Integrated analyses reveal the diagnostic and predictive values of COL5A2 and association with immune environment in Crohn's disease.

The pathogenesis of Crohn's disease (CD) involves abnormal immune cell infiltration and dysregulated immune response. Therefore, thorough research on immune cell abnormalities in CD is crucial for improved treatment of this disease. Single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data of CD were obtained from the Gene Expression Omnibus (GEO) database. Cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT), weighted gene co-expression network analysis (WGCNA), protein-protein interaction (PPI) networks evaluated the proportion of immune infiltrating cells, constructed co-expression network and identified key genes, respectively. Based on the dataset (GSE134809), 15 cell clusters were defined and labeled as different cell types. Among the 11 modules, the yellow module had the closest relationship with plasma cells (cluster 5). Confirmed using RNA sequencing and IHC assay, the expression of COL5A2 in CD samples was higher than that in control samples. Furthermore, the COL5A2 protein expression remarkably decreased in the group of patients who responded to anti-tumor necrosis factor (TNF) treatments, compared to the non-response group. The comprehensive analyses described here provided novel insight into the landscape of CD-associated immune environment. In addition, COL5A2 were identified as potential diagnostic indicators for CD, as well as promising predictive markers for CD patients.

The gut microbiota participates in the effect of linaclotide in patients with irritable bowel syndrome with constipation (IBS-C): a multicenter, prospective, pre-post study.

BACKGROUND: Interindividual variation characterizes the relief experienced by constipation-predominant irritable bowel syndrome (IBS-C) patients following linaclotide treatment. Complex bidirectional interactions occur between the gut microbiota and various clinical drugs. To date, no established evidence has elucidated the interactions between the gut microbiota and linaclotide. We aimed to explore the impact of linaclotide on the gut microbiota and identify critical bacterial genera that might participate in linaclotide efficacy. METHODS: IBS-C patients were administered a daily linaclotide dose of 290 µg over six weeks, and their symptoms were then recorded during a four-week posttreatment observational period. Pre- and posttreatment fecal samples were collected for 16S rRNA sequencing to assess alterations in the gut microbiota composition. Additionally, targeted metabolomics analysis was performed for the measurement of short-chain fatty acid (SCFA) concentrations. RESULTS: Approximately 43.3% of patients met the FDA responder endpoint after taking linaclotide for 6 weeks, and 85% of patients reported some relief from abdominal pain and constipation. Linaclotide considerably modified the gut microbiome and SCFA metabolism. Notably, the higher efficacy of linaclotide was associated with enrichment of the Blautia genus, and the abundance of Blautia after linaclotide treatment was higher than that in healthy volunteers. Intriguingly, a positive correlation was found for the Blautia abundance and SCFA concentrations with improvements in clinical symptoms among IBS-C patients. CONCLUSION: The gut microbiota, especially the genus Blautia, may serve as a significant predictive microbe for symptom relief in IBS-C patients receiving linaclotide treatment. TRIAL REGISTRATION: This trial was registered with the Chinese Clinical Trial Registry (Chictr.org.cn, ChiCTR1900027934).

Sodium-glucose cotransporter 2 inhibitors, inflammation, and heart failure: a two-sample Mendelian randomization study.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are increasingly recognized for their role in reducing the risk and improving the prognosis of heart failure (HF). However, the precise mechanisms involved remain to be fully delineated. Evidence points to their potential anti-inflammatory pathway in mitigating the risk of HF. METHODS: A two-sample, two-step Mendelian Randomization (MR) approach was employed to assess the correlation between SGLT-2 inhibition and HF, along with the mediating effects of inflammatory biomarkers in this relationship. MR is an analytical methodology that leverages single nucleotide polymorphisms as instrumental variables to infer potential causal inferences between exposures and outcomes within observational data frameworks. Genetic variants correlated with the expression of the SLC5A2 gene and glycated hemoglobin levels (HbA1c) were selected using datasets from the Genotype-Tissue Expression project and the eQTLGen consortium. The Genome-wide association study (GWAS) data for 92 inflammatory biomarkers were obtained from two datasets, which included 14,824 and 575,531 individuals of European ancestry, respectively. GWAS data for HF was derived from a meta-analysis that combined 26 cohorts, including 47,309 HF cases and 930,014 controls. Odds ratios (ORs) and 95% confidence interval (CI) for HF were calculated per 1 unit change of HbA1c. RESULTS: Genetically predicted SGLT-2 inhibition was associated with a reduced risk of HF (OR 0.42 [95% CI 0.30-0.59], P < 0.0001). Of the 92 inflammatory biomarkers studied, two inflammatory biomarkers (C-X-C motif chemokine ligand 10 [CXCL10] and leukemia inhibitory factor) were associated with both SGLT-2 inhibition and HF. Multivariable MR analysis revealed that CXCL10 was the primary inflammatory cytokine related to HF (MIP = 0.861, MACE = 0.224, FDR-adjusted P = 0.0844). The effect of SGLT-2 inhibition on HF was mediated by CXCL10 by 17.85% of the total effect (95% CI [3.03%-32.68%], P = 0.0183). CONCLUSIONS: This study provides genetic evidence supporting the anti-inflammatory effects of SGLT-2 inhibitors and their beneficial impact in reducing the risk of HF. CXCL10 emerged as a potential mediator, offering a novel intervention pathway for HF treatment.

A new artificial intelligence system for both stomach and small bowel capsule endoscopy.

BACKGROUND AND AIMS: Despite the benefits of artificial intelligence (AI) in small bowel (SB) capsule endoscopy (CE) image reading, information on its application in the stomach and SB CE is lacking. METHODS: In this multicenter, retrospective diagnostic study, gastric imaging data were added to the deep learning (DL)-based SmartScan (SS), which has been described previously. A total of 1,069 magnetically controlled gastrointestinal (GI) CE examinations (comprising 2,672,542 gastric images) were used in the training phase for recognizing gastric pathologies, producing a new AI algorithm named SS Plus. 342 fully automated, magnetically controlled CE (FAMCE) examinations were included in the validation phase. The performance of both senior and junior endoscopists with both the SS Plus-Assisted Reading (SSP-AR) and conventional reading (CR) modes was assessed. RESULTS: SS Plus was designed to recognize 5 types of gastric lesions and 17 types of SB lesions. SS Plus reduced the number of CE images required for review to 873.90 (1000) (median, IQR 814.50-1,000) versus 44,322.73 (42,393) (median, IQR 31,722.75-54,971.25) for CR. Furthermore, with SSP-AR, endoscopists took 9.54 min (8.51) (median, IQR 6.05-13.13) to complete the CE video reading. In the 342 CE videos, SS Plus identified 411 gastric and 422 SB lesions, whereas 400 gastric and 368 intestinal lesions were detected with CR. Moreover, junior endoscopists remarkably improved their CE image reading ability with SSP-AR. CONCLUSIONS: Our study shows that the newly upgraded DL-based algorithm SS Plus can detect GI lesions and help improve the diagnostic performance of junior endoscopists in interpreting CE videos.

Intrinsic edge states and strain-tunable spin textures in the Janus 1T-VTeCl monolayer.

Using first-principles calculations and micro-magnetic simulations, we investigate the electronic structures, the effect of biaxial strain on the topological characteristics, magnetic anisotropy energy (MAE), Dzyaloshinskii-Moriya interaction (DMI) and spin textures in the Janus 1T phase VTeCl (1T-VTeCl) monolayer. Our results show that 1T-VTeCl has an intrinsic edge state, and a topological phase transition with a sizeable band gap is achieved by applying biaxial strain. Interestingly, the MAE can be switched from the in-plane to the off-plane with a compressive strain of -5%. Microscopically, the origin of MAE is mainly associated with the large spin-orbit coupling (SOC) from the heavy nonmagnetic Te atoms rather than that from the V atoms. Furthermore, the induced DMI (0.09 meV) can occur stabilizing magnetic merons without applying temperatures and magnetic fields. Then, the skyrmions, frustrated antiferromagnetism and vortex are induced after applying a suitable compressive strain. Our study provides compelling evidence that the 1T-VTeCl monolayer with topological properties holds great potential for application in spintronic devices, as well as information storage devices based on different magnetic phases achievable through strain engineering.

Electronic properties, skyrmions and bimerons in Janus CrXY (X, Y = S, Se, Te, Cl, Br, I, and X ≠ Y) monolayers.

Using first-principles calculations, we systematically investigate the electronic properties, chiral skyrmions and bimerons in two-dimensional (2D) Janus CrXY (X, Y = S, Se, Te, Cl, Br, I, and X ≠ Y) monolayers. We found that the categories of nonmagnetic atoms (X and Y in CrXY) determine whether CrXY is a ferromagnetic metal or a semiconductor. Unexpectedly, the CrBrS monolayer of these CrXY materials is a room temperature ferromagnetic semiconductor with a Curie temperature of 303 K, and it possesses an off-plane magnetic anisotropy energy of 0.06 meV. Besides, a strong Dzyaloshinskii-Moriya interaction (DMI) of 3.10 meV is found in CrTeI and is mainly induced by the strong spin-orbit coupling of the nonmagnetic atoms Te(I) rather than that of the magnetic Cr atoms. Furthermore, using micromagnetic simulations, skyrmions can be stabilized in CrSeBr without external magnetic fields. More importantly, the bimerons in CrSeCl with in-plane magnetic anisotropy can be transformed into skyrmions or a ferromagnetic state by controlling the direction of external magnetic fields. Our work investigates fourteen kinds of Janus monolayers, serving as guidelines for materials research on DMI, skyrmions and bimerons.

The potential role of circulating exosomes in protecting myocardial injury in acute myocardial infarction via regulating miR-190a-3p/CXCR4/CXCL12 pathway.

Exosomes of different origins have been found to be protective against ischemic-induced myocardial injury. This study examined the protective effects of circulating exosomes in the mice model of acute myocardial infarction (AMI) and explored the underlying molecular mechanisms. The effects of exosomes on myocardial injury were assessed in the AMI mice model. The in vivo studies showed that circulating exosomes reduced the infarcted size, improved the morphology of heart tissues and also reduced apoptosis of the heart tissues. In addition, the model mice showed an increase in the CD34 + /VEGFR2 + cell population and CD31, CXCR4 and CXCL12 expression after exosomes treatment. MiR-190a-3p was significantly down-regulated in the exosomes derived from the culture medium of hypoxia-treated human cardiomyocytes (HCMs). Further analysis revealed that miR-190a-3p could physically interact with CXCR4/CXCL12 by targeting the respective 3'UTRs. These exosomes could up-regulated CXCR4 and CXCL12 expression in the EPCs; in addition, miR-190a-3p mimics repressed CXCR4/CXCL12 expression in EPCs, while its inhibitor had opposite effects. The in vitro functional assays showed that miR-190a-3p overexpression suppressed the cell viability, proliferation, migration, adhesion and tube formation of EPCs; while miR-190a-3p inhibitor had the opposite effects; exosomes derived from the culture medium of hypoxia-treated HCMs exhibited similar actions of miR-190a-3p inhibitor. Moreover, miR-190a-3p was down-regulated in exosomes from serum in the AMI group when compared to that from sham group. Treatment with exosomes from serum in the AMI group promoted cell proliferation, migration, adhesion and tube formation of EPCs when compared to that in the sham group. More importantly, IT1t attenuated the enhanced effects of miR-190a-3p inhibition on EPC proliferation, migration, adhesion and tube formation. In conclusion, circulating exosomes exerted protective effects on myocardial injury in the AMI mice model, and down-regulation of miR-190a-3p in the circulating exosomes may exert protective effects against myocardial injury. Hypoxia induced the downregulation of miR-190a-3p in the culture medium of HCMs, and the mechanistic investigations indicated that exosomes of hypoxia-conditioned HCM culture medium promoted the cell viability, proliferation, migration, adhesion and tube formation of EPCs via regulating miR-190a-3p/CXCR4/CXCL12 pathway.

Longitudinal variation of circulating Inc-ITSN1-2: A novel biomarker reflecting disease severity, inflammation, recurrence, and death risk in acute ischemic stroke patients.

BACKGROUND: Long noncoding RNA intersectin 1-2 (lnc-ITSN1-2) regulates inflammation and neuronal apoptosis; meanwhile, the latter two factors participate in the pathogenesis of acute ischemic stroke (AIS). Therefore, this study detected lnc-ITSN1-2 at multiple time points, aiming to explore its longitudinal variation and clinical value in the management of AIS patients. METHODS: The current study enrolled 102 AIS patients, then detected their lnc-ITSN1-2 in peripheral blood mononuclear cell (PBMC) at baseline (D0), day (D)1, D3, D7, month (M)1, M3, M6, and year (Y)1 after admission using RT-qPCR. Additionally, lnc-ITSN1-2 in PBMC of 50 controls was also detected. RESULTS: Lnc-ITSN1-2 was up-regulated in AIS patients than that in controls (p < 0.001). Lnc-ITSN1-2 positively associated with NIHSS score, TNF-α, and IL-17A (all p < 0.050) but was not linked with IL-6 (p = 0.093) in AIS patients. Notably, lnc-ITSN1-2 was gradually increased from D0 to D3; while it switched to decrease from D3 to Y1 in AIS patients. Lnc-ITSN1-2 disclosed similar longitudinal variation during 1 year in non-recurrent (p < 0.001), recurrent (p = 0.001), and survived patients (p < 0.001), while the variation of lnc-ITSN1-2 in died patients was not obvious (p = 0.132). More importantly, lnc-ITSN1-2 at D0, D3, D7, M1, M3, M6, and Y1 was higher in recurrent AIS patients than that in non-recurrent AIS patients (all p < 0.050); moreover, lnc-ITSN1-2 at D3, D7, M1, M3, and M6 was up-regulated in died AIS patients than AIS survivors (all p < 0.050). CONCLUSION: The dynamic variation of Inc-ITSN1-2 could serve as a biomarker reflecting disease severity, inflammatory cytokines, recurrence, and death risk in AIS patients.

The relation of blood cell division control protein 42 level with disease risk, comorbidity, tumor features/markers, and prognosis in colorectal cancer patients.

BACKGROUND: Cell division control protein 42 (CDC42) is involved in colorectal cancer (CRC) progression by modulating CD8+ T cell activation, immune escape, and direct oncogenetic biological processes. This study aimed to explore the correlation of blood CDC42 with disease risk, comorbidities, disease features, tumor markers, and prognosis among CRC patients. METHODS: CDC42 in peripheral blood mononuclear cells was detected by reverse transcription-quantitative polymerase chain reaction from 250 resectable CRC patients and 50 healthy controls (HCs). CDC42 was divided by quartiles, as well as high and low expressions in CRC patients for correlation and survival analysis. RESULTS: CDC42 was elevated in CRC patients vs. HCs (p < 0.001), which had a good ability to distinguish CRC patients from HCs with the area under the curve (95% confidence interval) of 0.889 (0.841-0.937). In CRC patients, CDC42 was not associated with demographics or comorbidities (all p > 0.05), while its higher quartile was linked to increased T stage (p < 0.001), N stage (p = 0.009), TNM stage (p < 0.001), abnormal carcinoembryonic antigen (p = 0.043), and adjuvant chemotherapy administration (p = 0.002). Higher CDC42 quartile (p = 0.002) and CDC42 high (vs. low) (p < 0.001) were related to worse disease-free survival (DFS); meanwhile, elevated CDC42 quartile (p = 0.002) and CDC42 high (vs. low) (p = 0.001) were also linked to poor overall survival (OS). Multivariate Cox's regression analysis presented that CDC42 quartile 3 and 4 (vs. quartile 1) independently predicted declined DFS and OS (all p < 0.05). CONCLUSION: Circulating CDC42 relates to higher disease risk, T, N, and TNM stage, abnormal tumor marker, and poor prognosis among CRC patients.

The role of blood lnc-ZFAS1 in acute ischemic stroke: correlation with neurological impairment, inflammation, and survival profiles.

BACKGROUND: Long non-coding RNA zinc finger antisense 1 (lnc-ZFAS1) has been reported to inhibit neuronal damage in acute ischemic stroke (AIS). However, the role of lnc-ZFAS1 in AIS patients remains unclear. Therefore, we assessed the relationship of lnc-ZFAS1 with neurological impairment, inflammation, and prognosis in AIS patients. METHODS: Totally, 241 AIS patients and 120 controls were enrolled. lnc-ZFAS1 in peripheral blood mononuclear cells was evaluated using reverse transcription-quantitative polymerase chain reaction. Besides, a 3-year follow-up was conducted to assess recurrence-free survival (RFS) and overall survival (OS) in AIS patients. RESULTS: lnc-ZFAS1 was reduced in AIS patients compared to that in controls (Z = -10.693, p < 0.001). In AIS patients, lnc-ZFAS1 was negatively correlated with National Institutes of Health Stroke Scale score (rs  = -0.335, p < 0.001), C-reactive protein (rs  = -0.284, p < 0.001), tumor necrosis factor-alpha (rs  = -0.293, p < 0.001), interleukin-1ß (rs  = -0.149, p = 0.021), and interleukin-6 (rs  = -0.161, p = 0.012), but not underlying diseases (all p > 0.05). Besides, lnc-ZFAS1 was divided into high and low levels based on the median expression in AIS patients. Indeed, high lnc-ZFAS1 predicted better RFS (χ2  = 6.222, p = 0.013); the 1-year, 2-year, and 3-year RFS rates were 94.2%, 88.3%, and 85.5%, respectively, in patients with high lnc-ZFAS1, then 87.5%, 79.2%, and 71.6%, respectively, in those with low lnc-ZFAS1. However, lnc-ZFAS1 was not correlated with OS (χ2  = 1.404, p = 0.236); the 1-year, 2-year, and 3-year OS rates were 98.3%, 95.8%, and 94.0%, respectively, in patients with high lnc-ZFAS1, then 96.7%, 93.9%, and 89.6%, respectively, in those with low lnc-ZFAS1. CONCLUSION: Lower lnc-ZFAS1 expression is connected with increased neurological impairment and inflammation as well as worse RFS in AIS patients.

Fullerene-based 0D ferroelectrics/multiferroics for ultrahigh-density and ultrafast nonvolatile memories.

Recently, the existence of room-temperature ferroelectricity has been experimentally confirmed in a number of two-dimensional (2D) materials. With a switching barrier large enough to be stable against thermal fluctuation, ferroelectricity in even lower dimensions like 1D or 0D may be explored for data storage of higher density, which has been scarcely reported. Here, we show the first-principles design of 0D ferroelectrics/multiferroics based on polar functionalized fullerene. It turns out that the ferroelectric polarization of endohedral metallofullerenes can be reversed with the diffusion of metal ions inside when the fullerene is fixed on a substrate. If its bonding with the substrate is relatively weak, the rotation of fullerene will be more favorable in energy for ferroelectric switching. The switching barriers of both modes, for the candidates with considerable magnetic moments and dipole moments, are all in the ideal range for working under ambient conditions. Moreover, compared with conventional ferroelectrics for data storage, they may be endowed with a high areal density (∼105 Gbit per in2) and high writing speed (∼102 GHz) that are respectively more than 2 and 3 orders of magnitude higher.

Quantum Chemistry Study on Gas Reaction Mechanism in AlN MOVPE Growth.

By using the density functional theory of quantum chemistry, the gas reaction mechanism in the AlN MOVPE process has been investigated, especially after the amide DMAlNH2 formation. Two reaction paths are distinguished after the amide DMAlNH2 formation and oligomerization: the intramolecular path and the intermolecular path, both involved with methane elimination. By inspections of the changes of the Gibbs energy ΔG between products and reactants, as well as the Gibbs energy of activation divided by RT, ΔG*/RT, to account for thermal activation at different temperatures, the most probable gas reaction paths, and gas products for AlN thin film growth are determined both thermodynamically and kinetically. Our results indicate that under metal organic vapor phase epitaxy condition, for the intramolecular path, (MMAlNH)2 is the most probable gas reaction products; for the intermolecular path, both Al(NH2)3 and (AlNHNH2)2 are the most probable gas reaction products. We also prove that (AlN)2 and (AlN)3 clusters are thermodynamically unfavored in the gas phase.

Sodium bismuth dichalcogenides: candidates for ferroelectric high-mobility semiconductors for multifunctional applications.

The combination of ferroelectricity with narrow-gap high-mobility semiconductors may not only entail both functions of nonvolatile memory and efficient manipulation of signals, but may also facilitate efficient ferroelectric photovoltaics and thermoelectrics. However, these applications are hindered by the wide gap and poor mobility of current ferroelectrics. A recent study (J. Am. Chem. Soc., 2018, 140, 3736) reported a facile, general, low-temperature, and size tunable solution phase synthesis of NaBiS2 and NaBiSe2 that are made of relatively abundant or biocompatible elements, which enables their large-scale practical applications. Herein we show first-principles evidence of their ferroelectricity with a large polarization (∼33 µC cm-2), a moderate bandgap (∼1.6 eV) and a high electron-mobility (∼104 cm2 V-1 s-1). Although they have a relatively small switching barrier, their ferroelectricity can be robust under ambient conditions with enhanced polarization upon either application of a small tensile strain or ion doping, where distortion can be increased and multiferroics may also be obtained, despite reduced mobility. Considering previous reports on photovoltaics and thermoelectrics of similar compounds, sodium bismuth dichalcogenides might be tuned for higher performance with the coexistence of these desirable properties.

Physical interaction between human ribonucleotide reductase large subunit and thioredoxin increases colorectal cancer malignancy.

Ribonucleotide reductase (RR) is the rate-limiting enzyme in DNA synthesis, catalyzing the reduction of ribonucleotides to deoxyribonucleotides. During each enzymatic turnover, reduction of the active site disulfide in the catalytic large subunit is performed by a pair of shuttle cysteine residues in its C-terminal tail. Thioredoxin (Trx) and glutaredoxin (Grx) are ubiquitous redox proteins, catalyzing thiol-disulfide exchange reactions. Here, immunohistochemical examination of clinical colorectal cancer (CRC) specimens revealed that human thioredoxin1 (hTrx1), but not human glutaredoxin1 (hGrx1), was up-regulated along with human RR large subunit (RRM1) in cancer tissues, and the expression levels of both proteins were correlated with cancer malignancy stage. Ectopically expressed hTrx1 significantly increased RR activity, DNA synthesis, and cell proliferation and migration. Importantly, inhibition of both hTrx1 and RRM1 produced a synergistic anticancer effect in CRC cells and xenograft mice. Furthermore, hTrx1 rather than hGrx1 was the efficient reductase for RRM1 regeneration. We also observed a direct protein-protein interaction between RRM1 and hTrx1 in CRC cells. Interestingly, besides the known two conserved cysteines, a third cysteine (Cys779) in the RRM1 C terminus was essential for RRM1 regeneration and binding to hTrx1, whereas both Cys32 and Cys35 in hTrx1 played a counterpart role. Our findings suggest that the up-regulated RRM1 and hTrx1 in CRC directly interact with each other and promote RR activity, resulting in enhanced DNA synthesis and cancer malignancy. We propose that the RRM1-hTrx1 interaction might be a novel potential therapeutic target for cancer treatment.

ATR-CHK1-E2F3 signaling transactivates human ribonucleotide reductase small subunit M2 for DNA repair induced by the chemical carcinogen MNNG.

BACKGROUND: N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), an alkylating agent and an environmental carcinogen, causes DNA lesions and even carcinomas. DNA damage responses induced by MNNG activate various DNA repair genes and related signaling pathways. The present study aimed to investigate the regulatory mechanisms of human RR small subunit M2 (hRRM2) in response to MNNG. RESULTS: In this study, we demonstrated that the RRM2 gene was transactivated by MNNG exposure more strongly than the other small subunit, p53R2. The upregulated RRM2 translocated to the nucleus for DNA repair. Further study showed that E2F3 transactivated RRM2 expression by directly binding to its promoter after MNNG exposure. The transactivation was enhanced by the upregulation of NFY, which bound to the RRM2 promoter adjacent to the E2F3 binding site and interacted with E2F3. In response to MNNG treatment, E2F3 accumulated mainly through its phosphorylation at S124 and was dependent on ATR-CHK1 signaling. In comparison, p53R2 played a relatively weaker role in the MNNG-induced DNA damage response, and its transcription was regulated by the ATR-CHK2-E2F1/p53 pathway. CONCLUSIONS: We suggest that MNNG-stimulated ATR/CHK1 signaling stabilizes E2F3 by S124 phosphorylation, and then E2F3 together with NFY co-transactivate RRM2 expression for DNA repair. GENERAL SIGNIFICANCE: We propose a new mechanism for RRM2 regulation to maintain genome stability in response to environmental chemical carcinogens.

Apelin promotes mesenchymal stem cells survival and vascularization under hypoxic-ischemic condition in vitro involving the upregulation of vascular endothelial growth factor.

BACKGROUND: Mesenchymal stem cells (MSCs) transplantation has been regarded as an optimal therapeutic approach for cardiovascular disease. However, the inferior survival and low vascularization potential of these cells in the local infarct site reduce the therapeutic efficacy. In this study, we investigated the influence of apelin on MSCs survival and vascularization under hypoxic-ischemic condition in vitro and explored the relevant mechanism. METHODS: MSCs were obtained from C57BL/6 mice and cultured in vitro. Cells of the third passage were divided into MSCs and MSCs+apelin groups. In the MSCs+apelin group, MSCs were stimulated with apelin-13 (5µM). The two groups experienced exposure to hypoxia (1% O2) and serum deprivation for 24h, using normoxia (20% O2) as a negative control during the process. Human umbilical vein endothelial cells (HUVECs) were used and incubated with conditioned media from both groups to promote vascularization for another 6h. Vascular densities were assessed and relevant biomarkers were detected thereafter. RESULTS: Compared with MSCs group, MSCs+apelin group presented more rapid growth. The proliferation rate was much higher. Cells apoptosis percentage was significantly declined both under normoxic and hypoxic conditions. Media produced from MSCs+apelin group triggered HUVECs to form a larger number of vascular branches on matrigel. The expression and secretion of vascular endothelial growth factor (VEGF) were significantly increased. CONCLUSION: Apelin could effectively promote MSCs survival and vascularization under hypoxic-ischemic condition in vitro, and this procedure was associated with the upregulation of VEGF. This study provides a new perspective for exploring novel approaches to enhance MSCs survival and vascularization potential.

Correlation analysis of renal ultrasound elastography and clinical and pathological changes in patients with chronic kidney disease
.

OBJECTIVE: To analyze the correlations of renal tissue elastography with clinical biochemical indicators and pathological changes in patients with chronic kidney disease (CKD) as well as to explore the potential for renal tissue elastography as a new, noninvasive method for the dynamic monitoring of renal disease progression, efficacy assessment, and prognosis evaluation. METHODS: Patients admitted to the Department of Nephrology of the First Affiliated Hospital of China Medical University from August 2014 to January 2015 who had undergone renal biopsies were selected. A total of 113 patients with CKD and 16 healthy controls were enrolled in this study, including 61 males and 52 females. In total, 23 cases of IgA nephropathy, 39 cases of membranous nephropathy, 15 cases of minimal-change nephropathy (MCN), and 7 cases of focal segmental glomerulosclerosis were included. The Young's moduli (YM) of the renal cortex and medulla were measured using an AixPlorer Doppler ultrasound with full digital color from Supersonic Imagine. The correlations between the YM of renal tissue and clinical biochemical indicators of blood and urine and the differences in Young's moduli among the different pathological changes in the patients with CKD were analyzed. RESULTS: The YM of the CKD patients was significantly higher than that of the control group (p < 0.05), and the YM of the renal cortex and medulla gradually increased with the progression of CKD. The YM of the renal cortex in the stage-G5 CKD patients was significantly higher than that of the CKD patients in stages G1 - G3 (p < 0.05). The YM of the renal medulla of the CKD patients in stages G3 - 5 was significantly higher than that of the CKD patients in stages G1 - G2. On univariate analysis, the YM of the renal cortex was correlated with systolic blood pressure, serum creatinine, cystatin C, serum albumin, serum phosphorus, calcium and phosphorus products, uric acid, iPTH, urinary N-acetyl-glucosaminidase (NAG), eGFR, and hemoglobin levels. And the YM of the renal medulla was correlated with systolic blood pressure, serum creatinine, serum albumin, uric acid, iPTH, urinary microalbumin (MA), urinary NAG, and hemoglobin levels. On multivariate analysis, serum cystatin C (ß = 0.485, p = 0.018) and uric acid (ß = 0.418, p = 0.039) levels were independently correlated with the YM of the renal cortex, while serum creatinine (ß = 0.380, p = 0.019) and uric acid (ß = 0.482, p = 0.004) levels, as well as smoking (ß = 0.337, p = 0.009), were independently correlated with the YM of the renal medulla. The YMs of the renal cortex in patients with membranous nephropathy and IgA nephropathy were significantly higher than those in the patients with CN (p < 0.05). The YM of the renal cortices of the patients in phases IV and V of IgA nephropathy based on the Lee grading system were significantly higher than those of the patients in phases II and III (p < 0.05). According to the Oxford classification for IgA nephropathy, the Young's moduli of the renal cortex and medulla in T1 and T2 patients were significantly higher than those in T0 patients (p < 0.05). The YM of the renal cortex and medulla showed no statistically-significant differences among the different stages of membranous nephropathy. CONCLUSIONS: The YM of the renal cortex and medulla are associated with the progression of renal insufficiency, and renal ultrasound elastography shows promise as a new means of assessing the stage of CKD. Renal ultrasound elastography is expected to become a new, noninvasive method for the early diagnosis of CKD and the dynamic monitoring of disease progression as well as the assessment of efficacy and prognosis.
.

Long noncoding RNAs: Novel molecules in cardiovascular biology, disease and regeneration.

Remarkable breakthroughs made in genomic technologies have facilitated the discovery of thousands of novel transcripts that do not template protein synthesis. Numerous RNAs termed as long noncoding RNAs (lncRNAs) generated from this pervasive transcription function vividly in gene regulatory networks and a variety of biological and cellular processes. Here, we make a brief description of the known and putative functions of lncRNAs in cardiovascular biology and disease. The association between lncRNAs and stem cells mediated cardiomyocytes differentiation and neovascularization is discussed then. It will provide a new clue for further studies on these novel molecules in cardiovascular disease and bring bright prospects for their future applications in cardiac regenerative medicine.

Cardiac stem cells transplantation enhances the expression of connexin 43 via the ANG II/AT1R/TGF-beta1 signaling pathway in a rat model of myocardial infarction.

BACKGROUND: In this study, we hypothesized that CSCs mediated the expression of Cx43 after transplantation post MI via the ANG II/AT1R/TGF-beta1 signaling pathway. METHODS: Myocardial infarction (MI) was induced in twenty male Sprague-Dawley rats. The rats were randomized into two groups and were then received the injection of 5 × 10(6) CSCs labeled with PKH26 in phosphate buffer solution (PBS) or equal PBS alone into the infarct anterior ventricular free wall two weeks after MI. Six weeks later, relevant signaling molecules involved were all examined. RESULTS: In the CSCs group, an increased expression of Cx43 could be observed in different zones of the left ventricle (P<0.01). There was a significant reduction of the angiotensin II (ANG II) level in plasma and different regions of the left ventricular cardiac tissues (P<0.05; P<0.01). The angiotensin II type I receptor (AT1R) was decreased accompanied with an enhanced expression of angiotensin II type II receptor (AT2R) (P<0.01). Transforming growth factor beta-1(TGF-beta1) was downregulated (P<0.01). The expression of mothers against decapentaplegic homolog (SMAD) proteins including SMAD2 and SMAD3 was attenuated whereas SMAD7 was elevated (P<0.01, P<0.01, P<0.05). In addition, the expression of mitogen-activated protein kinases (MAPKs) including extracellular kinases 1/2 (ERK1/2) and p38 was also found to be reduced (P<0.01). CONCLUSION: CSCs transplantation could enhance the level of Cx43 after MI. They might function through intervening the ANGII/AT1R/TGF-beta1 signaling pathway to regulate the expression of Cx43.

Significant Association between Carotid Artery Kinking and Leukoaraiosis in Middle-Aged and Elderly Chinese Patients.

BACKGROUND: Leukoaraiosis (LA) and carotid artery morphologic variations are 2 common imaging manifestations. The purpose of this study was to determine whether carotid artery morphologic variations are correlated with LA. METHODS: A total of 702 patients, aged 50 years or older, admitted to our hospital from November 1, 2013, to January 30, 2014, were prospectively enrolled in this study. All participants underwent magnetic resonance imaging to assess the presence and severity of LA. Carotid artery morphologic variations were classified into tortuosity, kinking, and coiling by computed tomography angiography. Logistic regression analyses were performed to examine the relationship between carotid artery morphologic variations, its components, and LA. RESULTS: The frequency of hemisphere with LA and carotid artery with carotid artery morphologic variations was 49.9% and 70.3% in the cohort, respectively. Carotid kinking was associated with an increased risk of ipsilateral LA after multivariable adjustment (odds ratio [OR], 2.29; 95% confidence interval [CI], 1.57-3.36 for left side; OR, 2.51; 95% CI: 1.68-3.74 for right side), whereas carotid tortuosity and coiling were not related to LA. Moreover, the prevalence of carotid kinking gradually increased with advancing grades of ipsilateral LA. CONCLUSIONS: The present study demonstrated that carotid artery kinking may be associated with an increased risk of LA in middle-aged and elderly Chinese patients. Further prospective studies are needed to confirm these findings.