Characteristics and source analysis of potentially toxic elements pollution in atmospheric fallout around non-ferrous metal smelting slag sites-taking southwest China as an example.

More accurate source analysis of potentially toxic elements (PTEs) in atmospheric fallout that endanger biodiversity and human health remains needed. This study determined the concentrations of seven PTEs, including Pb, Cd, As, Cu, Zn, Ni, and Cr, by inductively coupled plasma mass spectrometry (ICP-MS), and the sources of PTE pollution were quantified using multivariate statistical analysis, including principal component analysis (PCA), cluster analysis (CA), and Pearson correlation analysis, and Moran index was applied for mutual verification and supplementation. PCA and CA revealed that the same mixed sources of Pb, Cd, As, Cu, and Zn were found in the atmospheric dust fall in the study area, while Ni and Cr had the same source of pollution. Pearson correlation analysis provided that there were strong correlations between Pb-Cd, Pb-As, Pb-Cu, Cd-As, Cd-Cu, As-Cu, and Ni-Cr, indicating commonality between the two sources of heavy metal pollution. Additionally, the Moran index showed that strong spatial correlations were observed between Pb, Cd, As, Cu, and Zn, whose sources were mainly related to non-ferrous metal processing smelter smelting slag sites and an environmental company in the study area. However, no spatial correlation was found between Ni and Cr, which mainly originated from the local geological background.

Overexpression of Twist1 in vascular endothelial cells promotes pathological retinal angiogenesis in mice.

Retinal angiogenesis is a critical process for normal retinal function. However, uncontrolled angiogenesis can lead to pathological neovascularization (NV), which is closely related to most irreversible blindness-causing retinal diseases. Understanding the molecular basis behind pathological NV is important for the treatment of related diseases. Twist-related protein 1 (TWIST1) is a well-known transcription factor and principal inducer of epithelial-mesenchymal transition (EMT) in many human cancers. Our previous study showed that Twist1 expression is elevated in pathological retinal NV. To date, however, the role of TWIST1 in retinal pathological angiogenesis remains to be elucidated. To study the role of TWIST1 in pathological retinal NV and identify specific molecular targets for antagonizing pathological NV, we generated an inducible vascular endothelial cell (EC)-specific Twist1 transgenic mouse model ( Tg-Twist1 iEC+ ). Whole-mount retinas from Tg-Twist1 iEC+ mice showed retarded vascular progression and increased vascular density in the front end of the growing retinal vasculature, as well as aneurysm-like pathological retinal NV. Furthermore, overexpression of Twist1 in the ECs promoted cell proliferation but disturbed cell polarity, thus leading to uncontrolled retinal angiogenesis. TWIST1 promoted pathological NV by activating the Wnt/ß-catenin signaling pathway and inducing the expression of NV formation-related genes, thereby acting as a 'valve' in the regulation of pathological angiogenesis. This study identified the critical role of TWIST1 in retinal pathological NV, thus providing a potential therapeutic target for pathological NV.

Chalcone derivatives ameliorate lipopolysaccharide-induced acute lung injury and inflammation by targeting MD2.

Acute lung injury (ALI) and its severe form acute respiratory distress syndrome (ARDS) are known as the common causes of respiratory failure in critically ill patients. Myeloid differentiation 2 (MD2), a co-receptor of toll like receptor 4 (TLR4), plays an important role in LPS-induced ALI in mice. Since MD2 inhibition by pharmacological inhibitors or gene knockout significantly attenuates ALI in animal models, MD2 has become an attractive target for the treatment of ALI. In this study we identified two chalcone-derived compounds, 7w and 7x, as new MD2 inhibitors, and investigated the therapeutic effects of 7x and 7w in LPS-induced ALI mouse model. In molecular docking analysis we found that 7w and 7x, formed pi-pi stacking interactions with Phe151 residue of the MD2 protein. The direct binding was confirmed by surface plasmon resonance analysis (with KD value of 96.2 and 31.2 µM, respectively) and by bis-ANS displacement assay. 7w and 7x (2.5, 10 µM) also dose-dependently inhibited the interaction between lipopolysaccharide (LPS) and rhMD2 and LPS-MD2-TLR4 complex formation. In mouse peritoneal macrophages, 7w and 7x (1.25-10 µM) dose-dependently inhibited LPS-induced inflammatory responses, MAPKs (JNK, ERK and P38) phosphorylation as well as NF-κB activation. Finally, oral administration of 7w or 7x (10 mg ·kg-1 per day, for 7 days prior LPS challenge) in ALI mouse model significantly alleviated LPS-induced lung injury, pulmonary edema, lung permeability, inflammatory cells infiltration, inflammatory cytokines expression and MD2/TLR4 complex formation. In summary, we identify 7w and 7x as new MD2 inhibitors to inhibit inflammatory response both in vitro and in vivo, proving the therapeutic potential of 7w and 7x for ALI and inflammatory diseases.

Analyzing the role of soil and rice cadmium pollution on human renal dysfunction by correlation and path analysis.

The aim of this study was to investigate the role of soil and rice pollution on human renal dysfunction. The participants were 97 inhabitants (46 men and 51 women) who are aged 50 to 60 years old and have been living in Xiaogan (Hubei, China) from birth. We collected samples of soil, rice, and urinary correspondingly. Urinary N-acetyl-ß-D-glucosaminidase (NAG) and ß-2-microglobulin (ß2MG) were used as indicators of renal dysfunction, and urinary cadmium (U-Cd) was used as indicator of total internal cadmium exposure. We made a hypothesis that soil cadmium concentration (S-Cd) and rice cadmium concentration (R-Cd) could be used as indicators of environmental cadmium exposure. Correlation and path analysis were used to estimate the relationships among the levels of rice cadmium (R-Cd), soil cadmium (S-Cd), urinary cadmium (U-Cd), and renal damage indicators (NAG and ß2MG). Our results showed that there was positive significant relationship between S-Cd (R-Cd, U-Cd), and U-NAG (U-ß2MG). The standard multiple regression describing the relationship between S-Cd (R-Cd, U-Cd) and U-NAG was Y1 = 1.26X1-6.53X2 + 9.32, where Y is U-NAG, X1 is U-Cd, X2 is S-Cd. The equation of U-ß2MG was Y = 49.32X1 + 3085.99X2 + 143.42, where Y is U-ß2MG, X1 is U-Cd, X2 is R-Cd. It is obvious that the effect of S-Cd and R-Cd on NAG or U-ß2MG cannot be ignored. Through our study, we can find that the effects of S-Cd on renal health even as significant as R-Cd. To protect people from the damage of cadmium pollution, it is vital to monitor the situation of soil and rice cadmium pollution.

Estimation of the benchmark dose of urinary cadmium as the reference level for renal dysfunction: a large sample study in five cadmium polluted areas in China.

BACKGROUND: Itai-itai disease primarily results from cadmium (Cd) exposure and is known as one of the four major pollution diseases in Japan. Cd pollution is more serious in several areas of China than in Japan. However, there is still a lack of information regarding the threshold level of Cd exposure for the adverse health effects in the general Chinese population. This study aims to evaluate the reference value of urinary Cd (UCd) for renal dysfunction in a Chinese population as the benchmark dose lower confidence limit (BMDL) based on a large sample survey. METHODS: A total of 6103 participants who lived in five Cd polluted areas of China participated in this study. We analyzed UCd levels as a biomarker of exposure and urinary ß2-microglobulin (Uß2-MG) levels as a renal tubular effect biomarker. The BMD studies were performed using BMD software. The benchmark response (BMR) was defined as a 10% additional risk above the background. RESULTS: There was a positive correlation between the UCd levels and the prevalence of Uß2-MG. The BMD of UCd for Uß2-MG was estimated for each province. The findings showed that the BMD levels were related to the participants' geographic region, which may be partially due to the large differences in Cd exposure level, ethnic group, lifestyle and diet of the sample population in these study areas. The reference level of UCd for the renal effects was further evaluated by combining the five sets of data from all 6103 subjects. The overall BMDLs of UCd for Uß2-MG with an excess risk of 10% were 2.00 µg/g creatinine (µg/g cr) in males and 1.69 µg/g cr in females, which were significantly lower than the World Health Organization (WHO) threshold level of 5 µg/g cr for Cd-related renal effects. CONCLUSIONS: The selection of the sample population and geographic region affected the BMDL evaluation. Based on the findings of this survey of a large sample population, the UCd BMDLs for Uß2-MG in males with BMRs at 10% were 2.00 µg/g cr. The BMD was slightly lower in females, which indicated that females may be relatively more sensitive to Cd exposure than males.

Benchmark Dose Estimation for Cadmium-Induced Renal Effects Based on a Large Sample Population from Five Chinese Provinces.

A survey involving 6103 participants from five Chinese provinces was conducted to evaluate the threshold value of urinary cadmium (UCd) for renal dysfunction as benchmark dose low (BMDL). The urinary N-acetyl-ß-D-glucosaminidase (UNAG) was chosen as an effect biomarker. The UCd BMDLs for UNAG ranged from 2.18 µg/g creatinine (cr) to 4.26 µg/g cr in the populations of different provinces. The selection of the sample population and area affect the evaluation of the BMDL. The reference level of UCd for renal effects was further evaluated based on the data of all 6103 subjects. With benchmark responses (BMR) of 10%/5%, the overall UCd BMDLs for males in the total population were 3.73/2.08 µg/g cr. The BMD was slightly lower in females, thereby indicating that females may be relatively more sensitive to Cd exposure than are males.

Body burden of cadmium and its related factors: a large-scale survey in China.

A survey of more than 6000 participants from four distinct non-polluted and polluted regions in China was conducted to evaluate the body burden of cadmium (Cd) on the Chinese populations using urinary Cd (UCd) as a biomarker. The findings revealed that the UCd level was 1.24 µg/g creatinine (µg/g cr) for the sample population from non-polluted Shanghai, and the UCd levels exceeded 5 µg/g cr, which is the health-based exposure limit set by the World Health Organization (WHO), in 1.1% of people. The mean UCd levels in moderately polluted (Hubei and Liaoning) and highly polluted areas (Guizhou) were 4.69 µg/g cr, 3.62 µg/g cr and 6.08 µg/g cr, respectively, and these levels were 2.9 to 4.9 times the levels observed in Shanghai. Notably, the UCd levels exceeded the recently updated human biomonitoring II values (i.e., intervention or "action level") in 44.8%-87.9% of people from these areas compared to only 5.1%-21.4% of people in Shanghai. The corresponding prevalence of elevated UCd levels (>WHO threshold, 5 µg/g cr) was also significantly higher (30.7% to 63.8% vs. 1.1%), which indicates that elevated Cd-induced health risks to residents in these areas. Age and region were significant determinants for UCd levels in a population, whereas gender did not significantly influence UCd.

Arabidopsis phosphatidylinositol monophosphate 5-kinase 2 is involved in root gravitropism through regulation of polar auxin transport by affecting the cycling of PIN proteins.

Phosphatidylinositol monophosphate 5-kinase (PIP5K) catalyzes the synthesis of PI-4,5-bisphosphate (PtdIns(4,5)P(2)) by phosphorylation of PI-4-phosphate at the 5 position of the inositol ring, and is involved in regulating multiple developmental processes and stress responses. We here report on the functional characterization of Arabidopsis PIP5K2, which is expressed during lateral root initiation and elongation, and whose expression is enhanced by exogenous auxin. The knockout mutant pip5k2 shows reduced lateral root formation, which could be recovered with exogenous auxin, and interestingly, delayed root gravity response that could not be recovered with exogenous auxin. Crossing with the DR5-GUS marker line and measurement of free IAA content confirmed the reduced auxin accumulation in pip5k2. In addition, analysis using the membrane-selective dye FM4-64 revealed the decelerated vesicle trafficking caused by PtdIns(4,5)P(2) reduction, which hence results in suppressed cycling of PIN proteins (PIN2 and 3), and delayed redistribution of PIN2 and auxin under gravistimulation in pip5k2 roots. On the contrary, PtdIns(4,5)P(2) significantly enhanced the vesicle trafficking and cycling of PIN proteins. These results demonstrate that PIP5K2 is involved in regulating lateral root formation and root gravity response, and reveal a critical role of PIP5K2/PtdIns(4,5)P(2) in root development through regulation of PIN proteins, providing direct evidence of crosstalk between the phosphatidylinositol signaling pathway and auxin response, and new insights into the control of polar auxin transport.