Heavy metal pollution near an abandoned mercury-bearing waste recovery enterprise in southwestern China: Spatial distribution and its sources in soil and plants.

The contribution of smelting of nonferrous metals to heavy metals in surface soil have become increasingly important over the past decade. In this study, the distribution of heavy metals around an abandoned mercury-bearing waste recovery enterprise were investigated. Soil (14) and plant (18) samples were collected in the surrounding area. The total concentration of heavy metals and methyl mercury content were measured by ICP-MS and HPLC-ICP-MS. The results show that the average contents of Cd, Cr, Pb, Hg and As in all soil samples are higher than the second-level values of Soil environmental quality-Risk control standard for soil contamination of development land (GB 36600-2018). Hg in the leaves ranged from 0.003 to 0.174 mg kg-1. Besides, the Pearson correlation analysis results indicate that Hg has a different environmental behavior compared to the other heavy metal under certain environmental or geographical conditions. But the mantel test statistical analysis results show that the Cr (P < 0.01), Cu, Pb, and Fe (P < 0.05) in the soil may have similar pollution sources with carbonate-bound mercury and iron-manganese oxide-bound mercury. The Hg concentrations show no correlation among plant leaves and soil, but significantly influenced by the distance and wind direction. These findings suggest that Hg in plant leaves may be derived from the deposition of atmospheric mercury from secondary mercury plant. The results will supplement those for relevant policy making for mercury-bearing waste recovery enterprises to improve urban environmental quality and human health.

High fat diet induces brain injury and neuronal apoptosis via down-regulating 3-ß hydroxycholesterol 24 reductase (DHCR24).

Hyperlipidemia (HLP) is one of the risk factors for memory impairment and cognitive impairment. However, its pathological molecular mechanism remained unclear. 3ß-hydroxysterol Δ24- reductase (DHCR24) is a key enzyme in cholesterol synthesis and has been reported to decrease in the affected areas in the brain of neurodegenerative disorders. In this study, hyperlipidemic mouse model was established to study the effect of high blood lipid on brain. The data obtained from HPLC analysis demonstrated that the cholesterol level in the brain of mice with hyperlipidemia was significantly elevated compared to the control group. While the pathological damages were observed in both cerebral cortex and hippocampus in the brain of hyperlipidemic mice. Furthermore, the protein level of DHCR24 was downregulated accompanied by elevated ubiquitination level in the hyperlipidemic mice brain. The mouse neuroblastoma cells N2a were exposed to the excess cholesterol loading, the cells underwent apoptosis and the mRNA and protein of DHCR24 in cholesterol-loaded N2a cells were significantly reduced. In addition, the expression level of endoplasmic reticulum stress marker protein (Bip and Chop) was markedly increased in response to the cholesterol loading. More importantly, overexpression of DHCR24 in N2a reversed neuronal apoptosis induced by the cholesterol loading. Conclusively, these findings suggested that hyperlipidemia could cause brain tissue injuries via down-regulating DHCR24, and overexpression of DHCR24 may alleviate hyperlipidemia-induced neuronal cells damage by reversing the endoplasmic reticulum stress-mediated apoptosis.

Scavenger receptor-AI targeted theranostic nanoparticles for regression of atherosclerotic plaques via ABCA1 modulation.

ATP-binding cassette transporter A1 (ABCA1) plays a crucial role in atherosclerotic formation through mediated cholesterol efflux in macrophage-derived foam cells. In this study, a scavenger receptors AI (SR-AI) targeted theranostic nanoparticles was constructed for atherosclerosis regression via ABCA1 activation in foam cells. ABCA1-upregulator 5242331 and IR780 were encapsulated in PLGA-PEG micelles which were conjugated with SR-AI targeting peptide (PP1) to formulate the nanoparticles (SAU-NPs). Immunostaining revealed that SR-AI was highly expressed both in macrophage foam cells and in atherosclerotic plaque of ApoE-/- mice. The SAU-NPs have shown more active targeting to plaque lesion with higher stability compared with non-SR-AI targeted nanoparticles. The transformation from macrophage to foam cells was inhibited by SAU-NPs carried 5242331. Cholesterol deposition was effectively reduced in foam cells by SAU-NPs through activating the LXRα-ABCA1/ABCG1/SR-BI pathway. In conclusion, theranostic SAU-NPs which carried ABCA1-upregulator 5242331 exert beneficial effects on atherosclerosis regression via LXRα activation.

Quercetin and AMPK: A Dynamic Duo in Alleviating MG-Induced Inflammation via the AMPK/SIRT1/NF-κB Pathway.

Mycoplasma gallisepticum (MG) is recognized as a principal causative agent of avian chronic respiratory disease, inflicting substantial economic losses upon the poultry industry. However, the extensive use of conventional antibiotics has resulted in the emergence of drug resistance and various challenges in their clinical application. Consequently, there is an urgent need to identify effective therapeutic agents for the prevention and treatment of mycoplasma-induced respiratory disease in avian species. AMP-activated protein kinase (AMPK) holds significant importance as a regulator of cellular energy metabolism and possesses the capacity to exert an anti-inflammatory effect by virtue of its downstream protein, SIRT1. This pathway has shown promise in counteracting the inflammatory responses triggered by pathogenic infections, thus providing a novel target for studying infectious inflammation. Quercetin possesses anti-inflammatory activity and has garnered attention as a potential alternative to antibiotics. However, there exists a gap in knowledge concerning the impact of this activation on MG-induced inflammatory damage. To address this knowledge gap, we employed AlphaFold2 prediction, molecular docking, and kinetic simulation methods to perform a systematic analysis. As expected, we found that both quercetin and the AMPK activator AICAR activate the chicken AMPKγ1 subunit in a similar manner, which was further validated at the cellular level. Our project aims to unravel the underlying mechanisms of quercetin's action as an agonist of AMPK against the inflammatory damage induced by MG infection. Accordingly, we evaluated the effects of quercetin on the prevention and treatment of air sac injury, lung morphology, immunohistochemistry, AMPK/SIRT1/NF-κB pathway activity, and inflammatory factors in MG-infected chickens. The results confirmed that quercetin effectively inhibits the secretion of pro-inflammatory cytokines such as IL-1ß, TNF-α, and IL-6, leading to improved respiratory inflammation injury. Furthermore, quercetin was shown to enhance the levels of phosphorylated AMPK and SIRT1 while reducing the levels of phosphorylated P65 and pro-inflammatory factors. In conclusion, our study identifies the AMPK cascade signaling pathway as a novel cellular mediator responsible for quercetin's ability to counter MG-induced inflammatory damage. This finding highlights the potential significance of this pathway as an important target for anti-inflammatory drug research in the context of avian respiratory diseases.

A novel random forest integrative approach based on endogenous CYP3A4 phenotype for predicting tacrolimus concentrations and dosages in Chinese renal transplant patients.

WHAT IS KNOWN AND OBJECTIVE: Personalized treatment with tacrolimus has remained a challenge. The present study aimed to evaluate the potential of an integrative approach to predict individual tacrolimus concentrations and dosages based on endogenous CYP3A4 phenotype, CYP3A5 genotype and clinical variables. METHODS: A random forest (RF) algorithm which incorporated an endogenous CYP3A4 phenotype (assessed by urinary ratio of 6ß-hydroxycortisol and 6ß-hydroxycortisone to cortisol and cortisone), CYP3A5*3 genotype and other clinical determinants of tacrolimus disposition was performed in 182 medically stable renal transplant recipients. RESULTS AND DISCUSSION: The results suggested that endogenous CYP3A4 phenotype was the most important determinant of tacrolimus concentrations and dose requirements. RF models provided high goodness of fit (R2 ) with .92 and .95 for the prediction of tacrolimus trough concentrations and dosages, respectively, as well as high predictability (Q2 ) with 0.63 and 0.70, respectively. Significant correlations existed between experimental and predictive data. WHAT IS NEW AND CONCLUSION: In summary, endogenous CYP3A4 phenotype is a critical biomarker for the determination of tacrolimus disposition. This predictive RF approach based on CYP3A4 biomarker with the combination of CYP3A5*3 genotype and other clinical variables can be used for predicting tacrolimus concentrations and dosages, which may serve as a useful tool in individualized tacrolimus dosing.

Simultaneous determination and determination of sildenafil and its active metabolite in human plasma using LC-MS/MS method.

A sensitive and selective high-performance liquid chromatography-tandam mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous quantification of sildenafil and its metabolite N-desmethyl sildenafil in human plasma. Sildenafil-d8 was used as an internal standard. The analytes were extracted by precipitation extraction and chromatographed on a C18 column using mobile phase A of water (containing 0.1% formic acid) and mobile phase B of acetonitrile (containing 0.1% formic acid) with gradient elution. Quantification was done using multiple reaction monitoring mode to monitor the precursor-to-product ion transitions of m/z 475.4 → m/z 283.3 for sildenafil, m/z 461.4 → m/z 283.2 for N-desmethyl sildenafil and m/z 483.3 → m/z 108.1 for IS in positive ionization mode. The calibration curve was established over the range of 2.00-1,000 ng/ml and the correlation coefficient was >0.99. The intra-day and inter-day relative standard deviations were <6.5% for sildenafil and 6.3% for N-desmethyl sildenafil respectively. Accuracy determinaed at four concentrations was 86.50-105.67% for sildenafil and 96.83-114.40% for N-desmethyl sildenafil. This method was successfully applied to a pharmacokinetic description of sildenafil and the effect of food intake on the pharmacokinetics of sildenafil was also demonstrated in healthy Chinese volunteers.

Right ventricle may be involved in regional diastolic dysfunction earliest in primary hypertension patients.

BACKGROUND: Impaired ventricular diastolic function is common in hypertensive patients and is one of the major causes of heart failure. Both left and right ventricle diastolic dysfunction have been reported, but the order of involvement is not clear. METHOD: A total of 161 primary hypertensive patients and 40 healthy volunteers were enrolled. Pulsed wave tissue Doppler was used to measure regional diastolic dysfunction (defined as early peak diastolic [Em] and late diastolic [Am] velocity ratios (Em/Am) < 1) at right ventricular tricuspid valve annulus lateral side (RAVP1), right ventricular tricuspid valve annulus septum side (RAVP2), left ventricular mitral valve annulus septum side (LAVP1) and left ventricular mitral annulus lateral side (LAVP2). RESULTS: The prevalence of regional diastolic dysfunction at RAVP1, RAVP2, LAVP1, and LAVP2 was all higher in the hypertensive group (P < .001 for all). In both the hypertensive group and the control group, more cases were presented with RAVP1 diastolic dysfunction, while the least number of cases had LAVP2 diastolic dysfunction. In patients with stage 1 hypertension, most cases had RAVP1, or RAVP1 and RAVP2/LAVP1 diastolic dysfunction, while in patients with more advanced hypertension stages, significantly more cases had both RAVP1 and LAVP2, or all four locations diastolic dysfunction (P < .001). A similar trend was observed in patients with longer hypertension duration (duration of 6-9.9 years and 10-18 years compared with 2-5.9 years of duration, P < .001). CONCLUSIONS: With a more advanced stage and longer duration of hypertension, the range of regional diastolic dysfunction increased, showing a trend from the right ventricular wall, to the septum and left the ventricular wall. In primary hypertension, regional diastolic dysfunction in the right ventricle might happen earlier than that in the septum and the left ventricle.

Ankle-brachial index and brachial-ankle pulse wave velocity are associated with albuminuria in community-based Han Chinese.

BACKGROUND/OBJECTIVES: Our study aimed to explore whether the ankle-brachial index (ABI) and brachial-ankle pulse wave velocity (baPWV) were associated with albuminuria in community-based Han Chinese. METHODS: Total 2127 subjects (860 men and 1267 women) aged 60 years and over were recruited in Beijing. Albuminuria was assessed by the urinary albumin-to-creatinine ratio (UACR) of ≥30 mg/g. BaPWV was divided by quartile. The logistic regression was used to determine the odds ratio (OR) and 95% confidence intervals (CIs) of ABI and baPWV with albuminuria. RESULTS: ABI was associated with albuminuria in the interaction model (OR 0.89, 95% CI 0.81-0.99 by every 0.1 unit increase of ABI), especially in hypertension (OR 0.82, 95% CI 0.73-0.92) and diabetes (OR 0.83, 95% CI 0.68-0.98) groups. BaPWV groups were also significantly associated with albuminuria, ORs of having albuminuria for baPWV quartile II, III, and IV were 1.02(0.65-1.52), 1.05(0.72-1.61), and 1.18(1.04-1.47) in the interaction model. For hypertension and diabetes patients, only the baPWV quartile IV group had higher OR. CONCLUSIONS: ABI and baPWV were associated with albuminuria after adjusting for other risk factors in Chinese community-based elderly Han population. The association of ABI with albuminuria was stronger in hypertension and diabetes patients.

miR-483-5p-Containing exosomes treatment ameliorated deep vein thrombosis­induced inflammatory response.

Peripheral vascular condition, known as deep vein thrombosis (DVT), is a common ailment that may lead to deadly pulmonary embolism. Inflammation is closely connected to venous thrombosis, which results in blood stasis, leading to ischemia and hypoxia, as indicated by research. The objective of this research was to investigate the mechanism by which exosomes derived from adipose stem cells (ADSCs) prevent deep vein thrombosis. Our data showed that Exo-483 effectively reduced the thrombus weight in DVT rats by intravenous injection. Exo-483 decreased the expression of tissue factor (TF) protein, the influx of inflammatory cells into the thrombosed vein wall, and the levels of cytokines in the serum. Furthermore, Exo-483 suppressed the expression of Mitogen-activated protein kinase 1 (MAPK1) and decreased the expression of NLRP3 inflammasomes. In an oxygen-glucose deprivation (OGD) cell model, the tube-forming and migratory abilities of primary human umbilical vein endothelial cells (HUVEC) and EA.hy926 cells were suppressed by Exo-483 pretreatment.Exo-483 is also linked to regulating Dynamin-related protein 1 (DRP1) production downstream of MAPK1.By decreasing the mitochondrial localization and phosphorylation at the S616 site of DRP1, it diminishes the expression of NLRP3 inflammasomes. Moreover, according to Bioinformatics analysis, miR-483-5p was anticipated to target MAPK1. The research conducted by our team revealed that the miR-483-5p exosome derived from ADSCs exhibited anti-inflammatory properties through the modulation of downstream DRP1-NLRP3 expression by targeting MAPK1.The findings of this research propose that miR-483-5p may be regarded as an innovative treatment target for DVT.

U-Shaped Relationship of Sodium-to-chloride Ratio on admission and Mortality in Elderly Patients with Heart Failure: A Retrospective Cohort Study.

Serum sodium and chloride have clinical significance in the prognosis of heart failure. Little is known regarding the prognostic value of sodium-to-chloride (Na/Cl) ratio in patients with heart failure. This study sought to investigate the association between Na/Cl ratio on admission and mortality risk of elderly patients with acute heart failure in a retrospective cohort. We included 1819 patients (aged over 60) from the Zigong Heart Failure Study. Patients were grouped according to Na/Cl ratio and followed up for all-cause mortality at 3 months. Restricted cubic spline, cox proportional hazard regression and Kaplan-Meier curve were used to examine the correlation between serum Na/Cl ratio on admission and mortality risk. Restricted cubic spline analysis suggested a U-shaped association between Na/Cl ratio on admission and 3 months mortality risk (P nonlinearity <0.001), with the nadir of risk at 1.34. After adjustment for multivariate, patients with Na/Cl ratio <1.3 or ≥ 1.4 had hazard ratios for mortality of 3.58 (95% CI, 1.63-7.84) and 2.66 (95% CI, 1.23-5.72) compared with those with Na/Cl ratio of 1.3-1.4. The cumulative hazard of mortality estimates significantly differed across Na/Cl ratio groups (log-rank P<0.001). Subgroup analysis showed there were no interactions with absent or present of hyponatremia and hypochloremia (P for interaction all >0.05). Both low and high Na/Cl ratios were associated with an increased mortality risk in elderly patients with acute heart failure. Further studies need to verify these 2 biochemical phenotypes and develop corresponding treatment strategies.

Temporal and spatial analysis of anthropogenic mercury and CO2 emissions from municipal solid waste incineration in China: Implications for mercury and climate change mitigation.

The contribution of municipal solid waste incineration (MSWI) to anthropogenic mercury and CO2 emissions have become increasingly important over the past decade. This study developed an inventory of anthropogenic mercury emissions and CO2 emissions during the period of 2014-2020, of MSWI process in China using a bottom-up inventory at the plant level. Overall, national MSWI anthropogenic mercury emissions increased from 2014 to 2020 by province. It was estimated that total 8321.09 kg of anthropogenic mercury emissions from 548 MSWI plants were scattered in 31 provinces of mainland China in 2020. The average intensity of mercury emission in China was 0.06 g·t-1 in 2020, which was much lower than the pre-2010 level. Furthermore, the increased CO2 emission generated by MSWI from 2014 to 2020 is 1.97 times. Anthropogenic mercury emissions and CO2 emissions were concentrated mainly in developed coastal provinces and cities. The general uncertainty of national mercury emissions and CO2 emissions was estimated to be -123% to 323% and -130% to 335%, respectively. Furthermore, future emissions were predicted from 2030 to 2060 based on different scenarios of the independent and collaborative effects of control proposals, the results indicate that the enhancement of advanced air pollution control technologies and effective management of MSWI represent pivotal factors in realizing future reductions in CO2 and mercury emissions. The findings will supplement those for mercury and CO2 emissions, and be useful for relevant policy-making and to improve urban air quality, as well as human health.

[Correlation of endogenous androgen and androgen receptor level with coronary artery diseases in elderly males].

OBJECTIVE: To investigate the correlation of endogenous androgen and androgen receptor (AR) level with coronary artery diseases (CAD) in elderly males and elucidate the potential mechanism of gender difference in the prevalence of CAD. METHODS: A total of 296 male patients from different centers were divided into the CAD group (n = 237) and the control group (n = 59) according to the results of coronary angiography. Their mean ages were 68.6 ± 6.8 and 66.2 ± 6.5 years old respectively. The serum levels of FT (free testosterone), TT (total testosterone), E2 (estradiol), LH (luteinizing hormone), FSH (follicle-stimulating hormone), SHBG (sex hormone-binding globulin) and DHEA (dehydroepiandrosterone) were measured in all participants. And the androgen receptors of peripheral lymphocytes were assessed by flow cytometry. RESULTS: The serum level of FT was lower in the CAD group than that in the control group [(24.1 ± 22.2) × 10(-9) mmol/L vs (34.1 ± 31.8) × 10(-9) mmol/L, P = 0.06]. But two groups showed no statistic differences in the levels of TT, E(2), LH, FSH, SHBG, DHEA and lymphocyte AR (56.3% ± 24.00 vs 57.1% ± 20.8%). As demonstrated by the logistic regression analysis, the level of FT was negatively correlated with the CAD risk (OR = 0.98, P = 0.0049) and positively correlated with the peripheral lymphocyte AR level. However age was negatively correlated with the levels of FT and AR. CONCLUSION: The deficiency of endogenous androgen contributes to a high prevalence of CAD in elderly males. The age-related decreases of FT and AR impair the physiological functions of androgen so as to accelerate the progression of coronary atherosclerosis.

Suppression of neuronal cholesterol biosynthesis impairs brain functions through insulin-like growth factor I-Akt signaling.

Some relationship between abnormal cholesterol content and impairment of insulin/insulin-like growth factor I (IGF-1) signaling has been reported in the pathogenesis of Alzheimer's disease (AD). However, the underlying mechanism of this correlation remains unclear. It is known that 3-ß hydroxycholesterol Δ 24 reductase (DHCR24) catalyzes the last step of cholesterol biosynthesis. To explore the function of cholesterol in the pathogenesis of AD, we depleted cellular cholesterol by targeting DHCR24 with siRNA (siDHCR24) or U18666A, an inhibitor of DHCR24, and studied the effect of the loss of cholesterol on the IGF-1-Akt signaling pathway in vitro and in vivo. Treatment with U18666A reduced the cellular cholesterol level and blocked the anti-apoptotic function of IGF-1 by impairing the formation of caveolae and the localization of IGF-1 receptor in caveolae of the PC12 cells. Downregulation of the DHCR24 expression induced by siRNA against DHCR24 also yielded similar results. Furthermore, the phosphorylation levels of IGF-1 receptor, insulin receptor substrate (IRS), Akt, and Bad in response to IGF-1 were all found to decrease in the U18666A-treated cells. Rats treated with U18666A via intracerebral injection also exhibited a significant decrease in the cholesterol level and impaired activities of IGF-1-related signaling proteins in the hippocampus region. A significant accumulation of amyloid ß and a decrease in the expression of neuron-specific enolase (NSE) was also observed in rats with U18666A. Finally, the Morris water maze experiment revealed that U18666A-treated rats showed a significant cognitive impairment. Our findings provide new evidence strongly supporting that a reduction in cholesterol level can result in neural apoptosis via the impairment of the IGF-1-Akt survival signaling in the brain.

Age-related decrease in expression of peroxisome proliferator-activated receptor alpha and its effects on development of dyslipidemia.

BACKGROUND: Ageing is associated with increased incidence of dyslipidemia. To investigate potential molecular mechanisms, the effects of age and fibrate administration on peroxisome proliferator-activated receptor alpha (PPARalpha) expression in livers of young and old rats were studied. METHODS: A total of 16 young (2-month-old) and 16 old rats (24-month-old) were randomly assigned to a control group and fenofibrate group (fenofibrate in a total therapeutic dosage of 0.5% in ratio to each treated rat weight in 14 days). RT-PCR was applied to evaluate hepatic mRNA expression of PPARalpha and its target genes. Western blotting was used to determine PPARalpha protein level in liver tissue. RESULTS: When compared with 2-month-old rats, the liver tissue from 24-month-old rats showed reduced expression of PPARalpha mRNA (52%, P < 0.05) and protein (109%, P < 0.01). Consequently, the mRNA levels of PPAR target genes, LPL, ACO, ACS and CPT-1 were markedly lowered by 19%, 8%, 13% and 9% respectively, and apoCIII increased by 24% in livers from 24-month-old rats, compared with values obtained from 2-month-old rats (P < 0.05). Fenofibrate therapy significantly lowered plasma triglyceride and total cholesterol levels in old rats, accompanied with improvement in hepatic expression of genes, including LPL, ACO, ACS, CPT-1 and apoCIII, but no change was found in PPARalpha expression in livers from either 24-month or 2-month-old rats. CONCLUSIONS: The decrease in the hepatic PPARalpha expression is probably directly related to the lipid metabolic disturbances observed in old animals. The beneficial effects of fenofibrate administration in old rats suggests that fibrates may be useful for treating lipid disturbances in old people.

Effect of aging on the expression of peroxisome proliferator-activated receptor gamma and the possible relation to insulin resistance.

BACKGROUND: The morbidity of insulin resistance tends to increase with aging. However, studies on molecular mechanisms underlying insulin resistance in aging process is still in paucity. OBJECTIVE: The effect of aging on peroxisome proliferator-activated receptor gamma (PPARgamma) expression, and in addition, the possible association of PPARgamma expression with insulin resistance in aging process were investigated. METHODS: The minimal model technique (MMT) based on frequently sampled intravenous glucose tolerance test was adopted and SI and glucose effectiveness of young and aged rats were compared. RT-PCR and Western blot were used to determine the expression of PPARgamma at mRNA and protein level in adipose tissue and skeletal muscle, as well as in human colic omentum, respectively. RESULTS: MMT result implied existence of various degrees of insulin resistance in aged rats. The expression of PPARgamma at both mRNA and protein levels in adipose tissue of aged rats dramatically decreased; consequently, the expression of its target gene lipoprotein lipases mRNA also markedly decreased compared with those in young rats. Furthermore, the level of PPARgamma mRNA and glucose transporter-4 mRNA in skeletal muscle of aged rats attenuated significantly. The expression of PPARgamma mRNA in omental adipose tissue of old men was significantly decreased, accompanied by a tendency of higher insulin resistance index, compared with those of the young. CONCLUSION: Aging may be associated with diminished PPARgamma expression affecting insulin resistance in the aged individuals.