Effects of S-Allylcysteine-Rich Garlic Extract and Dietary Inorganic Nitrate Formula on Blood Pressure and Salivary Nitric Oxide: An Open-Label Clinical Trial Among Hypertensive Subjects.

INTRODUCTION:  The conversion of dietary inorganic nitrate (NO3-) to nitric oxide (NO) is a non-canonical pathway that plays an important role in NO biology, especially under pathological conditions. Inorganic NO3- supplementation is a proven method for controlling mild hypertension. Recent reports have suggested that another gaseous transmitter, hydrogen sulfide (H2S), influences NO biosynthesis and metabolism. Here, data are presented from an open-label clinical trial examining the effect of an encapsulated formulation (Vascanox® HP) that combines dietary sources of inorganic NO3- and S-allylcysteine (SAC), a source of H2S from garlic, on NO bioavailability and blood pressure in subjects experiencing elevated blood pressure or mild hypertension. METHODS:  An open-label clinical trial was conducted among patients with hypertension. Participants took Vascanox® for four weeks. Blood pressure was measured at baseline, two weeks, and four weeks. Salivary nitrite (NO2-), a surrogate of NO bioavailability, and NO3- were assessed prior to and two, six, and 24 hours after dosing on the first day of the study and prior to and two hours after dosing at subsequent study visits using saliva NO test strips. Changes in study outcomes over time were evaluated via analysis of variance (ANOVA) and paired t-tests. RESULTS:  Twelve participants completed the clinical trial. Vascanox® HP decreased systolic blood pressure by ~11 mmHg (p < 0.001) at two weeks and persisted beyond four weeks with daily supplementation. It also decreased the diastolic blood pressure of hypertensive subjects but not normotensive ones. The magnitude of the decrease was 11 mmHg (p < 0.01) at four weeks of study. Measurements of salivary concentrations of NO2- revealed high peak levels (743 uM) at two hours post-administration and a slow decay to elevated levels (348 uM) at 24 hours. NO2- salivary concentrations, a surrogate biomarker of NO bioavailability, remained above baseline for the duration of the study. CONCLUSIONS:  Vascanox® HP was shown to be a safe, effective, quick-acting, and long-lasting dietary supplement for controlling mild hypertension.

Inverse association between hypertension treatment and COVID-19 prevalence in Japan.

OBJECTIVES: Cell entry of SARS-CoV-2 depends on angiotensin-converting enzyme II. Angiotensin-converting enzyme II is homologous with, but acts antagonistically to, angiotensin-converting enzyme and has the critical function of protecting the lungs. Angiotensin-converting enzyme inhibitors are major antihypertensive agents. Thus, we aimed to analyze the impact of the prevalence of preexisting hypertension on the local spread of COVID-19. METHODS: Data on SARS-CoV-2 infection and the estimated number of patients who received medical treatment on the basis of disease classification using the International Statistical Classification of Diseases and Related Health Problems (10th Revision) in each prefecture were obtained from the official Japanese notifications database. We analyzed the association between the proportion of patients with each disease and SARS-CoV-2-infection prevalence. RESULTS: The ratio of patients treated for diseases of the circulatory system, especially hypertensive disorders, per population demonstrated the most significant negative correlation with SARS-CoV-2-infection prevalence (Spearman's rank correlation, P < 0.01). Age group analysis revealed a significant negative correlation in age groups 35-44, 45-54, 55-64, 75-84, and ≥85. CONCLUSIONS: Our findings suggest that hypertension treatment may play a protective role against the local spread of SARS-CoV-2 infection.

Effect of a plant-based bioequivalent inorganic nitrate (NO3-) complex with vitamins, antioxidants and phytophenol rich food extracts in hypertensive individuals - A randomized, double-blind, placebo-controlled study.

BACKGROUND: This study assessed efficacy of plant based bioequivalent nitrate complex, consist of vitamins, natural antioxidants and phytophenol rich food extracts to elevate nitric oxide (NO) bioavailability as determined by saliva conversion of nitrate (NO3-) to nitrite (NO2-) a required step to produce NO, in relationship to lowering blood pressure (BP) in both men and women. METHODS: 67 individuals (26 men; mean age of 59.3 ± 9.0 yrs) with mean baseline systolic and diastolic BP >120 and 80 mmHg respectively were randomized to receive daily dosing of 314 mM NO3- or NO3- free (placebo) tablets in double-blinded study for 12 weeks (wks). Inorganic NO3- tablets consist of NO3- rich beetroot extract, thiamine nitrate, and potassium nitrate in the presence of ascorbic acid, to facilitate NO bioavailability. RESULTS: The primary endpoint of the study was reduction in BP at 12 wks by improving endothelial function. At study conclusion, mean ± SD reduction in systolic BP (SBP) in the inorganic NO3- group was 12.5 ± 13.3 mmHg (p = 0.0007), as compared to 6.19 ± 11.39 mmHg (p = 0.004) in the placebo group, for a placebo-corrected reduction of -6.31 mmHg (95% CI 10.89-2.31, p = 0.04). NO3- also reduced diastolic BP by 4.7 ± 10.3 mmHg (p = 0.01), while no significant reduction in placebo group (1.98 ± 9.38 mmHg, p = 0.24) was noted. Endothelial function improved at 12 weeks by 0.8 ± 3.1 (p = 0.03) in active group when compared to 0.1 ± 1.8 (p = 0.82) in placebo group. CONCLUSION: Endothelial function improved robustly reducing both systolic and diastolic BP in hypertensive individuals with daily supplementation of dietary NO3-. CLINICALTRIALS. GOV ID: NCT03909789.

2-methoxyestradiol up-regulates death receptor 5 and induces apoptosis through activation of the extrinsic pathway.

2-Methoxyestradiol (2ME2), a natural metabolite of estradiol, is a potent antitumor and antiangiogenic agent. In vitro, 2ME2 inhibits the proliferation of a wide variety of cell lines and primary cultures, and in numerous models in vivo, it has been shown to be an effective inhibitor of tumor growth and angiogenesis. 2ME2 is currently in several Phase I and Phase II clinical trials under the name Panzem. Although various molecular targets have been proposed for this compound, the mechanism by which 2ME2 exerts its effects is still uncertain. This study shows that 2ME2 uses the extrinsic pathway for induction of apoptosis. 2ME2 treatment results in up-regulation of death receptor 5 (DR5) protein expression in vitro and in vivo and renders cells more sensitive to the cytotoxic activities of the DR5 ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). 2ME2-induced apoptosis requires caspase activation and kinetic studies show the sequential activation of caspase-8, caspase-9, and caspase-3. Blockage of death receptor signaling by expression of dominant-negative Fas-associated death domain severely attenuates the ability of 2ME2 to induce apoptosis. Because 2ME2 administration has not manifested dose-limiting toxicity in the clinic, DR5 expression may serve as a surrogate marker for biological response.

Tissue factor/factor VIIa inhibitors block angiogenesis and tumor growth through a nonhemostatic mechanism.

An association between cancer and thrombosis has been recognized for more than a century. However, the manner by which tumor growth is regulated by coagulation in vivo remains unclear. To assess the role of coagulation on tumor growth, in vivo, we tested coagulation inhibitors specific for either tissue factor (TF)/factor VIIa (fVIIa) complexes or factor Xa (fXa) for antitumor activity. Here, we show that two inhibitors of TF/fVIIa, TF pathway inhibitor (TFPI) and the nematode anticoagulant protein rNAPc2, inhibit both primary and metastatic tumor growth in mice. In addition, we show that rNAPc2 is also a potent inhibitor of angiogenesis. In contrast, rNAP5, a second nematode anticoagulant protein that specifically inhibits fXa, does not exhibit antitumor activity. Because the hemostatic activity of TF/fVIIa is mediated through activation of fXa, these data suggest that proteolytic activity of TF/fVIIa promotes tumor growth and angiogenesis through a novel proangiogenic mechanism and independently of hemostasis.

2-Methoxyestradiol inhibits proliferation and induces apoptosis independently of estrogen receptors alpha and beta.

2-Methoxyestradiol (2ME(2)) is an endogenous metabolite of 17beta-estradiol (E(2)) that arises from the hydroxylation and subsequent methylation at the 2-position. In vitro 2ME(2) inhibits a large variety of tumor and nontumor cell lines from diverse origins, as well as several stages of the angiogenic cascade. In vivo it has been shown to be a very effective inhibitor of tumor growth and angiogenesis in numerous models. Although various molecular targets have been proposed for this compound, the mechanism of action is still uncertain. As this molecule emerges as a drug candidate it is important to assess the estrogen receptors (ERs) as molecular targets for 2ME(2). The purpose of this study was to investigate whether 2ME(2) is able to engage ERs as an agonist and whether its antiproliferative activities are mediated through ERs. We confirm that 2ME(2) has a lower binding affinity for ERalpha as compared with E(2) and other E(2) metabolites and antagonists, and we demonstrate that the affinity of 2ME(2) for ERbeta is even lower. When assessed in the presence of galangin, a cytochrome P450 enzyme inhibitor, at concentrations at which 2ME(2) interacts with ERalpha in an in vitro binding assay, it does not stimulate the proliferation of an estrogen-dependent breast carcinoma cell line. Similar IC(50) values for inhibition of proliferation and induction of apoptosis are obtained in estrogen-dependent and estrogen-independent human breast cancer cell lines, irrespective of the expression of ERalpha and ERbeta. Moreover, the estrogen antagonist ICI 182,780 does not inhibit the antiproliferative activity of 2ME(2). In E(2)-responsive cells such as MCF-7 and human umbilical vascular endothelial cells, high levels of E(2) inhibit the antiproliferative activity of ICI 182,780 but not of 2ME(2). Collectively, these results suggest that 2ME(2) is distinct among estradiol metabolites because of its inability to engage ERs as an agonist, and its unique antiproliferative and apoptotic activities are mediated independently of ERalpha and ERbeta.