infarct volume and microvascular ultrastructure. Moreover, mannitol led to the loss of endothelial integrity, manifested by the decreased expression of occludin, junctional adhesion molecule-1 (JAM-1) and zonula occluden-1 (ZO-1) and the discontinuity of occludin staining around the periphery of endothelial cells. Meanwhile, after mannitol treatment, energy-dependent vimentin and F-actin, ATP content, and ATP5D expression were down-regulated, while MMP2 and MMP9 expression increased in the ischemic penumbra. All the insults after mannitol treatment were attenuated by addition of intravenous DHI. The results suggest DHI as a potential remedy to attenuate mannitol-related BBB disruption, and the potential of DHI to upregulate energy metabolism and inhibit the activity of MMPs is likely attributable to its effects observed.

ETB receptor-mediated vasodilation is regulated by estradiol in young women.

The endothelin-B (ETB) receptor is a key regulator of vascular endothelial function in women. We have previously shown that the ETB receptor mediates vasodilation in young women, an effect that is lost after menopause. However, the direct impact of changes in estradiol (E2) on ETB receptor function in women remains unclear. Therefore, the purpose of this study was to test the hypothesis that E2 exposure modulates ETB receptor-mediated dilation in young women. Fifteen young women (24 ± 4 yr, 24 ± 3 kg/m2) completed the study. Endogenous sex hormone production was suppressed with daily administration of a gonadotropin-releasing hormone antagonist (GnRHant; Ganirelix) for 10 days; E2 (0.1 mg/day, Vivelle-Dot patch) was added back on days 4-10. We measured vasodilation in the cutaneous microcirculation (microvascular endothelial function) via local heating (42°C) on day 4 (GnRHant) and day 10 (GnRHant + E2) using laser Doppler flowmetry coupled with intradermal microdialysis during perfusions of lactated Ringer's (control) and ETB receptor antagonist (BQ-788, 300 nM). During GnRHant, vasodilatory responses to local heating were enhanced with ETB receptor blockade (control: 83 ± 9 vs. BQ-788: 90 ± 5%CVCmax, P = 0.004). E2 administration improved vasodilation in the control site (GnRHant: 83 ± 9 vs. GnRHant + E2: 89 ± 8%CVCmax, P = 0.036). Furthermore, cutaneous vasodilatory responses during ETB receptor blockade were blunted after E2 administration (control: 89 ± 8 vs. BQ-788: 84 ± 8%CVCmax, P = 0.047). These data demonstrate that ovarian hormones, specifically E2, modulate ETB receptor function and contribute to the regulation of microvascular endothelial function in young women.NEW & NOTEWORTHY The endothelin-B (ETB) receptor mediates vasodilation in young women, an effect lost following menopause. It is unclear whether these alterations are due to aging or changes in estradiol (E2). During endogenous hormone suppression (GnRH antagonist), blockade of ETB receptors enhanced cutaneous microvascular vasodilation. However, during E2 administration, blockade of ETB receptors attenuated vasodilation, indicating that the ETB receptor mediates dilation in the presence of E2. In young women, ETB receptors mediate vasodilation in the presence of E2, an effect that is lost when E2 is suppressed.

A novel naphthalimide derivative reduces platelet activation and thrombus formation via suppressing GPVI.

Naphthalimide derivatives have multiple biological activities, including antitumour and anti-inflammatory activities. We previously synthesized several naphthalimide derivatives; of them, compound 5 was found to exert the strongest inhibitory effect on human DNA topoisomerase II activity. However, the effects of naphthalimide derivatives on platelet activation have not yet been investigated. Therefore, the mechanism underlying the antiplatelet activity of compound 5 was determined in this study. The data revealed that compound 5 (5-10 µM) inhibited collagen- and convulxin- but not thrombin- or U46619-mediated platelet aggregation, suggesting that compound 5 is more sensitive to the inhibition of glycoprotein VI (GPVI) signalling. Indeed, compound 5 could inhibit the phosphorylation of signalling molecules downstream of GPVI, followed by the inhibition of calcium mobilization, granule release and GPIIb/IIIa activation. Moreover, compound 5 prevented pulmonary embolism and prolonged the occlusion time, but tended to prolong the bleeding time, indicating that it can prevent thrombus formation but may increase bleeding risk. This study is the first to demonstrate that the naphthalimide derivative compound 5 exerts antiplatelet and antithrombotic effects. Future studies should modify compound 5 to synthesize more potent and efficient antiplatelet agents while minimizing bleeding risk, which may offer a therapeutic potential for cardiovascular diseases.

A Randomized, Multicenter, Open-Label, Blinded End Point, Phase 2, Feasibility, Efficacy, and Safety Trial of Preoperative Microvascular Protection in Patients Undergoing Major Abdominal Surgery.

BACKGROUND: The endothelial glycocalyx, a carbohydrate-rich layer coating all endothelial surfaces, plays a fundamental role in the function of microcirculation. The primary aim of this study was to evaluate the feasibility of using dexamethasone and albumin to protect the endothelial glycocalyx in patients undergoing abdominal surgery. Secondary and exploratory outcomes included efficacy and safety. METHODS: We conducted a multicenter, open-label, blinded end point, phase 2, randomized trial. Patients undergoing colorectal, pancreas, or liver surgery were recruited and randomized to receive either intravenous dexamethasone (16 mg) and 20% albumin (100 mL) at induction of anesthesia, then 200 mL of 20% albumin with each subsequent 1000 mL of crystalloid administered (dexamethasone and albumin [Dex-Alb] group), or crystalloid fluid only with no dexamethasone (control group). Feasibility end points included patient recruitment and retention, consent rate, and successful study drug administration. The primary efficacy end point was the measurement of plasma syndecan-1 level on postoperative day (POD) 1, and secondary end points were heparan sulfate levels and inflammatory markers measured at 4 perioperative timepoints. Safety end points included errors in administration of the intervention, hyperglycemia, occurrence of postoperative complications, and patient retention. RESULTS: Seventy-two patients were randomized. All feasibility end points were achievable. There were no statistically significant differences observed in median (interquartile range) syndecan-1 levels on POD 1 (39 ng·mL-1 [20-97] in the Dex-Alb group versus 41 ng·mL-1 [19-84] in the control group; difference in medians -2.1, 95% confidence interval [CI], -13 to 8.6; P = .69). The Dex-Alb group had lower POD 1 heparan sulfate levels (319 ng·mL-1 [161-717] in the Dex-Alb group versus 1422 [670-2430] ng·mL-1 in the control group; difference in medians -1085, 95% CI, -1779 to -391) and C-reactive protein (CRP) levels on POD 1 (48 [29-77] mg·L-1 in the Dex-Alb group versus 85 mg·L-1 [49-133] in the control group; difference in medians -48, 95% CI, -75 to -21). Fewer patients had one or more postoperative complication in the Dex-Alb group than in the control group (6 [17%] vs 18 patients [50%]; odds ratio = 0.2, 95% CI, 0.06-0.6). CONCLUSIONS: Intravenous dexamethasone and albumin administration was feasible but did not reduce syndecan-1 on POD 1 in patients undergoing abdominal surgery. Given the clinically important CIs observed between the groups for heparan sulfate, CRP, and postoperative complications, a larger trial assessing the associations between dexamethasone and albumin administration and these outcomes is warranted.

A2A receptor agonists and P2Y12 receptor antagonists modulate expression of thrombospondin-1 (TSP-1) and its secretion from Human Microvascular Endothelial Cells (HMEC-1).

BACKGROUNDS AND AIMS: To address the problem of resistance to standard antiplatelet therapy in some patients, our team proposed a purinoceptor-dependent dual therapy. Its efficacy is also determined by the condition of the vascular endothelium which, by secreting numerous factors, is involved in hemostasis. Among them, thrombospondin-1 is important in the context of thrombotic events. Therefore we sought to determine if the novel dual purinoceptor-dependent concept is associated with TSP-1 changes in vascular endothelial cells. METHODS AND RESULTS: TSP-1 expression in human microvascular endothelial cells was determined at transcriptional and protein level. We performed real-time PCR, the Western blot analysis and ELISA test. We found that TSP-1 mRNA and protein expression levels significantly changed in response to P1R agonists treatment. Furthermore, we have observed that co-administration of selective A2AR agonists (UK-432,097 or MRE0094) with P2Y12R antagonists altered TSP-1 expression levels, and the direction of these changes was not synergistic. MRE0094 applied with ARC69931MX or R-138727 increased mRNA expression from 39 to 56 or 57%, respectively (*P < 0.05 vs. MRE0094; ***P < 0.001 vs. control). Also, in the case of the P2Y12R antagonists used together with UK-432,097, there was an increase from 53 to 71 and 70% (*P < 0.05 vs. UK-432,097; ***P < 0.001 vs. control). The observed trends in gene expression were reflected in the protein expression and the level of its secretion from HMEC-1. CONCLUSION: The article presents evidence which proves that the purinoceptor-dependent concept is associated with TSP-1 changes in endothelial cells (EC). Moreover, Human Microvascular Endothelial Cells treatment applied together with agonists (MRE0094 or UK-432,097) and P2Y12R antagonist did not result in any synergistic effect, implicating a possible crosstalk between G proteins in GPCRs dependent signaling. Therefore, we suggest that understanding of the specific mechanism underlying TSP-1 alterations in EC in the context of the dual purinoceptor-dependent approach is essential for antiplatelet therapies and should be the subject of future research.

Assessment of microvascular function and pharmacological regulation in genetically confirmed familial hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) is a genetic lipid disorder leading to accelerated atherosclerosis, premature cardiovascular disease and death. Microvascular endothelial dysfunction is one of the earliest vascular pathology manifestations and may precede symptomatic atherosclerosis. METHODS: In this paper, microvascular endothelial function was assessed in FH patients and healthy controls using flow mediated skin fluorescence (FMSF), based on measurements of nicotinamide adenine dinucleotide fluorescence intensity during brachial artery occlusion (ischemic response, IR) and immediately after occlusion (hyperemic response, HR). Low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) were used to assess its relation with microvascular parameters evaluated in vivo. RESULTS: LDL-C levels were significantly correlated to both HRmax (r = -0.548, p = 0.001) and HRindex (r = -0.514, p = 0.003). Similarly, there was a significant inverse correlation of TC levels and both HRmax (r = -0.538, p = 0.002) and HRindex (r = -0.512, p = 0.003). All FMSF parameters were found lower in FH patients compared to age- and sex-matched healthy controls. Hyperemic response (HRmax) was significantly higher in FH patients examined on statins compared to those without any lipid-lowering treatment (19.9 ± 3.1 vs. 16.4 ± 4.2 respectively, p = 0.022). CONCLUSIONS: This study shows that, in patients with FH, microvascular endothelial-dependent hyperemic response is impaired and inversely correlated to plasma cholesterol levels. Microvascular function was found better in FH patients receiving statins.

Mineralocorticoid and Estrogen Receptors in Endothelial Cells Coordinately Regulate Microvascular Function in Obese Female Mice.

[Figure: see text].

Changes in the microvascular reactivity during spinal anesthesia.

PURPOSE: Anesthesia alters microcirculation and tissue oxygen saturation (StO2). We sought to examine changes in StO2 using near-infrared spectroscopy and a vascular occlusion test (VOT) during spinal anesthesia. METHODS: This prospective observational study was included 51 patients without comorbidities who underwent elective surgery under spinal anesthesia. We measured the StO2 in the lower extremity during VOT before and after intrathecal injection. RESULTS: The baseline, minimum, and maximum StO2 values during VOT significantly increased after intrathecal injection (baseline StO2 from 68.6 ± 7.3% to 77.1 ± 10.1%, minimum StO2 from 39.7 ± 14.9% to 48.8 ± 17.6%, and maximum StO2 from 74.2 ± 7.5% to 80.2 ± 10.0%, all P < 0.0001). The occlusion slope and ischemic stimulus did not significantly change after intrathecal injection. The reperfusion slope was 1.38 ± 0.69%/sec before intrathecal injection and significantly decreased to 1.15 ± 0.61%/sec after intrathecal injection (P = 0.0001). CONCLUSIONS: Our results showed that despite an increased perfusion, reperfusion rate was significantly decreased by spinal anesthesia. Further studies are required to confirm how these contradictory results (improving oxygenation while reducing microvascular reactivity) actually affect the clinical impact of spinal anesthesia on microvascular function.

Angiogenic potential of airbrushed fucoidan/polycaprolactone nanofibrous meshes.

Implantation of biomaterials and hybrid constructs in tissue engineering approaches presents major limitations such as inflammatory reaction and the lack of vasculature integration. Therefore, new strategies are needed to enhance implant function, immune protection, and revascularization. In this work, we developed fibrous meshes composed of fucoidan (Fu), a sulfated polysaccharide extracted from brown algae, and polycaprolactone (PCL), a synthetic biodegradable polymer, using the airbrush technique. The chemical characterization by FTIR, EDS, and XPS confirmed the presence of the two polymers in the structure of airbrushed nanofibrous meshes (ANFM). Moreover, these nanofibrous exhibited good wettability and mechanical properties envisaging their application as templates for biomaterials and cell culture. The developed ANFM were directly cultured with human pulmonary microvascular endothelial (HPMEC-ST1.6R) cells for up to 7 days. Biological results demonstrated that ANFM comprising Fu promoted cellular attachment, spreading, and proliferation of human endothelial cells. The angiogenic potential of ANFM was further evaluated by onplantation of PCL and PCL/Fu ANFM in chick chorioallantoic membrane (CAM). In ovo and ex ovo results showed that the incorporation of Fu increased the pro-angiogenic potential of ANFM. Altogether, the results suggest that airbrush biocomposite meshes could be used as a biomaterial substrate to promote vascularization.

Platelet-rich plasma enhances mechanical strength of strattice in rat model of ventral hernia repair.

Incisional hernia is a common complication of hernia repair despite the development of various synthetic and bio-synthetic repair materials. Poor long-term mechanical strength, leading to high recurrence rates, has limited the use of acellular dermal matrices (ADMs) in ventral hernia repair (VHR). Biologically derived meshes have been an area of increasing interest. Still these materials bring the risk of more aggressive immune response and fibrosis in addition to the mechanical failures suffered by the synthetic materials. Platelet-rich plasma (PRP), a growth-factor-rich autologous blood product, has been shown to improve early neovascularization, tissue deposition, and to decrease the rates of recurrence. Here, we demonstrate that PRP promotes the release of growth factors stromal derived factor (SDF)-1, transforming growth factor-beta, and platelet-derived growth factor in a dose-dependent manner. Additionally, we utilize an aortic ring angiogenesis assay to show that PRP promotes angiogenesis in vitro. A rat model of VHR using StratticeTM ADM demonstrates similar findings in vivo, corresponding with the increased expression of vascular endothelial growth factor and collagen type 1 alpha 1. Finally, we show that the molecular and cellular activity initiated by PRP results in an increased mechanical stiffness of the hernia repair mesh over time. Collectively, these data represent an essential step in demonstrating the utility and the mechanism of platelet-derived plasma in biomaterial-aided wound healing and provide promising preclinical data that suggest such materials may improve surgical outcomes.

Naringenin prevents TNF-α-induced gut-vascular barrier disruption associated with inhibiting the NF-κB-mediated MLCK/p-MLC and NLRP3 pathways.

The microvasculature endothelium accurately regulates the passage of molecules across the gut-vascular barrier (GVB), which plays an essential role in intestinal immunity. Naringenin is reported to have therapeutic potential against several intestinal disorders. However, the effect of naringenin on GVB disruption has been rarely studied. This study aims to investigate the effect of naringenin on GVB function and the potential mechanism. In the present study, the in vitro GVB disruption of rat intestinal microvascular endothelial cells (RIMVEC) was induced by 50 ng mL-1 of tumor necrosis factor-α (TNF-α). The integrity of the in vitro GVB was determined by Evans blue (EB)-albumin efflux assay and trans-endothelial electrical resistance (TER). Meanwhile, the expression of tight junction proteins and the related NF-κB, MLCK/p-MLC and NLRP3 pathways were determined using enzyme-linked immunosorbent assay (ELISA), real-time quantitative polymerase chain reaction (RT-qPCR), western blot analysis and immunofluorescence. The results show that naringenin (100 µM) inhibits TNF-α-induced interleukin (IL)-6 hypersecretion, alleviates GVB disruption and mitigates the change in the tight junction protein expression pattern. Naringenin inhibits the GVB-disruption-associated activation of the MLCK/p-MLC system and TLR4/NF-κB/NLRP3 pathways. Furthermore, naringenin shows a similar effect to that of NF-κB inhibitor Bay 11-7082 in reducing the TNF-α-induced activation of NLRP3, p-MLC and secondary GVB disruption. The results suggest that naringenin evidently alleviates TNF-α-induced in vitro GVB disruption via the maintenance of a tight junction protein pattern, partly with the inhibition of the NF-κB-mediated MLCK/p-MLC and NLRP3 pathway activation.

The acute and postprandial effects of sugar moiety on vascular and metabolic health outcomes in adolescents.

This study explored the cardiometabolic responses to sugar moieties acutely, and following a subsequent mixed meal tolerance test (MMTT). Twenty-one healthy adolescents (N = 10 female, 14.3 ± 0.4 years) completed 3 experimental and 1 control condition, in a counterbalanced order. These consisted of different drinks to compare the effect of 300 mL of water (control), or 300 mL of water mixed with 60 g of glucose, fructose or sucrose, on vascular function (flow-mediated dilation (FMD), microvascular reactivity (total hyperaemic response; TRH), and cerebrovascular reactivity (CVR)), and blood samples for uric acid, glucose, triglycerides and lactate concentrations. FMD increased 1 h after glucose and sucrose (P < 0.001, ES ≥ 0.92) but was unchanged following fructose and water (P ≥ 0.19, ES ≥ 0.09). CVR and TRH were unchanged 1 h following all conditions (P > 0.57, effect size (ES) > 0.02). Following the MMTT, FMD was impaired in all conditions (P < 0.001, ES > 0.40) with no differences between conditions (P > 0.13, ES < 0.39). Microvascular TRH was increased in all conditions (P = 0.001, ES = 0.88), and CVR was preserved in all conditions after MMTT (P = 0.87, ES = 0.02). Blood uric acid concentration was elevated following fructose consumption and the MMTT (P < 0.01, ES > 0.40). Consumption of a sugar sweetened beverage did not result in vascular dysfunction in healthy adolescents; however, the vascular and metabolic responses were dependent on sugar moiety. Novelty: Glucose consumption acutely increases peripheral vascular function in healthy adolescents. Acute sugar sweetened beverage consumption (sucrose) does not result in adverse vascular outcomes. Elevations in uric acid are observed with fructose consumption, which may have implications over repeated exposure.

Apelin/APJ relieve diabetic cardiomyopathy by reducing microvascular dysfunction.

Microcirculatory injuries had been reported to be involved in diabetic cardiomyopathy, which was mainly related to endothelial cell dysfunction. Apelin, an adipokine that is upregulated in diabetes mellitus, was reported to improve endothelial cell dysfunction and attenuate cardiac insufficiency induced by ischemia and reperfusion. Therefore, it is hypothesized that apelin might be involved in alleviating endothelial cell dysfunction and followed cardiomyopathy in diabetes mellitus. The results showed that apelin improved endothelial cell dysfunction via decreasing apoptosis and expression of adhesion molecules and increasing proliferation, angiogenesis, and expression of E-cadherin, VEGFR 2 and Tie-2 in endothelial cells, which resulted in the attenuation of the capillary permeability in cardiac tissues and following diabetic cardiomyopathy. Meanwhile, the results from endothelial cell-specific APJ knockout mice and cultured endothelial cells confirmed that the effects of apelin on endothelial cells were dependent on APJ and the downstream NFκB pathways. In conclusion, apelin might reduce microvascular dysfunction induced by diabetes mellitus via improving endothelial dysfunction dependent on APJ activated NFκB pathways.

Engineered nanomedicines for tumor vasculature blockade therapy.

Tumor vasculature blockade therapy (TVBT), including angiogenesis inhibition, vascular disruption, and vascular infarction, provides a promising treatment modality for solid tumors. However, low selectivity, drug resistance, and possible severe side effects have limited the clinical transformation of TVBT. Engineered nanoparticles offer potential solutions, including prolonged circulation time, targeted transportation, and controlled release of TVBT agents. Moreover, engineered nanomedicines provide a promising combination platform of TVBT with chemotherapy, radiotherapy, photodynamic therapy, photothermal therapy, ultrasound therapy, and gene therapy. In this article, we offer a comprehensive summary of the current progress of engineered nanomedicines for TVBT and also discuss current deficiencies and future directions for TVBT development. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies.

Melatonin and prolonged physical activity attenuated the detrimental effects of diabetic condition on murine cardiac tissue.

In this study, the combined effects of four-week swimming training and melatonin were examined on the oxidative response, inflammation, apoptosis, and angiogenesis capacity of cardiac tissue in the mouse model of diabetes. The mice were randomly allocated into five groups (n = 10 per group) as follows: Control; Diabetic group; Diabetic + Melatonin group; Diabetic + Exercise group; and Diabetic + Exercise + Melatonin group. 50 mg/kg streptozotocin was intraperitoneally administrated. In melatonin-treated groups, melatonin was injected intraperitoneally at 3 mg/kg body weight for four weeks and twice weekly. Swimming exercises were performed for four weeks. We measured cardiac superoxide dismutase, glutathione peroxidase enzymes, malondialdehyde, and total antioxidant capacity. The expression of tumor necrosis factor-α, Caspase­3, Sirtuin1, and Connexin-43 was measured using real-time PCR analysis. The vascular density was analyzed by immunohistochemistry using CD31 and α-smooth muscle actin antibodies. The combination of melatonin and exercise elevated cardiac superoxide dismutase, glutathione peroxidase coincided with the reduction of malondialdehyde and increase of total antioxidant capacity as compared to the diabetic mice (p < 0.05). In Diabetic + Exercise + Melatonin mice, tumor necrosis factor-α, Caspase­3 was significantly down-regulated compared to the Diabetic group (p < 0.05). Melatonin and exercise suppressed the expression of Connexin-43 and Sirtuin1 in diabetic mice in comparison with the control mice (p < 0.05). H & E staining showed necrosis and focal hyperemia reduction in the Diabetic + Exercise + Melatonin group compared to the Diabetic group. Data showed a decrease of CD31+ and α-smooth muscle actin+ vessels in the Diabetic group as compared to the normal samples (p < 0.05). The number of CD31+ vessels, but not α-smooth muscle actin+ type, increased in the Diabetic + Exercise + Melatonin group compared to the Diabetic mice. These data demonstrated that exercise along with melatonin administration could diminish the detrimental effects of diabetes on cardiac tissue via using different mechanisms.