Creechhyde5749

IMC also prevented diet- driven hepatic cholesterol accumulation, and caused both up-regulation of the host hepatic bile acid synthetic enzyme CYP7A1, and altered the expression of hepatic genes critical for bile acid feedback regulation. These studies suggest that the gut microbiota-driven TMAO pathway is closely linked to both microbe and host sterol and bile acid metabolism. Collectively, as gut microbe-targeting choline TMA lyase inhibitors move through the drug discovery pipeline from preclinical models to human studies, it will be important to understand how these drugs impact both microbe and host cholesterol and bile acid metabolism.AIM Microvascular dysfunction often precedes other age-related macrovascular conditions and predicts future cardiovascular risk. Sirtuin 1 (Sirt1) has recently emerged as a protein that protects the vasculature and reduces the risk of cardiovascular diseases. We tested the hypothesis that lower Sirt1 during childhood is associated with a reduced microvascular function during adulthood. METHODS AND RESULTS Thirty-four adults (34 ± 3 yrs) from the Augusta Heart Study returned to participate in the present clinical observational study. Sirt1 was assessed in samples collected during both adulthood and participant's childhood (16 ± 3 yrs) and data were divided based on childhood Sirt1 concentrations less then 3 ng/dl (LowCS; n=16) and ≥3 ng/dl (HighCS; n=18). MVF was evaluated in all the adults using Laser Doppler flowmetry coupled with three vascular reactivity tests 1) local thermal hyperemia (LTH), 2) post-occlusive reactive hyperemia (PORH) and 3) iontophoresis of acetylcholine (ACh). The hyperemic response to LTH was significantly (p≤0.044) lower in the LowCS than in the HighCS group. Similarly, the LowCS also exhibited an ameliorated (p≤0.045) response to the PORH test and lower (p≤0.008) vasodilation in response to iontophoresis of Ach when compared to the HighCS. Positive relationships were identified between childhood Sirt1 and all MVF reactivity tests (r≥0.367; p≤0.004). CONCLUSIONS Novel observations suggest that lower Sirt1 during childhood is associated with premature microvascular dysfunction in adulthood. These findings provide evidence that Sirt1 may play a critical role in microvascular function and may have therapeutic potential for the prevention of age-associated vascular dysfunction in humans.OBJECTIVE Mitochondria are important regulators of cerebral vascular function in health and disease, but progress in understanding their roles has been hindered by methodological limitations. We report the first in vivo imaging of mitochondria specific to the cerebral endothelium in real time in the same mouse for extended periods. METHODS Mice expressing Dendra2 fluorescent protein in mitochondria (mito-Dendra2) in the cerebral vascular endothelium were generated by breeding PhAM floxed and Tie2-Cre mice. We used mito-Dendra2 expression, cranial window implantation, and two-photon microscopy to visualize mitochondria in the cerebral vascular endothelium of mice. Immunohistochemistry and mitochondrial staining were used to confirm the localization of the mitochondrial signal to endothelial cells and the specificity of mito-Dendra2 to mitochondria. Mito-Dendra2 and Rhodamine B-conjugated dextran allowed simultaneous determinations of mitochondrial density, vessel diameters, area, and mitochondria/vessel ratio in vivo, repeatedly, in the same mouse. RESULTS Endothelial expression of mito-Dendra2 was confirmed in vitro on brain slices and aorta. In addition, we observed an overlapping mito-Dendra2 and Chromeo mitochondrial staining of cultured brain microvascular endothelial cells. Repeated imaging of the same location in the cerebral microcirculation in the same mouse demonstrated stability of mito-Dendra2. While the overall mitochondrial signal was stable over time, mitochondria within the same endothelial cell were mobile. CONCLUSIONS Our results indicate that the mito-Dendra2 signal and vascular parameters are suitable for real time and longitudinal examination of mitochondria in vivo in the cerebral vasculature of mice.Unilateral carotid body denervation has been proposed as treatment for sympathetic-related human diseases such as systolic heart failure, hypertension, obstructive sleep apnea, and cardio-metabolic diseases. selleck inhibitor The long-term therapeutic effects of carotid body removal will be maintained if the remnant "buffer nerves", that is, the contralateral carotid nerve and the aortic nerves that innervate second order neurons at the solitary tract nuclei (NTS), do not modify their contributions to the cardiovascular chemoreflexes. Here, we studied the cardiovascular chemoreflexes one month after unilateral carotid body denervation either by excision of the petrosal ganglion (petrosal ganglionectomy, that eliminates central carotid afferents) or exeresis of a segment of one carotid nerve (carotid neurectomy, that preserves central afferents). Cardiovascular chemoreflexes were induced by i.v. injections of sodium cyanide in pentobarbitone-anesthetized adult cats. After one month of unilateral petrosal ganglionectomy, without significant changes in basal arterial pressure, the contribution of the contralateral carotid nerve to the chemoreflex increases in arterial pressure was enhanced, without changes in the contribution provided by the aortic nerves. By contrast, after one month of unilateral carotid neurectomy, the contribution of remnant buffer nerves to cardiovascular chemoreflexes remained unmodified. These results indicate that a carotid nerve interruption, involving denervation of second order chemosensory neurons at the NTS, will trigger cardiovascular chemoreflexes plasticity on the contralateral carotid pathway. Then, unilateral carotid body denervation as therapeutic tool should consider the maintenance of the integrity of carotid central chemoafferents to prevent plasticity on remnant buffer nerves.Chlamydia pneumoniae (C. pneumoniae) infection could play a role in atherosclerosis. Toll-like receptor 2 (TLR2) and C-X-C motif chemokine receptor 4 (CXCR4) have been respectively shown to be involved in atherosclerosis. However, whether and how TLR2/CXCR4 crosstalk is involved in C. pneumoniae infection-induced atherosclerosis remains to be determined. Our study aims to demonstrate that C. pneumoniae infection induced the crosstalk between TLR2 and CXCR4 to mediate C. pneumoniae infection-induced VSMC migration and even accelerate atherosclerosis. We firstly found that C. pneumoniae infection increased the aortic lesion size (en face), cross sectional lesion area and lipid content in aortic root lesion, which were both significantly reduced in ApoE-/-TLR2-/- or CXCR4-blocked ApoE-/- mice, and were almost reversed in CXCR4-blocked ApoE-/-TLR2-/- mice. Subsequently, our data showed that C. pneumoniae infection-induced increases in VSMC contents in the atherosclerotic lesion were remarkably suppressed in ApoE-/-TLR2-/- mice or CXCR4-blocked ApoE-/- mice, and were further decreased in CXCR4-blocked ApoE-/-TLR2-/- mice.