Hypoxia-Inducible Factor-1α: The Master Regulator of Endothelial Cell Senescence in Vascular Aging

Aging is one of the hottest topics in biomedical research. Advances in research and medicine have helped to preserve human health, leading to an extension of life expectancy. However, the extension of life is an irreversible process that is accompanied by the development of aging-related conditions such as weakness, slower metabolism, and stiffness of vessels. It also debated that aging can be considered an actual disease with aging-derived comorbidities, including cancer or cardiovascular disease. Currently, cardiovascular disorders, including atherosclerosis, are considered as premature aging and represent the first causes of death in developed countries, accounting for 31% of annual deaths globally. Emerging evidence has identified hypoxia-inducible factor-1α as a critical transcription factor with an essential role in aging-related pathology, in particular, regulating cellular senescence associated with cardiovascular aging. In this review, we will focus on the regulation of senescence mediated by hypoxia-inducible factor-1α in age-related pathologies, with particular emphasis on the crosstalk between endothelial and vascular cells in age-associated atherosclerotic lesions. More specifically, we will focus on the characteristics and mechanisms by which cells within the vascular wall, including endothelial and vascular cells, achieve a senescent phenotyp

Magnitude of benefit of the addition of bevacizumab to first-line chemotherapy for metastatic colorectal cancer: meta-analysis of randomized clinical trials

<p>Abstract</p> <p>Background</p> <p>Although the addition of bevacizumab to 1^stline chemotherapy provides a significant survival benefit for advanced colorectal cancer, the magnitudes of both advantages and toxicities have not been extensively investigated.</p> <p>Methods</p> <p>A literature-based meta-analysis was conducted; Hazard Ratios were extracted from randomized trials for primary end-points (Progression Free Survival, PFS, Overall Survival OS). The log of event-based risk ratio were derived for secondary endpoints (objective/partial response rate, ORR/PR; severe hypertension, bleeding and proteinuria). Absolute differences and the number needed to treat/harm (NNT/NNH) were calculated. A meta-regression analysis with clinical predictors and a sensitivity analysis according to the trial phase-design were conducted as well.</p> <p>Results</p> <p>Five trials (2,728 pts) were selected. The addition of bevacizumab to 1^stline chemotherapy significantly increased both PFS (although with significant heterogeneity) and OS over exclusive chemotherapy by 17.1% and 8.6% (NNT 6 and 12), regardless of the study setting (non significant interaction between phase II and III). The chance to improve PR was significantly increased by 6.5% (NNT 15), with a trend for ORR. The risk of hypertension was significantly increased by 6.2% (NNH 16). According to the meta-regression analysis, female gender and rectal primary site were significant predictors for PFS benefit.</p> <p>Conclusions</p> <p>Notwithstanding all the concerns related to costs and the significant HTN risk, the significant outcome improvement provided by bevacizumab in first-line treatment for unselected advanced colorectal cancer patients, should be considered when choosing the appropriate up-front therapy.</p

Child health promotion in underserved communities: The FAMILIA trial

Background: Preschool-based interventions offer promise to instill healthy behaviors in children, which can be a strategy to reduce the burden of cardiovascular disease later. However, their efficacy in underserved communities is not well established. Objectives: The purpose of this study was to assess the impact of a preschool-based health promotion educational intervention in an underserved community. Methods: This cluster-randomized controlled study involved 15 Head Start preschools in Harlem, New York. Schools and their children were randomized 3:2 to receive either a 4-month (50 h) educational intervention to instill healthy behaviors in relation to diet, physical activity, body/heart awareness, and emotion management; or their standard curriculum (control). The primary outcome was the change from baseline in the overall knowledge, attitudes, and habits (KAH) score of the children at 5 months. As secondary outcomes, we evaluated the changes in KAH subcomponents and emotion comprehension. Linear mixed-effects models were used to test for intervention effects. Results: The authors enrolled 562 preschool children age 3 to 5 years, 51% female, 54% Hispanic/Latino, and 37% African-American. Compared with the control group, the mean relative change from baseline in the overall KAH score was ∼2.2 fold higher in the intervention group (average absolute difference of 2.86 points; 95% confidence interval: 0.58 to 5.14; p = 0.014). The maximal effect was observed in children who received >75% of the curriculum. Physical activity and body/heart awareness components, and knowledge and attitudes domains, were the main drivers of the effect (p values <0.05). Changes in emotion comprehension trended toward favoring intervened children. Conclusions: This multidimensional school-based educational intervention may be an effective strategy for establishing healthy behaviors among preschoolers from a diverse and socioeconomically disadvantaged community. Early primordial prevention strategies may contribute to reducing the global burden of cardiovascular disease. (Family-Based Approach in a Minority Community Integrating Systems-Biology for Promotion of Health [FAMILIAThis study is funded by the American Heart Association under grant No. 14SFRN20490315. The CNIC is supported by the Ministerio de Ciencia, Innovación y Universidades and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). Dr. Fernandez-Jimenez is a recipient of funding from the European Union Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 707642. Dr. Bansilal is an employee of Bayer Pharmaceutical

Neutralizing antibodies to Omicron after the fourth SARS-CoV-2 mRNA vaccine dose in immunocompromised patients highlight the need of additional boosters

IntroductionImmunocompromised patients have been shown to have an impaired immune response to COVID-19 vaccines.MethodsHere we compared the B-cell, T-cell and neutralizing antibody response to WT and Omicron BA.2 SARS-CoV-2 virus after the fourth dose of mRNA COVID-19 vaccines in patients with hematological malignancies (HM, n=71), solid tumors (ST, n=39) and immune-rheumatological (IR, n=25) diseases. The humoral and T-cell responses to SARS-CoV-2 vaccination were analyzed by quantifying the anti-RBD antibodies, their neutralization activity and the IFN-γ released after spike specific stimulation.ResultsWe show that the T-cell response is similarly boosted by the fourth dose across the different subgroups, while the antibody response is improved only in patients not receiving B-cell targeted therapies, independent on the pathology. However, 9% of patients with anti-RBD antibodies did not have neutralizing antibodies to either virus variants, while an additional 5.7% did not have neutralizing antibodies to Omicron BA.2, making these patients particularly vulnerable to SARS-CoV-2 infection. The increment of neutralizing antibodies was very similar towards Omicron BA.2 and WT virus after the third or fourth dose of vaccine, suggesting that there is no preferential skewing towards either virus variant with the booster dose. The only limited step is the amount of antibodies that are elicited after vaccination, thus increasing the probability of developing neutralizing antibodies to both variants of virus.DiscussionThese data support the recommendation of additional booster doses in frail patients to enhance the development of a B-cell response directed against Omicron and/or to enhance the T-cell response in patients treated with anti-CD20

Role of endothelial pathways in modulating the endogenous fibrinolytic system in humans

The endothelium plays a crucial role in the control of flow, coagulation, fibrinolysis and inflammation. To date, several clinical studies have focused on the assessment of endothelium-dependent vasomotion as a surrogate measure of endothelial function. However, endothelium-dependent vasodilation may not be representative of other important aspects of endothelial function, such as the regulation of fibrinolytic system. This is a crucial aspect to investigate since the initiation, progression and resolution of thrombus associated with eroded or unstable coronary plaque are critically dependent on the efficacy of endogenous fibrinolysis. In particular, the acute release of tissue-type plasminogen activator (t-PA), the main activator of fibrinolysis, from the endothelium strongly contributes to the defense against intravascular thrombosis. The aim of the following studies was to investigate the role of endothelial pathways in the regulation of endothelial t-PA release in physiological condition and in patients with essential hypertension. The first aim was to determine the possible regulatory role of nitric oxide (NO)-synthase pathway in modulating endothelial t-PA release in healthy conditions and in a clinical condition characterized by impaired NO availability and increased cardiovascular risk, such as essential hypertension. In healthy volunteers and essential hypertensive patients, we studied local t-PA release and forearm blood flow changes (strain-gauge plethysmography) induced by intrabrachial administration of acetylcholine (0.45-1.5 µg/100mL/min), and of sodium nitroprusside (0.5-1.0 µg/100 mL/min), an endothelium-dependent and –independent agonist, respectively. Acetylcholine was also repeated in the presence of intra-arterial infusion of the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) (100 µg/100mL/ min). In normotensive subjects, vasodilation to acetylcholine was blunted by L-NMMA. In these subjects, acetylcholine infusion induced a significant, dose-dependent increase in net forearm t-PA release. The inhibition of NO synthase with L-NMMA significantly reduced basal as well as acetylcholine-induced t-PA release. In essential hypertensive patients, vasodilation to acetylcholine was reduced as compared to controls and resistant to L-NMMA. In contrast to what observed in healthy controls, in hypertensive patients acetylcholine had no effect on t-PA release and L-NMMA failed to affect either tonic or agonist-induced t-PA release. In conclusion, both tonic and agonist-induced release of NO are directly involved on t-PA release by endothelial cells. Essential hypertension, characterized by a reduction in both tonic and stimulated NO availability, is also associated with impaired capacity of t-PA release. Taken together these findings suggest major role of impaired nitric oxide availability in worsening not only endothelium-dependent vasodilation but also t-PA release from endothelial cells. The second aim of our studies was to determine the relationship between adrenergic stimuli and NO in modulating t-PA release from endothelial cells in the forearm microcirculation of healthy subjects and essential hypertensive patients. Sympathetic activation is a well known stimulus for fibrinolysis and it is also involved in the determination of cardiovascular risk in essential hypertension. However, whether a cross-talk between adrenergic stimuli and NO pathway in modulating t-PA release exists is still unknown. In this study we assessed the release of t-PA in the forearm microcirculation of healthy subjects and essential hypertensive patients under specific intra-arterial adrenergic stimuli. Adrenaline induced t-PA release was significantly higher in healthy subjects as compared to hypertensive patients. L-NMMA infusion blunted adrenaline-induced t-PA release in healthy subjects but not in hypertensive patients. In healthy controls, t-PA release by adrenaline, not affected by the beta-blocker phentolamine co-infusion, was abolished in the presence of the beta-blocker propanolol. The beta-agonist isoproterenol induced a significant increase in t-PA release, an effect blunted by L-NMMA co-infusion. In hypertensive patients, response to isoproterenol was impaired and unaffected by L-NMMA. In conclusion, adrenergic-induced t-PA release is mediated by beta-adrenoreceptors via a mechanism which involves the activation of NO pathway. The reduced NO availability characterizing essential hypertension impairs adrenergic-stimulated t-PA release, thereby reducing endothelial fibrinolytic capacity in this clinical condition. Finally, in the third study we sough to evaluate the role of cytochrome P450 2C9 (CYP 2C9)-derived endothelium-derived hyperpolarizing factor (EDHF) in the modulation of local t-PA release in healthy subjects and in essential hypertensive patients by utilizing sulfaphenazole, a selective CYP 2C9 inhibitor. The vasoactive role of CYP 2C9-derived EDHF and its compensatory role in the presence of impaired NO availability are well documented. CYP 2C9-derived EDHF also modulates t-PA expression and release from culture endothelial cells. However, no regulatory role on endogenous fibrinolysis has been documented in humans. The release of t-PA was measured in the forearm microcirculation of 42 healthy subjects and 44 essential hypertensive patients following intra-brachial bradykinin (0.015 µg/100mL/min), either in the absence or in the presence of sulfaphenazole (0.03 µg/100 ml/min). The infusion of bradykinin was repeated in the presence of NG-monomethyl-L-arginine (L-NMMA) (100 µg/100mL/ min) and/or sulfaphenazole (0.03 µg/100 ml/min). Bradykinin-induced t-PA release was significantly (p<0.05) higher in healthy subjects as compared to hypertensive patients. Sulfaphenazole significantly (p<0.01) blunted t-PA release in both groups. In healthy subjects, L-NMMA infusion, significantly (p<0.01) reduced t-PA release. When L-NMMA was co-infused with sulfaphenazole stimulated t-PA release was further reduced (p<0.01). In hypertensive patients, while t-PA release was unaffected by L-NMMA, the co-infusion of sulfaphenazole alone or sulfaphenazole plus L-NMMA significantly (p<001) reduced bradykinin-induced t-PA release. These findings show that CYP 2C9-derived EDHF modulates bradykinin-induced t-PA release in humans. In essential hypertension, t-PA release depends exclusively on EDHF pathway, which is an ineffective compensatory mechanism in the presence of impaired NO availability

On reduction of the drug diflunisal in non-acqueous media

The electrochemical reduction of diflunisal was studied in dimethyl sulfoxide on static mercury drop electrode. Diflunisal yields one irreversible wave at -1.2 V (vs. Ag | AgCl | 1 M LiCl electrode) due to the reduction of the carboxylic functional group in the molecule. The electrochemical properties of the drug were compared with the ones of the chlorinated analogue. The study is based on cyclic voltammetry, tast polarography, and constant potential electrolysis. The experimental findings are supported by molecular orbital calculations. The mechanism of reduction of the carboxylic moiety was found to involve two electrons and two protons. The reduction pathway leads to formation of an aldehyde derivative