DNA methylation and lipid metabolism are involved in GA-induced maize aleurone layers PCD as revealed by transcriptome analysis.

BACKGROUND: The aleurone layer is a part of many plant seeds, and during seed germination, aleurone cells undergo PCD, which is promoted by GA from the embryo. However, the numerous components of the GA signaling pathway that mediate PCD of the aleurone layers remain to be identified. Few genes and transcriptomes have been studied thus far in aleurone layers to improve our understanding of how PCD occurs and how the regulatory mechanism functions during PCD. Our previous studies have shown that histone deacetylases (HDACs) are required in GA-induced PCD of aleurone layer. To further explore the molecular mechanisms by which epigenetic modifications regulate aleurone PCD, we performed a global comparative transcriptome analysis of embryoless aleurones treated with GA or histone acetylase (HAT) inhibitors. RESULTS: In this study, a total of 7,919 differentially expressed genes (DEGs) were analyzed, 2,554 DEGs of which were found to be common under two treatments. These identified DEGs were involved in various biological processes, including DNA methylation, lipid metabolism and ROS signaling. Further investigations revealed that inhibition of DNA methyltransferases prevented aleurone PCD, suggesting that active DNA methylation plays a role in regulating aleurone PCD. GA or HAT inhibitor induced lipoxygenase gene expression, leading to lipid degradation, but this process was not affected by DNA methylation. However, DNA methylation inhibitor could regulate ROS-related gene expression and inhibit GA-induced production of hydrogen peroxide (H2O2). CONCLUSION: Overall, linking of lipoxygenase, DNA methylation, and H2O2 may indicate that GA-induced higher HDAC activity in aleurones causes breakdown of lipids via regulating lipoxygenase gene expression, and increased DNA methylation positively mediates H2O2 production; thus, DNA methylation and lipid metabolism pathways may represent an important and complex signaling network in maize aleurone PCD.

ASPN Synergizes with HAPLN1 to Inhibit the Osteogenic Differentiation of Bone Marrow Mesenchymal Stromal Cells and Extracellular Matrix Mineralization of Osteoblasts.

OBJECTIVE: Bone marrow mesenchymal stromal cells (BMSCs) are major sources of osteogenic precursor cells in bone remodeling, which directly participate in osteoporosis (OP) progression. However, the involved specific mechanisms of BMSCs in OP warrant mass investigations. Initially, our bioinformatics analysis uncovered the prominent up-regulation of Asporin (ASPN) and proteoglycan link protein 1 (HAPLN1) in osteoblasts (OBs) of OP patients and their possible protein interaction. Hence, this study aimed to explore the effects of ASPN and HAPLN1 on osteogenic differentiation of BMSCs, extracellular matrix (ECM) mineralization of OBs, and osteoclastogenesis, hoping to offer research basis for OP treatment. METHODS: GSE156508 dataset was used for analysis and screening to acquire the differentially expressed genes in OBs of OP patients, followed by the predicative analysis via STRING. OP mouse models were induced by ovariectomy (OVX), and ASPN and HAPLN1 expression was determined. BMSCs and bone marrow macrophages (BMMs) were isolated from OVX mice and induced for osteogenic differentiation and osteoclastogenesis, respectively. After knockdown experiments, we assessed adipogenic differentiation and osteogenic differentiation in BMSCs. Osteogenic (OPN, OCN, and COL1A1) and osteoclast (Nfatc1 and c-Fos) marker protein expression was determined. The binding of ASPN to HAPLN1 was analyzed. RESULTS: High expression of ASPN and HAPLN1 and their protein interaction were observed in OBs of OP patients via bioinformatics and in bone tissues of OVX mice. ASPN interacted with HAPLN1 in BMSCs of OVX mice. ASPN/HAPLN1 knockdown increased ALP, OPN, OCN, and COL1A1 protein expression and ECM mineralization in BMSCs while decreasing Nfatc1 and c-Fos expression in BMMs. These effects were aggravated by the simultaneous knockdown of ASPN and HAPLN1. CONCLUSION: Our results indicate that ASPN synergises with HAPLN1 to suppress the osteogenic differentiation of BMSCs and ECM mineralization of OBs and promote the osteoclastogenesis in OP.

The CHCHD2/Sirt1 corepressors involve in G9a-mediated regulation of RNase H1 expression to control R-loop.

R-loops are regulators of many cellular processes and are threats to genome integrity. Therefore, understanding the mechanisms underlying the regulation of R-loops is important. Inspired by the findings on RNase H1-mediated R-loop degradation or accumulation, we focused our interest on the regulation of RNase H1 expression. In the present study, we report that G9a positively regulates RNase H1 expression to boost R-loop degradation. CHCHD2 acts as a repressive transcription factor that inhibits the expression of RNase H1 to promote R-loop accumulation. Sirt1 interacts with CHCHD2 and deacetylates it, which functions as a corepressor that suppresses the expression of downstream target gene RNase H1. We also found that G9a methylated the promoter of RNase H1, inhibiting the binding of CHCHD2 and Sirt1. In contrast, when G9a was knocked down, recruitment of CHCHD2 and Sirt1 to the RNase H1 promoter increased, which co-inhibited RNase H1 transcription. Furthermore, knockdown of Sirt1 led to binding of G9a to the RNase H1 promoter. In summary, we demonstrated that G9a regulates RNase H1 expression to maintain the steady-state balance of R-loops by suppressing the recruitment of CHCHD2/Sirt1 corepressors to the target gene promoter.

Establishment and validation of a clinical nomogram model based on serum YKL-40 to predict major adverse cardiovascular events during hospitalization in patients with acute ST-segment elevation myocardial infarction.

Objective: This study aimed to investigate the predictive value of a clinical nomogram model based on serum YKL-40 for major adverse cardiovascular events (MACE) during hospitalization in patients with acute ST-segment elevation myocardial infarction (STEMI). Methods: In this study, 295 STEMI patients from October 2020 to March 2023 in the Second People's Hospital of Hefei were randomly divided into a training group (n = 206) and a validation group (n = 89). Machine learning random forest model was used to select important variables and multivariate logistic regression was included to analyze the influencing factors of in-hospital MACE in STEMI patients; a nomogram model was constructed and the discrimination, calibration, and clinical effectiveness of the model were verified. Results: According to the results of random forest and multivariate analysis, we identified serum YKL-40, albumin, blood glucose, hemoglobin, LVEF, and uric acid as independent predictors of in-hospital MACE in STEMI patients. Using the above parameters to establish a nomogram, the model C-index was 0.843 (95% CI: 0.79-0.897) in the training group; the model C-index was 0.863 (95% CI: 0.789-0.936) in the validation group, with good predictive power; the AUC (0.843) in the training group was greater than the TIMI risk score (0.648), p < 0.05; and the AUC (0.863) in the validation group was greater than the TIMI risk score (0.795). The calibration curve showed good predictive values and observed values of the nomogram; the DCA results showed that the graph had a high clinical application value. Conclusion: In conclusion, we constructed and validated a nomogram based on serum YKL-40 to predict the risk of in-hospital MACE in STEMI patients. This model can provide a scientific reference for predicting the occurrence of in-hospital MACE and improving the prognosis of STEMI patients.

Association of CHA2DS2-VASC Score with in-Hospital Cardiovascular Adverse Events in Patients with Acute ST-Segment Elevation Myocardial Infarction.

Background: Acute ST-elevation myocardial infarction (STEMI) is a common clinical critical illness, and accurate, reliable, simple, and easy-to-remember tools are needed in clinical practice to quickly identify the risk of this condition in STEMI patients. This study investigates the predictive value of the admission CHA2DS2-VASc score for in-hospital MACE in STEMI patients. Methods: A total of 210 STEMI patients who visited the Chest Pain Center of the Second People's Hospital of Hefei from December 2019 to December 2021 were retrospectively analyzed. They were divided into MACE and non-MACE groups. The receiver operating characteristic curve (ROC) was used to assess the predictive value of the CHA2DS2-VASc score for MACE events during hospitalization. Results: The CHA2DS2-VASc score was higher in the MACE group than in the non-MACE group (P < 0.05), and multivariate logistic regression analysis showed that the CHA2DS2-VASc score was an independent risk factor for MACE events during hospitalization in STEMI patients (OR = 1.391, 95%CI 1.044-1.853, P=0.024); ROC curve analysis showed that the area under the curve (AUC) of the CHA2DS2-VASc score was 0.744, the sensitivity was 0.64, the specificity was 0.694, and the optimal cutoff value was 3.5 in predicting the risk of MACE events during hospitalization in STEMI patients. There were no significant differences between the GRACE score (0.744 VS.0.827) and TIMI score (0.744VS.0.745) (P > 0.05). Conclusion: The CHA2DS2-VASc score can successfully predict the occurrence of in-hospital MACE events in STEMI patients.

The Value of Serum YKL-40 and TNF-α in the Diagnosis of Acute ST-Segment Elevation Myocardial Infarction.

Background: Acute ST-segment elevation myocardial infarction (STEMI) is a serious cardiovascular disease that poses a great threat to the life and health of patients. Therefore, early diagnosis is important for STEMI patient treatment and prognosis. The purpose of this study was to investigate the value of serum YKL-40 and TNF-α in the diagnosis of STEMI. Methods: From October 2020 to February 2022, 120 patients with STEMI were admitted to the Chest Pain Center of the Second People's Hospital of Hefei, and 81 patients with negative coronary angiography were selected as the control group. Serum YKL-40 and TNF-α concentrations were measured by sandwich ELISA. Pearson correlation was used to analyze the correlation between serum YKL-40, TNF-α, and serum troponin I (cTnI) in STEMI patients; multivariate logistic regression analysis was used to screen independent risk factors for STEMI. Three diagnostic models were constructed: cTnI univariate model (model A), combined serum YKL-40 and TNF-α model other than cTnI (model B), and combined cTnI and serum YKL-40 and TNF-α model (model C). We assessed the clinical usefulness of the diagnostic model by comparing AUC with decision curve analysis (DCA). Results: Serum YKL-40 and TNF-α in the STEMI group were significantly higher than those in the control group (P < 0.001). On Pearson correlation analysis, there was a significant positive correlation between serum YKL-40, TNF-α, and cTnI levels in STEMI patients. Multivariate logistic regression analysis showed that serum YKL-40 and TNF-α were independent risk factors for the development of STEMI. The results of ROC analysis showed that the area under the curve (AUC) of serum YKL-40 for predicting the occurrence of STEMI was 0.704. The AUC of serum TNF-α for predicting the occurrence of STEMI was 0.852. The AUC of cTnI as a traditional model, model A, for predicting the occurrence of STEMI was 0.875. Model B predicted STEMI with an AUC of 0.851. The addition of serum YKL-40 and serum TNF-α to the traditional diagnostic model composed of cTnI constituted a new diagnostic model; that is, the AUC of model C for predicting the occurrence of STEMI was 0.930. Model C had a better net benefit between a threshold probability of 70-95% for DCA. Conclusion: In this study, we demonstrate the utility of serum YKL-40 and TNF-α as diagnostic markers for STEMI and the clinical utility of diagnostic models by combining serum YKL-40 and TNF-α with cTnI.

The histone deacetylase 1/GSK3/SHAGGY-like kinase 2/BRASSINAZOLE-RESISTANT 1 module controls lateral root formation in rice.

Lateral roots (LRs) are a main component of the root system of rice (Oryza sativa) that increases root surface area, enabling efficient absorption of water and nutrients. However, the molecular mechanism regulating LR formation in rice remains largely unknown. Here, we report that histone deacetylase 1 (OsHDAC1) positively regulates LR formation in rice. Rice OsHDAC1 RNAi plants produced fewer LRs than wild-type plants, whereas plants overexpressing OsHDAC1 exhibited increased LR proliferation by promoting LR primordia formation. Brassinosteroid treatment increased the LR number, as did mutation of GSK3/SHAGGY-like kinase 2 (OsGSK2), whereas overexpression of OsGSK2 decreased the LR number. Importantly, OsHDAC1 could directly interact with and deacetylate OsGSK2, inhibiting its activity. OsGSK2 deacetylation attenuated the interaction between OsGSK2 and BRASSINAZOLE-RESISTANT 1 (OsBZR1), leading to accumulation of OsBZR1. The overexpression of OsBZR1 increased LR formation by regulating Auxin/IAA signaling genes. Taken together, the results indicate that OsHDAC1 regulates LR formation in rice by deactivating OsGSK2, thereby preventing degradation of OsBZR1, a positive regulator of LR primordia formation. Our findings suggest that OsHDAC1 is a breeding target in rice that can improve resource capture.

Construction and evaluation of nomogram model for individualized prediction of risk of major adverse cardiovascular events during hospitalization after percutaneous coronary intervention in patients with acute ST-segment elevation myocardial infarction.

Background: Emergency percutaneous coronary intervention (PCI) in patients with acute ST-segment elevation myocardial infarction (STEMI) helps to reduce the occurrence of major adverse cardiovascular events (MACEs) such as death, cardiogenic shock, and malignant arrhythmia, but in-hospital MACEs may still occur after emergency PCI, and their mortality is significantly increased once they occur. The aim of this study was to investigate the risk factors associated with MACE during hospitalization after PCI in STEMI patients, construct a nomogram prediction model and evaluate its effectiveness. Methods: A retrospective analysis of 466 STEMI patients admitted to our hospital from January 2018 to June 2022. According to the occurrence of MACE during hospitalization, they were divided into MACE group (n = 127) and non-MACE group (n = 339), and the clinical data of the two groups were compared; least absolute shrinkage and selection operator (LASSO) regression was used to screen out the predictors with non-zero coefficients, and multivariate Logistic regression was used to analyze STEMI Independent risk factors for in-hospital MACE in patients after emergency PCI; a nomogram model for predicting the risk of in-hospital MACE in STEMI patients after PCI was constructed based on predictive factors, and the C-index was used to evaluate the predictive performance of the prediction model; the Bootstrap method was used to repeat sampling 1,000 Internal validation was carried out for the second time, the Hosmer-Lemeshow test was used to evaluate the model fit, and the calibration curve was drawn to evaluate the calibration degree of the model. Receiver operating characteristic (ROC) curves were drawn to evaluate the efficacy of the nomogram model and thrombolysis in myocardial infarction (TIMI) score in predicting in-hospital MACE in STEMI patients after acute PCI. Results: The results of LASSO regression showed that systolic blood pressure, diastolic blood pressure, Killip grade II-IV, urea nitrogen and left ventricular ejection fraction (LVEF), IABP, NT-ProBNP were important predictors with non-zero coefficients, and multivariate logistic regression analysis was performed to analyze that Killip grade II-IV, urea nitrogen, LVEF, and NT-ProBNP were independent factors for in-hospital MACE after PCI in STEMI patients; a nomogram model for predicting the risk of in-hospital MACE after PCI in STEMI patients was constructed with the above independent predictors, with a C-index of 0.826 (95% CI: 0.785-0.868) having a good predictive power; the results of H-L goodness of fit test showed χ2 = 1.3328, P = 0.25, the model calibration curve was close to the ideal model, and the internal validation C-index was 0.818; clinical decision analysis also showed that the nomogram model had a good clinical efficacy, especially when the threshold probability was 0.1-0.99, the nomogram model could bring clinical net benefits to patients. The nomogram model predicted a greater AUC (0.826) than the TIMI score (0.696) for in-hospital MACE after PCI in STEMI patients. Conclusion: Urea nitrogen, Killip class II-IV, LVEF, and NT-ProBNP are independent factors for in-hospital MACE after PCI in STEMI patients, and nomogram models constructed based on the above factors have high predictive efficacy and feasibility.

Histone acetylation of 45S rDNA correlates with disrupted nucleolar organization during heat stress response in Zea mays L.

The role of the nucleolus in plant response to heat stress remains largely obscure. Our current efforts focused on exploring the underlying mechanism by which nucleolar disorganization is regulated in heat stressed-maize lines. Here, two maize lines, a heat-sensitive line, ZD958, and a heat-tolerant line, ZDH, were submitted to heat stress for investigating their association with the nucleolar disruption. Immunofluorescence staining showed that nucleolar disruption increased with prolonged treatment time. After heat treatment, a significant change in nucleolus organization was observed in the ZD958 line, but the ZDH line showed mild alteration. Moreover, actinomycin D (ActD)-induced nucleolus fission led to inhibition of maize growth under the normal condition. The ZD958 line exhibited a significant increase in the level of H3K9ac and H4K5ac of the 45S rDNA accompanied by a higher transcription of the 5'-external transcribed spacer (ETS) region, while the line ZDH showed a slight increase in histone acetylation levels and the transcriptional initiation at this site after heat treatment. To our knowledge, this is the first report providing a comparative insight between heat stress, rDNA histone modifications, and nucleolus disintegration in a heat-tolerant ZDH compared with a heat-sensitive line ZD958. Our investigation might assist maize breeders in obtaining heat-tolerant lines by targeting nucleoli using epigenetics.

Characteristic and evolution of HAT and HDAC genes in Gramineae genomes and their expression analysis under diverse stress in Oryza sativa.

MAIN CONCLUSION: Comprehensive characterization of Gramineae HATs and HDACs reveals their conservation and variation. The recent WGD/SD gene pairs in the CBP and RPD/HDA1 gene family may confer specific adaptive evolutionary changes. Expression of OsHAT and OsHDAC genes provides a new vision in different aspects of development and response to diverse stress. The histone acetylase (HAT) and histone deacetylase (HDAC) have been proven to be tightly linked to play a crucial role in plant growth, development and response to abiotic stress by regulating histone acetylation levels. However, the evolutionary dynamics and functional differentiation of HATs and HDACs in Gramineae remain largely unclear. In the present study, we identified 37 HAT genes and 110 HDAC genes in seven Gramineae genomes by a detailed analysis. Phylogenetic trees of these HAT and HDAC proteins were constructed to illustrate evolutionary relationship in Gramineae. Gene structure, protein property and protein motif composition illustrated the conservation and variation of HATs and HDACs in Gramineae. Gene duplication analysis suggested that recent whole genome duplication (WGD)/segmental duplication (SD) events contributed to the diversification of the CBP and RPD3/HDA1 gene family in Gramineae. Furthermore, promoter cis-element prediction indicated that OsHATs and OsHDACs were likely functional proteins and involved in various signaling pathways. Expression analysis by RNA-seq data showed that all OsHAT and OsHDAC genes were expressed in different tissues or development stages, revealing that they were ubiquitously expressed. In addition, we found that their expression patterns were altered in response to cold, drought, salt, light, abscisic acid (ABA), and indole-3-acetic acid (IAA) treatments. These findings provide the basis for further identification of candidate OsHAT and OsHDAC genes that may be utilized in regulating growth and development and improving crop tolerance to abiotic stress.

Higher serum level of Cystatin C: An additional risk factor of CAD.

ABSTRACT: Cystatin C has been proposed as a useful biomarker of early impaired kidney function and a predictor of mortality risk. The present study is to investigate the association between serum Cystatin C and the severity of coronary artery lesions, Gensini score (GS), and the risk of coronary artery disease (CAD).A total of 682 CAD patients (230 females, 452 males; mean age 62.6 ±â€Š10.7 years, range from 31 to 86 years) and 135 controls (41 females, 94 males; mean age 58.0 ±â€Š10.3 years, range from 38 to 84 years) were recruited in the present study. Enzyme-linked immunosorbent assay was applied to measure serum cystatin C levels and other serum indexes. The estimated glomerular filtration rate and GS were calculated.Serum low-density lipoprotein cholesterol (LDL-C), uric acid, Cystatin C, and homocysteine (HCY) were significantly elevated in CAD patients compared to controls. There were significant differences regarding total cholesterol, triglyceride, high-density lipoprotein, low-density lipoprotein, cystatin C, eGFR and GS among stable angina pectoris (SAP), unstable angina group (UAP), and acute myocardial infarction (AMI) patients. AMI group had an elevated serum Cystatin C, LDL-C, HCY, and GS than SAP and UAP patients. When stratified patient groups by the quartiles of Cystatin C, we found age, the proportion of male and patients with diabetes, HCY, and GS were increased in Q4 than in other quartile groups. Spearman correlation test revealed a positive relationship between Cystatin C, HCY, and GS. Multivariate logistic regression analysis revealed that serum Cystatin C level, presence of hypertension and diabetes, HCY, age, and male were the risk factors for coronary artery lesions.In summary, our results suggested that cystatin C is a promising clinical biomarker that provides complementary information to the established risk determinants. The serum Cystatin C level is strongly associated with GS and could be used to evaluate the severity of coronary artery lesions.

Effects of intragastric administration of La2O3 nanoparticles on mouse testes.

Lanthanum oxide (La2O3) nanoparticles (NPs) have been widely used in photoelectric and catalytic applications. However, their exposure and reproductive toxicity is unknown. In this study, the effect of the intragastric administration of two different-sized La2O3 particles in the testes of mice for 60 days was investigated. Although the body weight of mice treated or not treated with La2O3 NPs was not different and La2O3 NPs were distributed in the organs including the testis, liver, kidney, spleen, heart and brain. La2O3 NPs accumulate more than micro-sized La2O3 (MPs) in mice testes. The histopathological evaluation showed that moderate reproductive toxicity induced by La2O3 NPs in the testicle tissues. Furthermore, increased MDA, 8-OHdG levels and decreased SOD activities were detected in the La2O3 NP-treated groups. Moreover, qRT-PCR and western blotting data indicated that La2O3 NPs affecting the blood-testis barrier (BTB)-related genes in mice testes. Taken together, these findings suggested that La2O3 NPs activated inflammation responses and cross the BTB in the murine testes. This study provided useful information for risk analysis and regulation of La2O3 NPs by administrative agencies.

Protective effect of astaxanthin against La2O3 nanoparticles induced neurotoxicity by activating PI3K/AKT/Nrf-2 signaling in mice.

Lanthanum oxide nanoparticles (La2O3 NPs) are used in photoelectric and catalytic applications. Astaxanthin (ASX) is a red carotenoid pigment with antioxidant and anti-inflammatory properties, and the antioxidant activities promote neuroprotection. This study explored the effect of ASX supplementation on La2O3 NP-induced neurotoxicity in mice and the molecular mechanisms of such protective effects. Amongst our findings, we determined that ASX treatment significantly attenuated La2O3 NP-induced behavioural abnormalities, histopathological evidence of hippocampal injury and ultrastructural changes in the CA1 region of the hippocampus. ASX treatment also markedly inhibited the production of ROS and activated PI3K/AKT signaling, which facilitated the nuclear translocation of Nrf-2 and reversed the down-regulation of HO-1, NQO1 and GCLM proteins in the hippocampus that were induced by sub-chronic exposure to La2O3 NPs. Administration of ASX to mice receiving La2O3 NPs also resulted in decreased expression of iNOS, IL-1ß, TNF-α, COX-2, Bax and Caspase-3 and in increased expression of BDNF, NGF and Bcl-2 observed in response to La2O3 NPs. In conclusion, ASX had a markedly protective effect against the negative sequelae associated with La2O3 NP-induced neurotoxicity. This may result from the activation of the PI3K/AKT/Nrf-2 signaling and via the inhibition of oxidative stress, neuroinflammation and cellular apoptosis.

Betaine Alleviates Cognitive Deficits in Diabetic Rats via PI3K/Akt Signaling Pathway Regulation.

BACKGROUND: Diabetes mellitus is a metabolic disease which also causes cognitive deficits. Betaine (N,N,N-trimethylglycine), also known as trimethylglycine, has been shown to ameliorate diabetic symptoms in diabetic animals and improve cognitive ability in Alzheimer disease (AD) animals. However, the effects of betaine on cognitive deficits in diabetic animals have not been described yet. Therefore, in the current study, the effects of betaine on cognition in diabetic rats were evaluated. METHODS: We established a diabetic rat model by injecting streptozotocin (STZ) into rats and administrated betaine to these diabetic rats. We monitored the metabolism index, and glucose and insulin levels in blood and cerebrospinal fluid. We measured inflammatory cytokine levels, including TNF-α, IL-1ß, and IL-6, in serum and hippocampus. We also monitored oxidative stress in the hippocampus by measuring malondialdehyde (MDA) level and superoxide dismutase (SOD) activity. We measured the learning and memory ability of diabetic rats using the Morris water and Y maze tests and tested the phosphatidylinositol 3-kinase (PI3K)/Akt activation and p-mTOR level in the hippocampus. RESULTS: Betaine improved glucose metabolism and suppressed the production of inflammatory cytokines, including TNF-α, IL-1ß, and IL-6. Also, betaine decreased MDA concentration and increased SOD activity in the hippocampus of diabetic rats. Betaine ameliorated cognitive deficits in diabetic rats, and it promoted PI3K expression and Akt activation and decreased p-mTOR expression. CONCLUSION: Betaine alleviates cognitive deficits in STZ-induced diabetic rats via regulating the PI3K/Akt signaling pathway.

La2O3 Nanoparticles Induce Reproductive Toxicity Mediated by the Nrf-2/ARE Signaling Pathway in Kunming Mice.

PURPOSE: Lanthanum oxide (La2O3) nanoparticles (NPs) have been widely used in catalytic and photoelectric applications, but the reproductive toxicity is still unclear. This study evaluated the reproductive toxicity of two different-sized La2O3 particles in the testes. MATERIALS AND METHODS: Fifty Kunming mice were randomly divided into five groups. Mice were treated with La2O3 NPs by repeated intragastric administration for 90 days (control, nano-sized with 5, 10, 50 mg/kg BW and micro-sized with 50 mg/kg BW). Mice in the control group were treated with de-ionised water without La2O3 NPs. Sperm parameters, testicular histopathology, TEM assessment, hormone assay and nuclear factor erythroid 2-related factor 2 (Nrf-2) pathway were performed and evaluated. RESULTS: The body weight of mice treated with La2O3 NPs or not had no difference; sperm parameters and histological assessment showed that La2O3 NPs could induce reproductive toxicity in the testicle. Serum testosterone and gonadotropin-releasing hormone (GnRH) in the NH (nano-sized with 50 mg/kg BW) group were markedly decreased relative to control group, and an increase of luteinizing hormone (LH) in NH group was detected . Additionally, transmission electron microscopy revealed that the ultrastructural abnormalities induced by La2O3 NPs were more severe than La2O3 MPs in the testes. Furthermore, La2O3 NPs treatment inhibited the translocation of nuclear factor erythroid 2-related factor 2 (Nrf-2) from the cytoplasm into the nucleus as well as the expression of downstream genes NAD(P)H quinone oxidoreductase1 (NQO1), hemeoxygenase 1 (HO-1) and (glutathione peroxidase) GSH-Px, thus abrogating Nrf-2-mediated defense mechanisms against oxidative stress. CONCLUSIONS: The results of this study demonstrated that La2O3 NPs improved the spermatogenesis defects in mice. La2O3 NPs inhibited Nrf-2/ARE signaling pathway that resulted in apoptosis in the mice testes.

Long Non-coding RNA H19 Suppression Protects the Endothelium Against Hyperglycemic-Induced Inflammation via Inhibiting Expression of miR-29b Target Gene Vascular Endothelial Growth Factor a Through Activation of the Protein Kinase B/Endothelial Nitric Oxide Synthase Pathway.

It has been shown that non-coding RNAs (ncRNAs) play an important regulatory role in pathophysiological processes involving inflammation. The vascular endothelial growth factor A (VEGFA) gene also participates in the inflammatory process. However, the relationships between ncRNAs and VEGFA are currently unclear. Here, this study was designed to determine the relationship between long non-coding RNA (lncRNA) H19, mircoRNA29b (miR-29b), and VEGFA in the development of diabetes mellitus (DM). We demonstrate that H19 is upregulated and miR-29b downregulated in individuals with DM and directly binds miR-29b. VEGFA is the target of miR-29b in the vascular endothelium of individuals with DM. We found that positive modulation of miR29b and inhibition of H19 and VEGFA significantly attenuates high glucose-induced endothelial inflammation and oxidative stress. We also found that the protein kinase B/endothelial nitric oxide synthase (AKT/eNOS) signal pathway in endothelial cells is activated through regulation of miR29b and H19 endogenous RNAs. We conclude that H19 suppression protects the endothelium against high glucose-induced inflammation and oxidative stress in endothelial cells by upregulation of miR-29b and downregulation of VEGFA through AKT/eNOS signal pathway activation. These results suggest a novel link between dysregulated ncRNA expression, inflammation, and the signaling pathway in the vascular endothelium of individuals with DM, indicating a promising strategy for preventing cardiovascular disease in such individuals.

Upregulating MicroRNA-203 Alleviates Myocardial Remodeling and Cell Apoptosis Through Downregulating Protein Tyrosine Phosphatase 1B in Rats With Myocardial Infarction.

Myocardial infarction (MI) is one of cardiovascular diseases with high incidence and mortality. MicroRNAs, as posttranscriptional regulators of genes, are involved in many diseases, including cardiovascular diseases. The aim of the present study was to determine whether miR-203 was functional in MI therapy and how it worked. Left anterior descending artery ligation and hypoxia/reoxygenation (H/R) treatment were, respectively, performed to obtain MI rats and hypoxia-injured H9c2 cells. Western blot and quantitative real-time polymerase chain reaction were used to determine protein levels and messenger RNA of relevant genes, respectively. Lentivirus-mediated overexpression of miR-203 was performed to study the miR-203 functions on left ventricular remodeling, infarct size, and cardiomyocyte apoptosis. Compared with the sham group, miR-203 levels were significantly decreased in MI and H/R groups. However, overexpressing miR-203 greatly improved the cardiac function, reduced infarct size in rats after MI and weakened infarction-induced apoptosis by increasing Bcl-2 and reducing decreasing Bax, cleaved caspase-3, and cleaved caspase-9. In addition, Protein tyrosine phosphatase 1B (PTP1B) was proved as a target of miR-203 in cardiomyocytes, and it was negatively regulated by miR-203. Further experiments indicated that PTP1B overexpression could remarkably inhibit miR-203-mediated antiapoptosis of cardiomyocytes and alleviate protective effects of miR-203 on mitochondria after H/R treatment. Altogether, miR-203 prevented infarction-induced apoptosis by regulating PTP1B, including reducing proapoptosis proteins, inactivating caspase pathway, and protecting mitochondria. In conclusion, miR-203 had abilities to alleviate MI-caused injury on myocardium tissues and reduce mitochondria-mediated apoptosis, which might be a potential target used for MI therapy.

Dynamic changes in histone modification are associated with upregulation of Hsf and rRNA genes during heat stress in maize seedlings.

Histone modification plays a significant role in plant responses to abiotic stress. However, there are little scientific studies available on the involvement of dynamic changes in histone modification in the heat stress response in maize. The present investigation was aimed to analyze the epigenetic mechanisms involved in regulating the physiological and biochemical alterations in maize seedlings under heat stress. Our results and observations indicated an increase in electrolyte leakage and hydrolytic activity of the plasma membrane H+-ATPase as well as the high pigment content and reactive oxygen species (ROS) content under high temperature. Furthermore, decondensation of ribosomal DNA (rDNA) chromatin and a simultaneous increase in rRNA gene expression were observed during heat stress, accompanied by a genome-wide increase in the levels of histone H3K4me2 and H3K9ac. Additionally, chromatin immunoprecipitation (ChIP) analysis revealed that alterations in H3K4me2 and H3K9ac levels occurred in promoter regions, which were found to be associated with the upregulation of heat stress factor (Hsf) and rRNA genes. In conclusion, short-term heat stress induces dynamic histone alterations which are associated with Hsf and rRNA gene transcription, accompanied by perturbations of cell membranes and an increase in ROS during acclimation in maize seedlings.

Prognostic Factors for In-Hospital and Long-Term Survival in Patients with Acute ST-Segment Elevation Myocardial Infarction after Percutaneous Coronary Intervention.

Acute ST segment elevation myocardial infarction (STEMI) is one of the causes of death and disability in patients with cardiovascular diseases. This study aimed to investigate the prognostic factors of in-hospital and long-term survival in patients with acute STEMI undergoing percutaneous coronary intervention (PCI). Patients with STEMI undergoing PCI were divided into the death group (n = 54) and the survival group (n = 306) based on the outcomes during hospitalization. The routine blood and biochemistry tests, Killip classes and global registry of acute coronary events (GRACE) risk score were detected. The 1-, 2- and 3-year survival rates after PCI was observed through a 3-year follow-up. The survival factors, survival rates and multivariate analyses were conducted using Logistic regression analysis, Kaplan-Meier survival analysis and Cox proportional hazards regression. The incidence of cardiogenic shock and anterior wall MI (AWMI), the serum levels of γ-glutamyl endopeptidase (γ-GGT) and creatine kinase isoenzyme MB (CK-MB), Killip classes and GRACE risk score were higher in the death group, compared with the survival group. AWMI, cardiogenic shock, high serum levels of γ-GGT and CK-MB, Killip class III-IV and high GRACE risk scores were associated with in-hospital mortality. AWMI, cardiogenic shock, Killip class III-IV and high GRACE risk scores were correlated with a poor long-term survival. Our findings have demonstrated that AWMI, cardiogenic shock, high serum levels of γ-GGT and CK-MB, Killip class III-IV, and high GRACE risk scores are risk factors for in-hospital and long-term prognosis of acute STEMI patients.

Cardiac myocyte-protective effect of microRNA-22 during ischemia and reperfusion through disrupting the caveolin-3/eNOS signaling.

MicroRNA-22 (miR-22) was previously reported to elicit cardiac myocyte hypertrophy and had an anti-apoptotic effect on neurons. However, its effects on cardiac myocyte apoptosis and cardiac function during ischemia and reperfusion (I/R) are not clear. In the present study, we demonstrate that pre-administration of miR-22 mimic reduced I/R-induced cardiac dysfunction significantly in a rat model. We found that miR-22 overexpression inhibited cardiac myocyte apoptosis, and reduced cardiac remodeling during I/R. Significant cardiac myocyte apoptosis was also observed in a cardiac myocyte model after hypoxia/reoxygenation (H/R), a representative process of I/R. Further experiments showed that eNOS activity and the following NO production were significantly decreased during I/R and H/R, while such decrease was inhibited by overexpression of miR-22. Mechanistically, overexpression of miR-22 had little effect on the total protein level of eNOS, but restored the level of p-eNOS (Ser1177) which was down-regulated during H/R. Further RT-PCR results demonstrated that Caveolin 3 (Cav3), an upstream negative regulator of eNOS, was upregulated during H/R, resulting in a decrease of p-eNOS. However, such upregulation of Cav3 transcript level was inhibited directly by miR-22 during H/R, leading to a restored p-eNOS level and followed NO production in cardiac myocytes. Together, the present study revealed that miR-22 down-regulated Cav3, leading to restored eNOS activity and NO production, which further inhibited cardiac myocyte apoptosis and promoted cardiac function after I/R. Of clinical interest, the present study may highlight miR-22 as a potential therapeutic agent for reducing I/R induced cardiac injury.