Combining deep learning and crowd-sourcing images to predict housing quality in rural China.

Housing quality is essential to human well-being, security and health. Monitoring the housing quality is crucial for unveiling the socioeconomic development status and providing political proposals. However, depicting the nationwide housing quality in large-scale and fine detail is exceedingly rare in remote rural areas owing to the high cost of canonical survey methods. Taking rural China as an example, we collect massive rural house images for housing quality assessment by various volunteers and further build up a deep learning model based on the assessed images to realize an automatic prediction for huge raw house images. As a result, the model performance achieves a high R2 of 0.76. Afterward, the housing qualities of 10,000 Chinese villages are estimated based on 50,000 unlabeled geo-images, and an apparent spatial heterogeneity is discovered. Specifically, divided by Qinling Mountains-Huaihe River Line, housing quality in southern China is much better than in northern China. Our method provides high-resolution predictions of housing quality across the extensive rural area, which could be a complementary tool for automatical monitoring of housing change and supporting house-related policymaking.

In Vivo Visualization of γ-Glutamyl Transpeptidase Activity with an Activatable Self-Immobilizing Near-Infrared Probe.

γ-Glutamyl transpeptidase (GGT), a type of cell membrane-bound enzyme, is closely involved in a wide range of physiological and pathological processes, and a large number of fluorogenic probes have been developed to detect the activity of GGT. However, the use of these imaging reagents to visualize GGT activity in vivo is largely limited because of rapid diffusion and clearance of activated fluorophores. Herein, by merging quinone methide and a fluorogenic enzyme substrate, we report an activatable self-immobilizing near-infrared probe for the in vitro and in vivo imaging of GGT activity. This probe is initially fluorescently silent, but the selective activation by GGT is able to significantly increase its fluorescence intensity at 714 nm and covalently anchor activated fluorophores at the site of interest. We have shown that this probe induced a much stronger fluorescence on live GGT-overexpressing cells compared to regular fluorogenic probes and allowed wash-free and real-time imaging of enzyme activity. More importantly, the use of this probe in the imaging of GGT activity in U87MG tumor-bearing mice by i.v. administration indicates that this self-immobilizing reagent is capable of efficiently enhancing its retention at the detection target and thus leads to much improved detection sensitivity compared to regular fluorogenic probes. This study demonstrates the advantage of fluorogenic probes with activatable anchors in the noninvasive imaging of enzyme activity in highly dynamic in vivo systems.

Downregulation of DEC1 by RNA interference attenuates ischemia/reperfusion-induced myocardial inflammation by inhibiting the TLR4/NF-κB signaling pathway.

Inflammation has been implicated in the pathogenesis of myocardial ischemia/reperfusion (I/R) injury (MIRI). Previous studies have confirmed that deleted in esophageal cancer 1 (DEC1) is an important transcription factor in inflammation. However, the role of DEC1 in MIRI remains unclear. The present study aimed to determine whether the downregulation of DEC1 by RNA interference alleviated inflammation to protect against MIRI. Adult Sprague-Dawley rats (n=48) were randomly divided into four groups: Sham; I/R; adenovirus expressing green fluorescent protein control (Ad-G-Control); and DEC1-targeting RNA interference (Ad-G-DEC1) groups. Following gene delivery 4 days later, the rat myocardial I/R model was established and myocardial enzymes [creatine kinase (CK) and lactate dehydrogenase (LDH)] were detected. Hematoxylin and eosin (H&E) staining was performed to evaluate the myocardial damage and the infarct area was assessed using Evans Blue/triphenyltetrazolium chloride staining. The inflammatory mediators interleukin (IL)-ß and tumor necrosis factor (TNF)-α were also detected using ELISA kits to assess the inflammatory response. Finally, western blotting and reverse transcription-quantitative PCR were used to analyze the expression levels of associated proteins and mRNAs. Ad-G-DEC1 RNA interference markedly decreased DEC1 expression levels. In addition, following the downregulation of DEC1 expression, the infarct size, CK, LDH, Toll-like receptor (TLR)4, NF-κB, IL-ß and TNF-α levels were all significantly decreased. In conclusion, the results of the present study suggested that the downregulation of DEC1 may decrease the inflammation by suppressing the TLR4/NF-κB signaling pathway, which may represent a therapeutic target for MIRI.

A minor structure modification serendipitously leads to a highly carbapenemase-specific fluorogenic probe.

Reported herein is a fluorogenic probe for the detection of carbapenemase activity. This reagent features carbapenem as an enzyme recognition motif and a carbon-carbon double bond between carbapenem and the fluorophore, exhibiting high specificity to all carbapenemases, including metallo carbapenemases and serine carbapenemases, over other ß-lactamases.

TRAF5 protects against myocardial ischemia reperfusion injury via AKT signaling.

During the processes of myocardial ischemia reperfusion (I/R) injury, inflammation and apoptosis play an important role. I/R and its induced acute myocardial infarction (AMI) with high morbidity and mortality, and there is no effective treatment for it so far. TRAF5 has been shown to regulate inflammation and apoptosis in atherosclerosis, steatosis and melanoma cells, but its function in myocardial I/R injury is still unclear. This study demonstrates that the expression of TRAF5 is significant up-regulation in heart tissues of I/R injury mice and hypoxia/reoxygenation (H/R)-stimulated cardiomyocytes. TRAF5 knockout mice exhibites heavier heart damage, inflammatory response and cell death after myocardial I/R injury. Further, TRAF5 overexpression inhibites inflammation and apoptosis of H/R-stimulated cardiomyocytes. Mechanistically, we prove that TRAF5 promotes the activation of AKT. Overall, our study indicates that TRAF5 can regulate the processes of myocardial I/R injury. TRAF5 can be a new therapy target for myocardial I/R injury.

The inverted U-shaped effect of urban hotspots spatial compactness on urban economic growth.

The compact city, as a sustainable concept, is intended to augment the efficiency of urban function. However, previous studies have concentrated more on morphology than on structure. The present study focuses on urban structural elements, i.e. urban hotspots consisting of high-density and high-intensity socioeconomic zones, and explores the economic performance associated with their spatial structure. We use night-time luminosity data and the Loubar method to identify and extract the hotspot and ultimately draw two conclusions. First, with population increasing, the hotspot number scales sublinearly with an exponent of approximately 0.50-0.55, regardless of the location in China, the EU or the USA, while the intersect values are totally different, which is mainly due to different economic developmental level. Secondly, we demonstrate that the compactness of hotspots imposes an inverted U-shaped influence on economic growth, which implies that an optimal compactness coefficient does exist. These findings are helpful for urban planning.

TRAF1 Exacerbates Myocardial Ischemia Reperfusion Injury via ASK1-JNK/p38 Signaling.

Background After acute myocardial infarction, the recovery of ischemic myocardial blood flow may cause myocardial reperfusion injury, which reduces the efficacy of myocardial reperfusion. Ways to reduce and prevent myocardial ischemia/reperfusion (I/R) injury are of great clinical significance in the treatment of patients with acute myocardial infarction. TRAF1 (tumor necrosis factor receptor-associated factor 1) is an important adapter protein that is implicated in molecular events regulating immunity, inflammation, and cell death. Little is known about the role and impact of TRAF1 in myocardial I/R injury. Methods and Results TRAF1 expression is markedly induced in wild-type mice and cardiomyocytes after I/R or hypoxia/reoxygenation stimulation. I/R models were established in TRAF1 knockout mice and wild type mice (n=10 per group). We demonstrated that TRAF1 deficiency protects against myocardial I/R-induced loss of heat function, inflammation, and cardiomyocyte death. In addition, overexpression of TRAF1 in primary cardiomyocytes promotes hypoxia/reoxygenation-induced inflammation and apoptosis in vitro. Mechanistically, TRAF1 promotes myocardial I/R injury through regulating ASK1 (apoptosis signal-regulating kinase 1)-mediated JNK/p38 (c-Jun N-terminal kinase/p38) MAPK (mitogen-activated protein kinase) cascades. Conclusions Our results indicated that TRAF1 aggravates the development of myocardial I/R injury by enhancing the activation of ASK1-mediated JNK/p38 cascades. Targeting the TRAF1-ASK1-JNK/p38 pathway provide feasible therapies for cardiac I/R injury.

Highly selective and wash-free visualization of resistant bacteria with a relebactam-derived fluorogenic probe.

Reported herein is a relebactam-derived fluorogenic reagent for covalent labeling of serine ß-lactamases (SBLs), which are the major causes of bacterial resistance to ß-lactam antibiotics. This highly selective imaging reagent generates over 300-fold stronger near-infrared fluorescence signals upon covalently bonding to SBLs, allowing wash-free visualization of live antimicrobial-resistant bacteria.

A carbapenem-based fluorescence assay for the screening of metallo-ß-lactamase inhibitors.

Reported herein is a fluorescence assay for the rapid screening of metallo-ß-lactamase (MBL) inhibitors. This assay employs a fluorogenic carbapenem CPC-1 as substrate and is compatible with all MBLs, including B1, B2 and B3 subclass MBLs. The efficiency of this assay was demonstrated by the rapid inhibition screening of a number of molecules against B2 MBL CphA and 2,3-dimercaprol was identified as a potent CphA inhibitor.

Inhibition of autophagy via activation of PI3K/Akt/mTOR pathway contributes to the protection of hesperidin against myocardial ischemia/reperfusion injury.

Hesperidin has been reported to attenuate myocardial ischemia/reperfusion (I/R) injury; however, its effect on autophagy during myocardial I/R and the underlying mechanism remains unknown. The present study aimed to investigate whether hesperidin inhibited I/R­induced excessive myocardial autophagy through activating the phosphatidylinositol 3­kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway. Male adult rats were pretreated with hesperidin for a total of 3 days prior to ischemia in the absence or presence of LY294002, a PI3K inhibitor, and then subjected to ischemia for 30 min followed by reperfusion for 4 h. Myocardial infarct size was measured by Evans blue/triphenyltetrazolium chloride staining. Hematoxylin and eosin staining was used for observing the histological changes in the heart, and the serum levels of creatine kinase­MB (CK­MB) and cardiac troponin I (cTnI) were measured by enzyme­linked immunosorbent assay. Additionally, the protein levels of light chain (LC) 3Ⅱ, Beclin1, phosphorylated (p)­mTOR, p­Akt and p­PI3K were determined by western blot analysis. Hesperidin pretreatment significantly decreased the myocardial infarct size, myocardial damage and serum levels of CK­MB and cTnI. Furthermore, the expression levels of LC3Ⅱ and Beclin1 were significantly downregulated and the expression levels of p­mTOR, p­Akt and p­PI3K were markedly upregulated by hesperidin. However, the aforementioned effects as a result of hesperidin were significantly reversed by the presence of LY294002. These results demonstrated that hesperidin reduced myocardial I/R injury by suppressing excessive autophagy. Activation of the PI3K/Akt/mTOR pathway contributed to the inhibitory effect of hesperidin on excessive autophagy.

Downregulation of microRNA-17-5p improves cardiac function after myocardial infarction via attenuation of apoptosis in endothelial cells.

MicroRNA-17-5p (miR-17-5p) was indicated to suppress the formation of blood vessels, which is associated with cardiac function after myocardial infarction. In this study, the relationship between miR-17-5p and cardiac function was researched. Human umbilical vein endothelial cells were infected with adenoviruses. Apoptosis was determined by Annexin V-7AAD/PI. Real-time RT-PCR was used to evaluate miR-17-5p and ERK levels. Western blotting was used to determine the levels of ERK, the anti-apoptosis protein bcl-2 and apoptosis proteins, including bax, caspase 3, and caspase 9. An in vivo acute myocardial infarction (AMI) model was established in SD male rats. Heart function was evaluated by echocardiography prior to inducing AMI and after 7 and 28 days later. The heart was removed to perform histological examination, real-time RT-PCR, and western blotting, as described above. The result indicated that the ERK pathway was activated by miR-17-5p downregulation and an increase in the level of the anti-apoptosis protein bcl-2; however, the levels of apoptosis proteins (bax/caspase 3/caspase 9) were decreased. The results were completely reversed when miR-17-5p was up-regulated. At 7 and 28 days after the induction of AMI, in the miR-17-5p inhibition group, the infarction areas and collagen fibers were decreased, apoptosis in cardiac tissues was inhibited, and the endothelial growth process was promoted. Therefore, MiR-17-5p silencing protects heart function after AMI through decreasing the rate of apoptosis and repairing vascular injury.

The HMGB1­IL­17A axis contributes to hypoxia/reoxygenation injury via regulation of cardiomyocyte apoptosis and autophagy.

Both the high­mobility group box 1 protein (HMGB1) and interleukin (IL)­17A serve important roles in myocardial ischemia and reperfusion injury. The purpose of the present study was to evaluate whether HMGB1 could induce IL­17A secretion and lead to cardiomyocyte hypoxia/reoxygenation (H/R) injury. Neonatal rat cardiomyocytes were treated with HMGB1­neutralizing antibody, IL­17A­neutralizing antibody, recombinant HMGB1 (rHMGB1) and recombinant IL­17A (rIL­17A), respectively. Cell viabilities, lactate dehydrogenase and creatine kinase levels were measured. Apoptotic cells were assessed by flow cytometry. The expression of HMGB1, IL­17A, microtubule­associated proteins 1A/1B light chain 3B (LC3), Beclin­1, B­cell lymphoma (Bcl)­2 and Bcl­2­associated X protein were assessed by western blot analysis. The results demonstrated that HMGB1 significantly increased the expression of IL­17A. HMGB1 or IL­17A antibody significantly ameliorated H/R­induced cell injury and improved the cell viability. In contrast, rHMGB1 or rIL­17A aggravated cell injury and inhibited the cell viability. Furthermore, cardiomyocytes were treated with HMGB1 or IL­17A antibody significantly increased Bcl­2 protein expression and had fewer apoptotic cells, whereas rHMGB1 or rIL­17A­treated cardiomyocytes markedly decreased Bcl­2 protein expression and had more apoptotic cells. Moreover, HMGB1 or IL­17A antibodies significantly inhibited H/R induced autophagy dysfunction (as determined by the inhibition of Beclin­1 expression, a lower ratio of LC3­II to LC3­I), whereas rHMGB1 or rIL­17A may promote cardiomyocyte autophagy. Together, these results suggested that the HMGB1­IL­17A axis contributes to H/R injury via regulation of cardiomyocyte apoptosis and autophagy.

Promoting effects of IL­23 on myocardial ischemia and reperfusion are associated with increased expression of IL­17A and upregulation of the JAK2­STAT3 signaling pathway.

Interleukin (IL)­23, as a novel pro­inflammatory cytokine, is important in several inflammatory diseases, including myocardial ischemia and reperfusion (I/R) injury, however, the underlying mechanism remains to be elucidated. The present study was designed to investigate the specific role of IL­23 in myocardial I/R injury, and whether the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2­STAT3) signaling pathway, one of the important downstream signaling pathways of IL­23, and the IL­17A downstream pro­inflammatory cytokine, were involved. Anesthetized rats underwent different treatments with adenovirus (Ad) vectors (Ad­GFP, Ad­IL­23, Anti­IL­23 or Ad­IL­23+AG490) and were then subjected to ischemia for 30 min prior to 4 h reperfusion. The effects of the upregulation and downregulation of IL­23 on myocardial injury, inflammatory responses in myocardial tissue, and myocardial apoptosis were measured accordingly. In addition, the levels of phosphorylated (P­)JAK2 and P­STAT3 were measured to assess the activity of the JAK2­STAT3 signaling pathway. The results demonstrated that there was an increased expression of IL­23 in the myocardial tissue exposed to myocardial I/R injury (P<0.05). The upregulation of IL­23 significantly increased the infarct size and the expression levels of lactate dehydrogenase and creatine kinase (P<0.05). The upregulation of IL­23 significantly increased inflammatory responses, as reflected by the high expression levels of IL­17A, IL­6, tumor necrosis factor­α in the myocardial tissues (P<0.05). Furthermore, the upregulation of IL­23 significantly facilitated the decrease in the B­cell lymphoma 2 (Bcl­2)/Bcl­2­associated X protein ratio, and the increases in the myocardial apoptotic index and expression of caspase­3 induced by myocardial I/R (P<0.05). IL­23 also activated the JAK2­STAT3 signaling pathway, upregulating the expression levels of P­JAK2 and P­STAT3 in the myocardial tissues (P<0.05). Treatment with AG490, an inhibitor of JAK2­STAT3, partially attenuated the pro­inflammatory and pro­apoptotic effects of IL­23 (P<0.05). The results of the present study suggested that IL­23 aggravated myocardial I/R injury by promoting inflammatory responses and myocardial apoptosis, which may be associated with high expression levels of IL­17A and upregulation of the JAK2­STAT3 signaling pathway.

Short-Term Hesperidin Pretreatment Attenuates Rat Myocardial Ischemia/Reperfusion Injury by Inhibiting High Mobility Group Box 1 Protein Expression via the PI3K/Akt Pathway.

BACKGROUND/AIMS: Hesperidin pretreatment has been shown to protect against myocardial ischemia/reperfusion (I/R) injury, but the underlying mechanism is poorly understood. This study aimed to investigate the cardioprotective effects of a 3-day hesperidin pretreatment on I/R injury and to further explore whether its mechanism of action was associated with the inhibition of high mobility group box 1 protein (HMGB1) expression via the PI3K/Akt pathway. METHODS: In a fixed-dose study, hematoxylin and eosin staining and myocardial enzyme measurements were used to determine the optimal dose of hesperidin that elicited the best cardioprotective effects against I/R injury. Furthermore, rats were pretreated with 200 mg/kg hesperidin, and infarct size and the levels of myocardial enzymes, apoptosis, inflammatory and oxidative indices, and HMGB1 and p-Akt expression were measured. RESULTS: Our results indicated that while different 3-day hesperidin pretreatment doses promoted histopathological changes and reduced myocardial enzymes induced by I/R the optimal dose was 200 mg/kg. Moreover, the 200 mg/kg hesperidin pretreatment not only significantly decreased the infarct size as well as myocardial enzyme levels but also inhibited myocardial apoptosis, the inflammatory response and oxidative stress. Additionally, hesperidin downregulated HMGB1 expression and upregulated p-Akt expression in the myocardium. LY294002, a specific PI3K inhibitor, partially reversed the decreased HMGB1 expression, increased p-Akt expression induced by hesperidin and abolished the anti-apoptotic, anti-inflammatory and anti-oxidative effects of hesperidin. CONCLUSION: These findings suggest that short-term pretreatment with hesperidin protects against myocardial I/R injury by suppressing myocardial apoptosis, the inflammatory response and oxidative stress via PI3K/Akt pathway activation and HMGB1 inhibition.

Low-level environmental arsenic exposure correlates with unexplained male infertility risk.

Humans are exposed to arsenic via drinking water, dietary intake and inhaled particulates. Endemic chronic arsenic exposure related reproductive toxicity is well documented, but the effect of low-level general environmental arsenic exposure on unexplained male infertility (UMI) remains unclear. In this case-control study, we aimed to investigate the relationship between non-geogenic environmental arsenic exposure and UMI risk. One hundred and one infertile men with normal semen as cases and sixty one fertile men as controls were recruited. Five urinary arsenic species: pentavalent arsenate (Asi(V)), trivalent arsenite (Asi(III)), methylated to monomethylarsonic acid (MMA(V)), dimethylarsinic acid (DMA(V)), arsenobetaine (AsB) were quantitatively measured by liquid chromatography-inductively coupled plasma-mass spectrometry (LC-ICP-MS). To assess the semen quality, semen volume, sperm concentration, total motility, and progressive motility were measured. The nonparametric Mann-Whitney U test was used to compare the differences of arsenic species and index between the case and the control group; we observed that concentrations of Asi(V), AsB, MMA(V), DMA(V), total inorganic As and total As were significantly higher in the cases than the controls. The urine Asi(V) level increased more than twenty folds in case group. Moreover, higher redox index (Asi(V)/Asi(III)) and lower primary arsenic methylation index (PMI=MMA(V)/Asi) were observed for case group. Furthermore, through the logistic regression analysis, we observed that the urine Asi(V) level and PMI were most significantly associated with UMI risk among the observations. Specifically, in comparison to the first quartile, the subjects with higher Asi(V) levels were more likely to exhibit UMI with increasing adjusted odds ratios (AORs) (adjusted by age, body mass index, drinking status and smoking status) of 8.39 [95% confidence interval (CI), 2.59-27.17], 13.12 (95% CI, 3.44-50.12) and 36.51 (95% CI, 8.25-161.66) at the second, third and fourth quartiles, respectively. Also a concentration-dependent decrease of AOR was also observed for PMI in comparison to the fourth quartile: 15.43 [95% CI, 4.28-55.69], 9.69 (95% CI, 2.78-33.78) and 6.93 (95% CI, 2.21-21.76) at the first, second and third quartiles, respectively. These findings provide evidences that low-level environmental arsenic exposure was positively associated with UMI risk.

IL-23 Promotes Myocardial I/R Injury by Increasing the Inflammatory Responses and Oxidative Stress Reactions.

BACKGROUND/AIMS: Inflammation and oxidative stress play an important role in myocardial ischemia and reperfusion (I/R) injury. We hypothesized that IL-23, a pro-inflammatory cytokine, could promote myocardial I/R injury by increasing the inflammatory response and oxidative stress. METHODS: Male Sprague-Dawley rats were randomly assigned into sham operated control (SO) group, ischemia and reperfusion (I/R) group, (IL-23 + I/R) group and (anti-IL-23 + I/R) group. At 4 h after reperfusion, the serum concentration of lactate dehydrogenase (LDH), creatine kinase (CK) and the tissue MDA concentration and SOD activity were measured. The infarcte size was measured by TTC staining. Apoptosis in heart sections were measured by TUNEL staining. The expression of HMGB1 and IL-17A were detected by Western Blotting and the expression of TNF-α and IL-6 were detected by Elisa. RESULTS: After 4 h reperfusion, compared with the I/R group, IL-23 significantly increased the infarct size, the apoptosis of cardiomyocytes and the levels of LDH and CK (all P < 0.05). Meanwhile, IL-23 significantly increased the expression of eIL-17A, TNF-α and IL-6 and enhanced both the increase of the MDA level and the decrease of the SOD level induced by I/R (all P<0.05). IL-23 had no effect on the expression of HMGB1 (p > 0.05). All these effects were abolished by anti-IL-23 administration. CONCLUSION: The present study suggested that IL-23 may promote myocardial I/R injury by increasing the inflammatory responses and oxidative stress reaction.

Vagus nerve stimulation attenuates myocardial ischemia/reperfusion injury by inhibiting the expression of interleukin-17A.

Interleukin (IL)-17A has an important role in myocardial ischemia/reperfusion (I/R) injury, and vagal stimulation (VS) has been demonstrated to exert cardioprotective effects. The present study aimed to investigate the effects of VS on a rat model of myocardial I/R injury, and detected an association between VS and IL-17A. Anesthetized rats underwent VS (2 msec; 10 Hz) or were treated with anti-IL-17A neutralized monoclonal antibodies (mAbs) (200 µg; iv), and subjected to ischemia for 30 min prior to 4 h reperfusion. The following parameters were measured: Infarct size; lactate dehydrogenase (LDH), creatine kinase (CK), malondialdehyde (MDA), superoxide dismutase (SOD) and caspase-3 activity levels; tumor necrosis factor (TNF)-α and IL-6 expression levels; and the percentage of terminal deoxynucleotidyl-transferase mediated dUTP nick-end labeling (TUNEL) positive cells. High mobility group box 1 protein (HMGB1) and IL-17A expression levels were assessed by immunoblotting. Following 4 h reperfusion, VS was able to significantly decrease the infarct size and the activity levels of LDH and CK (P<0.05). Furthermore, VS administration significantly suppressed the increased MDA and decreased SOD activity levels, and significantly reduced caspase-3 activity and the percentage of TUNEL-positive cells (P<0.05). Treatment with anti-IL-17A mAbs demonstrated the same effects as VS. Furthermore, VS was able to significantly inhibit the increased expression levels of TNF-α, IL-6, HMGB1 and IL-17A induced by I/R (P<0.05). The results of the present study suggested that VS may attenuate myocardial I/R injury by reducing the expression of inflammatory cytokines, oxidative stress and the apoptosis of cardiomyocytes. Furthermore, VS may induce cardioprotective effects, which may be associated with the inhibition of IL-17A expression.

Beta-1-adrenergic receptors mediate Nrf2-HO-1-HMGB1 axis regulation to attenuate hypoxia/reoxygenation-induced cardiomyocytes injury in vitro.

UNLABELLED: BACKGROUD/AIMS: The aim of the study was to evaluate the effects of beta1-adrenergic receptors (ß1-ARs) -mediated nuclear factor erythroid 2-related factor 2 (Nrf2)-heme oxygenase-1 (HO-1)-high mobility group box 1 protein (HMGB1) axis regulation in hypoxia/reoxygenation (H/R)-induced neonatal rat cardiomyocytes. METHODS: The neonatal cultured cardiomyocytes were concentration-dependently pretreated by dobutamine (DOB), a selective ß1-adrenergic receptor agonist, in the absence and/or presence of LY294002 (a phosphatidylinositol 3-kinase (PI3K) inhibitor), SB203580 (a p38mitogen-activated-protein kinase (p38MAPK) inhibitor), Nrf2siRNA and HO-1siRNA, respectively, and then treated by H/R. The effects and mechanisms by which H/R-induced cardiomyocytes injury were evaluated. RESULTS: Significant increase of HO-1 was found in neonatal cultured cardiomyocytes treated with DOB, when compared to the control group. Significant change for Nrf2 translocation was also revealed in neonatal cultured cardiomyocytes treated with DOB. Insignificant decreases of NF-kappaB p65 activation and HMGB1 release were observed in H/R-induced neonatal cultured cardiomyocytes treated with DOB, when compared to the control group. Importantly, DOB treatment significantly increased the cell viability and decreased the levels of LDH and MDA in H/R-induced cardiomyocytes injury. However, DOB failed to increase HO-1, inhibit NF-kappaB p65 activation, prevent HMGB1 release and attenuate H/R-induced cardiomyocytes injury when the cultured cardiomyocytes were pretreated by Nrf2siRNA, HO-1siRNA, PI3K inhibitor (LY294002) and p38MAPK inhibitor (SB203580), respectively. CONCLUSIONS: ß1-ARs-mediated Nrf2-HO-1-HMGB1 axis regulation plays a critical protective role in H/R-induced neonatal rat cardiomyocytes injury in vitro via PI3K/p38MAPK signaling pathway.

Exposure to arsenic via drinking water induces 5-hydroxymethylcytosine alteration in rat.

Arsenic exposure has been implicated to alter DNA methylation process in vitro and in vivo, but it remains obscure whether it disrupts DNA demethylation process, which is pivotal for epigenetic regulation. The objective of this descriptive study was to investigate the relationship between arsenic exposure and 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC) alterations in various organs. In this study, we exposed male Sprague-Dawley rats to sodium arsenite (0.5, 2 or 10 ppm) via drinking water for 8 weeks. Spleen accumulated 2- to 3-fold higher arsenic levels than liver and heart. Lower arsenic levels were observed in the kidney, pancreas and lung. No significant arsenic-induced global 5mC alterations were observed in the majority of investigated organs. However, arsenic induced organ-specific alterations of 5hmC and/or 5hmC/5mC in some investigated organs, i.e. lung, heart, kidney, pancreas and spleen. Our observations suggest that 5hmC is a more sensitive biomarker of arsenic-induced impacts on epigenetic processes than 5mC. Moreover, demethylation via hydroxylation of 5mC appears to play a central role in the toxic mechanism of arsenic.

Urinary metabolomics revealed arsenic internal dose-related metabolic alterations: a proof-of-concept study in a Chinese male cohort.

Urinary biomonitoring provides the most accurate arsenic exposure assessment; however, to improve the risk assessment, arsenic-related metabolic biomarkers are required to understand the internal processes that may be perturbed, which may, in turn, link the exposure to a specific health outcome. This study aimed to investigate arsenic-related urinary metabolome changes and identify dose-dependent metabolic biomarkers as a proof-of-concept of the information that could be obtained by combining metabolomics and targeted analyses. Urinary arsenic species such as inorganic arsenic, methylarsonic acid, dimethylarsinic acid and arsenobetaine were quantified using high performance liquid chromatography (HPLC)-inductively coupled plasma-mass spectrometry in a Chinese adult male cohort. Urinary metabolomics was conducted using HPLC-quadrupole time-of-flight mass spectrometry. Arsenic-related metabolic biomarkers were investigated by comparing the samples of the first and fifth quintiles of arsenic exposure classifications using a partial least-squares discriminant model. After the adjustments for age, body mass index, smoking, and alcohol consumption, five potential biomarkers related to arsenic exposure (i.e., testosterone, guanine, hippurate, acetyl-N-formyl-5-methoxykynurenamine, and serine) were identified from 61 candidate metabolites; these biomarkers suggested that endocrine disruption and oxidative stress were associated with urinary arsenic levels. Testosterone, guanine, and hippurate showed a high or moderate ability to discriminate the first and fifth quintiles of arsenic exposure with area-under-curve (AUC) values of 0.89, 0.87, and 0.83, respectively; their combination pattern showed an AUC value of 0.91 with a sensitivity of 88% and a specificity of 80%. Arsenic dose-dependent AUC value changes were also observed. This study demonstrated that metabolomics can be used to investigate arsenic-related biomarkers of metabolic changes; the dose-dependent trends of arsenic exposure to these biomarkers may translate into the potential use of metabolic biomarkers in arsenic risk assessment. Since this was a proof-of-concept study, more research is needed to confirm the relationships we observed between arsenic exposure and biochemical changes.