Far-infrared radiation alleviates cisplatin-induced vascular damage and impaired circulation via activation of HIF-1α.

Severe vascular damage and complications are often observed in cancer patients during treatment with chemotherapeutic drugs such as cisplatin. Thus, development of potential options to ameliorate the vascular side effects is urgently needed. In this study, the effects and the underlying mechanisms of far-infrared radiation (FIR) on cisplatin-induced vascular injury and endothelial cytotoxicity/dysfunction in mice and human umbilical vein endothelial cells (HUVECs) were investigated. An important finding is that the severe vascular stenosis and poor blood flow seen in cisplatin-treated mice were greatly mitigated by FIR irradiation (30 minutes/day) for 1-3 days. Moreover, FIR markedly increased the levels of phosphorylation of PI3K and Akt, and VEGF secretion, as well as the expression and the activity of hypoxia-inducible factor 1α (HIF-1α) in cisplatin-treated HUVECs in a promyelocytic leukemia zinc finger protein (PLZF)-dependent manner. However, FIR-stimulated endothelial angiogenesis and VEGF release were significantly diminished by transfection with HIF-1α siRNA. We also confirmed that HIF-1α, PI3K, and PLZF contribute to the inhibitory effect of FIR on cisplatin-induced apoptosis in HUVECs. Notably, FIR did not affect the anticancer activity and the HIF-1α/VEGF cascade in cisplatin-treated cancer cells under normoxic or hypoxic condition, indicating that the actions of FIR may specifically target endothelial cells. It is the first study to demonstrate that FIR effectively attenuates cisplatin-induced vascular damage and impaired angiogenesis through activation of HIF-1α-dependent processes via regulation of PLZF and PI3K/Akt. Taken together, cotreatment with the noninvasive and easily performed FIR has a therapeutic potential to prevent the pathogenesis of vascular complications in cancer patients during cisplatin treatment.

Soluble Endoglin Stimulates Inflammatory and Angiogenic Responses in Microglia That Are Associated with Endothelial Dysfunction.

Increased soluble endoglin (sENG) has been observed in human brain arteriovenous malformations (bAVMs). In addition, the overexpression of sENG in concurrence with vascular endothelial growth factor (VEGF)-A has been shown to induce dysplastic vessel formation in mouse brains. However, the underlying mechanism of sENG-induced vascular malformations is not clear. The evidence suggests the role of sENG as a pro-inflammatory modulator, and increased microglial accumulation and inflammation have been observed in bAVMs. Therefore, we hypothesized that microglia mediate sENG-induced inflammation and endothelial cell (EC) dysfunction in bAVMs. In this study, we confirmed that the presence of sENG along with VEGF-A overexpression induced dysplastic vessel formation. Remarkably, we observed increased microglial activation around dysplastic vessels with the expression of NLRP3, an inflammasome marker. We found that sENG increased the gene expression of VEGF-A, pro-inflammatory cytokines/inflammasome mediators (TNF-α, IL-6, NLRP3, ASC, Caspase-1, and IL-1ß), and proteolytic enzyme (MMP-9) in BV2 microglia. The conditioned media from sENG-treated BV2 (BV2-sENG-CM) significantly increased levels of angiogenic factors (Notch-1 and TGFß) and pERK1/2 in ECs but it decreased the level of IL-17RD, an anti-angiogenic mediator. Finally, the BV2-sENG-CM significantly increased EC migration and tube formation. Together, our study demonstrates that sENG provokes microglia to express angiogenic/inflammatory molecules which may be involved in EC dysfunction. Our study corroborates the contribution of microglia to the pathology of sENG-associated vascular malformations.

Prediction and recommendation by machine learning through repetitive internal validation for hepatic veno-occlusive disease/sinusoidal obstruction syndrome and early death after allogeneic hematopoietic cell transplantation.

Using traditional statistical methods, we previously analyzed the risk factors and treatment outcomes of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) after allogeneic hematopoietic cell transplantation. Within the same cohort, we applied machine learning to create prediction and recommendation models. We analyzed 2572 transplants using eXtreme Gradient Boosting (XGBoost) to predict post-transplant VOD/SOS and early death. Using the XGBoost and SHapley Additive exPlanations (SHAP), we found influential factors and devised recommendation models, which were internally verified by repetitive ten-fold cross-validation. SHAP values suggested that gender, busulfan dosage, age, forced expiratory volume, and Disease Risk Index were significant factors for VOD/SOS. The areas under the receiver operating characteristic curves and the areas under the precision-recall curve of the models were 0.740, 0.144 for all VOD/SOS, 0.793, 0.793 for severe to very severe VOD/SOS, and 0.746, 0.304 for early death. According to our single feature recommendation, following the busulfan dosage was the most effective for preventing VOD/SOS. The recommendation method for six adjustable feature sets was also validated, and a subgroup corresponding to five to six features showed significant preventive power for VOD/SOS and early death. Our personalized treatment set recommendation showed reproducibility in repetitive internal validation, but large external cohorts should prospectively validate our model.

Topiramate treatment in Wistar rats during childhood induces sex-specific vascular dysfunction in adulthood.

The present study determined whether treatment during childhood with topiramate (TPM), a new generation antiepileptic drug, results in altered aortic reactivity in adult male and female rats. We also sought to understand the role of endothelium-derived contractile factors in TPM-induced vascular dysfunction. Male and female Wistar rats were treated with TPM (41 mg/kg/day) or water (TPM vehicle) by gavage during childhood (postnatal day, 16-28). In adulthood, thoracic aorta reactivity to phenylephrine (phenyl), as well as aortic thickness and expression of cyclooxygenases (COX-1 and COX-2), NOX2, and p47phox were evaluated. The aortic response to phenyl was increased in male and female rats from the TPM group when compared with the control group. In TPM male rats, the hyperreactivity to phenyl was abrogated by the inhibition of NADPH oxidase and COX-2, while in female rats, responses were restored only by inhibition of COX-2. In addition, TPM male rats presented aortic hypertrophy and increased expression of NOX-2 and p47phox, while TPM female rats showed increased COX-2 aortic expression. Taken together, for the first-time, the present study provides evidence that treatment with TPM during childhood causes vascular dysfunction in adulthood, and that the mechanism underlying the vascular effects of TPM is sex-specific.

Ultrasound arterial anomalies in patients exposed to nilotinib therapy for chronic myeloid leukemia.

INTRODUCTION: Patients exposed to nilotinib for chronic myeloid leukemia (CML) appear to be at risk of arterial complication. The prevalence and aspect of ultrasound asymptomatic arterial lesions are unknown. OBJECTIVE: To describe prevalence and characteristics of ultrasound arterial anomalies in patients treated with nilotinib for CML. METHODS: Patients treated with nilotinib from 2006 to 2015 in the department of the Paoli-Calmettes Institute, Marseille, were included retrospectively. A vascular ultrasound screening was carried out from 2010. The arterial lesions at the first examination were described: plaque and its echogenicity, stenosis or occlusion. A vascular arterial anomaly (VAA) was defined by the presence of a clinical and/or ultrasound anomaly. Patients with or without VAA at initial vascular examination were compared using bivariate and multivariate analysis. RESULTS: 74 patients were included (51.4% men, mean age 54.5 years); 25 patients had ultrasound arterial anomalies (33.8%). Carotid bulb was the most involved territory (44%). Arterial anomalies were: 88% plaques, 44%>50% stenosis and 12% occlusion. 72.7% plaques were echolucent or hypoechogenic. A VAA was present in 25 patients with initial vascular evaluation (33.8%). Patients with VAA at baseline were significantly older (64.9 vs 49.3, P<0.001), older at nilotinib initiation (60.8 vs 46.5, P<0.001), with more arterial hypertension (40% vs 12.2%, P=0.01), with more cardiovascular risk factors (P=0.03). In patient with no cardiovascular risk factor 12.5% had VAA (n=24). CONCLUSION: Nilotinib seems to be associated to arterial lesions of unstable lipid-like appearance. The most involved arterial territory was the carotid bulb and the most common lesion was echolucent or hypoechogenic plaque. VAA can occur in patients without cardiovascular risk factors. This result encourages us to systematically screen and follow all patients exposed to nilotinib even those without cardiovascular risk factors.

Pulmonary and vascular effects of acute ozone exposure in diabetic rats fed an atherogenic diet.

Air pollutants may increase risk for cardiopulmonary disease, particularly in susceptible populations with metabolic stressors such as diabetes and unhealthy diet. We investigated effects of inhaled ozone exposure and high-cholesterol diet (HCD) in healthy Wistar and Wistar-derived Goto-Kakizaki (GK) rats, a non-obese model of type 2 diabetes. Male rats (4-week old) were fed normal diet (ND) or HCD for 12 weeks and then exposed to filtered air or 1.0 ppm ozone (6 h/day) for 1 or 2 days. We examined pulmonary, vascular, hematology, and inflammatory responses after each exposure plus an 18-h recovery period. In both strains, ozone induced acute bronchiolar epithelial necrosis and inflammation on histopathology and pulmonary protein leakage and neutrophilia; the protein leakage was more rapid and persistent in GK compared to Wistar rats. Ozone also decreased lymphocytes after day 1 in both strains consuming ND (~50%), while HCD increased circulating leukocytes. Ozone increased plasma thrombin/antithrombin complexes and platelet disaggregation in Wistar rats on HCD and exacerbated diet effects on serum IFN-γ, IL-6, KC-GRO, IL-13, and TNF-α, which were higher with HCD (Wistar>GK). Ex vivo aortic contractility to phenylephrine was lower in GK versus Wistar rats at baseline(~30%); ozone enhanced this effect in Wistar rats on ND. GK rats on HCD had higher aortic e-NOS and tPA expression compared to Wistar rats. Ozone increased e-NOS in GK rats on ND (~3-fold) and Wistar rats on HCD (~2-fold). These findings demonstrate ways in which underlying diabetes and HCD may exacerbate pulmonary, systemic, and vascular effects of inhaled pollutants.

Carfilzomib-induced endothelial dysfunction, recovery of proteasome activity, and prediction of cardiovascular complications: a prospective study.

Carfilzomib (CFZ) improves survival in relapsed/refractory multiple myeloma but is associated with cardiovascular adverse events (CVAEs). We prospectively investigated the effect of CFZ on endothelial function and associations with CVAEs. Forty-eight patients treated with Kd (CFZ 20/56 mg/m2 and dexamethasone) underwent serial endothelial function evaluation, using brachial artery flow-mediated dilatation (FMD) and 26S proteasome activity (PrA) measurement in PBMCs; patients were followed until disease progression or cycle 6 for a median of 10 months. FMD and PrA decreased acutely after the first dose (p < 0.01) and FMD decreased at cycles 3 and 6 compared to baseline (p ≤ 0.05). FMD changes were associated with CFZ-induced PrA changes (p < 0.05) and lower PrA recovery during first cycle was associated with more prominent FMD decrease (p = 0.034 for group interaction). During treatment, 25 patients developed Grade ≥3 CVAEs. Low baseline FMD (HR 2.57 lowest vs. higher tertiles, 95% CI 1.081-6.1) was an independent predictor of CVAEs. During treatment, an acute FMD decrease >40% at the end of first cycle was also independently associated with CVAEs (HR = 3.91, 95% CI 1.29-11.83). Kd treatment impairs endothelial function which is associated with PrA inhibition and recovery. Both pre- and posttreatment FMD predicted CFZ-related CVAEs supporting its role as a possible cardiovascular toxicity biomarker.

The vascular endothelial growth factor trap aflibercept induces vascular dysfunction and hypertension via attenuation of eNOS/NO signaling in mice.

Aflibercept, as a soluble decoy vascular endothelial growth factor receptor, Which has been used as a first-line monotherapy for cancers. Aflibercept often causes cardiovascular toxicities including hypertension, but the mechanisms underlying aflibercept-induced hypertension remain unknown. In this study we investigated the effect of short-term and long-term administration of aflibercept on blood pressure (BP), vascular function, NO bioavailability, oxidative stress and endothelin 1 (ET-1) in mice and cultured endothelial cells. We showed that injection of a single-dose of aflibercept (18.2, 36.4 mg/kg, iv) rapidly and dose-dependently elevated BP in mice. Aflibercept treatment markedly impaired endothelial-dependent relaxation (EDR) and resulted in NADPH oxidases 1 (NOX1)- and NADPH oxidases 4 (NOX4)-mediated generation of ROS, decreased the activation of protein kinase B (Akt) and endothelial nitric oxide synthase (eNOS) concurrently with a reduction in nitric oxide (NO) production and elevation of ET-1 levels in mouse aortas; these effects were greatly attenuated by supplementation of L-arginine (L-arg, 0.5 or 1.0 g/kg, bid, ig) before aflibercept injection. Similar results were observed in L-arg-pretreated cultured endothelial cells, showing markedly decreased ROS accumulation and AKT/eNOS/NO signaling impairment induced by aflibercept. In order to assess the effects of long-term aflibercept on hypertension and to evaluate the beneficial effects of L-arg supplementation, we administered these two drugs to WT mice for up to 14 days (at an interval of two days). Long-term administration of aflibercept resulted in a sustained increase in BP and a severely impaired EDR, which are associated with NOX1/NOX4-mediated production of ROS, increase in ET-1, inhibition of AKT/eNOS/NO signaling and a decreased expression of cationic amino acid transporter (CAT-1). The effects caused by long-term administration were greatly attenuated by L-arg supplementation in a dose-dependent manner. We conclude that aflibercept leads to vascular dysfunction and hypertension by inhibiting CAT-1/AKT/eNOS/NO signaling, increasing ET-1, and activating NOX1/NOX4-mediated oxidative stress, which can be suppressed by supplementation of L-arg. Therefore, L-arg could be a potential therapeutic agent for aflibercept-induced hypertension.

Regulation of the parental gene GRM4 by circGrm4 RNA transcript and glutamate-mediated neurovascular toxicity in eyes.

Epigenetic memory plays crucial roles in gene regulation. It not only modulates the expression of specific genes but also has ripple effects on transcription as well as translation of other genes. Very often an alteration in expression occurs either via methylation or demethylation. In this context, "1-carbon metabolism" assumes a special significance since its dysregulation by higher levels of homocysteine; Hcy (known as hyperhomocysteinemia; HHcy), a byproduct of "1-Carbon Metabolism" during methionine biosynthesis leads to serious implications in cardiovascular, renal, cerebrovascular systems, and a host of other conditions. Currently, the circular RNAs (circRNAs) generated via non-canonical back-splicing events from the pre-mRNA molecules are at the center stage for their essential roles in diseases via their epigenetic manifestations. We recently identified a circular RNA transcript (circGRM4) that is significantly upregulated in the eye of cystathionine ß-synthase-deficient mice. We also discovered a concurrent over-expression of the mGLUR4 receptor in the eyes of these mice. In brief, circGRM4 is selectively transcribed from its parental mGLUR4 receptor gene (GRM4) functions as a "molecular-sponge" for the miRNAs and results into excessive turnover of the mGLUR4 receptor in the eye in response to extremely high circulating glutamate concentration. We opine that this epigenetic manifestation potentially predisposes HHcy people to retinovascular malfunctioning.

Occupational exposure to carbon black nanoparticles increases inflammatory vascular disease risk: an implication of an ex vivo biosensor assay.

BACKGROUND: Among manufactured or engineered nanoparticles, carbon black (CB) has largest production worldwide and is also an occupational respiratory hazard commonly seen in rubber industry. Few studies have assessed the risk for cardiovascular disease in carbon black exposed populations. An endothelial biosensor assay was used to quantify the capacity of sera from 82 carbon black packers (CBP) and 106 non-CBPs to induce endothelial cell activation ex vivo. The mediation effect of circulatory proinflammatory factors on the association between carbon black exposure and endothelial cell activation was assessed and further validated using in vitro intervention experiments. RESULTS: The average elemental carbon level inside carbon black bagging facilities was 657.0 µg/m3, which was 164-fold higher than that seen in reference areas (4.0 µg/m3). A global index was extracted from mRNA expression of seven candidate biosensor genes using principal component analysis and used to quantify the magnitude of endothelial cell activation. This global index was found to be significantly altered in CBPs compared to non-CBPs (P < 0.0001), however this difference did not vary by smoking status (P = 0.74). Individual gene analyses identified that de novo expression of key adhesion molecules (e.g., ICAM and VCAM) and chemotactic factors (e.g., CCL2, CCL5, and CXCL8) responsible for the recruitment of leukocytes was dramatically induced in CBPs with CXCL8 showing the highest fold of induction (relative quantification = 9.1, P < 0.0001). The combination of mediation analyses and in vitro functional validation confirmed TNF-α, IL-1ß, and IL-6 as important circulatory factors mediating the effects of carbon black exposure on endothelial cell activation responses. CONCLUSIONS: Inflammatory mediators in sera from CBPs may bridge carbon black exposure and endothelial cell activation response assessed ex vivo. CBPs may have elevated risk for cardiovascular diseases when comorbidity exists. Our study may serve as a benchmark for understanding health effects of engineered carbon based nanoparticles with environmental and occupational health relevance.

Anticancer Therapy-Related Increases in Arterial Stiffness: A Systematic Review and Meta-Analysis.

Background Cardio-oncology is a clinical discipline focused primarily on the early detection of anticancer therapy-related cardiomyopathy. However, there is growing evidence that the direct adverse consequences extend beyond the myocardium to affect the vasculature, but this evidence remains limited. In addition, there remains a paucity of clinically based strategies for monitoring vascular toxicity in these patients. Importantly, arterial stiffness is increasingly recognized as a surrogate end point for cardiovascular disease and may be an important vascular outcome to consider. Therefore, the aim of this systematic review and meta-analysis was to summarize evidence of increased arterial stiffening with anticancer therapy and evaluate the effect of treatment modifiers. Methods and Results A total of 19 longitudinal and cross-sectional studies that evaluated arterial stiffness both during and following anticancer therapy were identified using multiple databases. Two separate analyses were performed: baseline to follow-up (12 studies) and control versus patient groups (10 studies). Subgroup analysis evaluated whether stiffness differed as a function of treatment type and follow-up time. Standard mean differences and mean differences were calculated using random effect models. Significant increases in arterial stiffness were identified from baseline to follow-up (standard mean difference, 0.890; 95% CI, 0.448-1.332; P<0.0001; mean difference, 1.505; 95% CI, 0.789-2.221; P≤0.0001) and in patient versus control groups (standard mean difference, 0.860; 95% CI, 0.402-1.318; P=0.0002; mean difference, 1.437; 95% CI, 0.426-2.448; P=0.0052). Subgroup analysis indicated differences in arterial stiffness between anthracycline-based and non-anthracycline-based therapies (standard mean difference, 0.20; 95% CI, 0.001-0.41; P=0.048), but not follow-up time. Conclusions Significant arterial stiffening occurs following anticancer therapy. Our findings support the use of arterial stiffness as part of a targeted vascular imaging strategy for the identification of early cardiovascular injury during treatment and for the detection of long-term cardiovascular injury into survivorship.

Vascular effects of cancer treatments.

Chemotherapy, alone or in association with radiation therapy, has represented the cornerstone of cancer treatment for decades. However, in the last several years, an unprecedented progress in the understanding of cancer biology and the discovery of novel therapeutic targets have led to a paradigm shift in the management of patients with neoplastic diseases. The introduction of tyrosine kinase inhibitors, vascular endothelial growth factor pathway inhibitors, immunomodulatory agents, proteasome inhibitors, immune checkpoint inhibitors, and chimeric antigen receptor T cells, among others, has been associated with prolonged survival in many forms of cancer. A common feature of both chemotherapy and novel cancer treatments is the frequent occurrence of vascular toxicity, mainly mediated by injury to the endothelium. While the mechanisms may vary between agents, the clinical manifestations may overlap and range from hypertension, vasospastic and thrombotic arterial events (myocardial ischemia and infarction, peripheral ischemia, and limb gangrene), venous thromboembolism (deep vein thrombosis and pulmonary embolism) to capillary leak syndrome. Therefore, the effective management of patients with cancer requires a multidisciplinary team approach in which oncologist and cardiovascular medicine specialists work together to prevent, detect, and minimize acute vascular toxicity and long-term consequences of cancer therapy.

The Effect of Perimenopausal Transdermal Estradiol and Micronized Progesterone on Markers of Risk for Arterial Disease.

BACKGROUND: The arterial effects of hormone therapy remain controversial. This study tested the effects of transdermal estradiol plus intermittent micronized progesterone (TE + IMP) in healthy perimenopausal and early postmenopausal women on several mechanisms involved in the pathophysiology of arterial disease. METHODS: Healthy perimenopausal and early postmenopausal women, ages 45 to 60 years, were enrolled in this randomized, double-blind, placebo-controlled trial. Women were randomized to receive TE (0.1 mg/day) + IMP (200 mg/day for 12 days) or identical placebo patches and pills for 12 months. Outcomes included: change in stress reactivity composite z-score (combining inflammatory, cortisol, and hemodynamic responses to a standardized psychological laboratory stressor); flow-mediated dilation (FMD) of the brachial artery (an index of vascular endothelial function); baroreflex sensitivity; and metabolic risk (presence of the metabolic syndrome or insulin resistance), all assessed at baseline and at months 6 and 12. RESULTS: Of 172 women enrolled, those assigned to TE + IMP tended to have higher resting baroreflex sensitivity than those assigned to placebo across the 6- and 12-month visits. Although treatment groups did not differ in terms of the other prespecified outcomes, a significant treatment-by-age interaction was found for FMD and stress reactivity such that an age-related decrease in FMD and increase in stress reactivity were seen among women assigned to placebo but not those assigned to TE + IMP. Women on TE + IMP also had lower resting diastolic blood pressure, lower levels of low-density lipoprotein cholesterol, and higher baroreflex sensitivity during stress testing. CONCLUSIONS: TE + IMP tended to improve cardiac autonomic control and prevented age-related changes in stress reactivity and endothelial function among healthy perimenopausal and early postmenopausal women.

Common Vascular Toxicities of Cancer Therapies.

The introduction of targeted agents into modern cancer therapy pursued the goal of molecularly more specific, and thereby more effective and safer, therapies. Paradoxically, however, several toxicities were brought to greater attention, among these not only cardiac but also vascular toxicities. The latter reach far beyond venous thromboembolism and include a broad spectrum of presentations based on the vascular territories and pathomechanisms involved, including abnormal vascular reactivity, acute thrombosis, or accelerated atherosclerosis. This article provides an overview of the most common presentations and their management strategies.

Acute vascular events as a possibly related adverse event of immunotherapy: a single-institute retrospective study.

AIM: Immune-related toxicities of immune checkpoint inhibitors (CPIs) require prompt diagnosis and treatment. Atherosclerosis has an inflammatory component; we speculated this inflammation could be enhanced by CPIs. We aimed to evaluate the risk of acute vascular events (AVEs) on CPIs. METHODS: Patients treated by CPIs in Sheba Medical Center (Israel) between January 2015 and May 2018 were retrospectively identified from electronic medical records. AVEs were identified and verified by chart review. Age, sex, diabetes, hypertension, smoking, dyslipidemia, previous AVE, renal failure, cancer type and specific treatments were evaluated as potential risk factors. AVE rate on CPIs was compared with that on chemotherapy or on combined chemo-immunotherapy in patients with lung adenocarcinoma. Survival of patients with AVEs was compared with that of patients without AVEs. RESULTS: CPI was administered to 1215 patients. AVEs within six months after CPI initiation occurred in 2.6% (95% confidence interval [CI]: 1.8-3.6) of patients, more common than in later time periods. In lung adenocarcinoma, event rate was 5.2% (95% CI: 2.8-9.2). Lung adenocarcinoma, prior AVE, hypertension and dyslipidemia were correlated with AVEs. AVE rate in patients with non-small cell lung cancer adenocarcinoma was similar whether on chemotherapy or on CPI. Survival of patients with AVEs was worse than that of those without AVEs. CONCLUSION: The similarly increased rates of AVEs for patients on CPI, on chemotherapy or on both suggest that although CPI may not augment the risk of AVE over that of chemotherapy, it carries a similar and significant risk of such adverse event. Caution should be exercised for patients with risk factors for AVEs.

Egg White Hydrolysate: A new putative agent to prevent vascular dysfunction in rats following long-term exposure to aluminum.

Aluminum (Al) is toxic for humans and animals. Here, we have tested the potential for Egg White Hydrolysate (EWH) to protect against cardiovascular changes in rats exposed to both high and low dietary levels of Al. Indeed, EWH has been previously shown to improve cardio metabolic dysfunctions induced by chronic exposure to heavy metals. Male Wistar rats received orally: Group 1) Low aluminum level (AlCl3 at a dose of 8.3 mg/kg b.w. during 60 days) with or without EWH treatment (1 g/kg/day); Group 2) High aluminum level (AlCl3 at a dose of 100 mg/kg b.w. during 42 days) with or without EWH treatment. After Al treatment, rats co-treated with EWH did not show vascular dysfunction or increased blood pressure as was observed in non EWH-cotreated animals. Indeed, co-treatment with EWH prevented the following effects observed in both aorta and mesenteric arteries: the increased vascular responses to phenylephrine (Phe), the decreased ACh-induced relaxation, the reduction on endothelial modulation of vasoconstrictor responses and the nitric oxide bioavailability, as well as the increased reactive oxygen species production from NAD(P)H oxidase. Altogether, our results suggest that EWH could be used as a protective agent against the harmful vascular effects after long term exposure to Al.

Crocin attenuates lung inflammation and pulmonary vascular dysfunction in a rat model of bleomycin-induced pulmonary fibrosis.

Amongst the various forms of lung injury; pulmonary fibrosis remains the most intricate form with limited therapeutic options to both the patient and the physicians. Bleomycin (BLM) is a chemotherapeutic agent used for the treatment of various carcinomas; however, its therapeutic value is significantly limited by its associated pulmonary fibrosis. The current study highlights the prominent antioxidant, anti-inflammatory and anti-fibrotic effect of crocin against BLM-induced pulmonary fibrosis. Intratracheal BLM instillation induced significant biochemical, structural, functional and vascular pulmonary injury. BLM instillation increased oxidant load with quenching of antioxidant defenses together with increase inflammatory and fibrotic cytokines expression. Crocin significantly attenuated BLM-induced lung injury and its effect was comparable to the standard anti-fibrotic; halofuginone. The observed anti-inflammatory and anti-fibrotic and antioxidant impacts are thought to be embroiled in the therapeutic impacts of crocin. Down-regulation of TLR4, IL-10 expression is the major pathway involved in the observed anti-inflammatory effects and finally, down-regulation of tissue expression of TNF-α and TGF-ß1 is the major pathways implicated in the observed anti-fibrotic activities and modulation of Nrf2 and HO-1 pathways is the main mechanism involved in the observed antioxidant effects.

Perinatal iron deficiency combined with a high salt diet in adulthood causes sex-dependent vascular dysfunction in rats.

KEY POINTS: Perinatal iron deficiency causes changes in offspring mesenteric artery function in adulthood, particularly in males, which can be exacerbated by chronic intake of a high salt diet. Perinatal iron deficient male offspring exhibit enhanced conversion of big endothelin-1 to active endothelin-1, coinciding with decreased nitric oxide levels. Perinatal iron deficient male offspring have reduced nitric oxide-mediated endothelial-dependent vasodilatation coincident with increased vascular superoxide levels following consumption of a high salt diet. Perinatal iron deficiency has no apparent effects on vascular function in female offspring, even when fed a high salt diet. These results help us better understand underlying vascular mechanisms contributing to increased cardiovascular risk from perinatal stressors such as iron deficiency. ABSTRACT: Pre- and immediate postnatal stressors, such as iron deficiency, can alter developmental trajectories and predispose offspring to long-term cardiovascular dysfunction. Here, we investigated the impact of perinatal iron deficiency on vascular function in the adult offspring, and whether these long-term effects were exacerbated by prolonged consumption of a high salt diet in adulthood. Female Sprague Dawley rats were fed either an iron-restricted or -replete diet prior to and throughout pregnancy. Six weeks prior to experimentation at 6 months of age, adult offspring were fed either a normal or high salt diet. Mesenteric artery responses to vasodilators and vasoconstrictors were assessed ex vivo by wire myography. Male perinatal iron deficient offspring exhibited decreased reliance on nitric oxide with methacholine-induced vasodilatation (interaction P = 0.03), coincident with increased superoxide levels when fed the high salt diet (P = 0.01). Male perinatal iron deficient offspring exhibit enhanced big endothelin-1 conversion to active endothelin-1 (P = 0.02) concomitant with decreased nitric oxide levels (P = 0.005). Female offspring vascular function was unaffected by perinatal iron deficiency, albeit the high salt diet was associated with impaired vasodilation and decreased nitric oxide production (P = 0.02), particularly in the perinatal iron deficient offspring. These findings implicate vascular dysfunction in the sex-specific programming of cardiovascular dysfunction in the offspring by perinatal iron deficiency.

Nobiletin Prevents Trimethylamine Oxide-Induced Vascular Inflammation via Inhibition of the NF-κB/MAPK Pathways.

Dietary choline and its containing foods are biotransformed to trimethylamine (TMA) via gut microbial metabolism. Subsequently, as an intermediate molecule, TMA is quickly transported and oxidized in the liver by hepatic flavin monooxygenases to form trimethylamine oxide (TMAO). TMAO was treated as a waste byproduct from choline metabolism, but recent convincing evidence demonstrated the association between the small molecule TMAO and inflammation-related diseases, including blood vessel inflammation and vascular diseases. The scope of this study is to investigate the preventive effect of nobiletin on TMAO-induced blood vessel inflammation. Our results from Western blot showed that the inhibition of TMAO-induced cardiovascular inflammation was correlated with nobiletin-mediated inhibitory effects on NF-κB and MAPK/ERK related pathways. More specifically, nobiletin prevented the oxidative damage of vascular sites (proximal aorta), inhibited the activity of MAPK/ERK, reduced the expression of NF-κB p65 and phospho-NF-κB p65, and consequently decreased the inflammatory response. Flow cytometry analyses showed that nobiletin decreased TMAO-induced apoptosis of HUVEC cells and counteracted TMAO-induced HUVEC cell proliferation. Results from HE staining and immunohistochemical results also showed that nobiletin reduced the degree of inflammation of the proximal aorta in Sprague-Dawley rats. In summary, nobiletin significantly reduced TMAO-induced vascular inflammation via inhibition of the NF-κB/MAPK pathways.