Chronic SIRT1 supplementation in diabetic mice improves endothelial function by suppressing oxidative stress

Aims Enhancing SIRT1 activity exerts beneficial cardiovascular effects. In diabetes, plasma SIRT1 levels are reduced. We aimed to investigate the therapeutic potential of chronic recombinant murine SIRT1 (rmSIRT1) supplementation to alleviate endothelial and vascular dysfunction in diabetic mice (db/db). Methods and results Left internal mammary arteries obtained from patients undergoing coronary artery bypass grafting with or without a diagnosis of diabetes were assayed for SIRT1 protein levels. Twelve-week-old male db/db mice and db/+ controls were treated with vehicle or rmSIRT1 intraperitoneally for 4 weeks, after which carotid artery pulse wave velocity (PWV) and energy expenditure/activity were assessed by ultrasound and metabolic cages, respectively. Aorta, carotid, and mesenteric arteries were isolated to determine endothelial and vascular function using the myograph system. Arteries obtained from diabetic patients had significantly lower levels of SIRT1 relative to non-diabetics. In line, aortic SIRT1 levels were reduced in db/db mice compared to db/+ mice, while rmSIRT1 supplementation restored SIRT1 levels. Mice receiving rmSIRT1 supplementation displayed increased physical activity and improved vascular compliance as reflected by reduced PWV and attenuated collagen deposition. Aorta of rmSIRT1-treated mice exhibited increased endothelial nitric oxide (eNOS) activity, while endothelium-dependent contractions of their carotid arteries were significantly decreased, with mesenteric resistance arteries showing preserved hyperpolarization. Ex vivo incubation with reactive oxygen species (ROS) scavenger Tiron and NADPH oxidase inhibitor apocynin revealed that rmSIRT1 leads to preserved vascular function by suppressing NADPH oxidase (NOX)-related ROS synthesis. Chronic rmSIRT1 treatment resulted in reduced expression of both NOX1 and NOX4, in line with a reduction in aortic protein carbonylation and plasma nitrotyrosine levels. Conclusions In diabetic conditions, arterial SIRT1 levels are significantly reduced. Chronic rmSIRT1 supplementation improves endothelial function and vascular compliance by enhancing eNOS activity and suppressing NOX-related oxidative stress. Thus, SIRT1 supplementation may represent novel therapeutic strategy to prevent diabetic vascular disease

Fluid and melt inclusion study on mineralized and barren porphyries, Jinshajiang-Red River alkali-rich intrusive belt, and significance to metallogenesis

Alkali-rich Cu (Au, Mo) deposits are of increasing economic significance and are an attractive exploration target. They include some of the world's highest grade and largest porphyry related gold resources as well as some of the largest gold accumulations in epithermal settings. The Jinshajiang-Red River alkali-rich intrusive belt, with many porphyry Cu (Au, Mo) deposits, is a representative magmatic belt associated with mineralization. The Jinshajiang-Red River alkali-rich intrusive belt contains several Cu (Au, Mo) mineralized alkali-rich porphyry rocks including the Yulong quartz monzonite porphyry, the Machangqing granite porphyry, the Tongchang quartz syenite porphyry, and the Beiya quartz syenite porphyry. Additionally, there are also some barren alkali-rich porphyry rocks in the belt, such as the Yanshuiqing quartz syenite porphyry. Fluid inclusion petrography and microthermometry on those porphyry rocks are carried out in detail. The results show that the fluid inclusion assemblages in ore-bearing and barren porphyries are distinct: inclusions from barren porphyry are dominated by primary melt inclusions, and contain rare or no fluid inclusions, whereas inclusions from ore-bearing porphyries are dominated by fluid inclusions, and contain rare melt inclusions. Furthermore, halite, sylvite, calcite daughter minerals and an opaque phase in fluid inclusions from ore-bearing rocks are common, but rare in fluid inclusions from barren rocks. The results suggests that the evolution of ore forming fluids especially the halite, sylvite, calcite and opaque daughter minerals bearing fluid inclusions of quartz phenocrysts could be used to judge the degree of metasomatism and mineralization of a porphyry system

Petrogenesis and metallogenic implications of volcanic rocks from the Lawu basin, eastern Tibet: Insights into the intracontinental Eocene-Oligocene porphyry copper systems

Generally, porphyry Cu deposits are associated with the comagmatic porphyry (or subvolcanic)-volcanic systems of high magmatic H2O-fO(2) conditions. The volcanic rocks, as the counterpart of the porphyries, thus can provide some significant insights into the fertility of the porphyries to some extent. For this reason, we have used the Lawu volcanic rocks and spatial-temporal closely-related porphyries in the newly discovered porphyry Cu prospects (e.g., Seli, Zongguo, Mamupu) in the southern segment of the Yulong intracontinental porphyry Cu belt to illustrate the relationship between the porphyries and volcanic rocks, petrogenesis of the volcanic rocks, and then to evaluate the ore potential of the porphyries based on the magmatic H2O-fO(2) conditions. Both the Lawu volcanic rocks and Seli-Zonguo-Mamupu porphyries are shoshonitic and metaluminous, and have similar REE patterns, and Sr-Nd-Hf isotopic compositions, which suggest a comagmatic relation between the volcanic rocks and porphyries. An episodic magmatism model is proposed to explain the slightly younger age (similar to 36-35 Ma) and less evolved nature of volcanic rocks than the porphyries. The Lawu volcanic rocks of mainly intermediate composition (SiO2 = 54.25-64.68 wt%) have high K2O (4.75-5.94 wt%) and high K2O/Na2O ratios (1.69-2.00), broadly similar to the coeval Yulong fertile granitic porphyries and the Nangqian mafic lavas. The (Sr-87/Sr-86)(i) and epsilon(Nd)(t) values, uniform zircon epsilon H-f(t) and delta O-18 values, and lack of inherited zircons of the Lawu volcanic rocks don't support their formation by mixing between the mantle-derived Nangqian mafic lavas and crustderived Yulong felsic porphyries or assimilation and fractional crystallization (AFC) of mafic magmas. They are characterized by high Ba/Th, Ba/La and listric-shaped normalized rare earth element profile with significantly negative Nb-Ta-Ti anomalies, and have high initial Sr-87/Sr-86 ratios (0.7071-0.7079) and low epsilon(Nd)(t) values (- 5.71 to - 3.05), and low zircon epsilon(Hf)(t) (-1.53 to 4.09) and clearly high delta O-18 values (6.67-8.42 parts per thousand), suggesting that, they were probably formed by fractional crystallization (FC) of mantle-derived mafic magmas and originated from mantle domains modified by significant amount of H2O-rich marine sediments of the Paleo-Tethyan oceanic slab. Magmatic H2O contents calculated from deepest-crystallized amphiboles indicate that, the Lawu volcanic rocks and Zongguo porphyries have initial magmatic H2O contents as high as the Yulong fertile porphyries and typical porphyry Cu systems worldwide (commonly > 4 wt% H2O). Magmatic fO(2) (Delta FMQ) of the Lawu volcanic rocks (0.6-1.3, ave. 0.9 +/- 0.1) and the Zongguo porphyries (0.9-1.7, ave. 1.4 +/- 0.2) are clearly lower than the fertile porphyries in the giant Yulong deposit (Delta FMQ = 1.6-3.3, ave. 2.3 +/- 0.5) and typical porphyry Cu deposits in the world (commonly Delta FMQ > 2). The slightly lower magmatic H2O contents and slightly higher magmatic fO(2) of the Zongguo porphyries than the Lawu volcanic rocks were ascribed to variable degassing during magmatic evolution. These suggest that, in spite of the high magmatic H2O contents, the comagmatic porphyries (at least the Zongguo porphyries) of the Lawu volcanic rocks in the southern segment of the Yulong porphyry Cu belt are unlikely to produce large-scale porphyry Cu mineralization like the giant Yulong deposit, due to the low magmatic fO(2) conditions

Composite metallogenesis of sediment-hosted Pb-Zn-Ag-Cu base metal deposits in the Sanjiang Collisional Orogen, SW China, and its deep driving mechanisms

A great number of sediment-hosted Pb-Zn-Ag-Cu deposits occur in the Meso-Cenozoic sedimentary basins within the Sanjiang Tethyan orogeny, SW China, which compose a significant base metal metallogenic belt with an extension over 1000km along the northeastern margin of the Tibetan Plateau. For it is an important type in the continental collision-related deposit spectrum, further study upon these deposits is greatly helpful to understand and improve the theories of the continental collision metallogenesis and guide the exploration. Many studies suggest that these deposits are distinct from the SEDEX and MVT model in terms of ore controls, host rocks and other features, and that multiple sourced fluids associated with mineralization should have been driven by deep processes. However, it is intensively debated on the geotectonic settings of ore formation and spatial-temporal association with the collisional orogeny due to lack of highly resolved chronological data. Some studies indicate that they were resulted from composite mineralization, but these studies did not well document its mechanisms. A comprehensive study has thus been carried out on the geochronology, ore-forming fluids and metal sources, composite metallogenesis and mechanisms for the Pb-Zn-Ag and Cu polymetallic deposits in the Lanping and Changdu basins. The results show that the Cu deposits were mainly formed in 48 similar to 58Ma and the Pb-Zn deposits were formed in 28 similar to 33 Ma. Also, three types of composite mineralization have been recognized: 1) metamorphic fluids and basinal brines or meteoric water, represented by the Jinman-Liancheng Cu deposits; 2) basinal brine and meteoric water, represented by the Jinding deposit; and 3) basinal brine and magmatic fluid with an example of the Lanuoma Pb-Zn-Sb deposit. The Cu deposits happened synchronously with the main collisional compression of the India-Asian continental collision and metamorphic fluids were probably generated by subduction-caused high-pressure metamorphism. The Pb-Zn deposits were formed by basinal brine-dominated fluids driven by orogenic uplift as well as tectonic compression in the stage of the late collisional tectonic transform. Contemporaneous magmatism may have mainly played as heat sources or provided ore materials

Genesis of the Jinding Zn-Pb deposit, northwest Yunnan Province, China: Constraints from rare earth elements and noble gas isotopes

The giant sediment-hosted finding zinc-lead deposit is located in the Lanping Basin, northwestern Yunnan Province, China. The genesis of the deposit has long been debated and the sources of the ore-forming fluids and metals are controversial. This study presents rare earth element (REE) and noble gas isotope data that constrain the origins of the ore fluids and the heat source driving the hydrothermal circulation. The early-stage sulfides are enriched in light REEs and have high Sigma REE values (30.8-94.8 ppm) and weakly negative Eu (delta Eu 0.85-0.89) and Ce anomalies (delta Ce 0.84-0.95), suggesting that the fluids were likely derived from dissolution of Upper Triassic marine carbonates with input of REEs from aluminosilicate rocks in the basin. In contrast, the late-stage sulfides have irregular REE patterns, generally low Sigma REE values (0.24-10.8 ppm) and positive Eu (delta Eu 1.22-10.9) and weakly negative Ce anomalies (delta Ce 0.53-0.90), which suggest that the ore-forming fluids interacted with evaporite minerals. The He-3/He-4 (0.01-0.04 R-a) and Ar-40/Ar-36 values (301-340) of the ore-forming fluids indicate crustal and atmospheric origins for these noble gases. These findings are in agreement with the published fluid inclusion microthermometry data and the results of H, O, C, S, Pb and Sr isotope studies. Our data, in combination with published results, support a two-stage hydrothermal mineralization model, involving early-stage basinal brines and late-stage meteoric water that acquired metals and heat from crustal sources. (C) 2017 Elsevier B.V. All rights reserved