Tet2 deficiency in hematopoietic cells is associated with greater cardiac dysfunction in murine models of heart failure as a result of elevated IL-1β signaling. These data suggest that individuals with TET2-mediated clonal hematopoiesis may be at greater risk of developing heart failure and respond better to IL-1β-NLRP3 inflammasome inhibition.

Experiments using lentivirus vector/CRISPR methodology provided evidence suggesting that inactivating DNMT3A mutations in hematopoietic cells contributes to cardiovascular disease. Comparative analyses showed that inactivation of Tet2 and Dnmt3 was similar in their ability to promote Ang II-induced cardiac dysfunction and renal fibrosis in mice. However, gene-specific actions were indicated by differences in kinetics of hematopoietic stem/progenitor cell expansion and different patterns of inflammatory gene expression.

Curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] is the active ingredient of turmeric, which has a long history of being consumed as a dietary spice.1) In addition, turmeric is widely used in traditional Indian medicine to treat biliary disorders, anorexia, cough, diabetic complications, hepatic disorders, rheumatism, and sinusitis.2) Extensive investigation over the past five decades has indicated that curcumin reduces blood cholesterol, prevents low-density lipoprotein oxidation, inhibits platelet aggregation, suppresses thrombosis and myocardial infarction, suppresses symptoms associated with type 2 diabetes, rheumatoid arthritis, multiple sclerosis, and Alzheimer's disease, inhibits human immunodeficiency virus (HIV) replication, enhances wound healing, protects against liver injury, increases bile secretion, protects from cataract formation, and protects against pulmonary toxicity and fibrosis.3-5) Evidence indicates that the divergent effects of curcumin are dependent on its pleiotropic molecular effects.In spite of these attractive properties of curcumin, information on the therapeutic efficiency of curcumin has been limited, partly due to its poor oral bioavailability. 6) Curcumin was found to be poorly soluble in water, the maximum solubility of which in aqueous buffer (pH 5.0) was reported to be as low as 11 ng/ml.7) The limited solubility of curcumin, as well as extensive systemic metabolism, could be responsible for the low bioavailability of curcumin after oral delivery. [8][9][10] In addition, curcumin in solution may be sensitive to UV light, and so marked photochemical degradation could occur under UV exposure, 11) leading to difficulty in its handling for clinical use.A number of efforts have been made to design a soluble formulation of curcumin, but no suitable delivery options have been found so far. We have developed an effective preparation of curcumin, a nano-particle colloidal dispersion, with improved oral bioavailability, and named it THER-ACURMIN. It has the following unique properties: 1) it is an effective preparation for new health care products (beverages, food, and supplements) which may be taken at a much lower dosage; 2) it is soluble in water, which is a must for an effective beverage product; 3) the preparation is highly stable in light (UV), and, therefore, can be put into transparent PET bottles; 4) it is heat-stable, including high temperature sterilization conditions; 5) the preparation has no unpleasant odor or taste.The main purpose of this study was to provide evidence to support the improved bioavailability and alcohol-toxicity-reducing effect of THERACURMIN through oral delivery. We evaluated the plasma pharmacokinetics of this new curcumin preparation and compared the results with curcumin powder after oral administration in rats and healthy human subjects. We also investigated the effect of THERACURMIN on the toxicity of alcohol following drinking. MATERIALS AND METHODS Preparation of Curcumin Powder and THERACUR-MINCurcumin powder was extracted...

Peripheral artery disease (PAD) generates tissue ischemia through arterial occlusions and insufficient collateral vessel formation. Vascular insufficiency in PAD occurs despite higher circulating levels of vascular endothelial growth factor A (VEGF-A),1,2 a key regulator of angiogenesis. Here, we show that clinical PAD is associated with elevated anti-angiogenic VEGF-A splice isoform (VEGF-A165b), and a corresponding reduction of the pro-angiogenic VEGF-A165a isoform. In a murine model of PAD, VEGF-A165b was upregulated by conditions associated with impaired limb revascularization, including leptin-deficiency, diet-induced obesity, genetic ablation of the secreted frizzled-related protein 5 (Sfrp5) adipokine and transgenic overexpression of Wnt5a in myeloid cells. In PAD models, delivery of VEGF-A165b inhibited revascularization of ischemic hind limbs, whereas treatment with an isoform-specific neutralizing antibody reversed the impaired revascularization phenotype caused by metabolic dysfunction or perturbations in the Wnt5a/Sfrp5 regulatory system. These results indicate that inflammation driven expression of the anti-angiogenic VEGF-A isoform can contribute to impaired collateralization in ischemic cardiovascular disease.