Sodium-glucose cotransporter 2 inhibitors attenuate vascular calcification by suppressing endoplasmic reticulum protein thioredoxin domain containing 5 dependent osteogenic reprogramming.

AIMS: Vascular calcification is strongly linked to the development of major adverse cardiovascular events, but effective treatments are lacking. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are an emerging category of oral hypoglycemic drugs that have displayed marked effects on metabolic and cardiovascular diseases, including recently reported vascular medial calcification. However, the roles and underlying mechanisms of SGLT2 inhibitors in vascular calcification have not been fully elucidated. Thus, we aimed to further determine whether SGLT2 inhibitors protect against vascular calcification and to investigate the mechanisms involved. METHODS AND RESULTS: A computed tomography angiography investigation of coronary arteries from 1554 patients with type 2 diabetes revealed that SGLT2 inhibitor use was correlated with a lower Agatston calcification score. In the vitamin D3 overdose, 5/6 nephrectomy chronic kidney disease-induced medial calcification and Western diet-induced atherosclerotic intimal calcification models, dapagliflozin (DAPA) substantially alleviated vascular calcification in the aorta. Furthermore, we showed that DAPA reduced vascular calcification via Runx2-dependent osteogenic transdifferentiation in vascular smooth muscle cells (VSMCs). Transcriptome profiling revealed that thioredoxin domain containing 5 (TXNDC5) was involved in the attenuation of vascular calcification by DAPA. Rescue experiments showed that DAPA-induced TXNDC5 downregulation in VSMCs blocked the protective effect on vascular calcification. Furthermore, TXNDC5 downregulation disrupted protein folding-dependent Runx2 stability and promoted subsequent proteasomal degradation. Moreover, DAPA downregulated TXNDC5 expression via amelioration of oxidative stress and ATF6-dependent endoplasmic reticulum stress. Consistently, the class effects of SGLT2 inhibitors on vascular calcification were validated with empagliflozin in intimal and medial calcification models. CONCLUSIONS: SGLT2 inhibitors ameliorate vascular calcification through blocking endoplasmic reticulum stress-dependent TXNDC5 upregulation and promoting subsequent Runx2 proteasomal degradation, suggesting that SGLT2 inhibitors are potentially beneficial for vascular calcification treatment and prevention.

B-type natriuretic peptide levels at admission predict the prognosis of patients with infective endocarditis undergoing cardiac surgery.

Purpose: The objective of this study was to explore the relationship between elevated B-type natriuretic peptide (BNP) levels and the prognosis of patients with infective endocarditis (IE) undergoing cardiac surgery. Methods: In total, 162 IE patients with recorded BNP levels upon admission were included in the present study. The primary end point was all-cause mortality. Results: Multivariate Cox analysis revealed a significant association between log BNP and all-cause mortality. Kaplan-Meier analysis revealed a poorer prognosis for patients with BNP levels ≥ the 75th percentile. Furthermore, the linear trend test indicated a significant link between BNP quartiles and the primary end point within the models. Conclusion: Elevated BNP levels upon admission could predict all-cause mortality in IE patients undergoing cardiac surgery.

Infective endocarditis (IE) refers to an infection affecting the heart lining, heart valves or blood vessels. Despite advancements in medical and surgical interventions, the overall mortality rate remains high among IE patients after surgery. B-type natriuretic peptide (BNP) is a peptide released in response to increased stress on the ventricular and atrial walls and is commonly used as a biomarker for heart failure. This study was aimed to assess the potential of BNP in predicting all-cause mortality in IE patients. The results indicate that elevated BNP levels upon admission could predict a worse prognosis following endocarditis surgery. Additionally, elevated BNP levels upon admission were associated with an increased risk of death.

Low dosage fluorine ameliorates the bioaccumulation, hepatorenal dysfunction and oxidative stress, and gut microbiota perturbation of cadmium in rats.

Many "hot spot" geographic areas around the world with soils and crops co-polluted with cadmium (Cd) and fluorine (F), two of the most representative pollutants in the environment. However, it still exists argumentative on the dose-effect relationship between F and Cd so far. To explore this, a rat model was established to evaluate the effects of F on Cd-mediated bioaccumulation, hepatorenal dysfunction and oxidative stress, and the disorder of intestinal microbiota as well. 30 healthy rats were randomly assigned to Control group (C group), Cd 1 mg/kg (Cd group), Cd 1 mg/kg and F 15 mg/kg (L group), Cd 1 mg/kg and F 45 mg/kg (M group), and Cd 1 mg/kg and F 75 mg/kg (H group) for 12 weeks by gavage. Our results showed that Cd exposure could accumulate in organs, cause hepatorenal function damage and oxidative stress, and disorder of gut microflora. However, different dosages of F showed various effects on Cd-induced damages in liver, kidney, and intestine, and only the low supplement of F showed a consistent trend. After low supplement of F, Cd levels were declined by 31.29% for liver, 18.31% for kidney, and 2.89% for colon, respectively. The serum aspartate aminotransferase (AST), blood urea nitrogen (BUN), creatinine (Cr), and N-acetyl-ß-glucosaminidase (NAG) were significantly reduced (p < 0.01); The activity of superoxide dismutase (SOD) was elevated and mRNA expression level of NAD(P)H quinone oxidoreductase 1 (NQO1) was decreased in the liver and kidney (p < 0.05). Moreover, low F dosage up-regulated the abundance of Lactobacillus from 15.56% to 28.73% and the 6.23% of F/B ratio was declined to 3.70%. Collectively, this highlights that low dosage of F might be a potential strategy to ameliorate the hazardous effects by Cd-exposed in the environment.

Enantioselective toxicity effect and mechanism of hexaconazole enantiomers to human breast cancer cells.

The toxicity effects of chiral pesticides on living organisms have attracted an increasing public attention. This study aims to investigate the toxicity effect and mechanism of hexaconazole (HEX) to human breast cancer cell (MCF-7) at enantiomer levels. HEX exposure obviously inhibited cells activities in a dose-dependent manner. Under the conditions of VIP >1 and p < 0.05, a total of 255 and 177 differential metabolites (DMs), 17 and 15 amino acid- and lipid-related metabolic pathways were disturbed after (+)-HEX and (-)-HEX exposure, respectively. HEX exposure may affect cell membrane function, signal transduction, and cell differentiation. We further investigated the mechanism of enantioselective differences by using molecular docking which showed that CYP17A1 was the main enzyme that leading to endocrine disrupting effects with the binding energy of -6.30 and -6.08 kcal/mol compared to CYP19A1 enzyme which were -5.81 and -5.93 kcal/mol for (+)-HEX and (-)-HEX, respectively. The docking results explained the reasons why (+)-HEX achieved higher cytotoxicity and induced more seriously metabolic profiles than its antipode. These findings could provide a new insight to understand the enantioselective cytotoxicity effect and mechanism of HEX and will be conducive to assessing its risk to human health at enantiomer levels.

Determination of cadmium in Chinese pepper and its health implications based on bioaccessibility.

The contamination of cadmium (Cd) in agro-products causes major concern because of its potential dietary risks. In this study, a total of 647 pepper samples from 21 provinces in China were randomly collected according to the distribution of pepper production. Cd pollution levels in Chinses pepper and its health risks were evaluated based on bioaccessibility, which was measured by the physiologically based extraction test (PBET). The results showed that Cd concentration in all pepper ranged from 0.002 to 1.470 mg/kg, with an average of 0.222 mg/kg and a median of 0.132 mg/kg. The highest daily intake of Cd was observed in the female child group (4.037 × 10-5 mg/kg bw/day), which accounted for 4% of the maximum daily permissible dose - 0.001 mg/kg bw/day. The target hazard quotients of Cd were all lower than 1, indicating low potential non-carcinogenic health risks to residents via the consumption of pepper. Notably, carcinogenic risk values suggested potential adverse health effects to adults, while after considering the bioaccessibility of Cd in pepper (mean of 43.07%), those values had fallen under the acceptable level (1 × 10-4). This may indicate that dietary risk assessment of heavy metals in crops could not be conducted just based on their content; the bioaccessibility of metals is also an important factor for consideration.

Spatial distribution and risk assessment of fluorine and cadmium in rice, corn, and wheat grains in most karst regions of Guizhou province, China.

The pollution status of crops planted in Guizhou province of Southwestern China with high background values of Fluorine (F) and Cadmium (Cd) has attracted people's concern. The present study aimed to investigate the spatial distributions of F and Cd in rice, corn and wheat grains, and further evaluate their health risks to residents in Guizhou province. The contents of F and Cd were measured by fluoride ion-selective electrode and inductively coupled plasma mass spectrometry (ICP-MS) methods, respectively. Additionally, the inverse distance weighted (IDW) technique was conducted to analyze spatial distribution, and the health risk was estimated by target hazard quotient (THQ) and hazardous index (HI). The results indicate that Cd contents in samples varied from 0.000 to 0.463 for rice, 0.000 to 0.307 for corn, and 0.012 to 0.537 (mg/kg) for wheat, while F contents ranged from 0.825 to 5.193 (rice), 0.946 to 8.485 (corn), and 0.271 to 9.143 (wheat) mg/kg. The Cd exceeding ratios were 11.600% for rice, 13.500% for corn, and 45.100% for wheat grains, respectively. In terms of spatial distribution, high levels of F and Cd in rice were found in the northern and central in Guizhou, while Cd in corn was distributed in the eastern and F in corn were distributed in the west area of Guizhou. Moreover, the high levels of F and Cd in wheat were distributed in the western and eastern areas. The mean carcinogenic risks (R) of Cd in rice, corn, and wheat in children were 4.150 × 10-4, 1.670 × 10-4 and 3.470 × 10-4, respectively, and that in adults were 3.430 × 10-4, 0.471 × 10-4, and 2.190 × 10-4, respectively. The HI for adults in rice, corn and wheat grains were 0.756, 0.154, and 0.514, respectively, and that for children were 0.913, 0.549, and 0.814, respectively. Collectively, the potential risks produced by F and Cd to the local residents should not be ignored.

Co-exposure of potentially toxic elements in wheat grains reveals a probabilistic health risk in Southwestern Guizhou, China.

Bijie is located at a typical karst landform of Southwestern Guizhou, which presented high geological background values of potentially toxic elements (PTEs). Recently, whether PTE of wheat in Bijie is harmful to human health has aroused people's concern. To this end, the objectives of this study are to determine the concentrations of PTE [chromium (Cr), nickel (Ni), arsenic (As), lead (Pb), cadmium (Cd), and fluorine (F)] in wheat grains, identify contaminant sources, and evaluate the probabilistic risks to human beings. A total of 149 wheat grain samples collected from Bijie in Guizhou were determined using the inductively coupled plasma mass spectrometer (ICP-MS) and fluoride-ion electrode methods. The mean concentrations of Cr, Ni, As, Cd, Pb, and F were 3.250, 0.684, 0.055, 0.149, 0.039, and 4.539 mg/kg, respectively. All investigated PTEs met the standard limits established by the Food and Agriculture Organization except for Cr. For the source identification, Cr and Pb should be originated from industry activities, while Ni, As, and Cd might come from mixed sources, and F was possibly put down to the high geological background value. The non-carcinogenic and carcinogenic health risks were evaluated by the probabilistic approach (Monte Carlo simulation). The mean hazard quotient (HQ) values in the three populations were lower than the safety limit (1.0) with the exception of As (children: 1.03E+00). However, the mean hazard index (HI) values were all higher than 1.0 and followed the order: children (2.57E+00) > adult females (1.29E+00) > adult males (1.12E+00). In addition, the mean carcinogenic risk (CR) values for Cr, As, Pb, and Cd in three populations were all higher than 1E-06, which cannot be negligible. The mean threshold CR (TCR) values were decreased in the order of children (1.32E-02) > adult females (6.61E-03) > adult males (5.81E-03), respectively, all at unacceptable risk levels. Moreover, sensitivity analysis identified concentration factor (C W ) as the most crucial parameter that affects human health. These findings highlight that co-exposure of PTE in wheat grains revealed a probabilistic human health risk. Corresponding measures should be undertaken for controlling pollution sources and reducing the risks for the local populace.

Submucosal tunneling endoscopic resection of large submucosal tumors originating from the muscularis propria layer in the esophagus and gastric cardia.

AIMS: The aim of this study was to evaluate the short-term complications of submucosal tunneling endoscopic resection (STER) for large submucosal tumors (SMTs) originating from the muscularis propria (MP) layer in the esophagus and gastric cardia. METHODS: We performed 286 cases of STER from September 2012 to December 2017. The clinical data of patients with SMTs originating from the MP layer of 3.0-7.0 cm, who underwent STER procedure at the endoscopy center of Tianjin Medical University General Hospital, were collected retrospectively. Epidemiological data, tumor location, tumor size, procedure-related parameters, complications, and follow-up were included. RESULTS: A total of 27 (9.4 % [27/286]) patients were large-size SMTs, with a mean age of 51.9 ±â€Š9.4 years. The male/female ratio was 19:8. Of the 27 SMTs, 23 were located in the esophagus and 4 in the gastric cardia. The mean tumor size was 4.0 ± 1.1 cm. The en bloc resection rate was 85.2 % (23/27), and the complete resection rate was 100 % (27/27). Intra-operative perforation occurred in 2 patients (7.4 %) and post-operative perforation occurred in 2 patients (7.4 %). No other complications were observed. The average cost of the procedure was $3357.99 ± $1171.60 per inpatient stay (including both the procedure and an additional inpatient stay). The mean follow-up time was 15 ±â€Š10.1 months. No recurrence and metastasis occurred during the follow-up period. CONCLUSIONS: There is low risk of STER for the large-sized SMTs in the esophagus and gastric cardia, and the most common complication occurred during or after the procedure is perforation.

Long-term resveratrol consumption protects ovariectomized rats chronically treated with D-galactose from developing memory decline without effects on the uterus.

Resveratrol (Res) displays potent anti-oxidant activity and is a selective estrogen receptor modulator. The aim of the present study is to investigate whether Res consumption protects ovariectomized (OVX) rats chronically treated with D-galactose (D-gal) from developing memory decline and whether Res administration decreases pathological changes in the endometrium and lumen of the uterus compared with estradiol replacement therapy. Rats were divided into 6 groups: 1) Sham control group; 2) OVX+D-gal 100mg/kg group (OVX+D-gal); 3-5) OVX, D-gal and Res 20, 40, 80 mg/kg treated groups; and 6) OVX, D-gal and estradiol valerate 0.8 mg/kg treated group (ET). Twelve weeks later, in a Morris water maze test, the OVX+D-gal rats exhibited a significant memory impairment compared with the Sham control rats, which was accompanied by decreased total superoxide dismutase (T-SOD) and glutathione peroxidase (GSH-Px) activities and an increased thiobarbituric acid reactive substances (TBARS) level in the serum. In addition, the TBARS and protein carbonylation levels increased in the hippocampus. The beneficial roles of the 40 and 80 mg/kg Res treatments were manifested in the prevention of memory decline and markedly decreased oxidant stress indices. The disruption of the cristae in the mitochondria and the irregular nuclei and condensed chromatin in the pyramidal cells of the hippocampal CA1 region were also reduced after Res treatment. Furthermore, edema in the endometrium and lymphocyte infiltration was avoided in all three of the Res-treated groups compared with the ET group. These results suggest that Res is useful not only in protecting OVX+D-gal rats from developing memory decline by increasing the anti-oxidation but also in avoiding the effects on the uterus.