Proximity ligation initiated DNAzyme-powered catalytic hairpin assembly for sensitive and accurate microRNA analysis.

MicroRNAs (miRNAs) play a significant role in regulating diverse physiological processes, and are regarded as novel diagnostic biomarkers. However, the sensitive and reliable miRNA detection remains a huge challenge. Herein, we propose a proximity ligated initiated magnesium ion (Mg2+)-dependent DNAzyme-powered signal cascade for sensitive, accurate and reliable detection of miRNAs. Three signal amplification processes are involved in this approach, including the target miRNA recycle, DNAzyme powered substrate cleavage, and catalytic hairpin reaction (CHA). Based on this, the approach shows a low limit of detection of 523 aM and a wide detection range of 7 orders of magnitudes, which is comparable or superior to most of the former miRNA detection methods. In addition, the approach also possesses a high selectivity to target miRNA, suggesting a potential promising future of the approach for rapid detection of miRNAs in the application of developing novel tools for skin cancer diagnosis, and recovery evaluation.

The Epidemiology of Tinea Capitis in Guangxi Province, China.

The aim of this study was to analyze the epidemiological characteristics and pathogen spectrum of tinea capitis in Guangxi, southern China. A multicenter prospective descriptive study was conducted in 8 hospitals across Guangxi. From January 2019 to July 2022, one hundred seventy-one (171) patients diagnosed with tinea capitis were included. Demographic data, risk factors, and fungal data were collected. If necessary, species were further identified by morphological or molecular sequencing in the central laboratory. Of the 171 cases of tinea capitis, 74.3% occurred in patients aged 2-8 years. Children with tinea capitis were mainly boys (59.6%) and were more likely than adults to have a history of animal contact (44.2% vs. 33.3%) and zoophilic dermatophyte infection (76.9% vs. 46.7%, P = 0.008). The adults were mainly female (53%) and were more likely than children to have a history of infection with anthropophilic organisms (53.3% vs. 18.9%). The causative agents of tinea capitis in Guangxi were diverse, and the most common pathogen was Microsporum canis (M. cani, n = 98, 62%), followed by Trichophyton mentagrophytes (T. mentagrophytes n = 18, 11.4%) and Trichophyton tonsurans (T. tonsurans n = 12, 7.6%). In addition, tinea capitis caused by Nannizzia incurvata (N. incurvata) and Trichophyton verrucosum (T. verrucosum) was detected in the study. Notably, the proportion of patients with kerion in the study was 41.5% (n = 71), and most of those patients were children (n = 68), especially neglected children living in the rural mountainous areas of Guangxi, where they were unable to receive timely diagnosis and appropriate treatment. In conclusion, the causative agents of tinea capitis in Guangxi, South China, are diverse, and the incidence of kerion is high, indicating that diagnosis and treatment modalities in the region remain grossly inadequate. Clinicians and policy-makers should collaborate to adopt public health strategies to control the disease.

Prevalence And Correlation Analysis Between Post-Traumatic Stress Disorder And Analgesic Use In Survivors Of ICU In China.

Objectives: To investigate the prevalence of post-traumatic stress disorder in intensive care unit survivors, and disorder's correlation with analgesia use. METHODS: The single-centre retrospective cohort study was conducted at the First Affiliated Hospital of Jinan University, China, and comprised data from February 2021 to January 2022 related to patients of either gender aged =18 years who were admitted to the intensive care unit and were successfully transferred out to the general ward. Post- traumatic stress disorder Checklist-Civilian Version scale was used for follow-up within one month of getting transferred out of intensive care. Data was analysed using Empower Stats. RESULTS: Of the 121 patients with mean age 54.34±18.19 years, 52(43%) were positive for post-traumatic stress disorder; 32(61.5%) males and 20(38.5%) females with mean age 54.48±19.56 years.The remaining 69(57%) patients were negative; 40(58%) males and 29(42%) females with mean age 54.23±17.24 years (p>0.05). The positive rate of re- experiencing symptoms was noted in 68(56.20%) patients. Analgesia usage was positive in 61(50.4%) cases and negative in 60(49.6%) cases. Compared to the non-analgesic group, the risk of post-traumatic stress disorder occurrence in the analgesic group wassignificantly high (p=0.018). The duration of analgesia usage 24-48h was also significant (p=0.017). CONCLUSIONS: There was a high prevalence of post-traumatic stress disorder in intensive care unit survivors, which was affected by the use of analgesicsin intensive care settings.

A Novel Predictive Model Incorporating Ferroptosis-Related Gene Signatures for Overall Survival in Patients with Lung Adenocarcinoma.

BACKGROUND Lung adenocarcinoma (LUAD) is the predominant histological type of lung cancer with high morbidity and mortality. Ferroptosis is regarded as a new pattern of programmed cell death concerned with the progression of lung cancer characterized by lipid peroxidation. Nevertheless, the prognostic role of ferroptosis-related genes for LUAD warrant to be explored. MATERIAL AND METHODS RNA sequencing and relevant clinical patient data were obtained from public-access databanks. A prognostic model was constructed through the LASSO Cox regression in the cancer genome atlas cohort. The diagnostic value of the prognostic model was further evaluated in the gene expression omnibus cohort. RESULTS Most of the ferroptosis-related genes (69.9%) were differentially expressed between tumor and adjacent non-cancerous tissues. 43 differentially expressed genes showed a close association with the prognosis of LUAD patients (adjusted p-value <0.05). An 18-gene signature was built and applied to assign patients into high vs low-risk groups. Compared with the high-risk group, patients defined as the low-risk group suffered significantly prolonged OS. Both uni- and multivariate analyses demonstrated that the signature-based score served as a crucial role in influencing the OS of LUAD patients (hazard ratio >1, p<0.001). The immunity-related signaling pathway was enriched in the functional analysis and the infiltration of the immune cells showed a great difference between groups. CONCLUSIONS The predictive model could be applied for prognostic prediction for LUAD. Targeting ferroptosis could be a possible curative strategy against LUAD, and immunomodulation may be one of the potential mechanisms.

Integrating Network Pharmacology, Molecular Docking, and Experimental Validation to Investigate the Mechanism of (-)-Guaiol Against Lung Adenocarcinoma.

BACKGROUND Lung adenocarcinoma (LUAD) is the most common type of lung cancer, which poses a serious threat to human life and health. -(-)Guaiol, an effective ingredient of many medicinal herbs, has been shown to have a high potential for tumor interference and suppression. However, knowledge of pharmacological mechanisms is still lacking adequate identification or interpretation. MATERIAL AND METHODS The genes of LUAD patients collected from TCGA were analyzed using limma and WGCNA. In addition, targets of (-)-Guaiol treating LUAD were selected through a prediction network. Venn analysis was then used to visualize the overlapping genes, which were further condensed using the PPI network. GO and KEGG analyses were performed sequentially, and the essential targets were evaluated and validated using molecular docking. In addition, cell-based verification, including the CCK-8 assay, cell death assessment, apoptosis analysis, and western blot, was performed to determine the mechanism of action of (-)-Guaiol. RESULTS The genes included 959 differentially-expressed genes, 6075 highly-correlated genes, and 480 drug-target genes. Through multivariate analysis, 23 hub genes were identified and functional enrichment analyses revealed that the PI3K/Akt signaling pathway was the most significant. Experiment results showed that -(-)Guaiol can inhibit LUAD cell growth and induce apoptosis. Additional evidence suggested that the PI3K/Akt signaling pathway established an inseparable role in the antitumor processes of -(-)Guaiol, which is consistent with network pharmacology results. CONCLUSIONS Our results show that the effect of (-)-Guaiol in LUAD treatment involves the PI3K/Akt signaling pathway, providing a useful reference and medicinal value in the treatment of LUAD.

The effects of serum iron level without anemia on long-term prognosis of patients with coronary heart disease complicated with chronic heart failure: a retrospective cohort study.

The effects of serum iron level without anemia on long-term prognosis of patients with coronary heart disease (CHD) complicated with chronic heart failure (CHF) is still unclear. The objective of this study was to explore the effects of serum iron level without anemia on long-term prognosis of patients with CHD complicated with CHF. In this retrospective cohort study, 221 patients with CHD complicated with CHF were consecutively investigated. These patients were divided into three groups according to the tertiles of the serum iron level: low-iron group (n = 71), medium-iron group (n = 76) and high-iron group (n = 74). The overall serum iron without anemia was 13.0 ± 5.50 µmol/L and serum iron in each group was 7.58 ± 1.63 µmol/L, 11.94 ± 1.79 µmol/L, and 19.37 ± 3.81 µmol/L, respectively. Composite endpoint events were composed of major adverse cardiovascular and cerebrovascular events (MACCE), including recurrent heart failure, all-cause death, acute coronary syndrome (ACS) and ischemic stroke. The median follow-up duration was 239 days. After adjusting relevant confounding risk factors, we found that excessively low or high serum iron level is correlated to the MACCE in patients with CHD complicated with CHF and that the prognosis of patients with excessively high serum iron level is poorer than that of patients with excessively low serum iron level. We further revealed the effect of serum iron level on MACCE is U-shaped, but not linear relationship. Sensitivity analysis showed that the correlation between serum iron level and MACCE is stable. In addition, according to the test for interaction, the variables that modify the effect including CRP (P for interaction < 0.0001), diuretics (P for interaction = 0.0212) and antiplatelet drugs (P for interaction = 0.0167). This study showed that excessively low or high serum iron level without anemia is an independent risk factor of MACCE in patients with CHD complicating with CHF.

Influence of physical restraint on delirium of adult patients in ICU: A nested case-control study.

AIMS AND OBJECTIVES: To investigate the impact of physical restraint on delirium of adult patients in intensive care unit. BACKGROUND: Delirium is a common clinical syndrome in intensive care unit, correlated with various adverse clinical outcomes. Physical restraint is a precipitating factor for delirium; however, the effect of physical restraint on delirium, such as duration, number and appliance is still unclear. DESIGN: A nested case-control study. METHODS: A cohort of 593 intensive care unit patients were observed for 12 months, and 447 of them who received physical restraint were included for analysis. Delirium was assessed using the Confusion Assessment Method for the intensive care unit. During hospitalisation in intensive care unit, newly-onset delirium patients (the delirium group), and nondelirium patients of similar age, same gender, and conditions of mechanical ventilation and sedative drug usage (the nondelirium group) were included as the matching criteria. Patient data were acquired by reviewing medical and nursing electronic records. RESULTS: Among the 447 patients that had been physically restrained, 178 (39.8%) developed delirium. Delirium risk in patients with restraint ≥6 days was 26.30 times higher than in those <6 days. Patients who had two and three times of restraint had a 2.38-fold and 3.62-fold higher risk of delirium than those with one time of restraint. However, the appliance, site, time to apply and remove restraint had no effect on the incidence of delirium. CONCLUSIONS: The incidence of delirium is high when patients use physical restraint. Duration and number of restraint are positively related to delirium. Restrictions on the use of restraint in intensive care unit are required to reduce the occurrence of delirium. RELEVANCE TO CLINICAL PRACTICE: To reduce delirium risk of patients in intensive care unit, nurses need to assess the risk of physical restraint and consider alternative measures, thereby to achieve the minimisation of the use of restraint.

Meta-analysis of the association of HLA-DRB1 with rheumatoid arthritis in Chinese populations.

BACKGROUND: Individual studies have reported different results regarding the association of HLA alleles with RA in Chinese populations. This study was performed to systematically summarize results on the association of HLA-DRB1 with rheumatoid arthritis (RA) in China. METHODS: We examined the case-control studies concerned about the relationship between HLA-DRB1 and RA and differences of clinical and laboratory parameters between the HLA-DR4 (DR4)+ and DR4- in RA patients in Chinese populations. Odds ratios (ORs) and weighted mean difference (WMD) with corresponding 95% confidence intervals (CI) was used to describe the relationship. RESULTS: 22 studies with 1690 cases and 1793 controls were included. Chinese populations with RA had significantly higher frequencies of HLA-DRB1*04, *0401, *0404, *0405 and *0410 than controls (ORDRB1*04 =4.19, 95% CI =3.44-5.11, p<0.00001; ORDRB1*0401 =2.53, 95% CI =1.54-4.16, p=0.0003; ORDRB1*0404 =2.28, 95% CI =1.28-4.06, p=0.005; ORDRB1*0405=3.71, 95% CI =2.52-5.45, p<0.00001; ORDRB1*0410 =2.99, 95% CI =1.25-7.14, p=0.01 respectively). As to laboratory parameters, Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Rheumatoid factor (RF), Anti-cyclic citrullinated peptide antibodies (Anti-CCP ) in patients with DR4+ were higher than patients with DR4- (WMD=0.26, 95% CI =0.15-0.37, p<0.00001; WMD = 0.26, 95% CI =0.12-0.41, p=0.0005; WMD = 0.44, 95% CI =0.23-0.65, p<0.00001; WMD = 0.58, 95% CI =0.24-0.91, p=0.0007 respectively). As to clinical features, there was no difference in duration of morning stiffness, number of swollen joints, number of joint tenderness, X-ray phases and joint function between the DR4+ and DR4- in RA patients. CONCLUSIONS: It was found that HLA-DRB1*04, *0401, *0404, *0405 and *0410 are risk factors for RA in Chinese populations. ESR, CRP, RF, Anti-CCP are different between the DR4+ and DR4- in RA patients in Chinese populations, while there's no difference for indexes of clinical features.

Elucidation of the anti-lung cancer mechanism of Juan-Liu-San-Jie prescription based on network pharmacology and experimental validation.

Lung cancer is a malignancy characterized by high morbidity and mortality, with lung adenocarcinoma being the most prevalent subtype. Our preliminary studies have demonstrated that the Juan-Liu-San-Jie (JLSJ) prescription, a Traditional Chinese Medicine prescription, possesses anti-lung adenocarcinoma cancer properties. However, the molecular mechanism underlying the therapeutic effects of the JLSJ prescription for lung adenocarcinoma remains incompletely elucidated. To address the knowledge gap, the present study employed network pharmacology to identify potential therapeutic targets. Specifically, the study utilized TCMSP, TCMID, and related references, as well as ChemMapper, to identify and predict the main active components and potential targets. Additionally, differentially expressed genes associated with the disease were obtained from the microarray dataset GSE19804 and GSE118370. The protein-protein Interaction network and Target-pathway network were then constructed. We also conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, and subsequently presented the top 20 enriched pathways. The results indicated that the anti-lung cancer effects of JLSJ prescription may be attributed to its ability to mediate apoptosis of tumor cells, potentially through the PI3K/Akt signaling pathway. Then, a series of in vitro and in vivo experiments were conducted to validate the molecular mechanism predicted by network pharmacology. The findings of the in vivo study suggested that the JLSJ prescription could inhibit the growth of xenograft tumors of lung adenocarcinoma with fewer adverse effects. Also, the in vitro experiments corroborated that the JLSJ prescription could induce apoptosis of A549 cells. Furthermore, the upregulation of pro-apoptosis-related proteins and mRNAs, coupled with the downregulation of anti-apoptotic-related proteins and mRNAs, was observed. In conclusion, inducing apoptosis by inhibiting the PI3K/Akt signaling pathway was one of the underlying mechanisms by which the JLSJ prescription exerted its anti-lung adenocarcinoma effect.

To Explore the Mechanism of "Fuzi-Guizhi" for the Treatment of Osteoarthritis on the Basis of Network Pharmacology and Molecular Docking.

OBJECTIVE: The objective of this study is to analyze and verify the main drug components and targets of "Fuzi-Guizhi" in the treatment of osteoarthritis by using the network pharmacology platform. METHODS: The integrated pharmacology of "Fuzi-Guizhi" was analyzed by using the platform of integrated pharmacology of traditional Chinese medicine to explore its mechanism in the treatment of osteoarthritis. By establishing an arthritis model in vitro, the pharmacological effect of "aconitecassia twigs" on articular cartilage was evaluated and conducted for molecular docking. RESULTS: 28 candidate active components, 37 compound targets, and 583 osteoarthritis-related potential targets were screened, and 10 key target processes were screened in the protein interaction network model. Enrichment analysis showed that the 10 core targets involved 958 GO biologic function items and 76 KEGG signal pathways, which were mainly related to apoptosis and mitochondrial functional metabolism and "Fuzi-Guizhi" drug-containing serum inhibited the expression of Caspase-3 mRNA and protein in chondrocytes and promoted the synthesis of ATP. CONCLUSION: Our research is preliminary that the mechanism of action of "Fuzi-Guizhi" may inhibit chondrocyte degeneration by resisting mitochondrial apoptosis, and further experimental research is required to determine.

Toxic vascular effects of polystyrene microplastic exposure.

Polystyrene microplastics (PSMPs) are some of the most common microplastic components, and the resulting pollution has become a global problem. Extensive studies have been conducted on the toxic effects of PSMPs on the heart, lungs, liver, kidneys, nerves, intestines and other tissues. However, the impact of PSMPs on vascular toxicity is poorly understood at present. The aim of this study was to reveal the vascular toxicity of microplastics (MPs). Patients were assigned to a calcification group (25 patients) or a non-calcification group (22 patients) based on the presence or absence of calcification in the thoracic aorta wall. We detected 7 polymer types in human feces. Patients with vascular calcification (VC) had higher levels of total MPs, polypropylene (PP) and polystyrene (PS) in feces than patients without VC. The thoracic aortic calcification score was significantly positively correlated with the total MP abundance (Spearman r = 0.8109, p < 0.0001), PP (Spearman r = 0.7211, p = 0.0160) and PS (Spearman r = 0.6523, p = 0.0471) in feces. We then explored the effects of PSMP exposure on normal and vitamin D3 + nicotine (VDN)-treated rats. PSMP exposure induced mild VC in normal rats and aggravated VC in VDN-treated rats. PSMP exposure disturbed the gut microbiota, causing Proteobacteria and Escherichia_Shigella to be the dominant phylum and genus, respectively. It also induced intestinal inflammatory responses in normal rats, aggravated intestinal inflammation in VDN-treated rats, impaired the intestinal mucosal barrier, and increased intestinal permeability. This study provides a theoretical basis for the risk assessment of MP-induced cardiovascular disease.

Solasonine Causes Redox Imbalance and Mitochondrial Oxidative Stress of Ferroptosis in Lung Adenocarcinoma.

Ferroptosis, a type of iron-dependent oxidative cell death caused by excessive lipid peroxidation, is emerging as a promising cancer therapeutic strategy. Solasonine has been reported as a potential compound in tumor suppression, which is closely linked to ferroptosis. However, ferroptosis caused by solasonine is insufficiently identified and elaborated in lung adenocarcinoma, a fatal disease with high morbidity and mortality rates. First, the biochemical and morphological changes in Calu-1 and A549 cells exposed to solasonine are observed using a cell death assay and a microscope. The cell viability assay is performed after determining the executive concentration of solasonine to assess the effects of solasonine on tumor growth in Calu-1 and A549 cells. The ferroptosis is then identified by using ferroptosis-related reagents on CCK-8, lipid peroxidation assessment, Fe2+, and ROS detection. Furthermore, the antioxidant system, which includes GSH, Cys, GPx4, SLC7A11, and mitochondrial function, is measured to identify the potential pathways. According to the results, solasonine precisely exerts antitumor ability in lung adenocarcinoma cells. Ferroptosis is involved in the solasonine-induced cell death, as well as the accumulation of lipid peroxide, Fe2+, and ROS. Moreover, the failures of antioxidant defense and mitochondrial damage are considered to make a significant contribution to the occurrence of ferroptosis caused by solasonine. The study describes the potential process of ferroptosis caused by solasonine when dealing with lung adenocarcinoma. This encouraging evidence suggests that solasonine may be useful in the treatment of lung cancer.

Beneficial effect of the short-chain fatty acid propionate on vascular calcification through intestinal microbiota remodelling.

BACKGROUND: Vascular calcification is a major cause of the high morbidity and mortality of cardiovascular diseases and is closely associated with the intestinal microbiota. Short-chain fatty acids (SCFAs) are derived from the intestinal microbiota and can also regulate intestinal microbiota homeostasis. However, it remains unclear whether exogenous supplementation with propionate, a SCFA, can ameliorate vascular calcification by regulating the intestinal microbiota. This study was conducted to explore the roles of propionate and the intestinal microbiota in the process of vascular calcification. METHODS: In total, 92 patients were enrolled consecutively as the observational cohort to analyse the relationship between SCFAs and vascular calcification in both blood and faecal samples. A rat model of vascular calcification was induced by vitamin D3 and nicotine (VDN) to validate the effect of propionate. Differences in the intestinal microbiota were analysed by 16S ribosomal RNA gene sequencing. Faecal microbiota transplantation and Akkermansia muciniphila transplantation experiments were performed to evaluate the functions of the intestinal microbiota. RESULTS: The results of the observational cohort study revealed that the levels of SCFAs (particularly propionate) in both blood and faecal samples independently correlated negatively with calcification scores (P < 0.01). To verify the activities of propionate, it was provided to VDN-treated rats, and oral or rectal propionate delivery reshaped the intestinal microbiota, resulted in elevated SCFA production, improved intestinal barrier function and alleviated inflammation, ultimately ameliorating vascular calcification. Furthermore, we demonstrated that transplantation of the propionate-modulated intestinal microbiota induced beneficial outcomes similar to those with oral or rectal propionate administration. Interestingly, linear discriminant analysis (LDA) effect size (LEfSe) revealed that oral or rectal propionate administration and propionate-modulated intestinal microbiota transplantation both enriched primarily Akkermansia. Subsequently, we demonstrated that Akkermansia supplementation could ameliorate VDN-induced vascular calcification in rats. CONCLUSIONS: Propionate can significantly ameliorate vascular calcification in VDN-treated rats, and this effect is mediated by intestinal microbiota remodelling. The findings in our study indicate that the intestinal tract-vessel axis is a promising target for alleviating vascular calcification. Video Abstract.

Sub-Health Status Survey and Influential Factor Analysis in Chinese during Coronavirus Disease 2019 Pandemic.

PURPOSE: This study aimed to investigate sub-health status (SHS) of people living in China during the Coronavirus disease 2019 (COVID-19) COVID-19 pandemic. COVID-19 is a severe acute respiratory syndrome coronavirus (SARS-CoV) infection-induced acute infectious disease, which is featured by universal susceptibility and strong infectivity, and SHS (a status of low quality health) refers to a status of low-quality health. COVID-19 has gradually developed into a global pandemic, making the public in a high stress situation in physiological, psychological and social states in the short term. METHODS: From March 6 to 11, 2020, a large-scale cross-sectional survey was conducted by convenient sampling, and SHS assessment scale was used in the questionnaire. The ordinal logistic regression analysis was used to identify the factors affecting SHS. RESULTS: In this study, 17,078 questionnaires were delivered with 16,820 effective questionnaires collected, and 10,715 subjects (63.7%) were found with SHS, with moderate SHS primarily. Physiological sub-scale scored the highest, followed by psychological and social sub-scales. Ordinal logistic regression analysis indicated that man, only-child, workers and farmers were risk factors of SHS. Protective factors of SHS included living in rural areas and townships, laid-off retirees and education degree. CONCLUSION: It shows many people in China place in a poor health status during COVID-19 pandemic. It is necessary that relevant departments pay more attention to people with poor health such as men, only-child, urban people, workers and farmers, and groups with high education degree during and after pandemic stabilization.

Incidence, risk factors, and cumulative risk of delirium among ICU patients: A case-control study.

OBJECTIVES: Delirium is a common acute cognitive impairment syndrome among intensive care unit (ICU) patients. This study was aimed to investigate the incidence, risk factors, and cumulative risk of delirium among ICU patients. METHODS: A case-control study including clinical records of 452 patients were retrospectively analyzed. Delirium was assessed using the Confusion Assessment Method for the ICU and Richmond Agitation-Sedation Scale. RESULTS: We found that 163 out of the 452 patients (36.1%) had delirium. Multivariate analysis showed that use of sedatives, length of ICU hospitalization, and physical restraint were independent risk factors for delirium. The additive effect of all three factors resulted to an odds ratio of 30.950. CONCLUSION: The incidence of delirium remained high. Thus, nurses shall strengthen the monitoring of delirium, regularly access the patient's level of calmness, and limit the use of physical restraint.

High Level of Lipoprotein(a) as Predictor for Recurrent Heart Failure in Patients with Chronic Heart Failure: a Cohort Study.

BACKGROUND: Elevated plasma levels of Lipoprotein(a) [Lp(a)] are recognized as a significant risk factor for atherosclerotic vascular disease. However, there are limited data regarding association between Lp(a) and recurrent heart failure (HF) in patients with chronic HF caused by coronary heart disease (CHD). OBJECTIVE: Elevated levels of Lp(a) might have a prognostic impact on recurrent HF in patients with chronic HF caused by CHD. METHODS: A total of 309 patients with chronic HF caused by CHD were consecutively enrolled in this study. The patients were divided into 2 groups according to whether Lp(a) levels were above or below the median level for the entire cohort (20.6 mg/dL): the high Lp(a) group (n = 155) and the low Lp(a) group (n = 154). A 2-sided p < 0.05 was statistically considered significant. RESULTS: During the median follow-up period of 186 days, 31 cases out of a total of 309 patients (10.03%) could not be reached during follow-up. A Kaplan-Meier analysis demonstrated that patients with higher Lp(a) levels had a higher incidence of recurrent HF than those with lower Lp(a) levels (log-rank < 0.0001). A multivariate Cox regression analysis revealed that Lp(a) levels were independently correlated with the incidence of recurrent HF after adjustment of potential confounders (hazard ratio: 2.720, 95 % confidence interval: 1.730-4.277, p < 0.0001). CONCLUSIONS: In Chinese patients with chronic HF caused by CHD, elevated levels of Lp(a) are independently associated with recurrent HF.

Identification of six key miRNAs associated with breast cancer through screening large-scale microarray data.

Breast Cancer (BC) is one of the most common primary malignant tumors, which is life threatening. Previous studies have demonstrated that microRNAs (miRNA) may regulate or affect the incidence of BC. However, results of these studies are inconsistent, due to factors including the different sequencing platforms and sample selection methods used. To explore the key miRNAs involved in the pathogenesis of BC, and to use these miRNAs to monitor the tumor progression of BC, a systematic review was performed on the previous studies examining BC miRNA; the function of the target genes that were modulated by these key miRNAs were also analyzed. A total of 8 representative miRNA datasets examining the pathogenesis of BC were selected. Key miRNAs were identified by comparing the overlap between these datasets. Then, the target genes of these key miRNAs were predicted through TargetScan. Furthermore, functional enrichment analysis of target genes and transcription factor (TF) binding analysis was also performed using the Database for Annotation, Visualization and Integrated Discovery and Tfacts database, respectively. A total of 6 key miRNAs were identified by comparing the differentially expressed miRNAs datasets in the pathogenesis of BC. Compared with normal tissues, 3 miRNAs were upregulated: Hsa-miR-21b; hsa-miR-29b; and hsa-miR-155; and 3 miRNAs were downregulated: Hsa-miR-10b; hsa-miR-125; and hsa-miR-145. The target genes regulated by the up- and downregulated miRNAs were significantly enriched in the biological processes of 'transcriptional regulation', and these target genes depended on RNA polymerase II promoter and DNA template, respective to the up- and downregulated genes. The downregulated key miRNAs were specifically enriched in the biological processes of 'ephrin receptor signaling pathway' (GO: 0048013) and 'axon guidance' (GO: 0007411). TF analysis of the key miRNA target genes revealed that 104 TFs interacted with the 319 target genes of the upregulated miRNAs, while the 92 TFs interacted with the 254 target genes of the downregulated miRNAs. In total, there were 133 TFs and 63 (47.3%) TFs shared by the 2 types (up- and downregulated) of target genes. In summary, 6 key miRNAs in BC were identified by systematic review; the corresponding target genes and TFs that bind to these target genes were also identified, and the potential functions of target genes were revealed. These data may be beneficial to increasing the accuracy of BC treatment through monitoring miRNA.

Chidamide, a histone deacetylase inhibitor-based anticancer drug, effectively reactivates latent HIV-1 provirus.

Although combination antiretroviral therapy (cART) is highly effective in suppressing human immunodeficiency virus type 1 (HIV-1) replication, it fails to eradicate the virus from HIV-1-infected individuals because HIV-1 integrates into the resting CD4+ T cells, establishing latently infected reservoirs. Histone deacetylation is a key element in regulating HIV-1 latent infection. Chidamide, a new anticancer drug, is a novel type of selective histone deacetylase inhibitor. Here we showed that chidamide effectively reactivated HIV-1 latent provirus in different latently infected cell lines in a dose- and time-dependent manner. Chidamide had relatively low cytotoxicity to peripheral blood mononuclear cells (PBMCs) and other latent cell lines. We have demonstrated that chidamide reactivated HIV-1 latent provirus through the NF-κB signaling pathway. The replication of the newly reactivated HIV-1 could then be effectively inhibited by the anti-HIV-1 drugs Zidovudine, Nevirapine, and Indinavir. Therefore, chidamide might be used in combination with cART for functional HIV-1 cure.

Icariin stimulates osteogenic differentiation and suppresses adipogenic differentiation of rBMSCs via estrogen receptor signaling.

Icariin (ICA) is a major active ingredient in Herba epimedii, which is commonly used as a Chinese herbal medicine for the treatment of osteoporosis. Previous studies have revealed that ICA exerted a protective effect against bone loss and increased bone regeneration; however, the association between ICA and estrogen receptor (ER) signaling remains unclear. The aim of the present study was to determine the effect of ICA on rat bone marrow stromal cells (rBMSCs). Cell Counting Kit­8 assays were conducted to measure proliferation, alkaline phosphatase (ALP) activity was evaluated to assess osteoblast differentiation, and reverse transcription­quantitative polymerase chain reaction as well as western blotting were performed to detect the expression of cellular and molecular markers of osteogenic or adipogenic differentiation. The results demonstrated that treatment of rBMSCs with 10­6 M ICA stimulated rBMSC proliferation and ALP activity. Furthermore, ICA treatment increased the expression of the osteogenic markers runt­related transcription factor 2, collagen type 1 and bone morphogenetic Protein 2; however, it also decreased the expression of the adipogenic differentiation markers peroxisome proliferator­activated receptor gamma and CCAAT/enhancer­binding protein α. Treatment of rBMSCs with ICI182780, an ER antagonist, blocked the effects of ICA. Taken together, these findings indicated that ICA may stimulate osteoblast differentiation and inhibit adipogenic differentiation via the activation of the ER signaling pathway. Therefore, ICA has the potential to serve as a therapeutic alternative for the prevention and treatment of osteoporosis.

Combining metformin and nelfinavir exhibits synergistic effects against the growth of human cervical cancer cells and xenograft in nude mice.

Human cervical cancer is the fourth most common carcinoma in women worldwide. However, the emergence of drug resistance calls for continuously developing new anticancer drugs and combination chemotherapy regimens. The present study aimed to investigate the anti-cervical cancer effects of metformin, a first-line therapeutic drug for type 2 diabetes mellitus, and nelfinavir, an HIV protease inhibitor, when used alone or in combination. We found that both metformin and nelfinavir, when used alone, were moderately effective in inhibiting proliferation, inducing apoptosis and suppressing migration and invasion of human cervical cell lines HeLa, SiHa and CaSki. When used in combination, these two drugs acted synergistically to inhibit the growth of human cervical cancer cells in vitro and cervical cancer cell xenograft in vivo in nude mice, and suppress cervical cancer cell migration and invasion. The protein expression of phosphoinositide 3-kinase catalytic subunit PI3K(p110α), which can promote tumor growth, was remarkably downregulated, while the tumor suppressor proteins p53 and p21 were substantially upregulated following the combinational treatment in vitro and in vivo. These results suggest that clinical use of metformin and nelfinavir in combination is expected to have synergistic antitumor efficacy and significant potential for the treatment of human cervical cancer.