miR-29b-1-5p exacerbates myocardial injury induced by sepsis in a mouse model by targeting TERF2.

Myocardial damage is a critical complication and a significant contributor to mortality in sepsis. MicroRNAs (miRNAs) have emerged as key players in sepsis pathogenesis. In this study, we explore the effect and mechanisms of miR-29b-1-5p on sepsis-induced myocardial damage. Sepsis-associated Gene Expression Omnibus datasets (GSE72380 and GSE29914) are examined for differential miRNAs. The mouse sepsis-induced cardiac injury was established by Lipopolysaccharide (LPS) or cecal ligation and puncture (CLP). LPS-treated HL-1 mouse cardiomyocytes simulate myocardial injury in vitro. miR-29b-1-5p is co-upregulated in both datasets and in cardiac tissue from sepsis mouse and HL-1 cell models. miR-29b-1-5p expression downregulation was achieved by antagomir transduction and confirmed by real-time quantitative reverse transcription PCR. Survival analysis and echocardiography examination show that miR-29b-1-5p inhibition improves mice survival cardiac function in LPS- and CLP-induced sepsis mice. Hematoxylin and eosin and Masson's trichrome staining and Immunohistochemistry analysis of mouse myocardial α-smooth muscle actin show that miR-29b-1-5p inhibition reduces myocardial tissue injury and fibrosis. The inflammatory cytokines and cardiac troponin I (cTnI) levels in mouse serum and HL-1 cells are also decreased by miR-29b-1-5p inhibition, as revealed by enzyme-linked immunosorbent assay. The expressions of autophagy-lysosomal pathway-related and apoptosis-related proteins in the mouse cardiac tissues and HL-1 cells are evaluated by western blot analysis. The sepsis-induced activation of the autophagy-lysosomal pathway and apoptosis are also reversed by miR-29b-1-5p antagomir. MTT and flow cytometry measurement further confirm the protective role of miR-29b-1-5p antagomir in HL-1 cells by increasing cell viability and suppressing cell apoptosis. Metascape functionally enriches TargetScan-predicted miR-29b-1-5p target genes. TargetScan prediction and dual luciferase assay validate the targeting relationship between miR-29b-1-5p and telomeric repeat-binding factor 2 (TERF2). The expression and function of TERF2 in HL-1 cells and mice are also evaluated. MiR-29b-1-5p negatively regulates the target gene TERF2. TERF2 knockdown partly restores miR-29b-1-5p antagomir function in LPS-stimulated HL-1 cells. In summary, miR-29b-1-5p targetedly inhibits TERF2, thereby enhancing sepsis-induced myocardial injury.

Clinical efficacy and safety of the self-developed Zangsiwei Qingfei Mixture combined with conventional treatment in patients with acute exacerbation of chronic obstructive pulmonary disease. / è‡ªä¸»ç ”å‘çš„è—å››å‘³æ¸ è‚ºåˆå‰‚è”åˆå¸¸è§„æ²»ç–—å¯¹æ ¢æ€§é˜»å¡žæ€§è‚ºç–¾ç— æ€¥æ€§åŠ é‡æœŸæ‚£è€ çš„ä¸´åºŠç–—æ•ˆå’Œå®‰å ¨æ€§.

OBJECTIVES: Chronic obstructive pulmonary disease (COPD) is a significant global public health issue. Modern medical treatments have both benefits and limitations, prompting increasing attention from scholars worldwide on traditional ethnic medicine, and the Zangsiwei Qingfei Mixture is a newly developed formula derived from the effective components of classical Tibetan medicine to treat chronic respiratory diseases. This study aims to investigate the clinical efficacy and safety of the Zangsiwei Qingfei Mixture combined with conventional treatment in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). METHODS: Sixty AECOPD patients admitted to the Second Xiangya Hospital of Central South University from May 2021 to May 2023 were enrolled and randomly divided into 2 groups, with 30 patients in each group. The control group received conventional treatment, including bronchodilators, anti-infection agents, expectorants, and oxygen therapy. The experimental group received the Zangsiwei Qingfei Mixture in addition to conventional treatment. The treatment duration was 7 d for both groups. Baseline data such as gender, age, body mass index (BMI), smoking status, Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification, COPD course, and the number of COPD exacerbations in the past year were collected. The primary efficacy indicators were assessed using the modified Medical Research Council (mMRC) dyspnea scale and the modified Borg scale. Secondary indicators included arterial lactic acid (LAC) and serum tumor necrosis factor alpha (TNF-α) levels. Safety indicators included liver and kidney function [alanine transaminase (ALT), aspartate transaminase (AST), serum creatinine (SCr), serum uric acid (SUA)], coagulation function [activated partial thromboplastin time (APTT), prothrombin time (PT), fibrinogen (FIB), and D-dimer]. The generalized linear mixed model (GLMM) was used to evaluate the clinical efficacy and safety of the Zangsiwei Qingfei Mixture. RESULTS: Before treatment, there were no statistically significant differences in general baseline data, grading of mMRC dyspnea scale, score of modified Borg scale, arterial LAC, ALT, AST, SCr, SUA, APTT, FIB, and D-dimer between the 2 groups (all P>0.05). However, serum TNF-α and PT levels in the experimental group were significantly lower than those in the control group (both P<0.05). GLMM analysis showed that after adjusting for pre- and post-treatment, gender, age, BMI, smoking status, GOLD classification, COPD course, and the number of COPD exacerbations in the past year, the experimental group demonstrated significantly lower grading of mMRC dyspnea scale (coefficient=-0.329, P=0.036), score of modified Borg scale (coefficient=-1.077, P=0.001), serum TNF-α level (coefficient=-14.378, P<0.001), and arterial LAC level (coefficient=-0.409, P=0.012) compared to the control group. The Zangsiwei Qingfei Mixture had no significant effect on liver, kidney, or coagulation function indicators (all P>0.05). CONCLUSIONS: The Zangsiwei Qingfei Mixture combined with conventional treatment can improve clinical symptoms and promote homeostasis in AECOPD patients, demonstrating safety and reliability. Combining modern medicine with traditional ethnic medicine offers a feasible approach to treating chronic respiratory diseases in the future.

[Effect of Wenyang Zhenshuai Granules on autophagy and apoptosis of myocardial cells in septic rats via regulating miR-132-3p/UCP2 expression].

This study aimed to investigate the effect of Wenyang Zhenshuai Granules(WYZSG) on autophagy and apoptosis of myocardial cells in rats with sepsis via regulating the expression of microRNA-132-3p(miR-132-3p)/uncoupling protein 2(UCP2). Sixty SD rats were randomly divided into modeling group(n=50) and sham operation group(n=10). The sepsis rat model was constructed by cecal ligation and perforation in the modeling group. The successfully modeled rats were randomly divided into WYZSG low-, medium-and high-dose groups, model group and positive control group. Rats in the sham operation group underwent opening and cecum division but without perforation and ligation. Hematoxylin-eosin(HE) staining was used to observe the pathological changes of rat myocardial tissue. Myocardial cell apoptosis was detected by TdT-mediated dUTP nick end labeling(TUNEL) assay. Real-time quantitative polymerase chain reaction(RT-qPCR) was performed to detect the expression of miR-132-3p and the mRNA expressions of UCP2, microtubule-associated protein light chain 3(LC3-Ⅱ/LC3-Ⅰ), Beclin-1 and caspase-3 in rat myocardial tissue. The protein expressions of UCP2, LC3-Ⅱ/LC3-Ⅰ, Beclin-1 and caspase-3 in myocardial tissue were detected by Western blot. Dual luciferase reporter assay was used to verify the regulatory relationship between miR-132-3p and UCP2. The myocardial fibers of sepsis model rats were disordered, and there were obvious inflammatory cell infiltration as well as myocardial cell edema and necrosis. With the increase of the WYZSG dose, the histopathological changes of myocardium were improved to varying degrees. Compared with the conditions in the sham operation group, the survival rate and left ventricular ejection fraction(LVEF) of rats in the model group, positive control group and WYZSG low-, medium-and high-dose groups were decreased, and the myocardial injury score and apoptosis rate were increased. Compared with the model group, the positive control group and WYZSG low-, medium-and high-dose groups had elevated survival rate and LVEF, and lowered myocardial injury score and apoptosis rate. The expression of miR-132-3p and the mRNA and protein expressions of UCP2 in myocardial tissue in the model group, positive control group and WYZSG low-, medium-and high-dose groups were lower, while the mRNA and protein expressions of LC3-Ⅱ/LC3-Ⅰ, Beclin-1 and caspase-3 were higher than those in the sham operation group. Compared with model group, the positive control group and the WYZSG low-, medium-and high-dose groups had an up-regulation in the expression of miR-132-3p and the mRNA and protein expressions of UCP2, while a down-regulation in the mRNA and protein expressions of LC3-Ⅱ/LC3-Ⅰ, Beclin-1 and caspase-3. WYZSG inhibited excessive autophagy and apoptosis of myocardial cells in septic rats and improved myocardial injury, possibly by regulating the expression of miR-132-3p/UCP2.

[Risk factors for neonatal asphyxia and establishment of a nomogram model for predicting neonatal asphyxia in Hubei Enshi Tujia and Miao Autonomous Prefecture: a multicenter study]. / æ¹–åŒ—æ©æ–½åœŸå®¶æ—è‹—æ—è‡ªæ²»å·žæ–°ç”Ÿå„¿çª’æ¯å±é™©å› ç´ åˆ†æžåŠåˆ—çº¿å›¾é¢„æµ‹æ¨¡åž‹çš„æž„å»ºï¼šä¸€é¡¹å¤šä¸­å¿ƒç ”ç©¶.

OBJECTIVES: To investigate the risk factors for neonatal asphyxia in Hubei Enshi Tujia and Miao Autonomous Prefecture and establish a nomogram model for predicting the risk of neonatal asphyxia. METHODS: A retrospective study was conducted with 613 cases of neonatal asphyxia treated in 20 cooperative hospitals in Enshi Tujia and Miao Autonomous Prefecture from January to December 2019 as the asphyxia group, and 988 randomly selected non-asphyxia neonates born and admitted to the neonatology department of these hospitals during the same period as the control group. Univariate and multivariate analyses were used to identify risk factors for neonatal asphyxia. R software (4.2.2) was used to establish a nomogram model. Receiver operator characteristic curve, calibration curve, and decision curve analysis were used to assess the discrimination, calibration, and clinical usefulness of the model for predicting the risk of neonatal asphyxia, respectively. RESULTS: Multivariate logistic regression analysis showed that minority (Tujia), male sex, premature birth, congenital malformations, abnormal fetal position, intrauterine distress, maternal occupation as a farmer, education level below high school, fewer than 9 prenatal check-ups, threatened abortion, abnormal umbilical cord, abnormal amniotic fluid, placenta previa, abruptio placentae, emergency caesarean section, and assisted delivery were independent risk factors for neonatal asphyxia (P<0.05). The area under the curve of the model for predicting the risk of neonatal asphyxia based on these risk factors was 0.748 (95%CI: 0.723-0.772). The calibration curve indicated high accuracy of the model for predicting the risk of neonatal asphyxia. The decision curve analysis showed that the model could provide a higher net benefit for neonates at risk of asphyxia. CONCLUSIONS: The risk factors for neonatal asphyxia in Hubei Enshi Tujia and Miao Autonomous Prefecture are multifactorial, and the nomogram model based on these factors has good value in predicting the risk of neonatal asphyxia, which can help clinicians identify neonates at high risk of asphyxia early, and reduce the incidence of neonatal asphyxia.

An increased posterior tibial slope is associated with a higher risk of graft failure following ACL reconstruction: a systematic review.

PURPOSE: The posterior tibial slope (PTS) is considered a risk factor for anterior cruciate ligament (ACL) injury. However, the influence of PTS on graft failure following ACL reconstruction remains relatively unknown. Therefore, this systematic review was conducted to investigate whether PTS could be a potential risk factor for graft failure after ACL reconstruction. METHODS: PubMed, EMBASE, Cochrane Library, Web of Science, China National Knowledge Infrastructure Database, and Wanfang Database were comprehensively searched from inception to March 31, 2021. Observational studies reporting the associations of medial tibial plateau slope (MTPS) or lateral tibial plateau slope (LTPS) with graft failure after ACL reconstruction were evaluated. RESULTS: Twenty studies involving 12 case-control studies, 4 retrospective studies and 4 cross-sectional studies including 5326 patients met the final inclusion criteria. The high heterogeneity and the characteristics of nonrandomized controlled trials limited data synthesis. Fifteen of the 20 included studies detected a significant association between increased PTS and ACL graft failure, while 5 studies concluded that increased PTS was not associated with ACL graft failure. Ten studies suggested that MTPS is associated with ACL graft failure, and six studies suggested that LTPS is associated with ACL graft failure. The mean MTPS values for nonfailure group ranged from 3.5° ± 2.5° to 14.4° ± 2.8°. For the graft failure group, MTPS ranged from 4.71° ± 2.41° to 17.2° ± 2.2°. The mean LTPS values for nonfailure group ranged from 2.9° ± 2.1° to 11.9° ± 3.0°. For the graft failure group, LTPS ranged from 5.5° ± 3.0° to 13.3° ± 3.0°. The reported PTS values that caused ACL graft failure was greater than 7.4° to 17°. CONCLUSION: Based on the current clinical evidence, increased PTS is associated with a higher risk of ACL graft failure after ACL reconstruction. Despite various methods of measuring PTS have high reliability, there is still vast disagreement in the actual value of PTS. LEVEL OF EVIDENCE: IV.

The mechanosensory and mechanotransductive processes mediated by ion channels and the impact on bone metabolism: A systematic review.

Mechanical environments were associated with alterations in bone metabolism. Ion channels present on bone cells are indispensable for bone metabolism and can be directly or indirectly activated by mechanical stimulation. This review aimed to discuss the literature reporting the mechanical regulatory effects of ion channels on bone cells and bone tissue. An electronic search was conducted in PubMed, Embase and Web of Science. Studies about mechanically induced alteration of bone cells and bone tissue by ion channels were included. Ion channels including TRP family channels, Ca2+ release-activated Ca2+ channels (CRACs), Piezo1/2 channels, purinergic receptors, NMDA receptors, voltage-sensitive calcium channels (VSCCs), TREK2 potassium channels, calcium- and voltage-dependent big conductance potassium (BKCa) channels, small conductance, calcium-activated potassium (SKCa) channels and epithelial sodium channels (ENaCs) present on bone cells and bone tissue participate in the mechanical regulation of bone development in addition to contributing to direct or indirect mechanotransduction such as altered membrane potential and ionic flux. Physiological (beneficial) mechanical stimulation could induce the anabolism of bone cells and bone tissue through ion channels, but abnormal (harmful) mechanical stimulation could also induce the catabolism of bone cells and bone tissue through ion channels. Functional expression of ion channels is vital for the mechanotransduction of bone cells. Mechanical activation (opening) of ion channels triggers ion influx and induces the activation of intracellular modulators that can influence bone metabolism. Therefore, mechanosensitive ion channels provide new insights into therapeutic targets for the treatment of bone-related diseases such as osteopenia and aseptic implant loosening.

CT Radiomics for the Prediction of Synchronous Distant Metastasis in Clear Cell Renal Cell Carcinoma.

PURPOSE: The aim of this study was to construct and verify a computed tomography (CT) radiomics model for preoperative prediction of synchronous distant metastasis (SDM) in clear cell renal cell carcinoma (ccRCC) patients. METHODS: Overall, 172 patients with ccRCC were enrolled in the present research. Contrast-enhanced CT images were manually sketched, and 2994 quantitative radiomic features were extracted. The radiomic features were then normalized and subjected to hypothesis testing. Least absolute shrinkage and selection operator (LASSO) was applied to dimension reduction, feature selection, and model construction. The performance of the predictive model was validated through analysis of the receiver operating characteristic curve. Multivariate and subgroup analyses were performed to verify the radiomic score as an independent predictor of SDM. RESULTS: The patients randomized into a training (n = 104) and a validation (n = 68) cohort in a 6:4 ratio. Through dimension reduction using LASSO regression, 9 radiomic features were used for the construction of the SDM prediction model. The model yielded moderate performance in both the training (area under the curve, 0.89; 95% confidence interval, 0.81-0.97) and the validation cohort (area under the curve, 0.83; 95% confidence interval, 0.69-0.95). Multivariate analysis showed that the CT radiomic signature was an independent risk factor for clinical parameters of ccRCC. Subgroup analysis revealed a significant connection between the SDM and radiomic signature, except for the lower pole of the kidney subgroup. CONCLUSIONS: The CT-based radiomics model could be used as a noninvasive, personalized approach for SDM prediction in patients with ccRCC.

High-density Lipoprotein Cholesterol Is Negatively Correlated with Bone Mineral Density and Has Potential Predictive Value for Bone Loss.

BACKGROUND: Many studies have shown that lipids play important roles in bone metabolism. However, the association between high-density lipoprotein cholesterol (HDL-C) and bone mineral density (BMD) is unclear. Therefore, this study aimed to investigate the linear or nonlinear relation between HDL-C levels and BMD and addressed whether the HDL-C levels had the potential values for predicting the risk of osteoporosis or osteopenia. METHODS: Two researchers independently extracted all information from the National Health and Nutrition Examination Survey (NHANES) database. Participants over 20 years of age with available HDL-C and BMD data were enrolled in the final analysis. The linear relationship between HDL-C levels and BMD was assessed using multivariate linear regression models. Moreover, the nonlinear relationship was also characterized by fitted smoothing curves and generalized additive models. In addition, the odds ratio (OR) for osteopenia and osteoporosis was evaluated with multiple logistic regression models. RESULTS: The weighted multivariable linear regression models demonstrated that HDL-C levels displayed an inverse association with BMD, especially among females and subjects aged 30 to 39 or 50 to 59. Moreover, the nonlinear relationship characterized by smooth curve fittings and generalized additive models suggested that (i) HDL-C levels displayed an inverted U-shaped relationship with BMD among women 30 to 39 or over 60 years of age; (ii) HDL-C levels exhibited a U-shaped association with BMD among women 20 to 29 or 50 to 59 years of age. In addition, females with high HDL levels (62-139 mg/dL) had an increased risk of osteopenia or osteoporosis. CONCLUSION: This study demonstrated that HDL-C levels exhibit an inverse correlation with BMD. Especially in females, clinicians need to be alert to patients with high HDL-C levels, which may indicate an increased risk of osteoporosis or osteopenia. For these patients, close monitoring of BMD and early intervention may be necessary.

Comparative effectiveness of Se translocation between low-Se and high-Se rice cultivars under Se fertilization.

The production of natural selenium (Se)-rich food by using a high-Se crop cultivar is beneficial to human health and environmental safety; however, the underlying mechanism of different Se-accumulation ability between high- and low-Se rice cultivars remains unclear. A low-grain-Se cultivar and high-grain-Se cultivar of rice were used as test materials, and two levels of Se (0 and 0.5 mg kg-1) were arranged in a randomized design containing twelve replicates. The dynamic changes of shoot Se concentration and accumulation, xylem sap Se concentration, shoot and grain Se distribution, Se transporters genes (OsPT2, Sultr1;2, NRT1.1B) expression of the high- and low-Se rice cultivars were determined. The shoot Se concentration and accumulation of the high-Se rice showed a greater degree of reduction than those of the low-Se rice during grain filling stage, indicating that leaves of high-Se rice served as a Se source and supplied more Se for the growth centre grain. The expression levels of OsPT2, NRT1.1B and Sultr1;2 in the high-Se rice cultivar were significantly higher than those in the low-Se rice cultivar, which indicated that the high-Se rice cultivar possessed better transport carriers. The distribution of Se in grain of the high-Se rice cultivar was more uniform, whereas the low-Se cultivar tended to accumulate Se in embryo end. The stronger reutilization of Se from shoots to grains promoted by increased transporters genes expression and optimized grain storage space may explain how the high-Se rice cultivar is able to accumulate more Se in grain.

[A clinical epidemiological investigation of neonatal acute respiratory distress syndrome in southwest Hubei, China].

OBJECTIVE: To investigate the clinical features and outcome of neonatal acute respiratory distress syndrome (ARDS) in southwest Hubei, China. METHODS: According to the Montreux definition of neonatal ARDS, a retrospective clinical epidemiological investigation was performed on the medical data of neonates with ARDS who were admitted to Department of Neonatology/Pediatrics in 17 level 2 or level 3 hospitals in southwest Hubei from January to December, 2017. RESULTS: A total of 7 150 neonates were admitted to the 17 hospitals in southwest Hubei during 2017 and 66 (0.92%) were diagnosed with ARDS. Among the 66 neonates with ARDS, 23 (35%) had mild ARDS, 28 (42%) had moderate ARDS, and 15 (23%) had severe ARDS. The main primary diseases for neonatal ARDS were perinatal asphyxia in 23 neonates (35%), pneumonia in 18 neonates (27%), sepsis in 12 neonates (18%), and meconium aspiration syndrome in 10 neonates (15%). Among the 66 neonates with ARDS, 10 neonates (15%) were born to the mothers with an age of ≥35 years, 30 neonates (45%) suffered from intrauterine distress, 32 neonates (49%) had a 1-minute Apgar score of 0 to 7 points, 24 neonates (36%) had abnormal fetal heart monitoring results, and 21 neonates (32%) experienced meconium staining of amniotic fluid. Intraventricular hemorrhage was the most common comorbidity (12 neonates), followed by neonatal shock (9 neonates) and patent ductus arteriosus (8 neonates). All 66 neonates with ARDS were treated with mechanical ventilation in addition to the treatment for primary diseases. Among the 66 neonates with ARDS, 10 died, with a mortality rate of 15% (10/66), and 56 neonates were improved or cured, with a survival rate of 85% (56/66). CONCLUSIONS: Neonatal ARDS in southwest Hubei is mostly mild or moderate. Perinatal asphyxia and infection may be the main causes of neonatal ARDS in this area. Intraventricular hemorrhage is the most common comorbidity. Neonates with ARDS tend to have a high survival rate after multimodality treatment.

[Incidence of neonatal asphyxia and contributing factors for the develpment of severe asphyxia in Hubei Enshi Tujia and Miao Autonomous Prefecture: a multicenter study].

OBJECTIVE: To investigate the incidence of neonatal asphyxia and possible contributing factors for the development of severe asphyxia in Hubei Enshi Tujia and Miao Autonomous Prefecture, China. METHODS: A total of 16 hospitals in Hubei Enshi Tujia and Miao Autonomous Prefecture were selected as research centers. A retrospective analysis was performed for the clinical data of 22 294 live births in these 16 hospitals from January to December, 2016 to investigate the incidence rate of neonatal asphyxia and possible contributing factors for the development of severe asphyxia. RESULTS: Of the 22 294 neonates born alive, 733 (3.29%) were diagnosed with neonatal asphyxia, among whom 627 had mild asphyxia and 106 had severe asphyxia. The neonates with low maternal education level, maternal anemia during pregnancy, chorioamnionitis, abnormal amniotic fluid, abnormal umbilical cord, placenta previa, placental abruption, Tujia Minority, preterm birth, and low birth weight had a higher incidence of severe asphyxia (P<0.05). CONCLUSIONS: The incidence rate of neonatal asphyxia in Hubei Enshi Tujia and Miao Autonomous Prefecture is higher. Low maternal education level, maternal anemia during pregnancy, chorioamnionitis, abnormal amniotic fluid, abnormal umbilical cord, placenta previa, placental abruption, Tujia Minority, preterm birth, and low birth weight may be related to the development of severe neonatal asphyxia.

MiR-7, miR-9 and miR-375 contribute to effect of Exendin-4 on pancreatic ß-cells in high-fat-diet-fed mice.

PURPOSE: The purpose of this study was to test whether glucagon-like peptide-1 (GLP-1) receptor activation preserved pancreatic ß-cells via the regulation of microRNAs and target genes in high-fat-diet-fed mice. METHODS: C57BL/6 male mice were simultaneously treated with high-fat-diet (HFD) and GLP-1 analogue, Exendin-4 (Ex-4) (3 µg/kg/day or 30 µg/kg/day), i.p. or vehicle, for consecutive 13 weeks. Fasting blood glucose, postprandial blood glucose, ΔI30/ΔG30, HOMA-IR and HOMA-% ß were measured in each group. Pancreatic ß-cell mass was assessed by immunohistochemistry. The expression of miRNAs and related downstream genes were investigated using quantitative real-time PCR. RESULTS: Thirteen weeks of Ex-4 treatment significantly reduced body weight and food intake in HFD-fed mice (P.

Characterization of HJ-PI01 as a novel Pim-2 inhibitor that induces apoptosis and autophagic cell death in triple-negative human breast cancer.

AIM: Pim-2 is a short-lived serine/threonine kinase, which plays a key role in metastasis of breast cancer through persistent activation of STAT3. Although the crystal structure of Pim-2 has been reported, but thus far no specific Pim-2-targeted compounds have been reported. In this study, we identified a novel Pim-2 inhibitor, HJ-PI01, by in silico analysis and experimental validation. METHODS: The protein-protein interaction (PPI) network, chemical synthesis, molecular docking, and molecular dynamics (MD) simulations were used to design and discover the new Pim-2 inhibitor HJ-PI01. The anti-tumor effects of HJ-PI01 were evaluated in human breast MDA-MB-231, MDA-MB-468, MDA-MB-436, MCF-7 cells in vitro and in MDA-MB-231 xenograft mice, which were treated with HJ-PI01 (40 mg·kg(-1)·d(-1), ig) with or without lienal polypeptide (50 mg·kg(-1)·d(-1), ip) for 10 d. The apoptosis/autophage-inducing mechanisms of HJ-PI01 were elucidated using Western blots, immunoblots, flow cytometry, transmission electron microscopy and fluorescence microscopy. RESULTS: Based on the PrePPI network, the potential partners interacting with Pim-2 in regulating apoptosis (160 protein pairs) and autophagy (47 protein pairs) were identified. Based on the structural characteristics of Pim-2, a total of 15 compounds (HJ-PI01 to HJ-P015) were synthesized, which showed moderate or remarkable anti-proliferative potency in the human breast cancer cell lines tested. The most effective compound HJ-PI01 exerted a robust inhibition on MDA-MB-231 cells compared with chlorpromazine and the pan-Pim inhibitor PI003. Molecular dynamics (MD) simulation revealed that HJ-PI01 had a good binding score with Pim-2. Moreover, HJ-PI01 (300 nmol/L) induced death receptor-dependent and mitochondrial apoptosis as well as autophagic death in MDA-MB-231 cells. In MDA-MB-231 xenograft mice, administration of HJ-PI01 remarkably inhibited the tumor growth and induced tumor cell apoptosis in vivo. Co-administration of HJ-PI01 with lienal polypeptide could improve the anti-tumor activity of HJ-PI01 and reduce its toxicity. CONCLUSION: The newly synthesized compound, HJ-PI01, can induce death receptor/mitochondrial apoptosis and autophagic cell death by targeting Pim-2 in human breast cancer cells in vitro and in vivo.

Identification of two candidate innate immune genes by transcriptional profiling and RNA interference in mouse mammary gland epithelial cells stimulated with lipopolysaccharide.

Mammary epithelial cells (MECs) play an important role in immune responses and inflammatory diseases such as mastitis, which is mainly attributed to the activation of Toll-like receptors and the release of cytokines. However, the overall change of gene expression and biological pathways of MECs to microbial factors stimulation remains unknown. Here, we analyzed the gene expression profile in mouse MECs treated with lipopolysaccharide (LPS) for 24 h. Microarray analysis revealed that about 1548 genes differentially expressed, these genes mainly involved in 346 gene ontology terms and 128 molecular pathways, and particularly, some innate immune-associated pathways were significant. By analyzing data for pathway relation network, we prioritized differentially expressed genes with respect to LPS. The importance of changes, indicating that RNA interference-mediated inhibition of two genes identified in this analysis, transforming growth factor beta 1 (Tgf-ß1) and platelet-derived growth factor B (Pdgfb), reduced interleukin (IL)-6 and tumor necrosis factor α production respectively, in gene expression was verified. These findings delineate mouse MECs gene response patterns induced by LPS and identify Tgf-ß1 and Pdgfb that have been closely related to innate immunity.

[Geinsten inhibits the proliferation of VCaP castration-resistant prostate cancer cells].

OBJECTIVE: To explore the inhibitory effect of genistein (GEN) on the proliferation of VCaP castration-resistant prostate cancer (CRPC) cells. METHODS: VCaP CRPC cells were treated with GEN at the concentrations of 0, 12.5, 25, 50, 100, and 200 µmol/L for 24, 48, and 72 hours followed by determination of their proliferation by CCK-8 assay and their cycle by flow cytometry. The expression of Ki-67 in the cells was detected by immunocytochemistry and the levels of PSA, Cyclin D1, PCNA, and P53 determined by Western blot. RESULTS: After 72 hours of treatment with GEN at 12.5, 25, 50, 100, and 200 µmol/L, the inhibition rates of the VCaP cells were (25.38±0.02)%, (31.14±0.29)%, (45.27±0.03)%, (52.19±0.05)%, and (68.21±0.19)%, respectively, all significantly higher than in the 0 µmol/L group (ï¼»10.08±0.02ï¼½%)(P<0.05). GEN caused the arrest of the VCaP cells in the G2/M phase (P<0.05) and inhibited the expression of Ki-67. The expressions of PSA, Cyclin D1, and PCNA were gradually down-regulated while that of P53 up-regulated with the increased concentration of GEN (P<0.05). CONCLUSIONS: GEN inhibits the proliferation of VCaP CRPC cells by arresting the cell cycle with related protein expression changes.

Chinese medicinal herbs for mumps.

BACKGROUND: Mumps is an infectious disease caused by the mumps virus. Chinese physicians generally believe that Chinese medicinal herbs are effective in alleviating symptoms and reducing the duration of mumps. Herbalists tend to develop a treatment plan according to the individual's symptoms. OBJECTIVES: To evaluate the effectiveness and safety of Chinese medicinal herbs combined with routine treatments for mumps. SEARCH METHODS: We searched CENTRAL (2015, Issue 1), MEDLINE (1948 to January week 4, 2015), EMBASE (1974 to February 2015), CINAHL (1981 to February 2015), AMED (1985 to April 2014), the Chinese Biomedical Database (CBM) (1980 to February 2015), China National Knowledge Infrastructure (CNKI) (1979 to February 2015), VIP Information (1989 to February 2015), and relevant databases of ongoing trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) of Chinese medicinal herbs for mumps (with or without complications). DATA COLLECTION AND ANALYSIS: Two review authors independently evaluated trial quality and conducted data extraction. We contacted the trial authors for missing data regarding participant allocation. Some trials allocated participants according to the participants' admission sequence, making it a pseudo-random allocation. None of the trials concealed participants' allocation or used blinding. MAIN RESULTS: We did not identify any eligible trials for inclusion. We identified 108 studies that claimed to use random allocation. We excluded 104 studies because the allocation methods the authors had used were not actually randomised. We were unable to contact the trial authors of the remaining four studies. These trials require further evaluation and have been allocated to the 'Studies awaiting classification' section. AUTHORS' CONCLUSIONS: We did not find any RCTs for or against Chinese herbal medicine used in the treatment of mumps. We hope more high-quality RCTs will be conducted in the future.

Chemokine CXCL16 expression suppresses migration and invasiveness and induces apoptosis in breast cancer cells.

BACKGROUND: Increasing evidence argues that soluble CXCL16 promotes proliferation, migration, and invasion of cancer cells in vitro. However, the role of transmembrane or cellular CXCL16 in cancer remains relatively unknown. In this study, we determine the function of cellular CXCL16 as tumor suppressor in breast cancer cells. METHODS: Expression of cellular CXCL16 in breast cancer cell lines was determined at both RNA and protein levels. In vitro and in vivo studies that overexpressed or downregulated CXCL16 were conducted in breast cancer cells. RESULTS: We report differential expression of cellular CXCL16 in breast cancer cell lines that was negatively correlated with cell invasiveness and migration. Overexpression of CXCL16 in MDA-MB-231 cells led to a decrease in cell invasion and migration and induced apoptosis of the cells; downregulation of CXCL16 in MCF-7 cells increased cell migration and invasiveness. Consistent with the in vitro data, CXCL16 overexpression inhibited tumorigenesis in vivo. CONCLUSIONS: Cellular CXCL16 suppresses invasion and metastasis of breast cancer cells in vitro and inhibits tumorigenesis in vivo. Targeting of cellular CXCL16 expression is a potential therapeutic strategy for breast cancer.

Association Between Heart Rate at Diagnosis and Long-Term Recurrence Risk of Pulmonary Embolism in a Historical Cohort Study of Elder Women.

To investigate the association between heart rate (HR) at diagnosis and long-term pulmonary embolism (PE) recurrence among elderly (≥ 50 year-old) female patients after acute PE (APE). Hospitalized patients with APE were grouped separately according to whether they experienced recurrent PE and whether the HR was < 80 beats/min. Logistic regression and COX regression analysis were employed to assess the risk of PE recurrence. Kaplan-Meier method was applied to compare the recurrence-free survival of PE recurrence. Eighty-five patients were included, including 24 ones with HR < 80 beats/min and 11 recurrent PE cases. The mean time of PE recurrence were 71.7 ± 26.9 months (n = 6) and 27.7 ± 25.2 months (n = 5) among the patients with low HR and with high HR, respectively (P < .001). The HR (< 80 beats/min) was a negative predictor of PE recurrence (OR 0.071 (0.090-0.572), P = .013; HR 0.091 (0.016-0.523), P = .007), even after the adjustment for age, BMI, albumin, risk stratification, surgery, immobility ≥ 4 days, the blood cells counts, bilirubin and complications. The cumulative recurrence-free rates of PE recurrence at the 1st-, 2nd-, 5th-, and 10th-years for the low HR group were 100%, 100%, 87.5%, and 58.3%, compared to the 1st-, 2nd-, and 3rd-years of 94.0%, 93.4%, and 48.0% for the high HR group (log-rank = 0.019). The low HR (< 80 beats/min at diagnosis) among elderly (≥ 50 years old) female patients at APE diagnosis would benefit to the long-term PE recurrence. But limited recurrent cases should be noted.

Association of GATA3 expression in triple-positive breast cancer with overall survival and immune cell infiltration.

Breast cancer remains a leading cause of cancer-related mortality among women, with triple-positive breast cancer (TPBC) being a particularly aggressive subtype. GATA binding protein 3 (GATA3) plays a crucial role in the luminal differentiation of breast epithelium and T-cell differentiation. However, the relationship between GATA3 and immune infiltration in TPBC remains unclear. This study collected and analyzed TPBC data from The Cancer Genome Atlas (TCGA), METABRIC, and GSE123845 databases. Univariate and multivariate Cox regression analyses, along with Kaplan-Meier survival analyses, were employed to assess the prognostic value of GATA3 and other clinical features. Subsequently, Gene Set Enrichment Analysis (GSEA) was conducted to explore the potential biological functions and regulatory mechanisms of GATA3 in TPBC. Additionally, ssGSEA analysis revealed the connection between GATA3 and immune infiltration. And the effects of neoadjuvant chemotherapy and immunotherapy on GATA3 expression were also explored. Finally, clinical samples were used to detect the relationship between GATA3 expression and tumor infiltrating lymphocyte (TIL) levels. Our results demonstrated that GATA3 was significantly overexpressed in TPBC tissues compared to normal tissues (P < 0.05). A positive correlation between GATA3 mRNA and protein levels was observed (R = 0.55, P < 0.05). Notably, high GATA3 expression was associated with poor overall survival (HR = 1.24, 95% confidence interval (CI) 1.25-11.76, P < 0.05). GSEA indicated significant enrichment of immune-related gene sets in low GATA3 expression groups. Furthermore, pathologic complete response (pCR) patients exhibited significantly lower GATA3 expression compared to residual disease (RD) patients. Mutation analysis revealed higher PIK3CA and TP53 mutation rates in high GATA3 expression groups. Finally, clinical validation data showed that the degree of TILs was significantly higher in the low GATA3 expression group. In conclusion, this study suggests that high GATA3 expression may be associated with poor prognosis and may reduce immune infiltration in TPBC.

Construction of core-shell magnetic metal-organic framework composites Fe3O4@MIL-101(Fe, Co) for degradation of RhB by efficiently activating PMS.

Low catalytic efficiency and catalyst recovery are the key factors limiting the practical application of advanced oxidation processes. In this work, a core-shell magnetic nanostructure Fe3O4@MIL-101(Fe, Co) was prepared via a simple solvothermal method. The core-shell structure and magnetic recovery performance were characterized by various technologies. The results of dye degradation experiments proved that within 10 minutes, the Fe3O4@MIL-101(Fe, Co)/PMS system can degrade more than 95% of 10 mg per L Rhodamine (RhB) at an initial pH of 7, which possesses higher catalytic activity than the Fe3O4/PMS system and the MIL-101(Fe, Co)/PMS system. The effects of initial solution pH and coexisting anions in water on the degradation of RhB were further discussed. The results showed that Fe3O4@MIL-101(Fe, Co) displayed excellent degradation efficiency in a wide pH range of 3-11 and capability of resisting coexisting anions. It is worth mentioning that after five cycles, the RhB removal rate can still be maintained at over 90% after 10 minutes of reaction. Free radical quenching experiments were further studied, confirming that ˙OH and SO4-˙ were involved in the degradation of RhB, while the dominating active free radical was SO4-˙. The possible reaction mechanism of the RhB degradation process was also inferred.