Melatonin sensitises shikonin-induced cancer cell death mediated by oxidative stress via inhibition of the SIRT3/SOD2-AKT pathway

Recent research suggests that melatonin (Mel), an endogenous hormone and natural supplement, possesses anti-proliferative effects and can sensitise cells to anti-cancer therapies. Although shikonin (SHK) also possesses potential anti-cancer properties, the poor solubility and severe systemic toxicity of this compound hinders its clinical usage. In this study, we combined Mel and SHK, a potentially promising chemotherapeutic drug combination, with the aim of reducing the toxicity of SHK and enhancing the overall anti-cancer effects. We demonstrate for the first time that Mel potentiates the cytotoxic effects of SHK on cancer cells by inducing oxidative stress via inhibition of the SIRT3/SOD2-AKT pathway. Particularly, Mel-SHK treatment induced oxidative stress, increased mitochondrial calcium accumulation and reduced the mitochondrial membrane potential in various cancer cells, leading to apoptosis. This drug combination also promoted endoplasmic reticulum (ER) stress, leading to AKT dephosphorylation. In HeLa cells, Mel-SHK treatment reduced SIRT3/SOD2 expression and SOD2 activity, while SIRT3 overexpression dramatically reduced Mel-SHK-induced oxidative stress, ER stress, mitochondrial dysfunction and apoptosis. Hence, we propose the combination of Mel and SHK as a novel candidate chemotherapeutic regimen that targets the SIRT3/SOD2-AKT pathway in cancer

Blood Pressure Changes in Relation to Arsenic Exposure in a U.S. Pregnancy Cohort

Background: Inorganic arsenic exposure has been related to the risk of increased blood pressure based largely on cross-sectional studies conducted in highly exposed populations. Pregnancy is a period of particular vulnerability to environmental insults. However, little is known about the cardiovascular impacts of arsenic exposure during pregnancy. Objectives: We evaluated the association between prenatal arsenic exposure and maternal blood pressure over the course of pregnancy in a U.S. population. Methods: The New Hampshire Birth Cohort Study is an ongoing prospective cohort study in which \u3e 10% of participant household wells exceed the arsenic maximum contaminant level of 10 μg/L established by the U.S. EPA. Total urinary arsenic measured at 24–28 weeks gestation was measured and used as a biomarker of exposure during pregnancy in 514 pregnant women, 18–45 years of age, who used a private well in their household. Outcomes were repeated blood pressure measurements (systolic, diastolic, and pulse pressure) recorded during pregnancy. Results: Using linear mixed effects models, we estimated that, on average, each 5-μg/L increase in urinary arsenic was associated with a 0.15-mmHg (95% CI: 0.02, 0.29; p = 0.022) increase in systolic blood pressure per month and a 0.14-mmHg (95% CI: 0.02, 0.25; p = 0.021) increase in pulse pressure per month over the course of pregnancy. Conclusions: In our U.S. cohort of pregnant women, arsenic exposure was associated with greater increases in blood pressure over the course of pregnancy. These findings may have important implications because even modest increases in blood pressure impact cardiovascular disease risk

Hydrogen Sulfide Mitigates Kidney Injury in High Fat Diet-Induced Obese Mice

Obesity is prevalent worldwide and is a major risk factor for the development and progression of kidney disease. Hydrogen sulfide (H2S) plays an important role in renal physiological and pathophysiological processes. However, whether H2S is able to mitigate kidney injury induced by obesity in mice remains unclear. In this study, we demonstrated that H2S significantly reduced the accumulation of lipids in the kidneys of high fat diet- (HFD-) induced obese mice. The results of hematoxylin and eosin, periodic acid-Schiff, and Masson’s trichrome staining showed that H2S ameliorated the kidney structure, decreased the extent of interstitial injury, and reduced the degree of kidney fibrosis in HFD-induced obese mice. We found that H2S decreased the expression levels of tumor necrosis factor-α, interleukin- (IL-) 6, and monocyte chemoattractant protein-1 but increased the expression level of IL-10. Furthermore, H2S treatment decreased the protein expression of p50, p65, and p-p65 in the kidney of HFD-induced obese mice. In conclusion, H2S is able to mitigate renal injury in HFD-induced obese mice through the reduction of kidney inflammation by downregulating the expression of nuclear factor-kappa B. H2S or its releasing compounds may serve as a potential therapeutic molecule for obesity-induced kidney injury

A Prospective Study of Arsenic Exposure, Arsenic Methylation Capacity, and Risk of Cardiovascular Disease in Bangladesh

Millions of persons worldwide, including 13 million Americans (U.S. Environmental Protection Agency 2009) and over 50 million in Bangladesh (British Geological Survey 2007), have been chronically exposed to arsenic, a group 1 human carcinogen (International Agency for Research on Cancer 2004), through contaminated drinking water. Arsenic exposure from drinking water has been associated with cardiovascular disease (CVD) (Chen CJ et al. 1996; Chen Y et al. 2011; Chiou et al. 1997; Liao et al. 2012; Tseng et al. 2003; Yuan et al. 2007). However, prospective studies assessing susceptibility to CVD due to arsenic exposure are rare. Arsenic in drinking water is present as inorganic arsenic (iAS). Once ingested, iAs is methylated to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA). The relative distribution of urinary arsenic metabolites varies from person to person and has been interpreted to reflect arsenic methylation capacity (Hopenhayn-Rich et al. 1996; Vahter 1999). Mechanistic studies have shown that MMAIII is more toxic than iAs or any of the pentavalent metabolites (Petrick et al. 2000; Styblo et al. 2000). Incomplete methylation, indicated by a high percentage of urinary MMA (MMA%), has been consistently related to cancers (Chen YC et al. 2003; Pu et al. 2007; Steinmaus et al. 2006; Yu et al. 2000), and there is some evidence of stronger associations among smokers than nonsmokers (Pu et al. 2007; Steinmaus et al. 2006). However, the association between urinary MMA% and CVD risk is unknown, and research on the combined effects of arsenic and biomarkers of arsenic susceptibility on CVD risk is needed. We conducted a prospective case–cohort study nested in a large prospective cohort to assess associations of arsenic exposure from drinking water and arsenic methylation capacity, indicated using relative distribution of urinary arsenic metabolites, with CVD risk

Association between Arsenic Exposure from Drinking Water and Longitudinal Change in Blood Pressure among HEALS Cohort Participants

Background: Cross-sectional studies have shown associations between arsenic exposure and prevalence of high blood pressure; however, studies examining the relationship of arsenic exposure with longitudinal changes in blood pressure are lacking. Method: We evaluated associations of arsenic exposure in relation to longitudinal change in blood pressure in 10,853 participants in the Health Effects of Arsenic Longitudinal Study (HEALS). Arsenic was measured in well water and in urine samples at baseline and in urine samples every 2 years after baseline. Mixed-effect models were used to estimate the association of baseline well and urinary creatinine-adjusted arsenic with annual change in blood pressure during follow-up (median, 6.7 years). Result: In the HEALS population, the median water arsenic concentration at baseline was 62 μg/L. Individuals in the highest quartile of baseline water arsenic or urinary creatinine-adjusted arsenic had a greater annual increase in systolic blood pressure compared with those in the reference group (β = 0.48 mmHg/year; 95% CI: 0.35, 0.61, and β = 0.43 mmHg/year; 95% CI: 0.29, 0.56 for water arsenic and urinary creatinine-adjusted arsenic, respectively) in fully adjusted models. Likewise, individuals in the highest quartile of baseline arsenic exposure had a greater annual increase in diastolic blood pressure for water arsenic and urinary creatinine-adjusted arsenic, (β = 0.39 mmHg/year; 95% CI: 0.30, 0.49, and β = 0.45 mmHg/year; 95% CI: 0.36, 0.55, respectively) compared with those in the lowest quartile. Conclusion: Our findings suggest that long-term arsenic exposure may accelerate age-related increases in blood pressure. These findings may help explain associations between arsenic exposure and cardiovascular disease

A 4-Phase Combined Adhesion Threshold Algorithm for Wheel Slide Protection Systems in Rail Vehicles

The wheel slide protection control system for rail vehicles plays a crucial role in ensuring a consistent braking performance in all operating environments, making it a vital factor in the safety and efficiency of rail transportation. In this paper, a hybrid approach to wheel slide protection control is presented, which combines the rule-based control strategy and the model-based control methods using adhesion force estimation. Model-based control usually relies on mathematical models to characterize the vehicle dynamics, requiring online estimators to be designed or extra sensors to be added for practical application. Rule-based control operates on predefined rules and thresholds and the available data from vehicles in service. A comparative test was conducted between the traditional rule-based control strategy and the proposed combined control strategy using a semi-physical simulation test bench. The performance differences of the control strategies were analyzed from two perspectives: adhesion utilization and air consumption. It was observed that among the traditional 2-phase, 3-phase, 4-phase and the optimized 4-phase combined control method, the combined control strategy has the best adhesion utilization and the traditional 4-phase control strategy has the least air consumption

Confinement Inside a Crystalline Sponge Induces Pyrrole to Form N−H⋅⋅⋅π Bonded Tetramers

Based on the DFT‐level calculated molecular volume (V mol ) of pyrrole and its liquid density, pyrrole manifests the highest liquid density coefficient LD c (defined as [V mol • density • 0.6023]/FW) value of 0.7. Normal liquids have LD c < 0.63. This very high LD c is due to the strong N‐H … π interactions in solution and hence pyrrole can be considered to be a pseudo‐crystalline liquid. When trapped inside the confined space of the crystalline sponge a reorientation of the N‐H … π interaction is observed leading to specific cyclic N‐H … π tetramers and N‐H … π dimers, verified by single crystal X‐ray crystallographic and computational methods. These tetramers are of the same size as four pyrrole molecules in the solid‐state of pyrrole, yet the cyclic N‐H … π intermolecular interactions are circularly oriented instead of the linear zig‐zag structure found in the X‐ray structure of a solid pyrrole. The confinement thus acts as an external driving force for the tetramer formation.peerReviewe

Modeling the reuse intention and practices of secondhand clothing: evidence from a developing nation

Abstract This study explored the effect of perceived values on sustainability, problem awareness, the ascription of responsibility, sense of community, and anticipated guilt on reuse (sell and/or swap) intention of secondhand clothing through partial least squares structural equation modeling. This study adopted a cross-sectional design and collected quantitative data from 524 conveniently selected respondents in China through an online survey. The findings revealed that perceived values on sustainability, ascription of responsibility, sense of community, and anticipated guilt are the most important factors influencing reuse intention, whereas problem awareness is not a significant predictor. It has also been demonstrated that reuse intention promotes the development of reuse practices. Despite its large population, China is facing significant environmental challenges. The findings of this study may provide a viable option for the sustainable development of reusing secondhand clothing and also contribute to new knowledge on the factors that influence the reuse practices of secondhand clothing in China and even around the world

Rail temperature rise characteristics caused by linear eddy current brake of high-speed train

The rail temperature rises when the linear eddy current brake of high-speed train is working, which may lead to a change of rail physical characteristics or an effect on train operations. Therefore, a study concerning the characteristics of rail temperature rise caused by eddy current has its practical necessity. In the research, the working principle of a linear eddy current brake is introduced and its FEA model is established. According to the generation mechanism of eddy current, the theoretical formula of the internal energy which is produced by the eddy current is deduced and the thermal load on the rail is obtained. ANSYS is used to simulate the rail temperature changes under different conditions of thermal loads. The research result shows the main factors which contribute to the rising of rail temperature are the train speed, brake gap and exciting current. The rail temperature rises non-linearly with the increase of train speed. The rail temperature rise curve is more sensitive to the exciting current than the air gap. Moreover, the difference stimulated by temperature rising between rails of 60 kg/m and 75 kg/m is presented as well