Elevated reactive oxygen species (ROS) in type 2 diabetes cause cellular damage in many organs. Recently, the new class of glucose-lowering agents, SGLT-2 inhibitors, have been shown to reduce the ...risk of developing diabetic complications; however, the mechanisms of such beneficial effect are largely unknown. Here we aimed to investigate the effects of dapagliflozin on cell proliferation and cell death under oxidative stress conditions and explore its underlying mechanisms. Human proximal tubular cells (HK-2) were used. Cell growth and death were monitored by cell counting, water-soluble tetrazolium-1 (WST-1) and lactate dehydrogenase (LDH) assays, and flow cytometry. The cytosolic and mitochondrial (ROS) production was measured using fluorescent probes (H2DCFDA and MitoSOX) under normal and oxidative stress conditions mimicked by addition of H2O2. Intracellular Ca2+ dynamics was monitored by FlexStation 3 using cell-permeable Ca2+ dye Fura-PE3/AM. Dapagliflozin (0.1-10 μM) had no effect on HK-2 cell proliferation under normal conditions, but an inhibitory effect was seen at an extreme high concentration (100 μM). However, dapagliflozin at 0.1 to 5 μM showed remarkable protective effects against H2O2-induced cell injury via increasing the viable cell number at phase G0/G1. The elevated cytosolic and mitochondrial ROS under oxidative stress was significantly decreased by dapagliflozin. Dapagliflozin increased the basal intracellular Ca2+i in proximal tubular cells, but did not affect calcium release from endoplasmic reticulum and store-operated Ca2+ entry. The H2O2-sensitive TRPM2 channel seemed to be involved in the Ca2+ dynamics regulated by dapagliflozin. However, dapagliflozin had no direct effects on ORAI1, ORAI3, TRPC4 and TRPC5 channels. Our results suggest that dapagliflozin shows anti-oxidative properties by reducing cytosolic and mitochondrial ROS production and altering Ca2+ dynamics, and thus exerts its protective effects against cell damage under oxidative stress environment.
Non-ST-segment elevation acute coronary syndrome (NSTE-ACS) is the leading cause of morbidity and mortality from cardiovascular disease worldwide. Several recent studies have shown the relationship ...between the triglyceride-glucose (TyG) index and vascular disease; however, the role of the TyG index in NSTE-ACS has not been extensively assessed. Thus, we aimed to investigate the association of the TyG index with cardiovascular risk factors and outcomes in NSTE-ACS. Overall, 438 patients with NSTE-ACS were enrolled to examine the association of the TyG index with the SYNTAX score and major adverse cardiovascular events (MACEs). The TyG index was calculated as ln fasting triglyceride mg/dL×fasting glucose mg/dL/2. The severity of coronary lesions was quantified by the SYNTAX score. MACEs included cardiac death, nonfatal myocardial infarction, target vessel revascularization, congestive heart failure, and nonfatal stroke. All the patients underwent a 12-month follow-up for MACEs after admission. Multivariate regression analysis identified metabolic risk factors as independent parameters correlated with the TyG index. The prevalence of glucose metabolism disorder, metabolic syndrome, and MACEs increased with increasing TyG index. The TyG index showed a strong diagnostic performance for cardiovascular risk factors and was independently associated with the SYNTAX score (OR 6.055, 95% CI 2.915–12.579, P<0.001). The risk of MACEs (12.8% and 22.8% for the low TyG index and high TyG index groups, respectively; adjusted HR=1.791, 95% CI 1.045–3.068, P=0.034) significantly increased in the high TyG index group as compared with the low TyG index group. The multivariate Cox regression analysis further revealed that the TyG index was an independent predictor of MACEs (HR 1.878, 95% CI 1.130–3.121, P=0.015). In conclusion, the TyG index might be an independent predictor of coronary artery disease severity and cardiovascular outcomes in NSTE-ACS.
Full-waveform inversion (FWI) utilizes optimization methods to recover an optimal Earth model to best fit the observed seismic record in a sense of a predefined norm. Since FWI combines mathematic ...inversion and full-wave equations, it has been recognized as one of the key methods for seismic data imaging and Earth model building in the fields of global/regional and exploration seismology. Unfortunately, conventional FWI fixes background velocity mainly relying on refraction and turning waves that are commonly rich in large offsets. By contrast, reflections in the short offsets mainly contribute to the reconstruction of the high-resolution interfaces. Restricted by acquisition geometries, refractions and turning waves in the record usually have limited penetration depth, which may not reach oil/gas reservoirs. Thus, reflections in the record are the only source that carries the information of these reservoirs. Consequently, it is meaningful to develop reflection-waveform inversion (RWI) that utilizes reflections to recover background velocity including the deep part of the model. This review paper includes: analyzing the weaknesses of FWI when inverting reflections; overviewing the principles of RWI, including separation of the tomography and migration components, the objective functions, constraints; summarizing the current status of the technique of RWI; outlooking the future of RWI.
Cadmium (Cd) is a high‐risk pathogenic toxin for hepatic diseases. Excessive mitophagy is a hallmark in Cd‐induced hepatotoxicity. However, the underlying mechanism remains obscure. Mitochondrial ...calcium uniporter (MCU) is a key regulator for mitochondrial and cellular homeostasis. Here, Cd exposure upregulated MCU expression and increased mitochondrial Ca2+ uptake are found. MCU inhibition through siRNA or by Ru360 significantly attenuates Cd‐induced excessive mitophagy, thereby rescues mitochondrial dysfunction and increases hepatocyte viability. Heterozygous MCU knockout mice exhibit improved liver function, ameliorated pathological damage, less mitochondrial fragmentation, and mitophagy after Cd exposure. Mechanistically, Cd upregulates MCU expression through phosphorylation activation of cAMP‐response element binding protein at Ser133(CREBS133) and subsequent binding of MCU promoter at the TGAGGTCT, ACGTCA, and CTCCGTGATGTA regions, leading to increased MCU gene transcription. The upregulated MCU intensively interacts with voltage‐dependent anion‐selective channel protein 1 (VDAC1), enhances its dimerization and ubiquitination, resulting in excessive mitophagy. This study reveals a novel mechanism, through which Cd upregulates MCU to enhance mitophagy and hepatotoxicity.
After cadmium (Cd) exposure, the cytosolic Ca2+‐dependent increases and activation of cAMP‐response element binding protein (CREB) orchestrally upregulates mitochondrial calcium uniporter (MCU) gene transcription, and promotes its translocation into mitochondria. The upregulated MCU in mitochondria directly interacts with voltage‐dependent anion‐selective channel protein 1 (VDAC1) and further enhances the dimerization and ubiquitination of VDAC1, which then overactivates mitophagy and leads to hepatocyte death.
Microplastics are a global concern for their threat to marine ecosystems. Recent studies report a lack of smaller microplastics (<300 μm) in oceans attributed to a “loss in ocean”. Several hypotheses ...have been proposed to explain the absence of smaller microplastics, but their fate and transport remain an enigma. Our study recovered high concentrations of microplastics (32947 ± 15342 items kg−1 dry sediment) from sediments of a coastal plain river network in eastern China, with the <300 μm fraction accounting for ∼85% of total microplastic particles. Microplastic concentrations were generally higher in sediments from tributary streams and streams surrounded by industrial land use. The high variability of microplastics within the watershed indicates that the distribution of microplastics is regulated by several factors, such as distance to source(s), river flow characteristics, buoyancy behavior, degradation, etc. Fragment and foam forms dominated the small microplastics, while fibers were less prevalent in the <300 μm fraction and more abundant in downstream sites. The dominance of small microplastics in riverine sediments in this study provides a possible mechanism to explain the relative absence of small microplastics in the ocean, and advocates for quantification of the whole size spectrum of microplastics in future studies of riverine microplastic fluxes.
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•Lots of microplastics are recovered from the sediments of a plain river network.•Small (<300 μm) fraction (SMPs) dominated (∼85%) microplastics in the sediments.•Distribution patterns varied from different morpholocical types of microplastics.•Accumulation in freshwater sediments may contribute to the loss of SMPs in ocean.•Nile Red staining is a promising methods for quantifying abundant SMPs.
Understanding water uptake and drainage in shales has important implications for both hydrocarbon extraction and hydraulic fracturing fluid disposal. This study reports gravimetric water sorption ...isotherms and kinetics of water transport in shales. Moisture mass transport profiles during water uptake and drainage processes were numerically simulated. Quantitative parameters characterizing the water transport properties were calculated and their dependences on water saturation were analyzed. An approach was proposed to evaluate the permeability of shales using dynamic water sorption. The reliability of the estimated results was verified by the experimental values using gas permeability measurements.The apparent diffusion coefficients of water sorption on shales were found to be between 1.0 × 10−12 and 1.5 × 10−11 m2/s. The apparent diffusion coefficient first increases with water saturation and remains stable at a moderately saturated condition. However, this coefficient decreases for shales with high water saturation. Apparent diffusion coefficients for the sorption process are almost equal to those for the desorption process, except at the moderate saturation condition. Liquid water (including adsorbed water) contributes more than 80% to the water transport, whereas water vapor mainly contributes to shales with low water saturation. The liquid water permeability determined by water sorption is consistent with the crushed‐rock permeability measured by gas expansion. A further reasonable agreement is achieved between the analytical gas permeability, as a function of water saturation, and the experimental gas phase permeability. Water sorption kinetics provide an indirect method for assessing the water transport properties as a function of water saturation when direct measurements are not available.
Key Points
Water in shale reservoirs is strongly diffusion‐limited
Liquid water (including adsorbed water) contributes to more than 80% of total transport, whereas water vapor contributes to transport in low water‐saturated shales
Water permeability coefficients determined by moisture transport modeling are consistent with petrophysical measurements
Both the characteristics of lithofacies and tectonic movements are important factors in controlling the development, destruction, and preservation of pores in shale reservoirs. However, the main ...factors that control the structure of shale pores are complex and highly disputed, restricting the understanding of the mechanisms that lead to the accumulation of shale gas. In this study, mineral composition and geochemical analyses, high resolution field emission scanning electron microscopy (FE-SEM), and low-pressure gas adsorption (N2 and CO2) were conducted to evaluate the pore systems of different types shale in the Jiaoshiba area, Sichuan Basin. A total of three shale groups, including silica-rich high production shales, clay-rich low production shales, and silica-rich low production shales were identified on the basis of lithofacies and gas-bearing characteristics.
The highest values of TOC, pore volume, and specific surface area are found in the silica-rich high production shales, with an average of 4.182%, 33.04 × 10−3 cm3/g, and 38.71 m2/g, respectively. The total pore volume and specific surface area in the clay-rich low production shales are 19.85% and 28.62% lower than that of silica-rich high production shales. This suggests that the types of lithofacies have a more prominent influence on the specific surface area of the shales, while the pore volume plays a smaller role. However, the pressure in silica-rich low production shales is often released due to strong tectonic deformation. The OM pores in the silica-rich low production shales therefore tend to be both compressed and closed, with low surface porosity and of round shape. The total pore volume and specific surface area of silica-rich low production shales are 34.63% and 22.0% lower than that of the silica-rich high production shales. This indicates that tectonic movement has a significant influence on the shale pore volume, while specific surface area has a smaller influence.
•Effects of lithofacies and preservation conditions on shale pores structure are analyzed.•Lithofacies mainly controls specific surface area and adsorbed gas.•Preservation conditions mainly controls shale pore volume and free gas.
Background
To evaluate the association of preoperative clinical and sonographic features with central lymph node metastasis (CLNM) in patients with clinically node‐negative (cN0) papillary thyroid ...carcinoma (PTC) without capsule invasion.
Methods
Clinical and sonographic features of 635 cN0 PTC nodules without capsule invasion were retrospectively reviewed. CLNM was confirmed by pathology. Univariate and multivariate analyses were performed to analyze the predicting factors associated with CLNM in cN0 PTC without capsule invasion.
Results
In the 635 cN0 PTC nodules without capsule invasion, age ≤36 years, male, tumor size >8 mm, the distance between the tumor and the capsule ≤1.1 mm and calcification were independently associated with CLNM (P < .05).
Conclusions
CLNM was associated with age, sex, tumor size, the distance between the tumor and the capsule, and calcification in cN0 PTC without capsule invasion. Preoperative assessment of risk factors could help to select PTC patients who benefit from surgery.
Oleanolic acid (OA) is a triterpenoid that exists widely in fruits, vegetables and medicinal herbs. OA is included in some dietary supplements and is used as a complementary and alternative medicine ...(CAM) in China, India, Asia, the USA and European countries. OA is effective in protecting against various hepatotoxicants, and one of the protective mechanisms is reprogramming the liver to activate the nuclear factor erythroid 2‐related factor 2 (Nrf2). OA derivatives, such as CDDO‐Im and CDDO‐Me, are even more potent Nrf2 activators. OA has recently been shown to also activate the Takeda G‐protein‐coupled receptor (TGR5). However, whereas a low dose of OA is hepatoprotective, higher doses and long‐term use of OA can produce liver injury, characterized by cholestasis. This paradoxical hepatotoxic effect occurs not only for OA, but also for other OA‐type triterpenoids. Dose and length of time of OA exposure differentiate the ability of OA to produce hepatoprotection vs hepatotoxicity. Hepatotoxicity produced by herbs is increasingly recognized and is of global concern. Given the appealing nature of OA in dietary supplements and its use as an alternative medicine around the world, as well as the development of OA derivatives (CDDO‐Im and CDDO‐Me) as therapeutics, it is important to understand not only that they program the liver to protect against hepatotoxic chemicals, but also how they produce hepatotoxicity.
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