Topology-Optimized Splints vs Casts for Distal Radius Fractures: A Randomized Clinical Trial.

Importance: To date, there is currently no evidence-based medical support for the efficacy of topology-optimized splints in treating distal radius fractures. Objective: To assess the clinical efficacy and complication rates of topology-optimized splints in the treatment of distal radius fractures after closed manual reduction. Design, Setting, and Participants: This 12-week, multicenter, open-label, analyst-blinded randomized clinical trial (comprising a 6-week intervention followed by a 6-week observational phase) was carried out from December 3, 2021, to March 10, 2023, among 110 participants with distal radius fractures. Statistical analysis was performed on an intention-to-treat basis between June 3 and 30, 2023. Intervention: Participants were randomly assigned to 2 groups: the intervention group received topology-optimized splint immobilization and the control group received cast immobilization after closed manual reduction for 6weeks. After this period, immobilization was removed, and wrist rehabilitation activities commenced. Main Outcomes and Measures: The primary outcome was the Gartland-Werley (G-W) wrist score at 6 weeks (where higher scores indicate more severe wrist dysfunction). Secondary outcomes encompassed radiographic parameters, visual analog scale scores, swelling degree grade, complication rates, and 3 dimensions of G-W wrist scores. Results: A total of 110 patients (mean [SD] age, 64.1 [12.7] years; 89 women [81%]) enrolled in the clinical trial, and complete outcome measurements were obtained for 101 patients (92%). Median G-W scores at 6 weeks were 15 (IQR, 13-18) for the splint group and 17 (IQR, 13-18) for the cast group (mean difference, -2.0 [95% CI, -3.4 to -0.6]; P = .03), indicating a statistically significant advantage for the splint group. At 12 weeks, no clinically significant differences in G-W scores between the 2 groups were observed. Complication rates, including shoulder-elbow pain and dysfunction and skin irritation, were less common in the splint group (shoulder-elbow pain and dysfunction: risk ratio, 0.28 [95% CI, 0.08-0.93]; P = .03; skin irritation: risk ratio, 0.30 [95% CI, 0.10-0.89]; P = .02). Conclusions and Relevance: Findings of this randomized clinical trial suggest that patients with distal radius fractures that were managed with topology-optimized splints had better wrist functional outcomes and fewer complications at 6 weeks compared with those who received casting, with no difference at week 12. Therefore, topology-optimized splints with improved performance have the potential to be an advisable approach in the management of distal radius fractures. Trial Registration: Chinese Clinical Trial Registry: ChiCTR2000036480.

Chemical fertilizer reduction combined with organic fertilizer affects the soil microbial community and diversity and yield of cotton.

Introduction: The soil microbial community plays an important role in modulating cotton soil fertility. However, the effects of chemical fertilizer combined with organic fertilizer on soil chemical properties, microbial community structure, and crop yield and quality in arid areas are still unclear. This study aimed to explore the effects of different organic fertilizers on soil microbial community structure and diversity and cotton growth and yield. Methods: High-throughput sequencing was used to study the soil bacteria and fungi in different growth stages of cotton. The field fertilization experiment had five treatments. Results: The results indicated that the treatments of chemical fertilizer reduction combined with organic fertilizer significantly increased soil available nitrogen and phosphorus in cotton field. There were significant differences in the abundance of the bacterial and fungal communities in the dominant phyla among the treatments. At the phyla level, there were not significantly different in the diversity of bacteria and fungi among treatments. There were significant differences in the composition and diversity of bacterial and fungal communities during the entire cotton growth period (p = 0.001). The rhizosphere bacterial and fungal community structure was significantly affected by soil TK, NH4+, AK, TP, AN, and NO3-. The different fertilization treatments strongly influenced the modular structure of the soil bacterial and fungal community co-occurrence network. A reduction in chemical fertilizer combined with organic fertilizer significantly improved cotton stem diameter and seed yield, and the effect of the biological organic fertilizer on plant growth and yield formation was greater than that of ordinary organic fertilizer. Discussion: This study provide a scientific and technical basis for the establishment of environmentally friendly green fertilization technology for cotton in arid areas and the promotion of sustainable development of cotton industry.

Identification of non-small cell lung cancer with chronic obstructive pulmonary disease using clinical symptoms and routine examination: a retrospective study.

Background: Patients with non-small cell lung cancer (NSCLC) and patients with NSCLC combined with chronic obstructive pulmonary disease (COPD) have similar physiological conditions in early stages, and the latter have shorter survival times and higher mortality rates. The purpose of this study was to develop and compare machine learning models to identify future diagnoses of COPD combined with NSCLC patients based on the patient's disease and routine clinical data. Methods: Data were obtained from 237 patients with COPD combined with NSCLC as well as NSCLC admitted to Ningxia Hui Autonomous Region People's Hospital from October 2013 to July 2022. Six machine learning algorithms (K-nearest neighbor, logistic regression, eXtreme gradient boosting, support vector machine, naïve Bayes, and artificial neural network) were used to develop prediction models for NSCLC combined with COPD. Sensitivity, specificity, positive predictive value, negative predictive value, accuracy, F1 score, Mathews correlation coefficient (MCC), Kappa, area under the receiver operating characteristic curve (AUROC)and area under the precision-recall curve (AUPRC) were used as performance indicators to evaluate the performance of the models. Results: 135 patients with NSCLC combined with COPD, 102 patients with NSCLC were included in the study. The results showed that pulmonary function and emphysema were important risk factors and that the support vector machine-based identification model showed optimal performance with accuracy:0.946, recall:0.940, specificity:0.955, precision:0.972, npv:0.920, F1 score:0.954, MCC:0.893, Kappa:0.888, AUROC:0.975, AUPRC:0.987. Conclusion: The use of machine learning tools combining clinical symptoms and routine examination data features is suitable for identifying the risk of concurrent NSCLC in COPD patients.

Wogonin alleviates BaP-induced DNA damage and oxidative stress in human airway epithelial cells by dual inhibiting CYP1A1 activity and expression.

Benzo[a]pyrene (BaP) is a common air pollutant that has been reported to cause oxidative stress and carcinogenesis. Wogonin, a flavonoid compound extracted from the roots of Scutellaria baicalensis, has been found to possess a variety of pharmacological activities, including anti-inflammatory and anti-cancer effects. The purpose of this study was to examine the ability of wogonin to alleviate the cytotoxicity induced by BaP in human airway epithelial cells and explore the corresponding mechanism. Our study found that wogonin treatment inhibited DNA damage and reactive oxygen species overproduction induced by BaP in human airway epithelial cells. In vitro enzyme assays showed that wogonin significantly inhibited the enzymatic activity of CYP1A1. In addition, wogonin decreased the basal level of CYP1A1 and inhibited the CYP1A1 overexpression induced by BaP, whereas overexpression of CYP1A1 partially reversed the effect of wogonin on BaP-induced DNA damage. Meanwhile, a CYP1A1 inhibitor and CYP1A1 knockdown also showed these same effects. Further studies showed that wogonin regulates CYP1A1 expression by inhibiting CDK7 and CDK9 activity. The use of CDK7 or CDK9 inhibitors decreased BaP-induced cytotoxicity and CYP1A1 expression. Finally, we found that the methoxy group of wogonin was crucial for its inhibitory activity. In conclusion, our data indicated that wogonin could effectively relieve BaP induced cytotoxicity, and its mechanism was related to the dual inhibition of CYP1A1 activity and expression.

Discovery of anthraquinones as DPP-IV inhibitors: Structure-activity relationships and inhibitory mechanism.

Dipeptidyl peptidase IV (DPP-IV) is an integrated type II transmembrane protein that reduces endogenous insulin contents and increases plasma glucose levels by hydrolyzing glucagon-like peptide-1 (GLP-1). Inhibition of DPP-IV regulates and maintains glucose homeostasis, making it an attractive drug target for the treatment of diabetes II. Natural compounds have tremendous potential to regulate glucose metabolism. In this study, we examined the DPP-IV inhibitory activity of a series of natural anthraquinones and synthetic structural analogues on DPP-IV using fluorescence-based biochemical assays. The inhibitory efficiency differed among anthraquinone compounds with different structures. Alizarin (7), aloe emodin (11), emodin (13) emerged the outstanding inhibitory potential for DPP-IV with IC50 values lower than 5 µM. To clarifying the inhibitory mechanism, inhibitory kinetics were performed, which showed that alizarin red S (8) and 13 were effective non-competitive inhibitors of DPP-IV, while alizarin complexone (9), rhein (12), and anthraquinone-2-carboxylic acid (23) were mixed inhibitors. Emodin was determined as inhibitor with the strongest DPP-IV-binding affinity determined via molecular docking. Structure-activity relationship (SAR) demonstrated that hydroxyl group at C-1 and C-8 sites and hydroxyl, hydroxymethyl or carboxyl group at the C-2 or C-3 site were very essential for DPP-IV inhibition, replacement of hydroxyl group with amino group at C-1 could led to an increase of the inhibitory potential. Further fluorescence imaging showed that both compounds 7 and 13 significantly inhibited DPP-IV activity in RTPEC cells. Overall, the results indicated that anthraquinones would be a natural functional ingredient for inhibiting DPP-IV and provided new ideas for searching and developing potential antidiabetic compounds.

Exosomal miR-663b from "M1" macrophages promotes pulmonary artery vascular smooth muscle cell dysfunction through inhibiting the AMPK/Sirt1 axis.

BACKGROUND: Inflammatory mediators from macrophages are proven to be involved in pulmonary vascular remodeling in pulmonary hypertension (PH). Here, this study intends to explore the mechanism of "M1" macrophage-derived exosomal miR-663b in pulmonary artery smooth muscle cells (PASMCs) dysfunctions and pulmonary hypertension. METHODS: Hypoxia-treated PASMCs were utilized for constructing an in-vitro pulmonary hypertension model. THP-1 cells were treated with PMA (320 nM) and LPS (10 µg/mL) + IFN-γ (20 ng/ml) for eliciting macrophage "M1" polarization. Exosomes derived from "M1" macrophages were isolated and added into PASMCs. The proliferation, inflammation, oxidative stress, and migration of PASMCs were evaluated. RT-PCR or Western blot examined the levels of miR-663b and the AMPK/Sirt1 pathway. Dual luciferase activity assay and RNA pull-down assay were carried out for confirming the targeted association between miR-663b and AMPK. An in-vivo PH model was built. Macrophage-derived exosomes with miR-663b inhibition were used for treating the rats, and alterations of pulmonary histopathology were monitored. RESULTS: miR-663b was obviously up-regulated in hypoxia-elicited PASMCs and M1 macrophages. miR-663b overexpression boosted hypoxia-induced proliferation, inflammation, oxidative stress, and migration in PASMCs, whereas miR-663b low expression resulted in the opposite situation. AMPK was identified as a target of miR-663b, and miR-663b overexpression curbed the AMPK/Sirt1 pathway. AMPK activation ameliorated the damaging impact of miR-663b overexpression and "M1" macrophage exosomes on PASMCs. In vivo, "M1" macrophage exosomes with miR-663b low expression alleviated pulmonary vascular remodeling in pulmonary hypertension rats. CONCLUSION: Exosomal miR-663b from "M1" macrophage facilitates PASMC dysfunctions and PH development by dampening the AMPK/Sirt1 axis.

[Ecological Risk and Migration Patterns of Heavy Metals in Soil and Crops in the Lead-Zinc Mining Area in Guizhou, China].

An accumulation of heavy metals in soil poses a risk to the ecological environment and human health. In this study, the concentrations of heavy metals in soil and crops were examined in a lead-zinc mining area in Guizhou Province, China. The distribution and sources of heavy metals were analyzed using GIS spatial mapping. The potential ecological risks of heavy metals were assessed using the potential ecological risk index (RI), and the human health risk assessment method recommended by the United States Environmental Protection Agency (USEPA) was used to quantify the health risk of residents exposed to heavy metals in the soil around lead-zinc mines. According to the results, the average of concentrations of As, Cd, Cr, Cu, Hg, Ni, Pb, and Zn in the soil were 58, 7.9, 175, 64, 0.461, 65, 1539, and 2513 mg·kg-1, respectively, which were significantly higher than the background values in Guizhou Province. It was found that the As, Cd, Cu, Hg, Pb, and Zn concentrations were extremely irregular in the soil and that the concentrations decreased significantly with the distance to the smelters, which were greatly disturbed by human activities. Comprehensive evaluation of soil heavy metals using the potential ecological risk index revealed that the risks of soil heavy metals were pole-strength and strong levels, and Cd constituted the primary ecological risk factor. A total of 22% and 10% of the corn samples contained Pb and As above the heavy metal pollution thresholds in the national food safety standards. According to human health risk assessments, heavy metals in the soil present potential non-carcinogenic risks to adults or children, and pose a potential carcinogenic risk to children. Soil pH was an important controlling factor affecting the bioavailability, migration, and accumulation of Cd in soil-crop systems. This study provides data and theoretical support for the prevention and control of soil pollution in lead-zine mining areas.

Inhibition of miR-4640-5p alleviates pulmonary hypertension in chronic obstructive pulmonary disease patients by regulating nitric oxide synthase 1.

BACKGROUND: Pulmonary hypertension (PH) is a devastating disease characterized by vasoconstriction and vascular remodeling, leading to right ventricular failure and death. PH is a common complication of chronic obstructive pulmonary disease (COPD). Accumulating evidence demonstrate that microRNAs participate in the pathobiology of PH in COPD patients. In this study, we aimed to evaluate the expression and function of microRNA-4640-5p (miR-4640-5p) in PH. METHODS: The mRNA and protein levels were determined by quantitative polymerase chain reaction (qPCR) and western blot, separately. Functional assays and western blot were performed to determine the effects of miR-4640-5p and NOS1 on cell growth, migration. Besides, the dual-luciferase reporter assays were used to validate miR-4640-5p and NOS1 interactions. RESULTS: We found that miR-4640-5p expression was significantly higher in the lung tissues of COPD-PH patients than in the healthy controls while higher expression of miR-4640-5p was correlated with more severe COPD-PH. By using pulmonary artery smooth muscle cell (PASMC) in in vitro assays, we demonstrated that inhibition of miR-4640-5p suppressed cell proliferation and migration of PASMC via regulating mTOR/S6 signaling. Bioinformatics analysis and validation experiments revealed that nitric oxide synthase 1 (NOS1) was a direct downstream target of miR-4640-5p. Overexpression of NOS1 partially antagonized the effect of miR-4640-5p in regulating PASMC cell proliferation and migration. In addition, our findings suggested that miR-4640-5p/NOS1 axis regulated mitochondrial dynamics in PASMCs. Furthermore, in the hypoxia-induced PH rat model, inhibition of miR-4640-5p ameliorated PH with reduced right ventricular systolic pressure and Fulton index. CONCLUSIONS: miR-4640-5p regulates PH via targeting NOS1, which provides a potential diagnostic biomarker and therapeutic target for COPD-PH patients.

Research Status and Application Prospects of the Medicinal Mushroom Armillaria mellea.

Armillaria is one of the most common diseases underlying chronic root rot in woody plants. Although there is no particularly effective way to prevent it, soil disinfection is a common effective protective measure. However, Armillaria itself has important medicinal value and is a symbiotic fungus in the cultivation of Gastrodia elata and Polyporus umbellatus. Therefore, researching Armillaria is of great practical significance. In this review, the biological characteristics, cultivation methods, chemical components, food and medicinal value and efficacy of Armillaria were all reviewed, and its development and utilization direction were analyzed and discussed.

Dapagliflozin Inhibits Ventricular Remodeling in Heart Failure Rats by Activating Autophagy through AMPK/mTOR Pathway.

Objective: Heart failure (HF) is the end stage of heart disease caused by various factors which mainly involves ventricular remodeling (VR). In HF patients with reduced ejection fraction, dapagliflozin (DAPA) reduced the risk of worsening HF or cardiovascular death. Thus, we attempted to clarify the specific role of DAPA underlying HF progression. Methods: The HF rat model was established to mimic characteristics of HF in vivo. HE staining assessed histopathological changes in left ventricular myocardial tissue of rats in each group. ELISA measured plasma ANP and BNP levels of rats in each group. M-mode echocardiography detected cardiac function of rats in each group. TUNEL staining detected apoptosis of infarct margin cells in myocardial tissue of rats in each group. Western blot detected levels of apoptosis-related proteins, autophagy-related proteins, and AMPK/mTOR-related proteins in myocardial tissue of rats in each group. Immunohistochemical staining detected caspase-3 or LC3B level in myocardial tissue of rats in each group. The HF cellular model was established to mimic characteristics of HF in vitro. Flow cytometry detected H9C2 cell apoptosis under different conditions. Western blot detected levels of apoptosis-related proteins, autophagy-related proteins, and AMPK/mTOR-related proteins in H9C2 cells under different conditions. Immunofluorescence detected caspase-3 or LC3B level in H9C2 cells under different conditions. Results: DAPA attenuated left VR and improved cardiac function in HF rats. DAPA attenuated cardiomyocyte apoptosis in HF rats. DAPA facilitated cardiomyocyte autophagy in HF rats via the AMPK/mTOR pathway. DAPA repressed hypoxia-induced H9C2 cell apoptosis by facilitating autophagy. DAPA repressed hypoxia-induced H9C2 cell apoptosis via the AMPK/mTOR pathway. Conclusion: DAPA suppresses ventricular remodeling in HF through activating autophagy via AMPK/mTOR pathway, which provides a potential novel insight for seeking therapeutic plans of HF.

Rs420137, rs386360 and rs7763726 polymorphisms in fibronectin type III domain containing 1 are associated with susceptibility to coronary heart disease: Analysis in the Han population.

Background: Numerous genetic studies have shown that genes are related to the pathogenesis of coronary heart disease (CHD). The main aim of this study was to confirm whether fibronectin type III domain containing 1 (FNDC1) polymorphisms correlate with the risk of CHD. Methods: In this study, in order to assess the association between three FNDC1 single nucleotide polymorphisms (SNPs) and the risk of CHD, we conducted a case-control study involving 630 patients with CHD and 568 healthy controls using Agena MassARRAY (Agena Bioscience, San Diego, CA, USA). Genotype distribution in case and control groups was analyzed by Chi square test. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression models adjusted for age, sex, smoking, and alcohol consumption to assess the correlation between SNPs and CHD risk. Results: Our results indicated that FNDC1-rs420137, -rs386360, and -rs7763726 played important roles in enhancing the risk of CHD. Subgroup analysis revealed that rs420137 increased the susceptibility to CHD in males, smokers, and patients aged ≤62 years. Rs360 had an increased risk of CHD in males, patients at aged ≤62 years, smokers, and non-drinkers. Furthermore, the association of rs7763726 with increased CHD risk was also observed in males, patients aged ≤62 years, smokers, and drinkers. Last but not least, these three SNPs we selected were protective factors against hypertension in CHD individuals. Conclusion: Our research suggest that FNDC1-rs420137, -rs386360, and -rs7763726 variants may be regarded as novel biomarkers for predicting CHD risk and other specific mechanisms of action of CHD need to be further studied.

[Sources Identification, Ecological Risk Assessment, and Controlling Factors of Potentially Toxic Elements in Typical Lead-Zinc Mine Area, Guizhou Province, Southwest China].

Carbonatite and basalt are widely distributed in southwest China, and potentially toxic elements (PTEs) are associated with the naturally high background properties. It is important to carry out ecological risk assessments and identify potential sources of PTEs. A total of 3180 soil samples (0-20 cm) were collected in Hezhang county, a typical high background area of PTEs with the parent lithology of carbonatite and basalt. Samples were obtained from 18 large lead-zinc mines, which belong to a multi-ecological risk superimposed area with high ecological risk. The concentration of PTEs (Cd, Cr, As, Hg, Pb, Cu, Zn, and Ni) in the topsoil were analyzed, and statistical analysis (SA), geographic information system (GIS), enrichment factor (EF), potential ecological risk index (RI), and positive matrix factorization (PMF) methods were used to assess the ecological risk and quantify sources of PTEs. The mean values of PTEs concentrations in topsoil were 24.55, 2.25, 176.40, 89.60, 0.19, 64.20, 102.00, and 257.00 mg·kg-1 for As, Cd, Cr, Cu, Hg, Ni, Pb, and Zn, respectively, which were remarkably higher than the average background value (ABV) of soils in Guizhou Province. The average concentrations of Cd, Cr, Cu, Ni, Pb, and Zn exceeded the screening values specified for the soil contamination risk in agricultural land (GB 15618-2018) by 7.50, 1.18, 1.79, 1.07, 1.40, and 1.29 times, respectively. The EF showed that Cd had a large area of moderate pollution; Pb, Zn, and Cu had a small area of slight pollution; the EFs values of Hg, Cr, Ni, and As were near the baseline value (EF≈1), and contaminations were slight or nonexistent. The PMF indicated that there were five sources, namely pyrite mines, lead-zinc mines, natural sources of basalt and carbonatite, and agricultural activities; the risk contribution ratios were 5.25%, 27.37%, 28.94%, 17.91%, and 20.53%, respectively. The most toxic coefficients of Hg and Cd were mainly natural sources, with contribution ratios of 86.3% and 72.7%, respectively. The soil samples in the mining areas expectedly contained high ratios of Zn/Cd and Pb/Cd, which confirmed that PTEs in the soil were mainly derived from the smelting wastes. The contents of metal oxides such as Fe, Mn, and Si were the influencing factors of PTEs enrichment. On the contrary, soil samples exhibited much lower Zn/Cd and Pb/Cd ratios in non-mining areas, indicating that the main origin of these metals in soil was the smelting flue gas dusts and geological background.

Distribution of mercury in foliage, litter and soil profiles in forests of the Qinling Mountains, China.

Forest ecosystems have been confirmed to be a sink of the global mercury (Hg) in the biogeochemical cycle. However, few studies have investigated the distribution of Hg in forest ecosystems on a regional scale in China. This work aimed to investigate the concentrations, distribution and influential factors of Hg in the Qinling Mountains forests in central China. Foliage, litter and soil profile samples were collected at 24 sampling sites across the Qinling Mountains forests. The results of the present study showed that the concentrations of Hg in foliage, litter, organic soils and mineral soils were maintained at relatively low levels compared with those in subtropical forests of Southwest China. The average Hg concentrations followed the order litter (74 ± 34 ng g-1) > organic soil (71 ± 37 ng g-1) > mineral soil (34 ± 21 ng g-1) > foliage (31 ± 15 ng g-1). Mercury in foliage showed no obvious spatial pattern, likely due to differences in tree species and ages across the sampling sites. Higher concentrations of Hg in litter were observed on the southern slope (low altitude), while the distribution of Hg in organic soils was the opposite. Both the tree species and environmental parameters (altitude, temperature and precipitation) controlled the Hg concentrations in litter by regulating the decomposition rate of the litter. There were significantly positive correlations between the Hg concentrations and soil organic carbon, nitrogen and sulfur in all soil layers, indicating that organic matter has a high geochemical affinity for Hg in soils. Because of the lower turnover rate and the higher accumulation of organic matter in high altitude and low temperature areas, Hg loss from biogeochemical cycling processes was effectively reduced. The spatial distribution of Hg in forests soil can be shaped by the distribution of organic matter at the regional scale.

Overview of heavy metal pollution and health risk assessment of urban soils in Yangtze River Economic Belt, China.

Using national multi-purpose regional geochemical survey (NMPRGS) data, this overview systematically summarizes the pollution levels and health risks posed by 8 heavy metals (As, Cd, Pb, Zn, Hg, Cu, Cr and Ni) in urban soils of 86 cities above the prefecture level in Yangtze River Economic Belt (YREB). Meanwhile, the spatial distribution and main sources of heavy metal pollutants in urban soils of key cities are described in detail. On a regional scale, Hg and Cd contamination in urban soils of YREB is most prominent, and As, Cu, Pb and Zn contamination exists in several cities, while Cr and Ni contamination is almost not shown. The type of industrialization and the history of urbanization affect the soil heavy metal pollution in majority cities, and the influence of geological background on the content of heavy metals in urban soils cannot be ignored. Specifically, the urban pollution of Cd, As, Pb and Zn is mainly concentrated in Hunan and Hubei Provinces, which are highly developed in mining industry, especially in Zhuzhou, Chenzhou, Huangshi and Xiangtan cities, while the major soil Hg pollution occurs in Zhejiang and Jiangsu Provinces with rapid economic development, where Shaoxing, Ningbo, Suzhou and Wuxi are the key polluted cities. Heavy metals in the urban soils investigated generally posed low non-carcinogenic and carcinogenic risks to the adults. However, the non-carcinogenic risk to minors in some cities (e.g., Chenzhou and Huangshi) should be given cautious attention.

Erratum: Dihydroartemisinin suppresses proliferation, migration, the Wnt/ß-catenin pathway and EMT via TNKS in gastric cancer.

[This corrects the article DOI: 10.3892/ol.2021.12949.].

Dihydroartemisinin suppresses proliferation, migration, the Wnt/ß-catenin pathway and EMT via TNKS in gastric cancer.

Gastric cancer is a common malignancy worldwide. However, the molecular mechanisms underlying this malignancy remain unclear and there are a lack of effective drugs. The present study aimed to investigate the antitumor effect of Dihydroartemisinin (DHA) or inhibition of Tankyrases (TNKS), and determine the underlying molecular mechanisms of gastric cancer. Immunohistochemistry and immunofluorescence analyses were performed to detect the expression levels of TNKS, epithelial-to-mesenchymal transition (EMT) and Wnt/ß-catenin pathway-related proteins in gastric cancer tissues and adjacent normal tissues. The Cell Counting Kit-8 assay was performed to assess the viability of HGC-27 and AGS cells following treatment with different concentrations of HLY78 (a Wnt activator) or DHA. Following treatment with HLY78, DHA or small interfering (si)-TNKS1/si-TNKS2, colony formation and migratory abilities were assessed via the colony formation, wound healing and Transwell assays. Furthermore, western blot and immunofluorescence analyses were performed to detect the expression levels of TNKS, EMT- and Wnt/ß-catenin-related proteins. The results demonstrated that the expression levels of TNKS, AXI2, ß-catenin, N-cadherin and Vimentin were upregulated, whereas E-cadherin expression was downregulated in gastric cancer tissues compared with normal tissues. Furthermore, HLY78 and DHA suppressed the viability of HGC-27 and AGS cells, in a concentration-independent manner. Notably, TNKS knockdown or treatment with DHA suppressed colony formation, migration, TNKS expression, EMT and the Wnt/ß-catenin pathway. Opposing effects were observed following treatment with HLY78, which were ameliorated following co-treatment with DHA. Taken together, these results suggest that DHA or inhibition of TNKS can suppress the proliferation and migration of gastric cancer cells, which is partly associated with inactivation of the Wnt/ß-catenin pathway and EMT process.

Cinnabar protects serum-nutrient starvation induced apoptosis by improving intracellular oxidative stress and inhibiting the expression of CHOP and PERK.

Cinnabar has been used for treatment of various disorders for thousands of years. The medical use of cinnabar, however, has been controversial because of its heavy metal mercury content. A large quantity of studies indicate that the toxicity of cinnabar is far below other inorganic or organic mercury-containing compounds. Yet, the underlying molecular basis has remained unresolved. Here, we investigated the beneficial effects of cinnabar on serum-nutrient starvation-elicited cell injury. Our findings showed that treatment of human renal proximal tubular cells (HK-2) with 4 nM cinnabar effectively inhibited nutrient deprivation induced apoptosis, reduced intracellular reactive oxygen species generation and increased GSH content, which was contrary to the exacerbated apoptotic cell death and oxidative stress in cells treated with HgCl2 at equal mercury concentration. In addition, cinnabar exerted robust antioxidative and antiapoptotic effects in cells under dual challenges of nutrient deprivation and treatment of H2O2. The protein expression levels of both CHOP and PERK were remarkably down-regulated in the cells treated with cinnabar compared to the control cells or cells treated with HgCl2. Overall, our data indicates that cinnabar at low concentration exerts anti-oxidative stress and anti-apoptosis effects by inhibiting the expression of the endoplasmic reticulum stress pathway proteins CHOP and PERK.

[Migration, Transformation Characteristics, and Ecological Risk Evaluation of Heavy Metal Fractions in Cultivated Soil Profiles in a Typical Carbonate-Covered Area].

In China, high heavy metal concentrations in cultivated soil are mainly distributed in carbonate-covered areas. The migration and transformation of heavy metals in such soils are influenced by interactions between natural processes and human activities. This study examined the profiles of nine paddy soils, derived from carbonate rocks in Guangxi. The Cd, As, Zn, Cr, Cu, Hg, Ni, and Pb contents we determined, and soil properties such as pH, Corg content, and fractions of Cd, As, Zn, and Cr were tested. Based on the above data, we assessed the vertical distribution of heavy metal fractions, as well as the ecological risks and factors affecting the migration ability of heavy metals, under the influence of human activities and natural soil formation. The results show that compared with the carbonate rocks in Guangxi, the soil profile of the study area is significantly enriched with all eight heavy metals. Among them, Cd, As, Zn, and Cr exceeded China's agricultural land (paddy field) pollution risk screening values, and Cd and As partially exceed the risk intervention values. All fractions of Cd in the soil profiles are widely distributed. The proportion of water-soluble and ion-exchange Cd fractions with high ecological risk decreased significantly from the surface to greater depths in the soil profile. As, Zn, and Cr in the soil profile were mainly in residual states, and the proportion of water-soluble and ion-exchange fractions did not change considerably with increasing depth. The evaluation results of RAC and RSP show that Cd pollution risk in the study area is relatively high, whereas As, Zn, and Cr are generally pollution-free or risk-free. In naturally developed soil in the study area, the clay mineral content and degree of soil development have significant effects on Cd migration, whereas in the cultivated layer affected by human activities, the soil pH and organic matter content are the main controlling factors. The migration ability of soil As is mainly related to soil organic matter, Fe2O3 content, and soil development degree, but organic matter has an obviously enhanced effect in the tillage layer. The main controlling factor of Zn and Cr migration in soil is pH, and the effects are more intense under the disturbance of human activities.

Towards to understanding the preliminary loss and absorption of nitrogen and phosphorus under different treatments in cotton drip- irrigation in northwest Xinjiang.

Drip irrigation under plastic mulch is widely used in Xinjiang, Northwest China. It can not only save water, but also reduce nutrient loss and improve fertilizer utilization. However, it is not clear whether the leaching occurs or not, what is the leaching amount? What is the relationship among fertilization, irrigation regimes, loss, cotton absorption, and cotton field under different fertilization and irrigation management under drip irrigation? Studying these issues not only provides reference for the formulation of fertilization and irrigation systems, but also is of great significance for reducing non-point source pollution. A long-term positioning experiment was conducted from 2009 to 2012 in Baotou Lake farm in Korla City, Xinjiang, with drip-irrigated cotton (Gossypium hirsutum L.) under different N fertilizer and irrigation amounts. The treatments were designed comprising Control (CK,0 N, 0 P, and 0 K with an irrigation of 480 mm) and the following three other treatments: (1) Conventional fertilize and irrigation (CON, 357 kg N hm-2, 90 kg P hm-2, 0 kg K hm-2, and irrigation of 480 mm); (2) Conventional fertilization and Optimizing irrigation (OPT, 357 kg N hm-2, 90 kg P hm-2, 62 kg K hm-2, and irrigation of 420 mm); and (3) Optimizing fertilization and irrigation (OPTN, 240 kg N hm-2, 65 kg P hm-2, 62 kg K hm-2, and irrigation of 420 mm). The results found that the leaching would occur in arid area under drip irrigation. The loss of total N, NH4+, P, N and P loss coefficient was higher under conventional fertilize and irrigation treatment while the loss of NO3- was higher under conventional fertilization and optimizing irrigation treatment. The correlations among N, P absorption by cotton, loss of NH4+ and total phosphorus were quadratic function. The total nitrogen loss and cumulative nitrogen application was lineally correlated. The loss of NO3- and cumulative nitrogen application was exponential. The nitrogen and phosphorus absorption by cotton under conventional fertilization and optimizing irrigation treatment was 24.53% and 35.86% higher than that in conventional fertilize and irrigation treatment, respectively. The cotton yield under conventional fertilization and optimizing irrigation treatment obtained higher than that in other three treatments. Therefore, the conventional fertilization and optimizing irrigation treatment was the optimal management of water and fertilizer in our study. These results demonstrate that reasonable water, nitrogen and phosphorus fertilize could not only effectively promote the absorption of nitrogen and phosphorus, but also reduce nitrogen and phosphorus losses under drip fertigation and plastic mulching.

Potentiation of flutamide-induced hepatotoxicity in mice by Xian-Ling-Gu-Bao through induction of CYP1A2.

ETHNOPHARMACOLOGICAL RELEVANCE: Xian-Ling-Gu-Bao (XLGB) Fufang is herbal formula widely used to treat osteoporosis and other bone disorders. Because of its commonality in the clinical use, there is a safety concern over the use of XLGB combined with other androgen deprivation therapy (ADT) drugs such as flutamide (FLU) that is associated with reduced bone density. To date, there have been no evaluations on the side effects of the drug-drug interaction between XLGB and FLU. AIM OF THE STUDY: The present study was designed to investigate the hepatotoxicity in the context of the combined treatment of XLGB and FLU in a mouse model, and to determine whether the metabolic activation of FLU through induction of CYP1A2 plays a role in the increased hepatoxicity caused by the combination of XLGB and FLU. MATERIALS AND METHODS: C57 mice were administered with either XLGB (6,160 mg/kg), FLU (300 mg/kg), or with the combination of the two drugs. Animals were treated with XLGB for 5 days before the combined administration of XLGB and FLU for another 4 days. The serum of mice from single or the combined administration groups was collected for biochemical analysis. The mouse liver was collected to examine liver morphological changes, evaluate liver coefficient, as well as determine the mRNA expression of P450 isozymes (Cyp1a2, Cyp3a11 and Cyp2c37). For metabolism analysis, mice were treated with XLGB, FLU, or the combination of XLGB and FLU for 24 h. The urine samples were collected for the analysis of FLU-NAC conjugate by UPLC-Q-Orbitrap MS. The liver microsomes were prepared from fresh livers to determine the activity of metabolizing enzyme CYP1A2. RESULTS: The combined treatment of XLGB and FLU caused loss of mice body weight and elicited significant liver toxicity as evidenced by an increased liver coefficient and serum lactate dehydrogenase (LDH) activity as well as pathological changes of fatty lesion of liver tissue. FLU increased hepatic expression of Cyp1a2 mRNA that was further elevated in the liver of mice when administered with both FLU and XLGB. Treatment of FLU resulted in an increase in the expression of Cyp3a11 mRNA that was negated when mice were co-treated with FLU and XLGB. No significant difference in Cyp2c37 mRNA expression was observed among the different treatment groups as compared to the control. Analysis of metabolic activity showed that the combined administration caused a synergic effect in elevating the activity of the CYP1A2 enzyme. Mass spectrometry analysis identified the presence of FLU reactive metabolite derived FLU-NAC conjugate in the urine of mice treated with FLU. Strikingly, about a two-fold increase of the FLU-NAC conjugate was detected when treated with both FLU and XLGB, indicating an elevated amount of toxic metabolite produced from FLU in the present of XLGB. CONCLUSION: FLU and XLGB co-treatment potentiated FLU-induced hepatoxicity. This increased hepatoxicity was mediated through the induction of CYP1A2 activity which in turn enhanced bioactivation of FLU leading to over production of FLU-NAC conjugate and oxidative stress. These results offer warnings about serious side effects of the FLU-XLGB interaction in the clinical practice.