MicroRNA-122-5p promotes renal fibrosis and injury in spontaneously hypertensive rats by targeting FOXO3.

Hypertensive renal injury is accompanied by tubular interstitial fibrosis leading to increased risk for renal failure. This study aimed to explore the influences of miR-122-5p in hypertension-mediated renal fibrosis and damage. 14-week-old male SHR and WKY rats were randomly assigned to treat with rAAV-miR-122-5p or rAAV-GFP for 8 weeks. There were marked increases in miR-122-5p and Kim-1 levels and decreases in FOXO3 and SIRT6 levels in hypertensive rats. Transfection with rAAV-miR-122-5p triggered exacerbation of renal fibrosis, apoptosis and inflammatory injury in SHR, associated with downregulated levels of FOXO3, SIRT6, ATG5 and BNIP3 as well as upregulated expression of Kim-1, NOX4, CTGF, and TGF-ß1. In cultured primary mouse renal tubular interstitial fibroblasts, exposure to angiotensin II resulted in obvious downregulation of FOXO3, SIRT6, ATG5, BNIP3 and nitric oxide levels as well as augmented cellular migration, oxidative stress, and inflammation, which were exacerbated by miR-122-5p mimic while rescued by miR-122-5p inhibitor and rhFOXO3, respectively. Notably, knockdown of FOXO3 strikingly blunted cellular protective effects of miR-122-5p inhibitor. In summary, miR-122-5p augments renal fibrosis, inflammatory and oxidant injury in hypertensive rats by suppressing the expression of FOXO3. Pharmacological inhibition of miR-122-5p has potential therapeutic significance for hypertensive renal injury and fibrosis-related kidney diseases.

Predictors of mortality for patients with COVID-19 pneumonia caused by SARS-CoV-2: a prospective cohort study.

The aim of this study was to identify factors associated with the death of patients with COVID-19 pneumonia caused by the novel coronavirus SARS-CoV-2.All clinical and laboratory parameters were collected prospectively from a cohort of patients with COVID-19 pneumonia who were hospitalised to Wuhan Pulmonary Hospital (Wuhan City, Hubei Province, China) between 25 December 2019 and 7 February 2020. Univariate and multivariate logistic regression analysis revealed that age ≥65 years (OR 3.765, 95% CI 1.146­17.394; p=0.023), pre-existing concurrent cardiovascular or cerebrovascular diseases (OR 2.464, 95% CI 0.755­8.044; p=0.007), CD3+CD8+ T-cells ≤75 cells·µL−1 (OR 3.982, 95% CI 1.132­14.006; p<0.001) and cardiac troponin I ≥0.05 ng·mL−1 (OR 4.077, 95% CI 1.166­14.253; p<0.001) were associated with an increase in risk of mortality from COVID-19 pneumonia." has been corrected to: "Univariate and multivariate logistic regression analysis revealed that age ≥65 years (OR 3.765, 95% CI 1.201−11.803; p=0.023), pre-existing concurrent cardiovascular or cerebrovascular diseases (OR 2.464, 95% CI 1.279−4.747; p=0.007), CD3+CD8+ T-cells ≤75 cells·µL−1 (OR 3.982, 95% CI 1.761­9.004; p<0.001) and cardiac troponin I ≥0.05 ng·mL−1 (OR 4.077, 95% CI 1.778­9.349; p<0.001) were associated with an increase in risk of mortality from COVID-19 pneumonia. In a sex-, age- and comorbid illness-matched case-control study, CD3+CD8+ T-cells ≤75 cells·µL-1 and cardiac troponin I ≥0.05 ng·mL-1 remained as predictors for high mortality from COVID-19 pneumonia.We identified four risk factors: age ≥65 years, pre-existing concurrent cardiovascular or cerebrovascular diseases, CD3+CD8+ T-cells ≤75 cells·µL-1 and cardiac troponin I ≥0.05 ng·mL-1 The latter two factors, especially, were predictors for mortality of COVID-19 pneumonia patients.

Effect of Transcranial Alternating Current Stimulation for the Treatment of Chronic Insomnia: A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Clinical Trial.

BACKGROUND: Not all adults with chronic insomnia respond to the recommended therapeutic options of cognitive behavioral therapy and approved hypnotic drugs. Transcranial alternating current stimulation (tACS) may offer a novel potential treatment modality for insomnia. OBJECTIVES: This study aimed to examine the efficacy and safety of tACS for treating adult patients with chronic insomnia. METHODS: Sixty-two participants with chronic primary insomnia received 20 daily 40-min, 77.5-Hz, 15-mA sessions of active or sham tACS targeting the forehead and both mastoid areas in the laboratory on weekdays for 4 consecutive weeks, followed by a 4-week follow-up period. The primary outcome was response rate measured by the Pittsburgh Sleep Quality Index (PSQI) at week 8. Secondary outcomes were remission rate, insomnia severity, sleep onset latency (SOL), total sleep time (TST), sleep efficiency, sleep quality, daily disturbances, and adverse events at the end of the 4-week intervention and at the 4-week follow-up. RESULTS: Of 62 randomized patients, 60 completed the trial. During the 4-week intervention, 1 subject per group withdrew due to loss of interest and time restriction, respectively. Based on PSQI, at 4-week follow-up, the active group had a higher response rate compared to the sham group (53.4% [16/30] vs. 16.7% [5/30], p = 0.009), but remission rates were not different between groups. At the end of the 4-week intervention, the active group had higher response and remission rates than the sham group (p < 0.001 and p = 0.026, respectively). During the trial, compared with the sham group, the active group showed a statistically significant decrease in PSQI total score, a shortened SOL, an increased TST, improved sleep efficiency, and improved sleep quality (p < 0.05 or p < 0.001). Post hoc analysis revealed that, in comparison with the sham group, the active group had improved symptoms, except for daily disturbances, at the end of the 4-week intervention, and significant improvements in all symptoms at the 4-week follow-up. No adverse events or serious adverse responses occurred during the study. CONCLUSION: The findings show that the tACS applied in the present study has potential as an effective and safe intervention for chronic insomnia within 8 weeks.

[Research on Life Quality Scale for Patients with Idiopathic Pulmonary Fibrosis].

OBJECTIVE: To develop a life quality scale suitable for idiopathic pulmonary fibrosis (IPF) patients, objectively reflecting its changes. METHODS: Authors first put forward a theoretical structure model of a scale according to patient-reported outcome (PRO) scale formulation principle by combining basic theories of Chinese medicine (CM). Then authors developed an initial scale on the basis of various life quality scales for respiratory disease patients by using structural decision making. Totally 34 patients with confirmed diagnosis of IPF were tested by questionnaire. Items were screened using expert importance scoring method, factor analysis, correlation coefficient method, Cronbach's alpha coefficient method. IPF patient reported outcomes (IPF PRO, IP) were finally defined. RESULTS: A new IP scale was developed covering three areas and 38 items. Pearson correlation coefficient for correlation analysis of clinical symptom scores in ST-George Respiratory Questionnaire and IP scale was 0.828 (P < 0.01). Pearson correlation coefficient for correlation analysis of activity ability scores was 0.929 (P < 0.01). Pearson correlation coefficient for correlation analysis of total scores was 0.862 (P < 0.01). By reliability of IP scale itself (reliability) analysis, Cronbach's alpha coefficient was 0.713. By using factor analysis method for data analysis, KMO statistics was 0.902. CONCLUSION: IP scale fully reflected the connotation of IPF patients' quality of life, so it could be used as CM clinical therapeutic effect evaluation tool.

Inhibition of microglial activation contributes to propofol-induced protection against post-cardiac arrest brain injury in rats.

It has been suggested that propofol can modulate microglial activity and hence may have potential roles against neuroinflammation following brain ischemic insult. However, whether and how propofol can inhibit post-cardiac arrest brain injury via inhibition of microglia activation remains unclear. A rat model of asphyxia cardiac arrest (CA) was created followed by cardiopulmonary resuscitation. CA induced marked microglial activation in the hippocampal CA1 region, revealed by increased OX42 and P2 class of purinoceptor 7 (P2X7R) expression, as well as p38 MAPK phosphorylation. Morris water maze showed that learning and memory deficits following CA could be inhibited or alleviated by pre-treatment with the microglial inhibitor minocycline or propofol. Microglial activation was significantly suppressed likely via the P2X7R/p-p38 pathway by propofol. Moreover, hippocampal neuronal injuries after CA were remarkably attenuated by propofol. In vitro experiment showed that propofol pre-treatment inhibited ATP-induced microglial activation and release of tumor necrosis factor-α and interleukin-1ß. In addition, propofol protected neurons from injury when co-culturing with ATP-treated microglia. Our data suggest that propofol pre-treatment inhibits CA-induced microglial activation and neuronal injury in the hippocampus and ultimately improves cognitive function. We proposed a possible mechanism of propofol-mediated brain protection after cardiac arrest (CA). CA induces P2X7R upregulation and p38 phosphorylation in microglia, which induces release of TNF-α and IL-1ß and consequent neuronal injury. Propofol could inhibit microglial activation and alleviate neuronal damage. Our results suggest propofol-induced anti-inflammatory treatment as a plausible strategy for therapeutic intervention in post-CA brain injury.

The systemic immune-inflammation index is significantly associated with the severity of silicosis: a 9-year retrospective study in Beijing.

Background: Silicosis shows an increasing trend with the development of new industries. However, the potential biomarkers for predicting the disease severity are lacking. A novel inflammatory marker, the systemic immune-inflammation Index (SII), has not been studied in silicosis. Methods: In this retrospective study, we used data from a big database platform of a tertiary general hospital in Beijing, which was established based on the electronic medical records of the hospital. The clinical data of adult patients diagnosed with silicosis at the Department of Occupational Medicine and Toxicology from 2013 to 2022 were collected. The data extracted from the database were in de-identified form. Only patients with a first diagnosis of silicosis and without conditions that might affect the parameters of routine blood tests were included in the analysis. Analyses were performed to assess the relationship between SII and the advanced stage of silicosis. Results: A total of 246 participants were included in the study. Most of the patients were exposed to silica particles during excavation and digging (n = 149, 60.6%). SII level was significantly higher in patients with advanced stages of silicosis. A multivariate logistic regression analysis revealed that a higher SII level was associated with the advanced stage of silicosis [odds ratio (OR) = 1.002; 95% confidence interval (CI): 1.000-1.003, p < 0.001] after adjusting for all covariates. The best cutoff value of SII was 444.1. The results of the subgroup analysis also showed a significant correlation between SII level over 444.1 and the advanced stage of silicosis in groups stratified by gender, history of smoking, and duration of silica exposure. Moreover, our results showed a significant but weak negative correlation between the level of SII and some lung function parameters in silicosis. Conclusion: Higher SII is associated with the advanced stage of silicosis and impaired lung function. More long-term, large-scale studies are needed to confirm these findings.

Integrated ribosome and proteome analyses reveal insights into sevoflurane-induced long-term social behavior and cognitive dysfunctions through ADNP inhibition in neonatal mice.

A growing number of studies have demonstrated that repeated exposure to sevoflurane during development results in persistent social abnormalities and cognitive impairment. Davunetide, an active fragment of the activity-dependent neuroprotective protein (ADNP), has been implicated in social and cognitive protection. However, the potential of davunetide to attenuate social deficits following sevoflurane exposure and the underlying developmental mechanisms remain poorly understood. In this study, ribosome and proteome profiles were analyzed to investigate the molecular basis of sevoflurane-induced social deficits in neonatal mice. The neuropathological basis was also explored using Golgi staining, morphological analysis, western blotting, electrophysiological analysis, and behavioral analysis. Results indicated that ADNP was significantly down-regulated following developmental exposure to sevoflurane. In adulthood, anterior cingulate cortex (ACC) neurons exposed to sevoflurane exhibited a decrease in dendrite number, total dendrite length, and spine density. Furthermore, the expression levels of Homer, PSD95, synaptophysin, and vglut2 were significantly reduced in the sevoflurane group. Patch-clamp recordings indicated reductions in both the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs). Notably, davunetide significantly ameliorated the synaptic defects, social behavior deficits, and cognitive impairments induced by sevoflurane. Mechanistic analysis revealed that loss of ADNP led to dysregulation of Ca 2+ activity via the Wnt/ß-catenin signaling, resulting in decreased expression of synaptic proteins. Suppression of Wnt signaling was restored in the davunetide-treated group. Thus, ADNP was identified as a promising therapeutic target for the prevention and treatment of neurodevelopmental toxicity caused by general anesthetics. This study provides important insights into the mechanisms underlying social and cognitive disturbances caused by sevoflurane exposure in neonatal mice and elucidates the regulatory pathways involved.

[Proportion and prevention of venous thromboembolism among hospitalized patients with acute exacerbation of chronic obstructive pulmonary disease in Beijing].

OBJECTIVE: To explore the proportion and prevention status of venous thromboembolism (VTE) among hospitalized patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in Beijing. METHODS: Based on a multi-center retrospective study, a total of 636 hospitalized AECOPD patients from 17 class 2/3 hospitals in Beijing were examined from September 1, 2011 to March 31, 2012. They fulfilled one of the following criteria: respiratory failure type II, on invasive or non-invasive mechanical ventilation, hospitalization for pulmonary infection, bedridden duration ≥ 3 days and congestive heart failure. All investigators received standardized training and used a standardized questionnaire to collect data on VTE risk factors, the diagnosis of VTE and the utilization of VTE prophylaxis. According to Caprini score, they were categorized into 3 groups of lower risk (Caprini score ≤ 3), moderate risk (Caprini score 4-6) and high risk ( ≥ 7) to compare the intergroup differences in the VTE proportion and the utilization of VTE prophylaxis. RESULTS: A total of 636 patients were assessed. There were 416 males and 220 females with a mean (SD) age of 74.9 ± 9.3 years. Among them, 133 patients received lower extremity venous ultrasonic examination and 92 were diagnosed with deep venous thrombosis (DVT) including 2 patients with pulmonary thromboembolism (PTE). Thus the overall incidence of VTE was 14.5% (92/636) and increased with age (Ptrend = 0.044). The proportion of VTE in asymptomatic patients was higher in those symptomatic ones (21.1% vs 8.0%, P = 0.000). And it was the highest in high risk group, followed by lower risk and moderate risk groups at 17.9% (14/78), 16.0% (26/163) and 13.2% (52/395) respectively, There was no statistical significance (P = 0.450 for group difference, Ptrend = 0.946). Among 544 patients without VTE, only 19.1% (104/544) employed the pharmacologic and/or mechanical methods for preventing VTE. The prevention proportion gradually increased with rising Caprini score, i.e. 17.5%, 18.4% and 26.6% for lower, moderate and higher risk group respectively. There was no statistical significance (P = 0.266 for group difference, Ptrend = 0.201). CONCLUSIONS: The proportion of VTE is relatively higher. However, the preventive methods are significantly underutilized among hospitalized AECOPD patients in Beijing.

[Analysis of clinical features among severe or critical pregnant women in different trimesters with 2009 pandemic H1N1 infection].

OBJECTIVE: To explore the disease course and outcomes of severe or critical pregnant women with 2009 pandemic H1N1 (pH1N1) infection in China. METHODS: A retrospective observational study was conducted for 394 severe or critical pregnant women with pH1N1 influenza admitted into hospital in 27 Chinese provinces from September 1, 2009 to December 31, 2009. Their clinical features in different trimesters were analyzed. The viral infection of pH1N1 was verified by real-time reverse transcription (rRT)-PCR. Severe and critical cases were defined according to the 2009 H1N1 clinical guidelines. RESULTS: Among them, 374 (94.9%) were infected in the second or third trimester. Fever and cough were the most common symptoms in all trimesters. However, hemoptysis, dyspnea and associated pneumonia were likely to occur in the second or third trimester. The ratio of required mechanical ventilation in the second or third trimester (44.7%, 167/374) was significantly higher than that in the first trimester (3/20). Among 77 mortality cases, 72.7% (56/77) died in the third trimester. Pregnancy was terminated after the onset of pH1N1 symptoms in 52.5%(207/394) pregnant women. And 57.0%(118/207) of them had delivery < 37 weeks and 29.0%(60/207) fetuses deceased. CONCLUSION: A clinician should be on a high alert for pH1N1 infection in pregnant women, particularly in the second or third trimester.

Elabela blunts doxorubicin-induced oxidative stress and ferroptosis in rat aortic adventitial fibroblasts by activating the KLF15/GPX4 signaling.

Doxorubicin (DOX) is a chemotherapeutic drug for a variety of malignancies, while its application is restricted by the cardiovascular toxic effects characterized by oxidative stress. Ferroptosis is a novel iron-dependent regulated cell death driven by lipid peroxidation. Our study aimed to investigate the role of Elabela (ELA) in DOX-induced oxidative stress and ferroptosis. In cultured rat aortic adventitial fibroblasts (AFs), stimulation with DOX dramatically induced cytotoxicity with reduced cell viability and migration ability, and enhanced lactate dehydrogenase (LDH) activity. Importantly, ELA and ferrostatin-1 (Fer-1) mitigated DOX-mediated augmentation of reactive oxygen species (ROS) in rat aortic AFs, accompanied by upregulated levels of Nrf2, SLC7A11, GPX4, and GSH. In addition, ELA reversed DOX-induced dysregulation of apoptosis- and inflammation-related factors including Bax, Bcl2, interleukin (IL)-1ß, IL6, IL-10, and CXCL1. Intriguingly, knockdown of Krüppel-like factor 15 (KLF15) by siRNA abolished ELA-mediated alleviation of ROS production and inflammatory responses. More importanly, KLF15 siRNA impeded the beneficial roles of ELA in DOX-pretreated rat aortic AFs by suppressing the Nrf2/SLC7A11/GPX4 signaling. In conclusion, ELA prevents DOX-triggered promotion of cytotoxicity, and exerts anti-oxidative and anti-ferroptotic effects in rat aortic AFs via activation of the KLF15/GPX4 signaling, indicating a promising therapeutic value of ELA in antagonizing DOX-mediated cardiovascular abnormality and disorders.

Traditional Chinese medicine for smoking cessation: An umbrella review of systematic reviews and meta-analysis of randomized controlled trials.

INTRODUCTION: Traditional Chinese medicine (TCM) may have special advantages in facilitating smoking cessation, but consensus on effectiveness is lacking. We aim to comprehensively review, update, and refine current evidence on TCM effectiveness and safety. METHODS: Nine databases were searched from their inception up to 28 February 2023. Systematic reviews (SRs) and meta-analysis of TCM for smoking cessation were identified and retrieved. Additional databases and hand searches of RCTs from included SRs were performed for data pooling. Cochrane ROB tools and AMSTAR-2 were used to evaluate the methodological quality of RCTs and SRs, respectively. RCT data are presented as relative risks (RR) or mean differences (MD) with 95% confidence intervals (CI) using RevMan 5.4. RESULTS: Thirteen SRs involving 265 studies with 33081 participants were included. Among these 265 studies, 157 were duplicates (58.36%) and 52 were non-RCTs (19.62%). Combined with the remaining 56 RCTs identified through hand searches, 88 RCTs involving 12434 participants were finally included for data synthesis. All the SRs focused on acupoint stimulation, and the majority were of low or very low quality. The methodological quality of RCTs was either unclear or high risk. For continuous abstinence rate, TCM external interventions were better than placebo in 6 months to 1 year (RR=1.60; 95% CI: 1.14-2.25; I2=27%; n=5533 participants). Compared with placebo, TCM external application was effective in reducing nicotine withdrawal symptoms, and the effect was gradually stable and obvious in the fourth week (MD= -4.46; 95% CI: -5.43 - -3.49; n=165 participants). Twelve RCTs reported adverse events as outcome indicators for safety evaluation, and no serious adverse events occurred. CONCLUSIONS: Despite the methodological limitations of the original studies, our review suggests that TCM intervention shows potential effectiveness on the continuous abstinence rate. Extending the intervention time can enhance the effect of TCM on nicotine withdrawal symptoms. Referred to adverse events, more data for safety evaluation are required.

Clinical features and risk factors for severe and critical pregnant women with 2009 pandemic H1N1 influenza infection in China.

BACKGROUND: 2009 pandemic H1N1 (pH1N1) influenza posed an increased risk of severe illness among pregnant women. Data on risk factors associated with death of pregnant women and neonates with pH1N1 infections are limited outside of developed countries. METHODS: Retrospective observational study in 394 severe or critical pregnant women admitted to a hospital with pH1N1 influenza from Sep. 1, 2009 to Dec. 31, 2009. rRT-PCR testing was used to confirm infection. In-hospital mortality was the primary endpoint of this study. Univariable logistic analysis and multivariate logistic regression analysis were used to investigate the potential factors on admission that might be associated with the maternal and neonatal mortality. RESULTS: 394 pregnant women were included, 286 were infected with pH1N1 in the third trimester. 351 had pneumonia, and 77 died. A PaO(2)/FiO(2) ≤ 200 (odds ratio (OR), 27.16; 95% confidence interval (CI), 2.64-279.70) and higher BMI (i.e. ≥ 30) on admission (OR, 1.26; 95% CI, 1.09 to 1.47) were independent risk factors for maternal death. Of 211 deliveries, 146 neonates survived. Premature delivery (OR, 4.17; 95% CI, 1.19-14.56) was associated neonatal mortality. Among 186 patients who received mechanical ventilation, 83 patients were treated with non-invasive ventilation (NIV) and 38 were successful with NIV. The death rate was lower among patients who initially received NIV than those who were initially intubated (24/83, 28.9% vs 43/87, 49.4%; p = 0.006). Septic shock was an independent risk factor for failure of NIV. CONCLUSIONS: Severe hypoxemia and higher BMI on admission were associated with adverse outcomes for pregnant women. Preterm delivery was a risk factor for neonatal death among pregnant women with pH1N1 influenza infection. NIV may be useful in selected pregnant women without septic shock.

Oseltamivir compared with the Chinese traditional therapy maxingshigan-yinqiaosan in the treatment of H1N1 influenza: a randomized trial.

BACKGROUND: Observational studies from Asia suggest that maxingshigan-yinqiaosan may be effective in the treatment of acute H1N1 influenza. OBJECTIVE: To compare the efficacy and safety of oseltamivir and maxingshigan-yinqiaosan in treating uncomplicated H1N1 influenza. DESIGN: Prospective, nonblinded, randomized, controlled trial. (ClinicalTrials.gov registration number: NCT00935194) SETTING: Eleven hospitals from 4 provinces in China. PATIENTS: 410 persons [corrected] aged 15 to 69 [corrected] years with laboratory-confirmed H1N1 influenza. INTERVENTION: Oseltamivir, 75 mg twice daily; maxingshigan-yinqiaosan decoction (composed of 12 Chinese herbal medicines, including honey-fried Herba Ephedrae), 200 mL 4 times daily; oseltamivir plus maxingshigan-yinqiaosan; or no intervention (control). Interventions and control were given for 5 days. MEASUREMENTS: Primary outcome was time to fever resolution. Secondary outcomes included symptom scores and viral shedding determined by using real-time reverse transcriptase polymerase chain reaction. RESULTS: Significant reductions in the estimated median time to fever resolution compared with the control group (26.0 hours [95% CI, 24.0 to 33.0 hours]) were seen with oseltamivir (34% [95% CI, 20% to 46%]; P < 0.001), maxingshigan-yinqiaosan (37% [CI, 23% to 49%]; P < 0.001), and oseltamivir plus maxingshigan-yinqiaosan (47% [CI, 35% to 56%]; P < 0.001). Time to fever resolution was reduced by 19% (CI, 0.3% to 34%; P = 0.05) with oseltamivir plus maxingshigan-yinqiaosan compared with oseltamivir. The interventions and control did not differ in terms of decrease in symptom scores (P = 0.38). Two patients who received maxingshigan-yinqiaosan reported nausea and vomiting. LIMITATIONS: Participants were young and had mild H1N1 influenza virus infection. Missing viral data precluded definitive conclusions about viral shedding. CONCLUSION: Oseltamivir and maxingshigan-yinqiaosan, alone and in combination, reduced time to fever resolution in patients with H1N1 influenza virus infection. These data suggest that maxingshigan-yinqiaosan may be used as an alternative treatment of H1N1 influenza virus infection. PRIMARY FUNDING SOURCE: Beijing Science and Technology Project and Beijing Nova Program.

Sirtuin 7 mitigates renal ferroptosis, fibrosis and injury in hypertensive mice by facilitating the KLF15/Nrf2 signaling.

Hypertension is one of the leading causes of chronic kidney disease characterized with renal fibrosis. This study aimed to investigate roles and mechanisms of sirtuin 7 (SIRT7) in hypertensive renal injury. Mini-pumps were implanted to male C57BL/6 mice to deliver angiotensin (Ang) Ⅱ (1.5 mg/kg/d) or saline for 2 weeks. Ang Ⅱ infusion resulted in marked increases in systolic blood pressure levels, renal ferroptosis and interstitial fibrosis in hypertensive mice, concomitantly with downregulated SIRT7 and Krüppel-like factor 15 (KLF15) levels. Notably, administration of recombinant adeno-associated virus-SIRT7 or ferroptosis inhibitor ferrostatin-1 effectively mitigated Ang Ⅱ-triggered renal ferroptosis, epithelial-mesenchymal transition (EMT), interstitial fibrosis, renal functional and structural injury in hypertensive mice by blunting the KIM-1/NOX4 signaling and enforcing the KLF15/Nrf2 and xCT/GPX4 signaling, respectively. In primary cultured mouse renal tubular epithelial cells (TECs), Ang Ⅱ pretreatment led to repressed SIRT7 expression and augmented ferroptosis as well as partial EMT, which were substantially antagonized by rhSIRT7 or ferrostatin-1 administration. Additionally, both Nrf2 inhibitor ML385 and KLF15 siRNA strikingly abolished the rhSIRT7-mediated beneficial roles in mouse renal TECs in response to Ang Ⅱ with reduced expression of Nrf2, xCT and GPX4. More importantly, ML385 administration remarkably amplified Ang Ⅱ-mediated ROS generation, lipid peroxidation and ferroptosis in renal TECs, which were significantly reversed by ferrostatin-1. In conclusion, SIRT7 alleviates renal ferroptosis, lipid peroxidation, and partial EMT under hypertensive status by facilitating the KLF15/Nrf2 signaling, thereby mitigating renal fibrosis, injury and dysfunction. Targeting SIRT7 signaling serves as a promising strategy for hypertension and hypertensive renal injury.

Targeting the microRNA-34a as a Novel Therapeutic Strategy for Cardiovascular Diseases.

Cardiovascular diseases (CVDs) are still the main cause of morbidity and mortality worldwide and include a group of disorders varying from vasculature, myocardium, arrhythmias and cardiac development. MicroRNAs (miRs) are endogenous non-coding RNAs with 18-23 nucleotides that regulate gene expression. The miR-34 family, including miR-34a/b/c, plays a vital role in the regulation of myocardial physiology and pathophysiological processes. Recently, miR-34a has been implicated in cardiovascular fibrosis, dysfunction and related cardiovascular disorders as an essential regulator. Interestingly, there is a pivotal link among miR-34a, cardiovascular fibrosis, and Smad4/TGF-ß1 signaling. Notably, both loss-of-function and gain-of-function approaches identified the critical roles of miR-34a in cardiovascular apoptosis, autophagy, inflammation, senescence and remodeling by modulating multifunctional signaling pathways. In this article, we focus on the current understanding of miR-34a in biogenesis, its biological effects and its implications for cardiac pathologies including myocardial infarction, heart failure, ischaemia reperfusion injury, cardiomyopathy, atherosclerosis, hypertension and atrial fibrillation. Thus, further understanding of the effects of miR-34a on cardiovascular diseases will aid the development of effective interventions. Targeting for miR-34a has emerged as a potential therapeutic target for cardiovascular dysfunction and related diseases.

[Association between the erythrocyte sedimentation rate, serum C-reactive protein and risk of lung cancer].

OBJECTIVE: To explore the association between the erythrocyte sedimentation rate, serum C-reactive protein (CRP) and the risk of lung cancer. METHODS: One hundred and three patients with newly diagnosed lung cancer and 85 homochronous hospitalized patients with chronic respiratory diseases (including chronic obstructive pulmonary disease, asthma, bronchiectasis and pulmonary fibrosis) were included in this study. ESR, serum levels of CRP, CEA, CA19-9 and CA125 were analyzed in the two groups before the initiation of any therapy after hospitalization. The association with clinicopathological characteristics of lung cancer and the risk of lung cancer were estimated by logistic regression. RESULTS: Both the ESR and CRP levels were significantly higher in the lung cancer group, as compared with that in the chronic respiratory diseases group (P < 0.001). There was no significant association of ESR and CRP with lung cancer stage and type. Spearman correlation analysis showed a positive correlation between ESR and CRP (r = 0.56, P < 0.001), ESR and CA125 (r = 0.33, P < 0.001), and CRP and CA125 (r = 0.32, P < 0.001). The results of multivariate logistic analysis showed that the level of CRP was associated with an increased risk of lung cancer. Adjusting the confounding factors such as age, gender and smoking condition, the risk increased along with the elevation of CRP. Compared with the first quantile patients, the risk of the second quantile patients increased twice (OR: 2.46, 95%CI: 1.16 - 5.20), the risk of the third quantile patients increased ten-fold (OR: 10.52, 95%CI: 4.40 - 25.18). CONCLUSION: The level of CRP is associated with an increased risk of lung cancer. The results of this study suggest that early detection of CRP may have a potential predicting value for high risk group of lung cancer.

[Prediction value of blood lipid levels on newly identified carotid plaque in middle-aged and elderly Chinese population].

OBJECTIVE: To evaluate the prediction value of blood lipid levels on the newly-identified carotid plaque in middle-aged and elderly Chinese population. METHODS: All study subjects were recruited from two cohorts from 2002 to 2007 [the People's Republic of China/United States of America collaborative study (USA-PRC study) and the Chinese multi-provincial cohort study (CMCS)]. The baseline examination including cardiovascular disease risk factors and B-mode ultrasound of carotid artery was performed in 2002 and the second examination was made in September to October, 2007. The relationship between baseline lipids and carotid plaque incidence was analyzed in a total of 2000 subjects aged 47 to 79 years (mean 63 years). RESULTS: (1) During these 5 years, the prevalence of carotid plaque increased from 30.3% to 62.2% and from 21.5% to 51.5% for men and women, respectively. The newly-identified carotid plaque incidence was 41.8% for men and 34.1% for women. (2) The incidence of artery plaque significantly increased in both sexes in proportion to increase of baseline total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), and total to high-density cholesterol ratio (TC/HDL-C) levels (P < 0.05 or P < 0.01). (3) Cross-stratification analysis of LDL-C, triglyceride (TG) and HDL-C for carotid plaque incidence indicated the existence of conjoint effects between LDL-C and HDL-C, LDL and TG, as well as between TG and HDL-C, on the increased incidence of carotid plaque. (4) Multi-factorial analysis showed that higher LDL-C, non-HDL-C and TC/HDL-C were independent risk factors for development of new carotid plaque [OR = 1.44 (95%CI = 1.07 - 1.94), OR = 1.45 (95% CI = 1.08 - 1.96), OR = 1.59(95% CI = 1.14 - 2.23) in men;OR = 1.47 (95% CI = 1.13 - 1.92), OR = 1.35 (95% CI = 1.04 - 1.75), OR = 1.64 (95% CI = 1.20 - 2.23) in women]. CONCLUSIONS: The prevalence of carotid plaque increased rapidly in this cohort between 2002 and 2007. Elevated LDL-C, non-HDL-C and TC/HDL-C levels were independent predictors of newly developed carotid plaque.

Long-term effect of clopidogrel in patients with and without diabetes: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Previous studies have shown that patients with diabetes mellitus (DM) respond poorly to clopidogrel treatment. AIM: To systematically evaluate the efficacy of clopidogrel for the treatment of acute coronary syndromes or ischemic stroke in patients with or without DM. METHODS: PubMed, the Cochrane Central Register of Controlled Trials, and EMBASE were searched from 1980 on 27 June 2019 to identify relevant randomized controlled trials that compared the effect of a combination of clopidogrel and aspirin with aspirin alone. A random-effects meta-analysis was used to estimate the hazard ratio (HR) and its 95% confidence interval (CI). Sensitivity analysis was performed using a fixed-effect model. The I 2 statistic was used to evaluate the heterogeneity of the study data. RESULTS: Six randomized controlled trials, comprising 43352 participants (13491 with and 29861 without DM) who had received antiplatelet therapy for ≥ 3 mo, were included in the meta-analysis. Compared with aspirin alone, a combination of clopidogrel and aspirin significantly reduced the risk of any cardiovascular event in patients without DM (HR = 0.78, 95%CI: 0.71-0.86, P < 0.001; I 2 = 23%, P = 0.26). Clopidogrel plus aspirin also significantly reduced cardiovascular risk in patients with DM, although the effect was smaller (HR = 0.89, 95%CI: 0.81-0.99, P = 0.030; I 2 = 0%, P = 0.74). Nevertheless, there was no significant difference in the efficacy of clopidogrel at reducing the risk of cardiovascular events in patients with DM vs those without (P for interaction = 0.062). CONCLUSION: Thus, the present study shows that the addition of clopidogrel to aspirin significantly lowers cardiovascular risk in patients with or without DM who have experienced ischemic cardiovascular disease. The beneficial effect of the addition of clopidogrel to aspirin for patients with DM was lower than that in patients without DM, although the modifying effect of DM did not reach significance.

Blood Eosinophilia and Its Stability in Hospitalized COPD Exacerbations are Associated with Lower Risk of All-Cause Mortality.

Purpose: Peripheral blood eosinophilic counts are susceptible to many factors and have variability over time. There are limited studies on association of blood eosinophilia with long-term mortality of chronic obstructive pulmonary disease (COPD) patients and these results remain controversial. Our aims were to explore the association of blood eosinophilia at index hospitalization and stability of blood eosinophilia stability over 5 years with all-cause mortality of patients hospitalized for acute exacerbation of COPD (AECOPD). Patients and Methods: Eight hundred twenty-nine patients hospitalized for AECOPD between 2013 and 2014 were included in this study and grouped into two groups according to blood eosinophil with 150 cells/µL used as the cutoff value to form eosinophilic and non-eosinophilic groups. Two hundred forty-one COPD inpatients with at least three blood eosinophils measured from different hospitalizations were used for analysis of longitudinally eosinophilic stability and divided into three groups according to the same cutoff value: predominantly (PE), intermittently (IE) and rarely (RE) eosinophilic groups. Cox regression analysis was used to determine the association of blood eosinophilia and all-cause mortality. Results: In patients hospitalized for AECOPD, 261 (31.5%) at baseline and 41 (17%) based on at least three measurements of blood eosinophils had increased blood eosinophils. For all-cause mortality, eosinophilic COPD patients at index hospitalization had a lower all-cause mortality compared with non-eosinophilic COPD patients (hazard ratio 0.77, 95% confidence interval 0.6-0.99, P=0.04). In patients readmitted for AECOPD by longitudinal eosinophil stability, with the RE group used as reference, the PE group was associated with a lower all-cause mortality of AECOPD patients (hazard ratio 0.43, 95% confidence interval 0.22-0.85, P=0.016), compared to the IE group (hazard ratio 0.72, 95% confidence interval 0.47-1.11, P=0.133). Conclusion: Patients with increased eosinophils (using eosinophil 150 cells/µL as a cutoff value), especially predominantly increased eosinophil levels based on multiple measurements, had a lower risk of all-cause mortality. Blood eosinophilia can be used as a biomarker in hospitalized COPD exacerbations for predicting the risk of all-cause mortality.