Effects of dietary intervention on diabetic nephropathy: an umbrella review of systematic reviews and meta-analyses of randomized controlled trials.

Objective: To evaluate the quality of evidence, potential biases, and validity of all available studies on dietary intervention and diabetic nephropathy (DN). Methods: We conducted an umbrella review of existing meta-analyses of randomized controlled trials (RCTs) that focused on the effects of dietary intervention on DN incidence. The literature was searched via PubMed, Embase, Web of Science, and the Cochrane Database of Systematic Reviews. According to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE), evidence of each outcome was evaluated and graded as "high", "moderate", "low" or "very low" quality to draw conclusions. Additionally, we classified evidence of outcomes into 4 categories. Results: We identified 36 meta-analyses of RCTs and 55 clinical outcomes of DN from 395 unique articles. Moderate-quality evidence suggested that probiotic supplementation could significantly improve blood urea nitrogen (BUN), total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels in DN patients. Low-quality evidence indicated that probiotic supplementation significantly improved the serum creatinine concentration, urinary albumin-creatinine ratio (UACR), fasting blood glucose (FBG), HbA1c and high-density lipoprotein cholesterol (HDL-C) in DN patients. In addition, low-quality evidence suggested that a salt restriction diet could significantly improve the creatinine clearance rate (CrCl) in patients with DN. Low-quality evidence suggested that vitamin D supplementation could significantly improve the UACR in patients with DN. In addition, low-quality evidence has indicated that soy isoflavone supplementation could significantly improve BUN, FBG, total cholesterol (TC), triglyceride (TG) and LDL-C levels in patients with DN. Furthermore, low-quality evidence suggested that coenzyme Q10 supplementation could significantly improve HbA1c, TC and HDL-C in patients with DN, and dietary polyphenols also significantly improved HbA1c in patients with DN. Finally, low-quality evidence suggested that supplementation with antioxidant vitamins could significantly improve the serum creatinine concentration, systolic blood pressure, and HbA1c level in patients with DN. Given the small sample size, all significantly associated outcomes were evaluated as class IV evidence. Conclusion: Moderate to low amounts of evidence suggest that supplementation with probiotics, vitamin D, soy isoflavones, coenzyme Q10, dietary polyphenols, antioxidant vitamins, or salt-restricted diets may significantly improve clinical outcomes in patients with DN. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024512670.

VNS improves VSMC metabolism and arteriogenesis in infarcted hearts through m/n-AChR-Akt-SDF-1α in adult male rats.

Vagal nerve stimulation (VNS) provides a novel therapeutic strategy for injured hearts by activating cholinergic anti-inflammatory pathways. However, little information is available on the metabolic pattern and arteriogenesis of VSMCs after MI. VNS has been shown to stimulate the expression of CPT1α, CPT1ß, Glut1, Glut4 and SDF-1α in coronary VSMCs, decreasing the number of CD68-positive macrophages while increasing CD206-positive macrophages in the infarcted hearts, leading to a decrease in TNF-α and IL-1ß accompanied by a reduced ratio of CD68- and CD206-positive cells, which were dramatically abolished by atropine and mecamylamine in vivo. Knockdown of SDF-1α substantially abrogated the effect of VNS on macrophagecell alteration and inflammatory factors in infarcted hearts. Mechanistically, ACh induced SDF-1α expression in VSMCs in a dose-dependent manner. Conversely, atropine, mecamylamine, and a PI3K/Akt inhibitor completely eliminated the effect of ACh on SDF-1α expression. Functionally, VNS promoted arteriogenesis and improved left ventricular performance, which could be abolished by Ad-shSDF-1α. Thus, VNS altered the VSMC metabolism pattern and arteriogenesis to repair the infarcted heart by inducing SDF-1α expression, which was associated with the m/nAChR-Akt signaling pathway.

Geochemical characteristics and health risks of heavy metals in agricultural soils and crops from a coal mining area in Anhui province, China.

Soil contamination by heavy metals (HMs) in mining areas is a major issue because of its significant impact on the environmental quality and physical health of residents. Mining of minerals used in energy production, particularly coal, has led to HMs entering the surrounding soil through geochemical pathways. In this study, a total of 166 surface soil and 100 wheat grain samples around the Guobei coal mine in southeast China were collected, and trace metal levels were determined via inductively coupled plasma mass spectrometry (ICP-MS). The average HMs (Ni, As, Cr, Cu, Pb, Cd, and Zn) concentrations were lower than the screening values in China (GB 15618-2018) but higher than the soil background values in the Huaibei Bozhou area of Anhui Province (except Zn), indicating HMs enrichment. Based on the geoaccumulation index (Igeo) and ecological risk index (IER), Cd pollution levels were low, while for the other metals the samples were pollution-free, and therefore no ecological risk warning was issued for the mining area. Both Cr and Pb had a higher noncarcinogenic health risks for adults and children. The lifetime carcinogenic risks (LCR) of Cr, Pb, and Cd were within acceptable levels. A positive matrix factorization (PMF) model identified two factors that could explain the HMs sources: factor 1 for Zn, Cd, and Pb, factor 2 for Ni, As, Cr, and Cu. Furthermore, HMs enrichment was observed in surface soil and the Carboniferous-Permian coal seams in the Guobei coal mine, which may suggest that coal mining is an important source for HMs enrichment in surface soil. Overall, this study provides a theoretical basis for undertaking the management and assessment of soil HMs pollution around a coal mine.

Immunotherapy strategies for EGFR-mutated advanced NSCLC after EGFR tyrosine-kinase inhibitors failure.

Background: This study aimed to investigate the efficacy of immunotherapy, as monotherapy or in combination, comparing to chemotherapy with or without anti-angiogenesis for advanced non-small cell lung cancer (NSCLC) patients progressing to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs). Methods: We retrospectively analyzed patients with advanced NSCLC harboring EGFR mutations who received immune checkpoint inhibitors (ICI) and/or chemotherapy after EGFR-TKIs failure at Shanghai Chest Hospital between Aug 2016 and Oct 2022. According to the subsequent immunotherapy regimen, the patients were assigned to ICI monotherapy (IM), IO plus anti-angiogenesis (IA), ICI plus chemotherapy (IC), ICI plus chemotherapy plus anti-angiogenesis (ICA). Eligible patients undergoing standard chemotherapy were assigned to chemotherapy plus anti-angiogenesis (CA) and chemotherapy alone (CM). Efficacy was evaluated according to the RECIST 1.1version, and calculated the objective response rate (ORR) and disease control rate (DCR). Survival curves were plotted using the Kaplan-Meier method, and the median progression-free survival (PFS) was calculated. Differences among survival curves of the six groups were assessed using the log-rank test. Results: A total of 237 advanced NSCLC patients with EGFR mutations were included in this study. Of the 160 patients who received immunotherapy, 57 received ICI monotherapy, 27 received ICI plus anti-angiogenesis therapy, 43 received ICI plus chemotherapy, and 33 received ICI plus anti-angiogenesis plus chemotherapy. 77 patients received standard chemotherapy, of which 30 received chemotherapy plus anti-angiogenesis and 47 received chemotherapy alone. Patients in ICA group showed significant longer PFS than IM (7.2 vs 1.9 months, P=0.011), IA (7.2 vs 4.8 months, P=0.009) and CM group (7.2 vs 4.4 months, P=0.005). There was no significant difference in PFS between the ICA and IC (7.2 vs 5.6 months, P=0.104) or CA (7.2 vs 6.7 months, P=0.959) group. Meanwhile, the ICA group showed the highest ORR and DCR (36.4% and 90.9%) compared to the other five groups. The IC group had a higher ORR than the IA and CA group (32.6% vs 7.4% vs 10.0%, respectively), but the DCR was comparable (79.1% vs 74.1% vs 76.7%, respectively). The ORR of the CM group was 6.4% and the DCR was 66.0%. IM group showed the lowest ORR and DCR (1.8% and 36.8%). Treatment-related adverse events (TRAEs) of grade 3 or worse occurred in 9 (27.3%) patients in the ICA group, 6 (20.0%) in the CA group, 7 (14.9%) in the CM group, 5 (11.6%) in the IC group, 5 (8.8%) in the IM group, and 2 (7.4%) in the IA group. Conclusion: NSCLC patients with positive EGFR mutations after EGFR-TKIs failure received subsequent immunotherapy plus anti-angiogenesis and chemotherapy are likely to have more benefits in ORR, DCR and mPFS.

Vagus nerve stimulation-induced stromal cell-derived factor-l alpha participates in angiogenesis and repair of infarcted hearts.

AIMS: We aim to explore the role and mechanism of vagus nerve stimulation (VNS) in coronary endothelial cells and angiogenesis in infarcted hearts. METHODS AND RESULTS: Seven days after rat myocardial infarction (MI) was prepared by ligation of the left anterior descending coronary artery, the left cervical vagus nerve was treated with electrical stimulation 1 h after intraperitoneal administration of the α7-nicotinic acetylcholine inhibitor mecamylamine or the mAChR inhibitor atropine or 3 days after local injection of Ad-shSDF-1α into the infarcted heart. Cardiac tissue acetylcholine (ACh) and serum ACh, tumour necrosis factor α (TNF-α), interleukin 1ß (IL-1ß) and interleukin 6 (IL-6) levels were detected by ELISA to determine whether VNS was successful. An inflammatory injury model in human coronary artery endothelial cells (HCAECs) was established by lipopolysaccharide and identified by evaluating TNF-α, IL-1ß and IL-6 levels and tube formation. Immunohistochemistry staining was performed to evaluate CD31-positive vessel density and stromal cell-derived factor-l alpha (SDF-1α) expression in the MI heart in vivo and the expression and distribution of SDF-1α, C-X-C motif chemokine receptor 4 and CXCR7 in HCAECs in vitro. Western blotting was used to detect the levels of SDF-1α, V-akt murine thymoma viral oncogene homolog (AKT), phosphorylated AKT (pAKT), specificity protein 1 (Sp1) and phosphorylation of Sp1 in HCAECs. Left ventricular performance, including left ventricular systolic pressure, left ventricular end-diastolic pressure and rate of the rise and fall of ventricular pressure, should be evaluated 28 days after VNS treatment. VNS was successfully established for MI therapy with decreases in serum TNF-α, IL-1ß and IL-6 levels and increases in cardiac tissue and serum ACh levels, leading to increased SDF-1α expression in coronary endothelial cells of MI hearts, triggering angiogenesis of MI hearts with increased CD31-positive vessel density, which was abolished by the m/nAChR inhibitors mecamylamine and atropine or knockdown of SDF-1α by shRNA. ACh promoted SDF-1α expression and its distribution along with the branch of the formed tube in HCAECs, resulting in an increase in the number of tubes formed in HCAECs. ACh increased the levels of pAKT and phosphorylation of Sp1 in HCAECs, resulting in inducing SDF-1α expression, and the specific effects could be abolished by mecamylamine, atropine, the PI3K/AKT blocker wortmannin or the Sp1 blocker mithramycin. Functionally, VNS improved left ventricular performance, which could be abolished by Ad-shSDF-1α. CONCLUSIONS: VNS promoted angiogenesis to repair the infarcted heart by inducing SDF-1α expression and redistribution along new branches during angiogenesis, which was associated with the m/nAChR-AKT-Sp1 signalling pathway.

Mirikizumab as Induction and Maintenance Therapy for Ulcerative Colitis.

BACKGROUND: Mirikizumab, a p19-directed antibody against interleukin-23, showed efficacy in the treatment of ulcerative colitis in a phase 2 trial. METHODS: We conducted two phase 3, randomized, double-blind, placebo-controlled trials of mirikizumab in adults with moderately to severely active ulcerative colitis. In the induction trial, patients were randomly assigned in a 3:1 ratio to receive mirikizumab (300 mg) or placebo, administered intravenously, every 4 weeks for 12 weeks. In the maintenance trial, patients with a response to mirikizumab induction therapy were randomly assigned in a 2:1 ratio to receive mirikizumab (200 mg) or placebo, administered subcutaneously, every 4 weeks for 40 weeks. The primary end points were clinical remission at week 12 in the induction trial and at week 40 (at 52 weeks overall) in the maintenance trial. Major secondary end points included clinical response, endoscopic remission, and improvement in bowel-movement urgency. Patients who did not have a response in the induction trial were allowed to receive open-label mirikizumab during the first 12 weeks of the maintenance trial as extended induction. Safety was also assessed. RESULTS: A total of 1281 patients underwent randomization in the induction trial, and 544 patients with a response to mirikizumab underwent randomization again in the maintenance trial. Significantly higher percentages of patients in the mirikizumab group than in the placebo group had clinical remission at week 12 of the induction trial (24.2% vs. 13.3%, P<0.001) and at week 40 of the maintenance trial (49.9% vs. 25.1%, P<0.001). The criteria for all the major secondary end points were met in both trials. Adverse events of nasopharyngitis and arthralgia were reported more frequently with mirikizumab than with placebo. Among the 1217 patients treated with mirikizumab during the controlled and uncontrolled periods (including the open-label extension and maintenance periods) in the two trials, 15 had an opportunistic infection (including 6 with herpes zoster infection) and 8 had cancer (including 3 with colorectal cancer). Among the patients who received placebo in the induction trial, 1 had herpes zoster infection and none had cancer. CONCLUSIONS: Mirikizumab was more effective than placebo in inducing and maintaining clinical remission in patients with moderately to severely active ulcerative colitis. Opportunistic infection or cancer occurred in a small number of patients treated with mirikizumab. (Funded by Eli Lilly; LUCENT-1 and LUCENT-2 ClinicalTrials.gov numbers, NCT03518086 and NCT03524092, respectively.).

The spatiotemporal matching pattern of Ezrin/Periaxin involved in myoblast differentiation and fusion and Charcot-Marie-Tooth disease-associated muscle atrophy.

BACKGROUND: Clinically, Charcot-Marie-Tooth disease (CMT)-associated muscle atrophy still lacks effective treatment. Deletion and mutation of L-periaxin can be involved in CMT type 4F (CMT4F) by destroying the myelin sheath form, which may be related to the inhibitory role of Ezrin in the self-association of L-periaxin. However, it is still unknown whether L-periaxin and Ezrin are independently or interactively involved in the process of muscle atrophy by affecting the function of muscle satellite cells. METHOD: A gastrocnemius muscle atrophy model was prepared to mimic CMT4F and its associated muscle atrophy by mechanical clamping of the peroneal nerve. Differentiating C2C12 myoblast cells were treated with adenovirus-mediated overexpression or knockdown of Ezrin. Then, overexpression of L-periaxin and NFATc1/c2 or knockdown of L-periaxin and NFATc3/c4 mediated by adenovirus vectors were used to confirm their role in Ezrin-mediated myoblast differentiation, myotube formation and gastrocnemius muscle repair in a peroneal nerve injury model. RNA-seq, real-time PCR, immunofluorescence staining and Western blot were used in the above observation. RESULTS: For the first time, instantaneous L-periaxin expression was highest on the 6th day, while Ezrin expression peaked on the 4th day during myoblast differentiation/fusion in vitro. In vivo transduction of adenovirus vectors carrying Ezrin, but not Periaxin, into the gastrocnemius muscle in a peroneal nerve injury model increased the numbers of muscle myosin heavy chain (MyHC) I and II type myofibers, reducing muscle atrophy and fibrosis. Local muscle injection of overexpressed Ezrin combined with incubation of knockdown L-periaxin within the injured peroneal nerve or injection of knockdown L-periaxin into peroneal nerve-injured gastrocnemius muscle not only increased the number of muscle fibers but also recovered their size to a relatively normal level in vivo. Overexpression of Ezrin promoted myoblast differentiation/fusion, inducing increased MyHC-I+ and MyHC-II + muscle fiber specialization, and the specific effects could be enhanced by the addition of adenovirus vectors for knockdown of L-periaxin by shRNA. Overexpression of L-periaxin did not alter the inhibitory effects on myoblast differentiation and fusion mediated by knockdown of Ezrin by shRNA in vitro but decreased myotube length and size. Mechanistically, overexpressing Ezrin did not alter protein kinase A gamma catalytic subunit (PKA-γ cat), protein kinase A I alpha regulatory subunit (PKA reg Iα) or PKA reg Iß levels but increased PKA-α cat and PKA reg II α levels, leading to a decreased ratio of PKA reg I/II. The PKA inhibitor H-89 remarkably abolished the effects of overexpressing-Ezrin on increased myoblast differentiation/fusion. In contrast, knockdown of Ezrin by shRNA significantly delayed myoblast differentiation/fusion accompanied by an increased PKA reg I/II ratio, and the inhibitory effects could be eliminated by the PKA reg activator N6-Bz-cAMP. Meanwhile, overexpressing Ezrin enhanced type I muscle fiber specialization, accompanied by an increase in NFATc2/c3 levels and a decrease in NFATc1 levels. Furthermore, overexpressing NFATc2 or knocking down NFATc3 reversed the inhibitory effects of Ezrin knockdown on myoblast differentiation/fusion. CONCLUSIONS: The spatiotemporal pattern of Ezrin/Periaxin expression was involved in the control of myoblast differentiation/fusion, myotube length and size, and myofiber specialization, which was related to the activated PKA-NFAT-MEF2C signaling pathway, providing a novel L-Periaxin/Ezrin joint strategy for the treatment of muscle atrophy induced by nerve injury, especially in CMT4F.

Automatic breast cancer diagnosis based on hybrid dimensionality reduction technique and ensemble classification.

INTRODUCTION: Feature selection in the face of high-dimensional data can reduce overfitting and learning time, and at the same time improve the accuracy and efficiency of the system. Since there are many irrelevant and redundant features in breast cancer diagnosis, removing such features leads to more accurate prediction and reduced decision time when dealing with large-scale data. Meanwhile, ensemble classifiers are powerful techniques to improve the prediction performance of classification models, where several individual classifier models are combined to achieve higher accuracy. METHODS: In this paper, an ensemble classifier algorithm based on multilayer perceptron neural network is proposed for the classification task, in which the parameters (e.g., number of hidden layers, number of neurons in each hidden layer, and weights of links) are adjusted based on an evolutionary approach. Meanwhile, this paper uses a hybrid dimensionality reduction technique based on principal component analysis and information gain to address this problem. RESULTS: The effectiveness of the proposed algorithm was evaluated based on the Wisconsin breast cancer database. In particular, the proposed algorithm provides an average of 17% better accuracy compared to the best results obtained from the existing state-of-the-art methods. CONCLUSION: Experimental results show that the proposed algorithm can be used as an intelligent medical assistant system for breast cancer diagnosis.

Efficacy and Safety of Qili Qiangxin Capsule on Dilated Cardiomyopathy: A Systematic Review and Meta-Analysis of 35 Randomized Controlled Trials.

Objective: Qili Qiangxin Capsule (QQC), a Chinese patent medicine, is clinically effective in treating dilated cardiomyopathy (DCM). However, the meta-analysis of QCC combined with conventional western medicine (CWM) on DCM remains unexplored. This study aimed to systematically evaluate the efficacy and safety of QCC in the treatment of DCM. Methods: Searched the studies of the combination of QQC and CWM in the treatment of DCM, from databases like PubMed, Cochrane Library, Web of Science, Wan Fang Databases, Chinese Biomedical Literature Database, China Science and Technology Journal Database, China National Knowledge Infrastructure, prior to 15 January 2022. Two reviewers respectively regulated research selection, data extraction, and risk of bias assessment. Review Manager Software 5.4 was used for meta-analysis. Furthermore, GRADE pro3.6.1 software was selected to grade the current evidence in our findings. This meta-analysis has been registered in PROSPERO (CRD42022297906). Results: There were 35 studies pertaining to 3,334 patients included. The meta-analysis showed compared with CWM alone, the combination therapy had significant advantages in improving the clinical efficiency rate (RR = 1.24, 95% CI: 1.19 to 1.29, p < 0.00001), 6 min walking distance (6MWD) (MD = 41.93, 95%CI: 39.82 to 44.04, p < 0.00001), superior in ameliorating the left ventricular ejection fraction (LVEF) (MD = 5.73, 95%CI: 4.70 to 6.77, p < 0.00001), left ventricular end-diastolic dimension (LVEDD) (MD = -4.09, 95%CI: -4.91 to -3.27), p < 0.00001), left ventricular end-systolic diameter (LVESD) (MD = -4.73, 95%CI: -5.63 to -3.84), p < 0.00001) and BNP (MD = -101.09, 95%CI: -132.99 to -69.18), p < 0.00001), and also superior in reducing hypersensitive-C-Reactive Protein (hs-CRP) (MD = -3.78, 95%CI: -4.35 to -3.21), p < 0.00001), Interleukin- 6 (IL-6) (MD = -25.92, 95%CI: -31.35 to -20.50), p < 0.00001), tumor necrosis factor-α (TNF-α) (MD = -5.04, 95%CI: -6.13 to -3.95), p < 0.00001), high mobility group protein B1 (HMGB1) (MD = -4.34, 95%CI: -5.22 to -3.46), p < 0.00001), and adverse reactions (ARs) (RR = 0.70, 95%CI: 0.51-0.97), p = 0.03). The GRADE evidence quality rating presented with moderate or low quality of evidence for the available data. Conclusion: Compared with the control group, QQC combined with CWM may be effective in treating DCM. However, the conclusion of this study must be interpreted carefully due to the inferior quality and ambiguity of bias in the included trials. Systematic Review Registration: https://www.crd.york.ac.uk/prospero, identifier [CRD42022297906].

Identification of novel immunomodulators in lung squamous cell carcinoma based on transcriptomic data.

Cells in the tumor microenvironment are well known for their role in cancer development and prognosis. The processes of genetic changes and possible remodeling in the tumor microenvironment of lung squamous cell carcinoma, on the other hand, are mainly unclear. In this investigation, 1164 immunological differentially expressed genes (DEGs) were shown to have predictive significance. A prognostic model with high prediction accuracy was constructed using these genes and survival data. There were 1020 upregulated genes and 144 downregulated genes found, with 57 genes found to be important in the development of LUSC. We used least absolute shrinkage and selection operator (LASSO) regression analysis to determine the risk profiles of 9 genes based on the expression values of 57 prognosis-related genes. The AUCs of the developed prognostic model for predicting patient survival at 1, 3, and 5 years were 0.66, 0.61, and 0.63, respectively, based on the training data. For immune-correlation analysis in this survival model, we chose IGLC7, which was seen to predict patient survival with high accuracy. The effects on immune cells and synergistic effects with other immunomodulators were then investigated. We discovered that IGLC7 is involved in immune response and inflammatory activity using gene ontology analysis and genomic sequence variance analysis (GSVA), with a potential effect, especially on B cells and T cells. In conclusion, IGLC7 expression levels are related to the malignancy of LUSC based on the constructed prognostic model and can thus be a therapeutic target for patients with LUSC. Furthermore, IGLC7 may work in concert with other immune checkpoint members to regulate the immune microenvironment of LUSC. These discoveries might lead to a fresh understanding of the complicated interactions between cancer cells and the tumor microenvironment, particularly the population of immune cells, and a novel approach to future immunotherapeutic treatments for patients with LUSC.

Investigation on the biological activity of anthocyanins and polyphenols in blueberry.

Blueberry (Vaccinium spp.) is a fruit recognized in the world as healthy, and many of its active ingredients have important physiological functions. This study analyzed the antioxidant activity, antitumor activity, and immune function of anthocyanins and polyphenols extracted from blueberries. The crude extracts of anthocyanins and polyphenols were obtained from blueberries and then purified, and the extract exhibited excellent dose-dependent antitumor activity and antioxidant activity in vivo and in vitro. The purified anthocyanins and polyphenol compounds showed higher antioxidant activity, whereas the crude extract had a better inhibitory effect on tumor proliferation than pure extract, and the blueberry anthocyanin and polyphenol crude product mixture showed a more powerful tumor suppressor, which may be the result of the synergistic effect of multiple compounds. The crude extracts were also more efficient at improving immune function, as reflected by measurements of change in body weight, thymus and spleen indices, macrophage phagocytosis, lymphocyte transformation capacity, superoxide dismutase activity, malondialdehyde content, and serum nitric oxide levels. These results indicate that blueberry anthocyanins and polyphenol extracts can improve immune function and reduce the metastasis and proliferation of cancer cells. This study reveals the functions of important active substances in blueberries and provides support for the development of functional health products and therapeutic drugs. PRACTICAL APPLICATION: We compared the biological activity of crude and purified anthocyanins and polyphenol extracts from blueberries and tested their effects on improving immune function. This study contributes to a better understanding of the bioactivity of blueberry extracts and is valuable for further applications of blueberries in medicine.

Quantifying the influencing factors and multi-factor interactions affecting cadmium accumulation in limestone-derived agricultural soil using random forest (RF) approach.

Cadmium (Cd) is a highly toxic heavy metal that occurs widely in the environment and poses extensive threats to human health, animals, and plants. This study aims to identify and apportion multi-source and multi-phase Cd pollution from natural and anthropogenic inputs using ensemble models that include random forest (RF) in agricultural soils on Karst areas. The contributions of natural and anthropogenic factors to Cd accumulation were quantitatively assessed using the RF machine learning method. The results revealed that the main influencing factors were pH, organic carbon (Corg), and elevation. Moreover, the interaction effects of pH and Corg on distance and elevation were also quantified and visualised. It is observed that pH and Corg had stronger effects on soil Cd concentration than that of distance when pH > 7.02 and Corg > 1.53. In other words, higher Cd content in the soil along roadways may be caused by the interaction of distance, pH and Corg, with pH and Corg playing the dominant role in our case. Moreover, the maximum contribution of a single factor, elevation, to Cd concentration was about 0.13 mg/kg, and its interactions reached 1.082 mg/kg and 0.83 mg/kg, respectively, when combined with pH and Corg at 194.0 m. However, with increasing elevation, pH and Corg gradually took over the leading roles. This result not only gives us a quantitative understanding of the relationship between the factors that affect soil cadmium accumulation, but also provides an accurate method for source apportionment of heavy metals in soil.

[Transfer Factor and Health Risk Assessment of Heavy Metals in a Soil-Crop System in a High Incidence Area of Nasopharyngeal Carcinoma, Guangdong].

In order to reveal the transfer factor and perform health risk assessments of heavy metals in soil-crop systems in the high incidence area of nasopharyngeal carcinoma (NPC) in Guangdong province of China, the farmland system of Sihui City in the high incidence area of NPC was selected as the research object, and rice, lettuce, and corresponding soil samples were collected. As, Cu, Hg, Mn, Ni, Pb, and Cd in the soil and crop samples were analyzed. Based on the contents and chemical forms of seven heavy metals, the environmental pollution, bioavailability, and transfer factors of heavy metals in the soil-crop system were assessed using statistical analyses, pollution index evaluations, and transfer factor methods, and the health risks of adults and children in the study area were assessed using the health risk assessment model recommended by the U.S. Environmental Protection Agency. The results showed that the farmland soil in the study area was basically clean (P=0.43); Cd and Mn mainly existed in a bioavailable state, Hg mainly existed in a potentially available state, and As Cu, Ni, and Pb mainly existed in a residual state. The lettuce was safe (P=0.48), while the pollution index of rice (P=7.66) was higher than that of lettuce, and the main polluting element was Pb (PI=10.25). The results of soil pollution assessments are not completely consistent with those of crop pollution assessments, so they should be combined with the bioavailability of heavy metals and crop effects for correlation analyses. Cd and Cu are more easily absorbed by lettuce, while Cd, Cu, and As are more easily enriched by rice. Special attention should be paid to Cd and Cu pollution in farmland soils, and As pollution should be of focus in paddy fields. In the study area, the non-carcinogenic risk index (HI) value of edible lettuce for adults and children was less than 1 and the average value of the total carcinogenic risk index (Risk) of edible lettuce was less than 1×10-4. Therefore, the health risk of edible local lettuce was within the acceptable range. The average HI index of rice for adults and children was more than 1 and the main non-carcinogenic factor was Pb; the risk index of rice was more than 1×10-4, and the main carcinogenic factor was As. Rice consumption in the study area will cause certain health risks, and the threat to adults is greater than that to children. Therefore, As in rice may be related to the high incidence of NPC in Sihui City. It is suggested that the remediation of heavy metals in farmland soils be strengthened or that residents be forbidden to plant or eat local rice and other crops with greater health risks.

Vagus nerve stimulation optimized cardiomyocyte phenotype, sarcomere organization and energy metabolism in infarcted heart through FoxO3A-VEGF signaling.

Vagus nerve stimulation (VNS) restores autonomic balance, suppresses inflammation action and minimizes cardiomyocyte injury. However, little knowledge is known about the VNS' role in cardiomyocyte phenotype, sarcomere organization, and energy metabolism of infarcted hearts. VNS in vivo and acetylcholine (ACh) in vitro optimized the levels of α/ß-MHC and α-Actinin positive sarcomere organization in cardiomyocytes while reducing F-actin assembly of cardiomyocytes. Consistently, ACh improved glucose uptake while decreasing lipid deposition in myocytes, correlating both with the increase of Glut4 and CPT1α and the decrease of PDK4 in infarcted hearts in vivo and myocytes in vitro, attributing to improvement in both glycolysis by VEGF-A and lipid uptake by VEGF-B in response to Ach. This led to increased ATP levels accompanied by the repaired mitochondrial function and the decreased oxygen consumption. Functionally, VNS improved the left ventricular performance. In contrast, ACh-m/nAChR inhibitor or knockdown of VEGF-A/B by shRNA powerfully abrogated these effects mediated by VNS. On mechanism, ACh decreased the levels of nuclear translocation of FoxO3A in myocytes due to phosphorylation of FoxO3A by activating AKT. FoxO3A overexpression or knockdown could reverse the specific effects of ACh on the expression of VEGF-A/B, α/ß-MHC, Glut4, and CPT1α, sarcomere organization, glucose uptake and ATP production. Taken together, VNS optimized cardiomyocytes sarcomere organization and energy metabolism to improve heart function of the infarcted heart during the process of delaying and/or blocking the switch from compensated hypertrophy to decompensated heart failure, which were associated with activation of both P13K/AKT-FoxO3A-VEGF-A/B signaling cascade.

S100B is required for maintaining an intermediate state with double-positive Sca-1+ progenitor and vascular smooth muscle cells during neointimal formation.

INTRODUCTION: Accumulation of vascular smooth muscle cells (VSMCs) within the neointimal region is a hallmark of atherosclerosis and vessel injury. Evidence has shown that Sca-1-positive (Sca-1+) progenitor cells residing in the vascular adventitia play a crucial role in VSMC assemblages and intimal lesions. However, the underlying mechanisms, especially in the circumstances of vascular injury, remain unknown. METHODS AND RESULTS: The neointimal formation model in rats was established by carotid artery balloon injury using a 2F-Forgaty catheter. Most Sca-1+ cells first appeared at the adventitia of the vascular wall. S100B expressions were highest within the adventitia on the first day after vessel injury. Along with the sequentially increasing trend of S100B expression in the intima, media, and adventitia, respectively, the numbers of Sca-1+ cells were prominently increased at the media or neointima during the time course of neointimal formation. Furthermore, the Sca-1+ cells were markedly increased in the tunica media on the third day of vessel injury, SDF-1α expressions were obviously increased, and SDF-1α levels and Sca-1+ cells were almost synchronously increased within the neointima on the seventh day of vessel injury. These effects could effectually be reversed by knockdown of S100B by shRNA, RAGE inhibitor (SPF-ZM1), or CXCR4 blocker (AMD3100), indicating that migration of Sca-1+ cells from the adventitia into the neointima was associated with S100B/RAGE and SDF-1α/CXCR4. More importantly, the intermediate state of double-positive Sca-1+ and α-SMA cells was first found in the neointima of injured arteries, which could be substantially abrogated by using shRNA for S100B or blockade of CXCR4. S100B dose-dependently regulated SDF-1α expressions in VSMCs by activating PI3K/AKT and NF-κB, which were markedly abolished by PI3K/AKT inhibitor wortmannin and enhanced by p65 blocker PDTC. Furthermore, S100B was involved in human umbilical cord-derived Sca-1+ progenitor cells' differentiation into VSMCs, especially in maintaining the intermediate state of double-positive Sca-1+ and α-SMA. CONCLUSIONS: S100B triggered neointimal formation in rat injured arteries by maintaining the intermediate state of double-positive Sca-1+ progenitor and VSMCs, which were associated with direct activation of RAGE by S100B and indirect induction of SDF-1α by activating PI3K/AKT and NF-κB.

VEGF-A and VEGF-B Coordinate the Arteriogenesis to Repair the Infarcted Heart with Vagus Nerve Stimulation.

BACKGROUND/AIMS: Vagus nerve stimulation (VNS) suppresses arrhythmic activity and minimizes cardiomyocyte injury. However, how VNS affects angiogenesis/arteriogenesis in infarcted hearts, is poorly understood. METHODS: Myocardial infarction (MI) was achieved by ligation of the left anterior descending coronary artery (LAD) in rats. 7 days after LAD, stainless-steel wires were looped around the left and right vagal nerve in the neck for vagus nerve stimulation (VNS). The vagal nerve was stimulated with regular pulses of 0.2ms duration at 20 Hz for 10 seconds every minute for 4 hours, and then ACh levels by ELISA in cardiac tissue and serum were evaluated for its release after VNS. Three and 14 days after VNS, Real-time PCR, immunostaining and western blot were respectively used to determine VEGF-A/B expressions and α-SMA- and CD31-postive vessels in VNS-hearts with pretreatment of α7-nAChR blocker mecamylamine (10 mg/kg, ip) or mACh-R blocker atropine (10 mg/kg, ip) for 1 hour. The coronary function and left ventricular performance were analyzed by Langendorff system and hemodynamic parameters in VNS-hearts with pretreatment of VEGF-A/B-knockdown or VEGFR blocker AMG706. Coronary arterial endothelial cells proliferation, migration and tube formation were evaluated for angiogenesis following the stimulation of VNS in coronary arterial smooth muscle cells (VSMCs). RESULTS: VNS has been shown to stimulate VEGF-A and VEGF-B expressions in coronary arterial smooth muscle cells (VSMCs) and endothelial cells (ECs) with an increase of α-SMA- and CD31-postive vessel number in infarcted hearts. The VNS-induced VEGF-A/B expressions and angiogenesis were abolished by m-AChR inhibitor atropine and α7-nAChR blocker mecamylamine in vivo. Interestingly, knockdown of VEGF-A by shRNA mainly reduced VNS-mediated formation of CD31+ microvessels. In contrast, knockdown of VEGF-B powerfully abrogated VNS-induced formation of α-SMA+ vessels. Consistently, VNS-induced VEGF-A showed a greater effect on EC tube formation as compared to VNS-induced VEGF-B. Moreover, VEGF-A promoted EC proliferation and VSMC migration while VEGF-B induced VSMC proliferation and EC migration in vitro. Mechanistically, vagal neurotransmitter acetylcholine stimulated VEGF-A/B expressions through m/nACh-R/PI3K/Akt/Sp1 pathway in EC. Functionally, VNS improved the coronary function and left ventricular performance. However, blockade of VEGF receptor by antagonist AMG706 or knockdown of VEGF-A or VEGF-B by shRNA significantly diminished the beneficial effects of VNS on ventricular performance. CONCLUSION: VNS promoted angiogenesis/arteriogenesis to repair the infracted heart through the synergistic effects of VEGF-A and VEGF-B.

Data on the involvement of Meox1 in balloon-injury-induced neointima formation of rats.

In the previous report, Meox1 was found to promote SMCs phenotypic modulation and injury-induced vascular remodeling by regulating the FAK-ERK1/2-autophagy signaling cascade (Wu et al., 2017) [1]. Here, we presented new original data on the involvement of Mesoderm/mesenchyme homeobox gene l (Meox1) in balloon-injury-induced neointima formation of rat. In rat carotid artery balloon injury model to induce vascular remodeling, Meox1 was induced in vascular smooth muscle cell (SMCs) of rat carotid arteries. Most proliferating cell nuclear antigen (PCNA)-positive cells also expressed Meox1. These data suggested that Meox1 may be involved in SMCs proliferation during injury-induced neointima formation. Furthermore, knocked down its expression in injured arteries by adenoviral delivery of Meox1 short hairpin RNA (shRNA) (shMeox1), neointima formation was significantly inhibited. Elastin staining also confirmed the reduction of neointima in Meox1 shRNA-transduced arteries. Moreover, knockdown of Meox1 decreased the collagen production/deposition that was significantly increased in neointima induced by balloon injury.

S100B promotes injury-induced vascular remodeling through modulating smooth muscle phenotype.

S100B is a biomarker of nervous system injury, but it is unknown if it is also involved in vascular injury. In the present study, we investigated S100B function in vascular remodeling following injury. Balloon injury in rat carotid artery progressively induced neointima formation while increasing S100B expression in both neointimal vascular smooth muscle (VSMC) and serum along with an induction of proliferating cell nuclear antigen (PCNA). Knockdown of S100B by its shRNA delivered by adenoviral transduction attenuated the PCNA expression and neointimal hyperplasia in vivo and suppressed PDGF-BB-induced VSMC proliferation and migration in vitro. Conversely, overexpression of S100B promoted VSMC proliferation and migration. Mechanistically, S100B altered VSMC phenotype by decreasing the contractile protein expression, which appeared to be mediated by NF-κB activity. S100B induced NF-κB-p65 gene transcription, protein expression and nuclear translocation. Blockade of NF-κB activity by its inhibitor reversed S100B-mediated downregulation of VSMC contractile protein and increase in VSMC proliferation and migration. It appeared that S100B regulated NF-κB expression through, at least partially, the Receptor for Advanced Glycation End products (RAGE) because RAGE inhibitor attenuated S100B-mediated NF-κB promoter activity as well as VSMC proliferation. Most importantly, S100B secreted from VSMC impaired endothelial tube formation in vitro, and knockdown of S100B promoted re-endothelialization of injury-denuded arteries in vivo. These data indicated that S100B is a novel regulator for vascular remodeling following injury and may serve as a potential biomarker for vascular damage or drug target for treating proliferative vascular diseases.

Conformational Motions and Functionally Key Residues for Vitamin B12 Transporter BtuCD-BtuF Revealed by Elastic Network Model with a Function-Related Internal Coordinate.

BtuCD-BtuF from Escherichia coli is a binding protein-dependent adenosine triphosphate (ATP)-binding cassette (ABC) transporter system that uses the energy of ATP hydrolysis to transmit vitamin B12 across cellular membranes. Experimental studies have showed that during the transport cycle, the transporter undergoes conformational transitions between the "inward-facing" and "outward-facing" states, which results in the open-closed motions of the cytoplasmic gate of the transport channel. The opening-closing of the channel gate play critical roles for the function of the transporter, which enables the substrate vitamin B12 to be translocated into the cell. In the present work, the extent of opening of the cytoplasmic gate was chosen as a function-related internal coordinate. Then the mean-square fluctuation of the internal coordinate, as well as the cross-correlation between the displacement of the internal coordinate and the movement of each residue in the protein, were calculated based on the normal mode analysis of the elastic network model to analyze the function-related motions encoded in the structure of the system. In addition, the key residues important for the functional motions of the transporter were predicted by using a perturbation method. In order to facilitate the calculations, the internal coordinate was introduced as one of the axes of the coordinate space and the conventional Cartesian coordinate space was transformed into the internal/Cartesian space with linear approximation. All the calculations were carried out in this internal/Cartesian space. Our method can successfully identify the functional motions and key residues for the transporter BtuCD-BtuF, which are well consistent with the experimental observations.