Effect of Rivaroxaban and Clopidogrel Combination Therapy on In-Stent Responses After Everolimus-Eluting Stent Implantation in a Porcine Coronary Model.

AIM: According to recent clinical trials, a combination of direct oral anticoagulants with antiplatelet drugs is often recommended for atrial fibrillation patients who receive drug-eluting stents (DESs). Although the optimal combination comprises direct factor Xa inhibitors and a P2Y12 receptor antagonist (or aspirin), their influence on vascular responses to DESs remains unclear. METHODS: Pigs were given either aspirin and clopidogrel (dual antiplatelet therapy [DAPT] group), aspirin and rivaroxaban (AR group), or clopidogrel and rivaroxaban (CR group), followed by everolimus-eluting stent (Promus Element) implantation into the coronary artery. Stented coronary arteries were evaluated via intravascular optical coherence tomography (OCT) and histological analysis at 1 and 3 months. RESULTS: OCT revealed lower neointimal thickness in the DAPT group and comparable thickness among all groups at 1 and 3 months, respectively. Histological analyses revealed comparable neointimal area among all groups and the smallest neointimal area in the CR group at 1 and 3 months, respectively. In the DAPT and AR groups, the neointima continued to grow from 1 to 3 months. A shortened time course for neointima growth was observed in the CR group, with rapid growth within a month (maintained for 3 months). A higher incidence of in-stent thrombi was observed in the AR group at 1 month; no thrombi were found in either group at 3 months. More smooth muscle cells with contractile features were found in the CR group at both 1 and 3 months. CONCLUSIONS: Our results proved the noninferiority of the combination of rivaroxaban with an antiplatelet drug, particularly the dual therapy using rivaroxaban and clopidogrel, compared to DAPT after DES implantation.

Transcriptional Suppression of Diabetic Nephropathy with Novel Gene Silencer Pyrrole-Imidazole Polyamides Preventing USF1 Binding to the TGF-ß1 Promoter.

Upstream stimulatory factor 1 (USF1) is a transcription factor that is increased in high-glucose conditions and activates the transforming growth factor (TGF)-ß1 promoter. We examined the effects of synthetic pyrrole-imidazole (PI) polyamides in preventing USF1 binding on the TGF-ß1 promoter in Wistar rats in which diabetic nephropathy was established by intravenous administration of streptozotocin (STZ). High glucose induced nuclear localization of USF1 in cultured mesangial cells (MCs). In MCs with high glucose, USF1 PI polyamide significantly inhibited increases in promoter activity of TGF-ß1 and expression of TGF-ß1 mRNA and protein, whereas it significantly decreased the expression of osteopontin and increased that of h-caldesmon mRNA. We also examined the effects of USF1 PI polyamide on diabetic nephropathy. Intraperitoneal injection of USF1 PI polyamide significantly suppressed urinary albumin excretion and decreased serum urea nitrogen in the STZ-diabetic rats. USF1 PI polyamide significantly decreased the glomerular injury score and tubular injury score in the STZ-diabetic rats. It also suppressed the immunostaining of TGF-ß1 in the glomerulus and proximal tubules and significantly decreased the expression of TGF-ß1 protein from kidney in these rats. These findings indicate that synthetic USF1 PI polyamide could potentially be a practical medicine for diabetic nephropathy.

Taurine and magnesium supplementation enhances the function of endothelial progenitor cells through antioxidation in healthy men and spontaneously hypertensive rats.

Endothelial damage is repaired by endothelial progenitor cells (EPCs), which are pivotal in preventing cardiovascular diseases and prolonging lifespan. The WHO Cardiovascular Diseases and Alimentary Comparison Study demonstrated that dietary taurine and magnesium (Mg) intake suppresses cardiovascular diseases. We herein evaluate the effects of taurine and Mg supplementation on EPC function and oxidative stress in healthy men and spontaneously hypertensive rats (SHRs). Healthy men received taurine (3 g per day) or Mg (340 mg per day) for 2 weeks. SHRs and Wistar-Kyoto (WKY) rats were housed with high-salt drinking water (1% NaCl). The SHRs received 3% taurine solution and/or a high-Mg (600 mg per 100 g) diet for 4 weeks. Their peripheral blood mononuclear cells were separated to quantify EPC colony formation. Oxidative stress markers in their peripheral blood were evaluated using a free radical analytical system and a thiobarbituric acid reactive substance (TBARS) assay. Taurine and Mg supplementation significantly increased EPC colony numbers and significantly decreased free radical levels and TBARS scores in healthy men. Taurine and Mg supplementation significantly increased EPC colony numbers and significantly decreased TBARS scores and free radical levels in SHRs. Nicotinamide adenine dinucleotide phosphate oxidase component mRNA expression was significantly higher in the renal cortex of salt-loaded SHRs than in WKY rats, in which it was suppressed by taurine and Mg supplementation. Taurine and Mg supplementation increased EPC colony formation in healthy men and improved impaired EPC function in SHRs through antioxidation, indicating that the dietary intake of taurine and Mg may prolong lifespan by preventing the progression of cardiovascular diseases.

Effects of the herbal medicine composition "Saiko-ka-ryukotsu-borei-To" on the function of endothelial progenitor cells in hypertensive rats.

Endothelial progenitor cells (EPCs) are known to repair vascular injuries. Recent studies suggest that Saiko-ka-ryukotsu-borei-To (SKRBT), a traditional herbal medicine that has been used to treat stress-related neuropsychiatric disorders, has protective effects on cardiovascular diseases such as hypertension and arteriosclerosis. Spontaneously hypertensive rats (SHRs) were fed diets containing lyophilized SKRBT extract for 6 weeks. Peripheral blood mononuclear cells (MNCs) were isolated and cultured to assay EPC colony formation. Oxidative stress in MNCs was evaluated by thiobarbituric acid reactive substance (TBARS) assay and flowcytometric analyses. Treatment with SKRBT increased EPC colony numbers significantly (p<0.05) with decrease in oxidative stress and without affecting blood pressure in SHRs. Treatment with SKRBT did not reduce the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits in cardiovascular organs. Serum IL-6 level was significantly reduced. SKRBT is a feasible herbal medicine that protects against cardiovascular diseases through an increase in EPC function along with anti-oxidative effects, and may affect the link between chronic inflammation and cardiovascular disease.

Anti-arthritic activity of synthesized chondroitin sulfate E hexasaccharide.

The purpose of this study was to investigate the anti-arthritic effects of synthesized chondroitin sulfate E hexasaccharide (sCSE-6, CAS 866407-73-0), using a type II collagen-induced arthritis model in mice. sCSE-6 was administered subcutaneously on a daily basis to type II collagen (CII)-sensitized mice from day 0 to day 55. The severity of arthritis, as well as the immunohistological features of the arthritic mice, were analyzed. sCSE-6 inhibited the course of arthritis and restored the body weight loss of CII-immunized mice. An immunohistological analysis showed that bone/cartilage destruction in the arthritic mice was significantly attenuated by sCSE-6 treatment, with a marginal inhibition of synovial inflammation also observed. The beneficial effect of sCSE-6 on bone destruction, which is the most important factor in preventing arthritis, is particularly noteworthy. In summary, sCSE-6 inhibited arthritis and helped to prevent bone and cartilage destruction in a type II collagen-induced arthritis model in mice. The findings indicated that CSE oligosaccharides might be a novel potential therapeutic tool for rheumatoid arthritis.

Body distribution of trace elements in black-tailed gulls from Rishiri Island, Japan: age-dependent accumulation and transfer to feathers and eggs.

Body distribution and maternal transfer of 18 trace elements (V, Cr, Mn, Co, Cu, Zn, Se, Rb, Sr, Mo, Ag, Cd, Sb, Cs, Ba, Hg, Tl, and Pb) to eggs were examined in black-tailed gulls (Larus crassirostris), which were culled in Rishiri Island, Hokkaido Prefecture, Japan. Manganese, Cu, Rb, Mo, and Cd showed the highest levels in liver and kidney, Ag, Sb, and Hg in feather, and V, Sr, and Pb in bone. Maternal transfer rates of trace elements ranged from 0.8% (Cd) to as much as 65% (Tl) of maternal body burden. Large amounts of Sr, Ba, and Tl were transferred to the eggs, though maternal transfer rates of V, Cd, Hg, and Pb were substantially low. It also was observed that Rb, Sr, Cd, Cs, and Ba hardly were excreted into feathers. Concentrations of Co in liver, Ba in liver and kidney, and Mo in liver increased significantly with age, whereas Se in bone and kidney, Hg in kidney, and Cr in feather decreased with age in the known-aged black-tailed gulls (2-20 years old). It also was suggested that feathers might be useful to estimate contamination status of trace elements in birds, especially for Hg on a population basis, although the utility is limited on an individual basis for the black-tailed gulls. To our knowledge, this is the first report on the maternal transfer rate of multielements and also on the usefulness of feathers to estimate contamination status of Hg in birds on a population basis.