Long noncoding RNA lncPostn links TGF-ß and p53 signaling pathways to transcriptional regulation of cardiac fibrosis.

Cardiac fibroblasts are essential for the homeostasis of the extracellular matrix, whose remodeling in many cardiovascular diseases leads to fibrosis. Long noncoding RNAs (lncRNAs) are associated with cardiac pathologies, but their functions in cardiac fibroblasts and contributions to cardiac fibrosis remain unclear. Here, we aimed to identify fibroblast-enriched lncRNAs essential in myocardial infarction (MI)-induced fibrosis and explore the molecular mechanisms responsible for their functions. Global lncRNA profiling was performed in post-MI mouse heart ventricles and transforming growth factor-ß (TGF-ß)-treated primary cardiac fibroblasts and confirmed in published data sets. We identified the cardiac fibroblast-enriched lncPostn, whose expression is stimulated in cardiac fibrosis induced by MI and the extracellular growth factor TGF-ß. The promoter of lncPostn contains a functional TGF-ß response element, and lncPostn knockdown suppresses TGF-ß-stimulated cardiac fibroblast activation and improves cardiac functions post-MI. LncPostn stabilizes and recruits EP300 to the profibrotic periostin's promoter, representing a major mechanism for its transcriptional activation. Moreover, both MI and TGF-ß enhance lncPostn expression while suppressing the cellular growth gatekeeper p53. TGF-ß and p53 knockdown-induced profibrotic gene expression and fibrosis occur mainly through lncPostn and show additive effects. Finally, levels of serum lncPostn are significantly increased in patients' postacute MI and show a strong correlation with fibrosis markers, revealing a potential biomarker of cardiac fibrosis. Our findings identify the fibroblast-enriched lncPostn as a potent profibrotic factor, providing a transcriptional link between TGF-ß and p53 signaling pathways to regulate fibrosis in cardiac fibroblasts.NEW & NOTEWORTHY Cardiac fibroblasts are essential for the homeostasis of the extracellular matrix, whose remodeling in many cardiovascular diseases leads to fibrosis. Long noncoding RNAs are functional and contribute to the biological processes of cardiovascular development and disorders. Our findings identify the fibroblast-enriched lncPostn as a potent profibrotic factor and demonstrate that serum lncPostn level may serve as a potential biomarker of human cardiac fibrosis postacute myocardial infarction.

Metformin Protects Against Acute Kidney Injury Induced by Lipopolysaccharide via Up-Regulating the MCPIP1/SIRT1 Pathway.

In the present study, we aimed to explore the effect and underlying mechanism of metformin on lipopolysaccharide (LPS)-induced acute kidney injury (AKI). A total of 24 BALB/C mice were randomly divided into four groups: control group, LPS group and metformin group (50 or 100 mg/kg). The histological changes and cell apoptosis in kidney tissues were detected by hematoxylin-eosin staining and terminal-deoxynucleotidyl transferase-mediated nick end labeling assay, respectively. Enzyme-linked immunosorbent assay was applied to determine serum levels of blood urea nitrogen (BUN), kidney injury molecule-1 (Kim-1), creatinine (Cre), tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß). Western blotting analysis were carried out to confirm the expressions of monocyte chemotactic protein-inducible protein 1 (MCPIP1), silent information regulator sirtuin 1 (SIRT1), and NF-κB p65 (acetyl K310). Compared with the control group, the mice in LPS group had glomerular capillary dilatation, renal interstitial edema, tubular cell damage and apoptosis. The serum levels of BUN, KIM-1, Cre, TNF-α, and IL-1ß in LPS group were significantly higher than those in control group. Moreover, LPS also elevated the expressions of MCPIP1 and NF-κB p65 (acetyl K310) but decreased the expression of SIRT1 in kidney tissues. However, metformin distinctly decreased LPS-induced renal dysfunction, the serum levels of BUN, KIM-1, Cre, TNF-α, and IL-1ß. In addition, metformin markedly increased the expressions of MCPIP1 and SIRT1 but decreased the expression of NF-κB p65 (acetyl K310) in kidney tissues. Metformin prevented LPS-induced AKI by up-regulating the MCPIP1/SIRT1 signaling pathway and subsequently inhibiting NF-κB-mediated inflammation response.

Spherical Silver Nanoparticles Located on Reduced Graphene Oxide Nanocomposites as Sensitive Electrochemical Sensors for Detection of L-Cysteine.

A new, simple, and effective one-step reduction method was applied to prepare a nanocomposite with spherical polycrystalline silver nanoparticles attached to the surface of reduced graphene oxide (Ag@rGO) at room temperature. Equipment such as X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), and Fourier transform infrared spectroscopy (FTIR) was used to characterize the morphology and composition of the Ag@rGO nanocomposite. A novel electrochemical sensor for detecting L-cysteine was proposed based on fixing Ag@rGO onto a glassy carbon electrode. The electrocatalytic behavior of the sensor was studied via cyclic voltammetry and amperometry. The results indicate that due to the synergistic effect of graphene with a large surface area, abundant active sites, and silver nanoparticles with good conductivity and high catalytic activity, Ag@rGO nanocomposites exhibit significant electrocatalytic activity toward L-cysteine. Under optimal conditions, the constructed Ag@rGO electrochemical sensor has a wide detection range of 0.1-470 µM for L-cysteine, low detection limit of 0.057 µM, and high sensitivity of 215.36 nA M-1 cm-2. In addition, the modified electrode exhibits good anti-interference, reproducibility, and stability.

Metabolically healthy obesity is associated with higher risk of both hyperfiltration and mildly reduced estimated glomerular filtration rate: the role of serum uric acid in a cross-sectional study.

BACKGROUND: The impact of metabolically healthy obesity (MHO) on kidney dysfunction remains debatable. Moreover, few studies have focused on the early stages of kidney dysfunction indicated by hyperfiltration and mildly reduced eGFR. Thus, we aimed to investigate the association between the MHO and early kidney dysfunction, which is represented by hyperfiltration and mildly reduced estimated glomerular filtration rate (eGFR), and to further explore whether serum uric acid affects this association. METHODS: This cross-sectional study enrolled 1188 residents aged ≥ 40 years old from Yonghong Communities. Metabolically healthy phenotypes were categorized based on Adult Treatment Panel III criteria. Obesity was defined as body mass index (BMI) ≥ 25 kg/m2. Mildly reduced eGFR was defined as being in the range 60 < eGFR ≤ 90 ml/min/1.73m2. Hyperfiltration was defined as eGFR > 95th percentile after adjusting for sex, age, weight, and height. RESULTS: Overall, MHO accounted for 12.8% of total participants and 24.6% of obese participants. Compared to metabolically healthy non-obesity (MHNO), MHO was significantly associated with an increased risk of mildly reduced eGFR (odds ratio [OR] = 1.85, 95% confidence interval [CI] 1.13-3.01) and hyperfiltration (OR = 2.28, 95% CI 1.03-5.09). However, upon further adjusting for uric acid, the association between the MHO phenotype and mildly reduced eGFR was reduced to null. Compared with MHNO/non-hyperuricemia, MHO/non-hyperuricemia was associated with an increased risk of mildly reduced eGFR (OR = 2.04, 95% CI 1.17-3.58), whereas MHO/hyperuricemia was associated with an observably increased risk (OR = 3.07, 95% CI 1.34-7.01). CONCLUSIONS: MHO was associated with an increased risk of early kidney dysfunction, and the serum uric acid partially mediated this association. Further prospective studies are warranted to clarify the causality.

Landscape of molecular crosstalk between SARS-CoV-2 infection and cardiovascular diseases: emphasis on mitochondrial dysfunction and immune-inflammation.

BACKGROUND: SARS-CoV-2, the pathogen of COVID-19, is a worldwide threat to human health and causes a long-term burden on the cardiovascular system. Individuals with pre-existing cardiovascular diseases are at higher risk for SARS-CoV-2 infection and tend to have a worse prognosis. However, the relevance and pathogenic mechanisms between COVID-19 and cardiovascular diseases are not yet completely comprehended. METHODS: Common differentially expressed genes (DEGs) were obtained in datasets of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) infected with SARS-CoV-2 and myocardial tissues from heart failure patients. Further GO and KEGG pathway analysis, protein-protein interaction (PPI) network construction, hub genes identification, immune microenvironment analysis, and drug candidate predication were performed. Then, an isoproterenol-stimulated myocardial hypertrophy cell model and a transverse aortic constriction-induced mouse heart failure model were employed to validate the expression of hub genes. RESULTS: A total of 315 up-regulated and 78 down-regulated common DEGs were identified. Functional enrichment analysis revealed mitochondrial metabolic disorders and extensive immune inflammation as the most prominent shared features of COVID-19 and cardiovascular diseases. Then, hub DEGs, as well as hub immune-related and mitochondria-related DEGs, were screened. Additionally, nine potential therapeutic agents for COVID-19-related cardiovascular diseases were proposed. Furthermore, the expression patterns of most of the hub genes related to cardiovascular diseases in the validation dataset along with cellular and mouse myocardial damage models, were consistent with the findings of bioinformatics analysis. CONCLUSIONS: The study unveiled the molecular networks and signaling pathways connecting COVID-19 and cardiovascular diseases, which may provide novel targets for intervention of COVID-19-related cardiovascular diseases.

TRIM29 promotes podocyte pyroptosis in diabetic nephropathy through the NF-kB/NLRP3 inflammasome pathway.

Diabetic nephropathy (DN) is one of the most common complications of diabetes. Gradual loss of podocytes is a sign of DN and pyroptosis mechanistically correlates with podocyte injury in DN; however, the mechanism(s) involved remain unknown. Here we reveal that TRIM29 is overexpressed in high glucose (HG)-treated murine podocytes cells and that TRIM29 silencing significantly inhibits podocyte damage due to HG treatment, as evidenced by lower desmin expression and greater nephrin expression. Additionally, flow cytometry analysis showed that TRIM29 silencing significantly inhibited HG treatment-induced pyroptosis, which was confirmed by immunoblotting for NLRP3, active Caspase-1, GSDMD-N, and phosphorylated NF-κB-p65. Conversely, overexpression of TRIM29 could trigger pyroptosis that was attenuated by NF-κB inhibition, indicating that TRIM29 promotes pyroptosis through the NF-κB pathway. Mechanistic studies revealed that TRIM29 interacts with IκBα to mediate its ubiquitination-dependent degradation, which in turn leads to NF-κB activation. Taken together, our data demonstrate that TRIM29 can promote podocyte pyroptosis by activating the NF-κB/NLRP3 pathway. Thus, TRIM29 represents a potentially novel therapeutic target that may also be clinically relevant in the management of DN.

Machine learning models for prediction of invasion Klebsiella pneumoniae liver abscess syndrome in diabetes mellitus: a singled centered retrospective study.

OBJECTIVE: This study aimed to develop and validate a machine learning algorithm-based model for predicting invasive Klebsiella pneumoniae liver abscess syndrome(IKPLAS) in diabetes mellitus and compare the performance of different models. METHODS: The clinical signs and data on the admission of 213 diabetic patients with Klebsiella pneumoniae liver abscesses were collected as variables. The optimal feature variables were screened out, and then Artificial Neural Network, Support Vector Machine, Logistic Regression, Random Forest, K-Nearest Neighbor, Decision Tree, and XGBoost models were established. Finally, the model's prediction performance was evaluated by the ROC curve, sensitivity (recall), specificity, accuracy, precision, F1-score, Average Precision, calibration curve, and DCA curve. RESULTS: Four features of hemoglobin, platelet, D-dimer, and SOFA score were screened by the recursive elimination method, and seven prediction models were established based on these variables. The AUC (0.969), F1-Score(0.737), Sensitivity(0.875) and AP(0.890) of the SVM model were the highest among the seven models. The KNN model showed the highest specificity (1.000). Except that the XGB and DT models over-estimates the occurrence of IKPLAS risk, the other models' calibration curves are a good fit with the actual observed results. Decision Curve Analysis showed that when the risk threshold was between 0.4 and 0.8, the net rate of intervention of the SVM model was significantly higher than that of other models. In the feature importance ranking, the SOFA score impacted the model significantly. CONCLUSION: An effective prediction model of invasion Klebsiella pneumoniae liver abscess syndrome in diabetes mellitus could be established by a machine learning algorithm, which had potential application value.

Quantitative colorimetric sensing of heavy metal ions via analyte-promoted growth of Au nanoparticles with timer or smartphone readout.

This work describes two new colorimetric nanosensors for label-free, equipment-free quantitative detection of nanomolar copper (II) (Cu2+) and mercury (II) (Hg2+) ions. Both are based on the analyte-promoted growth of Au nanoparticles (AuNPs) from the reduction of chloroauric acid by 4-morpholineethanesulfonic acid. For the Cu2+ nanosensor, the analyte can accelerate such a redox system to rapidly form a red solution containing dispersed, uniform, spherical AuNPs that is related to these particles' surface plasmon resonance property. For the Hg2+ nanosensor, on the other hand, a blue mixture consisting of aggregated, ill-defined AuNPs with various sizes can be created, showing a significantly enhanced Tyndall effect (TE) signal (in comparison with that produced in the red solution of AuNPs). By using a timer and a smartphone to quantitatively measure the time of producing the red solution and the TE intensity (i.e., the average gray value of the corresponding image) of the blue mixture, respectively, the developed nanosensors are well demonstrated to achieve linear ranges of 6.4 nM to 100 µM and 6.1 nM to 1.56 µM for Cu2+ and Hg2+, respectively, with detection limits down to 3.5 and 0.1 nM, respectively. The acceptable recovery results obtained from the analysis of the two analytes in the complex real water samples including drinking water, tap water, and pond water ranged from 90.43 to 111.56%.

Association between serum lipoprotein(a) and mildly reduced eGFR: a cross-sectional study.

Lipoprotein(a) [Lp(a)] is a risk factor for cardiovascular disease (CVD) and aortic stenosis. However, the data on the relationship between Lp(a) and mildly reduced estimated glomerular filtration rate (eGFR) has been disputed. This study was conducted to assess the relationship between Lp(a) concentrations and mildly reduced eGFR in healthy subjects.This community-based, cross-sectional study enrolled 1,064 volunteers aged ≥ 40 years who lived in Yonghong Community, Zhonglou District, Changzhou, China, between December 2016 and December 2017. A mildly reduced eGFR was defined as eGFR between 60 and 90 mL/min/1.73m2. A standardized questionnaire and biochemical measurements were used to gather information about participants. The serum concentration of Lp(a) was determined using the latex-enhanced immunoturbidimetric test. Of the total study population, 34.8% (n = 370) were men, and the mean age was 66.8 ± 8.5 years. A significant association existed between Lp(a) levels and the risk of mildly reduced eGFR. Individuals with the highest tertile of Lp(a) had higher odds of mildly reduced eGFR after adjusting for various confounders (adjusted odds ratio [OR]: 1.80, 95% confidence interval [CI]: 1.24-2.60, P = 0.0025) compared to those with the lowest tertile of Lp(a). Multivariable logistic regression of studies in which Lp(a) was presented as continuous variables showed consistent results (adjusted OR: 1.23 for 1-SD increment of Ln-Lp(a), 95% CI: 1.05-1.43). Subgroup analyses showed that study characteristics such as age, sex, obesity, diabetes, and hypertension status did not significantly affect the association (P for all interactions > 0.05). These results suggest that higher serum Lp(a) level was an independent risk factor for mildly reduced eGFR.

A next generation mathematical model for the in vitro to clinical translation of T-cell engagers.

T-cell engager (TCE) molecules activate the immune system and direct it to kill tumor cells. The key mechanism of action of TCEs is to crosslink CD3 on T cells and tumor associated antigens (TAAs) on tumor cells. The formation of this trimolecular complex (i.e. trimer) mimics the immune synapse, leading to therapeutic-dependent T-cell activation and killing of tumor cells. Computational models supporting TCE development must predict trimer formation accurately. Here, we present a next-generation two-step binding mathematical model for TCEs to describe trimer formation. Specifically, we propose to model the second binding step with trans-avidity and as a two-dimensional (2D) process where the reactants are modeled as the cell-surface density. Compared to the 3D binding model where the reactants are described in terms of concentration, the 2D model predicts less sensitivity of trimer formation to varying cell densities, which better matches changes in EC50 from in vitro cytotoxicity assay data with varying E:T ratios. In addition, when translating in vitro cytotoxicity data to predict in vivo active clinical dose for blinatumomab, the choice of model leads to a notable difference in dose prediction. The dose predicted by the 2D model aligns better with the approved clinical dose and the prediction is robust under variations in the in vitro to in vivo translation assumptions. In conclusion, the 2D model with trans-avidity to describe trimer formation is an improved approach for TCEs and is likely to produce more accurate predictions to support TCE development.

Clinicopathological features and resistance mechanisms in HIP1-ALK-rearranged lung cancer: A multicenter study.

Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) respond well to ALK tyrosine kinase inhibitors (TKIs), and echinoderm microtubule-associated protein-like 4 (EML4)-ALK-rearranged NSCLC accounts for the majority of those patients. However, few studies have evaluated ALK-TKIs treatment for patients with huntingtin-interacting protein 1 (HIP1)-ALK fusions. This retrospective study evaluated the clinicopathological characteristics, genomic features, response to ALK-TKIs, and resistance mechanisms in 11 cases with HIP1-ALK fusions from five Chinese centers. Patients who received crizotinib at the Chinese centers had an objective response rate of 90% [9/10 cases, 95% confident index (CI): 54.1%-99.5%], median progression-free survival of 17.9 months (95% CI: 5.8-NA months), and median overall survival of 58.8 months (95% CI: 24.7-NA months). One patient who received first-line lorlatinib treatment achieved partial response for > 26.5 months. Despite the small sample size, HIP1-ALK (H21:A20) variant was the most common variant (four of 11 cases, 36.4%) and associated with better outcomes. Among the 11 cases, there were eight patients having available specimens for genetic testing before ALK-TKIs treatment and four patients undergoing biopsy after ALK-TKIs failure. The most common coexisting gene was TP53 among 11 patients and two of four patients after crizotinib failure harbored acquired ALK mutations (e.g., L1152V/Q1146K and L1196M). Brigatinib treatment appeared to be effective for a patient who failed crizotinib treatment because of the L1152V/Q1146K mutations, which might be related to increased binding affinity to these mutants. Although HIP1-ALK-rearranged NSCLC appears to initially respond well to ALK-TKIs, crizotinib resistance may be correlated with the AKAP9-BRAF fusion, ALK compound mutations (L1152V/Q1146K), and the ALK L1196M mutation. Larger studies are needed to evaluate the significance of HIP1-ALK-rearranged NSCLC.

Triglyceride-glucose index as a marker in cardiovascular diseases: landscape and limitations.

The triglyceride-glucose (TyG) index has been identified as a reliable alternative biomarker of insulin resistance (IR). Recently, a considerable number of studies have provided robust statistical evidence suggesting that the TyG index is associated with the development and prognosis of cardiovascular disease (CVD). Nevertheless, the application of the TyG index as a marker of CVD has not systemically been evaluated, and even less information exists regarding the underlying mechanisms associated with CVD. To this end, in this review, we summarize the history of the use of the TyG index as a surrogate marker for IR. We aimed to highlight the application value of the TyG index for a variety of CVD types and to explore the potential limitations of using this index as a predictor for cardiovascular events to improve its application value for CVD and provide more extensive and precise supporting evidence.

Association Of Blood Lipocalin-2 Levels with Gestational Diabetes Mellitus: A Systematic Review and Meta-Analysis.

Lipocalin-2 (LCN2) is becoming recognized as a pleiotropic mediator of metabolic disorders. However, the relationship between LCN2 and gestational diabetes mellitus (GDM) is not well understood. We performed a systematic review and meta-analysis to explore it. A systematic search of Cochrane Library, PubMed, Embase, Scopus, Web of Science, Chinese National Knowledge Infrastructure, and Wan-fang Database was done for relevant articles published up to September 29, 2021. Standardized mean difference (SMD) with 95% confidence intervals (CI) was calculated to explore the association of LCN2 levels with GDM using Revman 5.3 and Stata 15.1. Fifteen case-control studies were included in this meta-analysis. The patients with GDM had significantly higher levels of blood LCN2 than parturients with normal glucose tolerance (SMD=3.41, 95% CI=2.24 to 4.58). Meta-regression and subgroup analysis were conducted to investigate the source of heterogeneity. Likely sources of heterogeneity were age and testing methods. This study found that GDM showed higher blood LCN2 levels than controls. However, caution is warranted on the interpretation of these findings. Standardized LCN2 measurement methods and longitudinal studies are required to disentangle and better understand the relationships observed.

miR-451a suppresses papillary thyroid cancer cell proliferation and invasion and facilitates apoptosis through targeting DCBLD2 and AKT1.

Papillary thyroid cancer (PTC) is a common malignancy. MicroRNAs (miRNAs) may act as oncogenes or tumor suppressor genes. However, the role of miR-451a in PTC is not fully understood. Hence, the objective of the study was to research the effect and mechanism of miR-451a in PTC. Differentially expressed miRNAs between GSE113629 and GSE103996 databases were assessed by Venn diagram. miR-451a and its downstream target genes were assessed by RT-PCR and Western blot. The proliferation, invasion, and apoptosis were determined by CCK-8, EdU, transwell, and flow cytometry assays. Dual-luciferase reporter assay were used to evaluated the target of miR-451a. Xenografted tumors was used to explore the function of miR-451a in vivo. Pathological changes and related protein expression were measured by HE staining and immunohistochemistry. MiR-451a was downregulated in PTC tissues and blood, and low expression of miR-451a was related to short overall survival, serious lymph node metastasis and high TNM grade in PTC patients. Moreover, increase of miR-451a restrained the proliferation and invasion and accelerated the apoptosis. Furthermore, miR-451a repressed VEGF signaling pathway. Importantly, miR-451a was demonstrated to target DCBLD2 and AKT1. Overexpression of DCBLD2 and AKT1 could restore the effect of miR-451a on PTC cells. In addition, miR-451a reduced the growth of xenografted tumors in vivo. The data suggested that miR-451a attenuated the proliferation, invasion and promoted apoptosis in PTC cells via inhibiting DCBLD2 and AKT1.

FOXM1-activated SIRT4 inhibits NF-κB signaling and NLRP3 inflammasome to alleviate kidney injury and podocyte pyroptosis in diabetic nephropathy.

Forkhead box M1 (FOXM1) has been reported to play a protective role against acute kidney injury by driving tubular regeneration. This study aims to probe the function of FOXM1 in diabetic nephropathy (DN) and the molecules involved. FOXM1 was poorly expressed in DN-diseased kidney tissues. A murine model of DN was established, and podocytes cells (MPC5) were treated with high-glucose (HG) for in vitro studies. FOXM1 overexpression improved kidney function and reduced pathological changes in mice, and it increased the expression of the podocyte marker Nephrin in kidney tissues. In vitro, FOXM1 increased viability and reduced pyroptosis of the HG-treated MPC5 cells, and it elevated the expression of the podocyte marker Nephrin whereas reduced the expression of pyroptosis-related NLRP3 inflammasome and cleaved caspase 1. FOXM1 bound to the promoter of sirtuin 4 (SIRT4) to induce transcriptional activation. Downregulation of SIRT4 blocked the protective roles of FOXM1 both in vivo and in vitro. Phosphorylation of nuclear factor-kappa B (NF-κB) in HG-treated cells was suppressed by FOXM1 but restored after SIRT4 inhibition. In conclusion, this study suggested that FOXM1 transcriptionally activates SIRT4 and inhibits NF-κB signaling and the NLRP3 inflammasome to alleviate kidney injury and podocyte pyroptosis in DN.

Impacts of Acupuncture Plus Acupoint Application on Intestinal Function and Expression of MAPK and ERK in Colon Tissue of Rats.

Context: Slow transit constipation (STC) has a high incidence worldwide, which not only seriously affects patients' normal lives but also may cause malignant intestinal lesions. Among the limited treatment options for STC, traditional Chinese medicine (TCM) is considered to be the key to STC treatment in the future. Objective: The study intended to examine the impacts of acupuncture plus acupoint application on MAPK and ERK in STC rats, with the aim of preliminarily exploring the relevant mechanisms for treating STC as well as providing new ideas and means for future clinical treatment. Design: The research team designed a randomized, controlled animal study. Setting: The study was carried out at department of Department of Rehabilitation, Affiliated Hospital of Medical School of Ningbo University, Ningbo, Zhejiang, China. Animals: The animals were 30 six-to-eight-week-old, Sprague Dawley (SD) rats, half male and half female and weighing a mean of 200 ± 20 g. Intervention: The rats were randomly assigned to one of three groups, 10 rats in each group: a negative control group that wasn't induced with STC and received no treatments; a positive control group, the model group (MG), that was induced with STC and received no treatments; and an intervention group that was induced with STC and received the investigated treatments. The intervention group was treated with acupuncture at Tianshu point (ST25) and received acupoint application from Chinese medicine. Outcome Measures: The study measured the alterations in the rats' body weight and feces, as well as the rats' intestinal motility, using intragastric administration of activated carbon. The rats were killed to obtain their intestinal tissues, for measuring expression of mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) using Western blotting and polymerase chain reaction (PCR). Results: Postintervention, at 28 days after induction of STC, the rats' weights weren't significantly different in the intervention and control groups (P > .05) but were significantly higher than that in the model group (P < .05). The rats' weights in the intervention and control groups gradually increased significantly, while those in the model group gradually decreased significantly (P < .05). The defecation volume and fecal water content (FWS) decreased in the significantly model group but increased significantly in the intervention group (P < .05). The intestinal motility test revealed no significant differences in the propulsion rate between the intervention and control groups (P > .05), but the rate was significantly lower in the model group than that of the intervention group (P < .05). The intestinal fecal residue in the model group was the highest among the three groups, followed in descending order by the intervention group and the control group, with the differences being statistically significant (P < .05). In addition, the MAPK and ERK in the model group significantly increased, and the values were significantly higher in the intervention group than those of the model group (P < .05). Conclusions: Acupuncture plus acupoint application can validly improve the defecation and intestinal motility of STC rats, possibly through inhibiting MAPK and ERK.

MicroRNA-577 aggravates bone loss and bone remodeling by targeting thyroid stimulating hormone receptor in hyperthyroid-associated osteoporosis.

Traditionally, hyperthyroid-associated osteoporosis has been considered to be the result of increased thyroid hormone levels. The pathogenesis of hyperthyroid-associated osteoporosis remains unclear. Thyroid stimulating hormone receptor (TSHR) is closely associated with osteoporosis. Our study aimed to explore the role of TSHR and its upstream microRNA (miRNA) in hyperthyroid-associated osteoporosis. Bioinformatics analysis (starBase and Targetscan) and a wide range of experiments including reverse-transcription quantitative polymerase chain reaction, luciferase reporter, western blot analysis of osteogenic differentiation markers including OSX, OCN, ALP, OPN, and COL1, hematoxylin and eosin staining, Alizarin Red staining assays were used to explore the function and mechanism of TSHR in hyperthyroid-associated osteoporosis. First, we observed that TSHR was downregulated in bone marrow mesenchymal stem cells (BMSCs) isolated from rats after culture in osteogenic medium for 7 days. Functionally, overexpression of TSHR accelerates BMSC osteogenic differentiation. Mechanistically, we predicted four potential miRNAs for TSHR. MiR-577 was validated to bind with TSHR. Rescue assays showed that miR-577 overexpression inhibited BMSC osteogenic differentiation via targeting TSHR. In vivo experiments showed that miR-577 aggravated bone loss and bone remodeling and our data showed that it is achieved by targeting TSHR in hyperthyroid-associated osteoporosis. This finding may deep our understanding of the pathogenesis of hyperthyroid-associated osteoporosis.

MiR-144 protects the heart from hyperglycemia-induced injury by regulating mitochondrial biogenesis and cardiomyocyte apoptosis.

Several lines of evidence have revealed the potential of microRNAs (miRNAs, miRs) as biomarkers for detecting diabetic cardiomyopathy, although their functions in hyperglycemic cardiac dysfunction are still lacking. In this study, mitochondrial biogenesis was markedly impaired induced by high glucose (HG), as evidenced by dysregulated mitochondrial structure, reduced mitochondrial DNA contents, and biogenesis-related mRNA levels, accompanied by increased cell apoptosis. MiR-144 was identified to be decreased in HG-induced cardiomyocytes and in streptozotocin (STZ)-challenged heart samples. Forced miR-144 expression enhanced mitochondrial biogenesis and suppressed cell apoptosis, while miR-144 inhibition exhibited the opposite results. Rac-1 was identified as a target gene of miR-144. Decreased Rac-1 levels activated AMPK phosphorylation and PGC-1α deacetylation, leading to increased mitochondrial biogenesis and reduced cell apoptosis. Importantly, the systemic neutralization of miR-144 attenuated mitochondrial disorder and ventricular dysfunction following STZ treatment. Additionally, plasma miR-144 decreased markedly in diabetic patients with cardiac dysfunction. The receiver-operator characteristic curve showed that plasma miR-144 could specifically predict diabetic patients developing cardiac dysfunction. In conclusion, this study provides strong evidence suggesting that miR-144 protects heart from hyperglycemia-induced injury by improving mitochondrial biogenesis and decreasing cell apoptosis via targeting Rac-1. Forced miR-144 expression might, thus, be a protective strategy for treating hyperglycemia-induced cardiac dysfunction.

Relationship of Bone Status with Serum Uric Acid and Bilirubin in Men with Type 2 Diabetes: A Cross-Sectional Study.

BACKGROUND Accumulating evidence has shown that serum uric acid and bilirubin are associated with some chronic diseases, owing to their antioxidant capacity, but the previous research produced discrepant results regarding the relation between uric acid, as well as bilirubin, and bone health. This study was designed to assess the relationship of serum uric acid and total bilirubin with bone mineral density and bone turnover markers in men with type 2 diabetes. MATERIAL AND METHODS In total, 631 male patients with type 2 diabetes were included. Data of patients' medical history, biochemical index, bone mineral density of the lumbar vertebra, femoral neck, and total hip, and bone turnover markers including osteocalcin (OC), amino-terminal propeptide of type I procollagen (PINP), type I collagen carboxy-terminal peptide (CTX), and parathyroid hormone were collected and retrospectively analyzed. RESULTS Both serum uric acid and total bilirubin were positively related to bone mineral density of the lumbar vertebra (b=0.179, p.

Adiponectin protects obesity-related glomerulopathy by inhibiting ROS/NF-κB/NLRP3 inflammation pathway.

BACKGROUND: Adiponectin is an adipocytokine that plays a key regulatory role in glucose and lipid metabolism in obesity. The prevalence of obesity has led to an increase in the incidence of obesity-related glomerulopathy (ORG). This study aimed to identify the protective role of adiponectin in ORG. METHODS: Small-interfering RNA (siRNA) against the gene encoding adiponectin was transfected into podocytes. The oxidative stress level was determined using a fluorometric assay. Apoptosis was analyzed by flow cytometry. The expressions of podocyte markers and pyrin domain containing protein 3 (NLRP3) inflammasome-related proteins were measured by qRT-PCR, immunohistochemistry, and Western blot. RESULTS: Podocytes treated with palmitic acid (PA) showed downregulated expressions of podocyte markers, increased apoptosis, upregulated levels of NLRP3 inflammasome-related proteins, increased production of inflammatory cytokines (IL-18 and IL-1ß), and induced activation of NF-κB as compared to the vehicle-treated controls. Decreased adiponectin expression was observed in the serum samples from high fat diet (HFD)-fed mice. Decreased podocin expression and upregulated NLRP3 expression were observed in the kidney samples from high fat diet (HFD)-fed mice. Treatment with adiponectin or the NLRP3 inflammasome inhibitor, MCC950, protected cultured podocytes against podocyte apoptosis and inflammation. Treatment with adiponectin protected mouse kidney tissues against decreased podocin expression and upregulated NLRP3 expression. The knockout of adiponectin gene by siRNA increased ROS production, resulting in the activation of NLRP3 inflammasome and the phosphorylation of NF-κB in podocytes. Pyrrolidine dithiocarbamate, an NF-κB inhibitor, prevented adiponectin from ameliorating FFA-induced podocyte injury and NLRP3 activation. CONCLUSIONS: Our study showed that adiponectin ameliorated PA-induced podocyte injury in vitro and HFD-induced injury in vivo via inhibiting the ROS/NF-κB/NLRP3 pathway. These data suggest the potential use of adiponectin for the prevention and treatment of ORG.