This study tested whether the pre-diabetic metabolic syndrome impairs coronary blood flow control sufficiently to alter the balance between coronary blood flow and myocardial metabolism. Experiments were conducted in dogs instrumented with catheters in the aorta, coronary sinus, and left ventricle and with flow transducers around the circumflex coronary artery and aorta. Coronary blood flow, myocardial oxygen consumption (MVO(2)), cardiac output, aortic pressure, left ventricular pressure and heart rate were measured at rest and during treadmill exercise in normal, control and high fat fed dogs. High fat feeding for approximately six weeks increased body weight 15%, increased aortic blood pressure 10%, and induced insulin resistance. Fasting plasma insulin levels were increased 2.4-fold while plasma glucose concentration was unchanged relative to controls (5.0 +/- 0.3 mM). The cardiac index increased with exercise but was not altered by high fat feeding. The metabolic syndrome reduced the slope of the relationship between coronary blood flow and MVO(2) ( P < 0.0001) and decreased coronary venous PO(2) at a given level of MVO(2) ( P < 0.05). These findings indicate that the metabolic syndrome impairs the balance between myocardial oxygen delivery and metabolism by tonically vasoconstricting the coronary circulation.

This investigation examined cardiac protective effects of normobaric intermittent hypoxia training. Six dogs underwent intermittent hypoxic training for 20 consecutive days in a normobaric chamber ventilated intermittently with N2 to reduce fraction of inspired oxygen (FiO2) to 9.5%-10%. Hypoxic periods, initially 5 mins and increasing to 10 mins, were followed by 4-min normoxic periods. This hypoxia-normoxia protocol was repeated, initially 5 times and increasing to 8 times. The dogs showed no discomfort during intermittent hypoxic training. After 20 days of hypoxic training, the resistance of ventricular myocardium to infarction was assessed in an acute experiment. The left anterior descending (LAD) coronary artery was occluded for 60 mins and then reperfused for 5 hrs. At 30 mins of LAD occlusion, radioactive microspheres were injected through a left atrial catheter to assess coronary collateral blood flow into the ischemic region. After 5 hrs reperfusion, the heart was dyed to delineate the area at risk (AAR) of infarction and stained with triphenyl tetrazolium chloride to identify infarcted myocardium. During LAD occlusion and reperfusion, systemic hemodynamics and global left ventricular function were stable. Infarction was not detected in 4 hearts and was 1.6% of AAR in the other 2 hearts. In contrast, 6 dogs sham-trained in a chamber ventilated with compressed air and 5 untrained dogs subjected to the same LAD occlusion/reperfusion protocol had infarcts of 36.8% +/- 5.8% and 35.2% +/- 9.5% of the AAR, respectively. The reduction in infarct size of four of the six hypoxia-trained dogs could not be explained by enhanced collateral blood flow to the AAR. Hypoxia-trained dogs had no ventricular tachycardia or ventricular fibrillation. Three sham-trained dogs had ventricular tachycardia and two had ventricular fibrillation. Three untrained dogs had ventricular fibrillation. In conclusion, intermittent hypoxic training protects canine myocardium from infarction and life-threatening arrhythmias during coronary artery occlusion and reperfusion. The mechanism responsible for this potent cardioprotection merits further study.

The standard-of-care therapeutics for the treatment of ocular neovascular diseases like wet age-related macular degeneration (AMD) are biologics targeting vascular endothelial growth factor signaling. There are currently no FDA approved small molecules for treating these blinding eye diseases. Therefore, therapeutic agents with novel mechanisms are critical to complement or combine with existing approaches. Here, we identified soluble epoxide hydrolase (sEH), a key enzyme for epoxy fatty acid metabolism, as a target of an antiangiogenic homoisoflavonoid, SH-11037. SH-11037 inhibits sEH in vitro and in vivo and docks to the substrate binding cleft in the sEH hydrolase domain. sEH levels and activity are up-regulated in the eyes of a choroidal neovascularization (CNV) mouse model. sEH is overexpressed in human wet AMD eyes, suggesting that sEH is relevant to neovascularization. Known sEH inhibitors delivered intraocularly suppressed CNV. Thus, by dissecting a bioactive compound's mechanism, we identified a new chemotype for sEH inhibition and characterized sEH as a target for blocking the CNV that underlies wet AMD.

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Introduction: Dysbiosis of gut microbiota impairs the homeostasis of immune and metabolic systems. Although previous studies have revealed the correlation between gut microbiota and various diseases, the function between gut microbiota and diabetic nephropathy (DN) has not been discovered distinctly. In this study, we tried to investigate the profile and function of gut microbiota in DN. Methods: A total of 100 people were enrolled in this study. Twenty were healthy people, 20 were diabetes patients, and 60 were DN patients. The DN patients were divided into three stages including stage III, IV, and V. We conducted taxonomic analyses in different groups. The distributions of phyla, classes, orders, families, and genera in different groups and samples were investigated. We also evaluated the correlations between clinical parameters and gut microbiota in 60 DN patients. Results: The gut microbiota in the healthy group, diabetes group, and DN group had 1764 operational taxonomic units (OTUs) in total. The healthy group had 1034 OTUs, the diabetes group had 899 OTUs, and the DN group had 1602 OTUs. The diversity of gut microbiota in the stage III DN group was smaller than that in the other groups. 24-h urinary protein was positively correlated with Alistipes and Subdoligranulum, cholesterol was positively correlated with Bacteroides and Lachnoclostridium, and estimated glomerular filtration rate was negatively correlated with Ruminococcus torques group. Discussion: The gut microbiota might play an important role in the development and pathogenesis of DN. A change in gut microbiota diversity is correlated with disease progression. Some kinds of gut microbiota including Alistipes, Bacteroides, Subdoligranulum, Lachnoclostridium, and Ruminococcus torques group might be detrimental factors in DN.

The ability of XZCBF to facilitate the excretion of uric acid and to lower its level in the model group was mediated by the upregulation of miR-34a and the inhibition of URAT1 mRNA expression, which suggests that XZCBF could be an option for the treatment of hyperuricemia in mice.

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease, and satisfactory therapeutic strategies have not yet been established. The Shen-Yan-Fang-Shuai Formula (SYFSF) is a traditional Chinese formula composed of Astragali radix, Radixangelicae sinensis, Rheum officinale Baill, and four other herbs. It has been widely used as an effective treatment for DKD patients in China. However, little is known about the molecular mechanisms underlying SYFSF's renoprotection. In this study, we compared the protective effect of SYFSF to irbesartan on the histology and renal cells in type 2 DKD rat model and high-glucose (HG) cultured mesangial cells, respectively. We found that SYFSF could significantly decrease urinary albumin, cholesterol, and triglyceride. And a decrease in serum creatinine was also found in SYFSF-treated group compared with irbesartan-treated rats. In addition, SYFSF inhibited the interstitial expansion and glomerulosclerosis in diabetic rats. Notably, SYFSF markedly downregulated the expression of MCP-1, TGF-β1, collagen IV, and fibronectin in diabetic rat models and HG-induced mesangial cell models. The renoprotection was closely associated with a reduced expression of TNF-α and phosphorylated NF-κBp65. Our study suggests that SYFSF may ameliorate diabetic kidney injury. The observed renoprotection is probably attributable to an inhibition of inflammatory response and extracellular matrix (ECM) accumulation mediated by TNF-α/NF-κBp65 signaling pathway.

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