Colchicine prevents ventricular arrhythmias vulnerability in diet-induced obesity rats.

AIMS: This study aimed to assess the role of colchicine in ventricular arrhythmias (VAs) induced by high fat diet (HFD)-fed rats. METHODS AND RESULTS: Male rats were divided into four groups: CTL, normal diet plus saline; CTC, normal diet plus colchicine; HFD, HFD plus saline; HFC: HFD plus colchicine. Metabolic parameters, ECG parameters, ventricular electrophysiological parameters, ventricular histology, Western blot and RT-qPCR were measured. Compared with the HFD group, colchicine treatment significantly improved metabolic parameters, reduced ventricular fibrosis, increased the expression of Cav1.2, Kv4.2, Nav1.5, and Cx43, reduced CaMKII, p-CaMKII, p-RyR2 (S2808), and p-RyR2 (S2814) expression in LV. Furthermore, colchicine inhibited the inflammatory responses, prolonged ventricular effective refractory period (ERP), reduced corrected QT interval (QTc) and Tpeak-Tend interval, so as to reduce the susceptibility to VAs in obesity rats. CONCLUSIONS: Colchicine could mitigate ventricular fibrosis, ventricular electrical remodeling, as well as the expression of ion channels, and inhibit obesity-induced inflammatory responses, which provides a new idea for colchicine to prevent VAs in obese individuals.

A Novel Human Acute Encephalitis Caused by Pseudorabies Virus Variant Strain.

BACKGROUND: Pseudorabies virus (PRV) is a common pathogen in multiple animal species, particularly in pigs. However, PRV infection in humans is rare and, to the best of our knowledge, PRV has never been isolated from human cases before. METHODS: Four acute encephalitis cases in humans were confirmed as PRV infection based on clinical symptoms, laboratory diagnosis, and metagenomic next-generation sequencing (mNGS). Cerebrospinal fluid (CSF) samples were collected and applied for virus isolation. Etiological and genetic characteristics of this PRV human isolate were further determined. RESULTS: The patients manifested respiratory dysfunction and acute neurological symptoms. The mNGS revealed PRV-specific nucleotide sequences in patients' CSF samples (7-6198 reads and 0.2446%-80.58% coverage). The PRV envelope glycoprotein B antibody, glycoprotein E antibody, and neutralizing antibody were positively detected. For the first time, a PRV strain, designated hSD-1/2019, was isolated and identified from a CSF sample, and transmission electron microscopy revealed that hSD-1/2019 had typical morphology similar to that of swine PRV. Phylogenetic analysis illustrated that hSD-1/2019 was genetically closest to those PRV variant strains currently circulating in pigs in China, and this strain showed similar etiological characteristics to Chinese PRV variant strains, while different from Chinese classical strain. Moreover, hSD-1/2019 showed high pathogenicity and induced acute neurological symptoms in pigs. CONCLUSIONS: A PRV strain was isolated from an acute human encephalitis case. This isolate showed close phylogenetic relationships and similar etiological characteristics to Chinese PRV variant strains, implying the great risk of PRV transmission from pigs to humans.

Tubular epithelial cells derived-exosomes containing CD26 protects mice against renal ischemia/reperfusion injury by maintaining proliferation and dissipating inflammation.

Ischemia-reperfusion injury (IR) is the leading cause of acute kidney injury (AKI). No effective drugs to treat IR-related AKI are currently available. Recent pre-clinical trials have evaluated the therapeutic potential of extracellular vesicles-exosomes to chronic kidney disease. Here, we found exosomes derived from the tubular epithelial cell in IR condition (ExoIR) enriched CD26, compared with control (ExoNormal). Tracking exosomes in vivo certified tubular epithelial cell uptake exosomes. We have isolated exosomes with overexpression of CD26 (ExoCD26+) from culture media from tubular epithelial cell line transferred by adenovirus vectors. After administration of exosomes (100 mg) or bovine serum albumin (BSA, equivalent protein control) in IR or sham operation mice after 72 h via tail vein injection, the renal function impairment and histology injury were relived in mice receiving ExoCD26+. Immunofluorescence staining with proliferating cell nuclear antigen revealed ExoCD26+ recovered proliferation of cells partly after IR injury. Cell cycle modulator, p53 and p21 were upregulated in IR mice receiving BSA control, ExoNormal, and ExoIR. ExoCD26+ significantly blunt this protein upregulation. Inflammatory cell infiltration and chemokine receptor (CXCR4) were dissipated in IR mice receiving ExoCD26+. Downstream chemokine of CXCR4, stromal derived factor-1 (SDF1) also decreased after administration of ExoCD26+ in IR mice. Finally, ExoCD26+ suppressed inundant collagenⅠ expression in IR kidney. In conclusion, Tubular epithelial cells derived-exosomes containing CD26 might be one of the therapy modes for IR-AKI by maintaining proliferation and dissipating inflammation.

The impact of COVID-19 on short-term prognosis of ST-segment elevation myocardial infarction patients receiving primary percutaneous coronary intervention in Wuhan China.

ST-segment elevation myocardial infarction (STEMI) is a common cardiovascular emergency for which timely reperfusion therapies are needed to minimize myocardial necrosis. The aim of this study was to investigate the impact of the COVID-19 pandemic and reorganization of chest pain centers (CPC) on the practice of primary percutaneous coronary intervention (PPCI) and prognosis of STEMI patients. This single-center retrospective survey included all patients with STEMI admitted to our CPC from January 22, 2020 to April 30, 2020 (during COVID-19 pandemic in Wuhan), compared with those admitted during the analogous period in 2019, in respect of important time points of PPCI and clinical outcomes of STEMI patients. In the present article, we observed a descending trend in STEMI hospitalization and a longer time from symptom onset to first medical contact during the COVID-19 pandemic as compared to the control period (4.35 h versus 2.58 h). With a median delay of 17 minutes in the door to balloon time (D2B), the proportion of in-hospital cardiogenic shock was significantly higher in the COVID-19 era group (47.6% versus 19.5%), and major adverse cardiac events (MACE) tend to increase in the 6-month follow-up period (14.3% versus 2.4%). Although the reorganization of CPC may prolong the D2B time, immediate revascularization of the infarct-related artery could be offered to most patients within 90 minutes upon arrival. PPCI remained the preferred treatment for patients with STEMI during COVID-19 pandemic in the context of timely implementation and appropriate protective measures.

Urinary exosomal CD26 is associated with recovery from acute kidney injury in intensive care units: a prospective cohort study.

OBJECTIVES: Currently there is no validated method to predict renal reversal and recovery after acute kidney injury (AKI). As exosomes have the potential for AKI prognosis and CD26 is involved in the mechanisms in AKI, this study aims to investigate whether urinary exosomal CD26 is associated with renal-related outcomes and explore its prospect as a novel prognosis biomarker. METHODS: This was a single-center, prospective cohort study. A total of 133 AKI patients and 68 non-AKI patients admitted to ICU in Qilu Hospital Shandong University from January 2017 to January 2018. Urine samples were collected at enrollment and the relative expression of CD26 (CD26 percentage) in urinary exosomes was examined, that was then categorized into a low-CD26 level and a high-CD26 level. RESULTS: CD26 percentage was significantly lower in the AKI cohort than in the control cohort. Within the AKI cohort, a high-CD26 level was associated with lower incidence of major adverse kidney events within 90 days, but higher incidence of reversal within 28 days. In AKI survivors, a high-CD26 level had a 4.67-, 3.50- and 4.66-fold higher odds than a low-CD26 level for early reversal, recovery and reversal, respectively, after adjustment for clinical factors. Prediction performance was moderate for AKI survivors but improved for non-septic AKI survivors. CONCLUSIONS: Urinary exosomal CD26 is associated with renal reversal and recovery from AKI and is thus a promising prognosis biomarker.

Listeria rhombencephalitis mimicking acute disseminated encephalomyelitis in a patient without predisposing medical conditions.

Listeria rhombencephalitis (L. rhombencephalitis) is an uncommon form of central nervous system infection caused by Listeria monocytogenes (LM). It often occurs to immunocompetent individuals. Here, we described the case of a 45-year-old female patient without medical histories, who presented for high-grade fever, headache, and focal neurological manifestations. She was initially empirically diagnosed with acute disseminated encephalomyelitis (ADEM) because of clinical symptoms, acute clinical course, and neuroimaging. However, the biochemical analysis of cerebral spinal fluid (CSF) questioned the diagnosis of ADEM. The final diagnosis of L. rhombencephalitis was based on CSF culture for LM. Thus, L. rhombencephalitis should be preferentially and empirically considered for a patient with significantly elevated lactic acid and moderately increased red cells in CSF at early time, accompanied with rapidly progressive neurological dysfunctions involved in the brain stem.

Serum 25-Hydroxyvitamin D and the risk of mortality in adult patients with Sepsis: a meta-analysis.

BACKGROUND: Vitamin D deficiency has been related to the risk of sepsis. However, previous studies showed inconsistent results regarding the association between serum 25-hydroxyvitamin D (25 (OH) D) and mortality risk in septic patients. We aimed to evaluate the relationship between serum 25 (OH) D at admission and mortality risk in adult patients in a meta-analysis. METHODS: Follow-up studies that provided data of multivariate adjusted relative risk (RR) between serum 25 (OH) D and mortality risk in septic patients were retrieved via systematic search of PubMed and Embase databases. A random effect model was used to pool the results. RESULTS: Eight studies with 1736 patients were included. Results of overall meta-analysis showed that lower 25 (OH) D at admission was independently associated with increased risk or mortality (adjusted RR: 1.93, p < 0.001; I2 = 63%) in patients with sepsis. Exploring subgroup association showed that patients with severe vitamin D deficiency (25 (OH) D < 10 ng/ml) was significantly associated with higher mortality risk (adjusted RR: 1.92, p < 0.001), but the associations were not significant for vitamin D insufficiency (25 (OH) D 20~30 ng/ml) or deficiency (25 (OH) D 10~20 ng/ml). Further analyses showed that the association between lower serum 25 (OH) D and higher mortality risk were consistent in studies applied different diagnostic criteria for sepsis (systemic inflammatory response syndrome, Sepsis-2.0, or Sepsis-3.0), short-term (within 1 month) and long-term studies (3~12 months), and in prospective and retrospective studies. CONCLUSIONS: Severe vitamin D deficiency may be independently associated with increased mortality in adult patients with sepsis. Large-scale prospective studies are needed to validate our findings.

Clinical characteristics of 116 hospitalized patients with COVID-19 in Wuhan, China: a single-centered, retrospective, observational study.

BACKGROUND: A cluster of acute respiratory illness, now known as Corona Virus Disease 2019 (COVID-19) caused by 2019 novel coronavirus (SARS-CoV-2), has become a global pandemic. Aged population with cardiovascular diseases are more likely be to infected with SARS-CoV-2 and result in more severe outcomes and elevated case-fatality rate. Meanwhile, cardiovascular diseases have a high prevalence in the middle-aged and elderly population. However, despite of several researches in COVID-19, cardiovascular implications related to it still remains largely unclear. Therefore, a specific analysis in regard to cardiovascular implications of COVID-19 patients is in great need. METHODS: In this single-centered, retrospective, observational study, 116 patients with laboratory-confirmed COVID-19 were enrolled, who admitted to the General Hospital of Central Theater Command (Wuhan, China) from January 20 to March 8, 2020. The demographic data, underlying comorbidities, clinical symptoms and signs, laboratory findings, chest computed tomography, treatment measures, and outcome data were collected from electronic medical records. Data were compared between non-severe and severe cases. RESULTS: Of 116 hospitalized patients with COVID-19, the median age was 58.5 years (IQR, 47.0-69.0), and 36 (31.0%) were female. Hypertension (45 [38.8%]), diabetes (19 [16.4%]), and coronary heart disease (17 [14.7%]) were the most common coexisting conditions. Common symptoms included fever [99 (85.3%)], dry cough (61 [52.6%]), fatigue (60 [51.7%]), dyspnea (52 [44.8%]), anorexia (50 [43.1%]), and chest discomfort (50 [43.1%]). Local and/or bilateral patchy shadowing were the typical radiological findings on chest computed tomography. Lymphopenia (lymphocyte count, 1.0 × 109/L [IQR, 0.7-1.3]) was observed in 66 patients (56.9%), and elevated lactate dehydrogenase (245.5 U/L [IQR, 194.3-319.8]) in 69 patients (59.5%). Hypokalemia occurred in 24 (20.7%) patients. Compared with non-severe cases, severe cases were older (64.0 years [IQR, 53.0-76.0] vs 56.0 years [IQR, 37.0-64.0]), more likely to have comorbidities (35 [63.6%] vs 24 [39.3%]), and more likely to develop acute cardiac injury (19 [34.5%] vs 4 [6.6%]), acute heart failure (18 [32.7%] vs 3 [4.9%]), and ARDS (20 [36.4%] vs 0 [0%]). During hospitalization, the prevalence of new onset hypertension was significantly higher in severe patients (55.2% vs 19.0%) than in non-severe ones. CONCLUSIONS: In this single-centered, retrospective, observational study, we found that the infection of SARS-CoV-2 was more likely to occur in middle and aged population with cardiovascular comorbidities. Cardiovascular complications, including new onset hypertension and heart injury were common in severe patients with COVID-19. More detailed researches in cardiovascular involvement in COVID-19 are urgently needed to further understand the disease.

Inhibition of cardiac hypertrophy by aromadendrin through down-regulating NFAT and MAPKs pathways.

Cardiac hypertrophy is a maladaptive response to pressure overload and it's an important risk factor for heart failure and other adverse cardiovascular events. Aromadendrin (ARO) has remarkable anti-lipid peroxidation efficacy and is a potential therapeutic medicine for the management of diabetes and cardiovascular diseases. In this study, we established the cardiac hypertrophy cell model in rat neonatal ventricular cardiomyocytes (RNVMs) with phenylephrine. The cell model was characterized by the increased protein synthesis and cardiomyocyte size, which can be normalized by ARO treatment in both concentration- and time-dependent manner. In transverse aortic constriction (TAC) induced cardiac hypertrophy model, ARO administration improved the impairment of cardiac function and alleviated the cardiac hypertrophy indicators, like ventricular mass/body weight, myocyte cross-sectional area, and the expression of ANP, BNP and Myh7. ARO treatment also suppressed the cardiac fibrosis and the correlated fibrogenic genes. Our further investigation revealed ARO could down-regulate pressure overload-induced Malondialdehyde (MDA) and 4-HNE expression, restore the decrease of GSH/GSSG ratio, meanwhile prevent nuclear translocation of NFAT and the activation of MAPKs pathways. Collectively, ARO has a protective effect against experimental cardiac hypertrophy in mice, suggesting its potential as a novel therapeutic drug for pathological cardiac hypertrophy.

Sphingosine-1-phosphate promotes the proliferation and attenuates apoptosis of Endothelial progenitor cells via S1PR1/S1PR3/PI3K/Akt pathway.

Sphingosine-1-phosphate (S1P) is a bioactive lysophospholipid that involves in numerous pathophysiological processes. Endothelial progenitor cells (EPCs) play a crucial role in endothelial repair and tumor angiogenesis. The aim of study was to determine the effects of S1P on proliferation and anti-apoptosis of EPCs and their signaling pathways. In this study, we showed that S1P, SEW2871 (a selective S1P receptor 1 (S1PR1) agonist), or CYM5541 (a selective S1P receptor 3 (S1PR3) allosteric agonist promotes the proliferation and attenuates apoptosis of bone marrow (BM)-derived EPCs. Futhermore, it was showed that S1P could promote EPCs proliferation, which could be significantly inhibited by pretreatment with CAY10444 (an S1PR3 antagonist), VPC23019 (a selective S1PR(1)/S1PR(3) antagonist), or LY294002 (a PI3K inhibitor). Moveover, we discovered that S1P could significantly attenuate H2 O2 -induced apoptosis and activation of caspase-3 in vitro, while W146 (an S1PR1 antagonist), VPC23019, or LY294002 could significantly increase the activation of caspase-3 and subsequent augmented apoptosis. Our results indicated that the protective effect of S1P is mediated by activating the PI3K/Akt pathway. In addition, S1P promotion of EPCs proliferation was observed to be mainly mediated through S1PR3 and attenuation of EPCs apoptosis induced by H2 O2 was mainly mediated through S1PR1; both of these effects are mediated by activating the PI3K/Akt pathway, which provides potentially useful therapeutic targets for coronary artery disease, diabetes mellitus, and cancer treatment.

Association of rs662799 in APOA5 with CAD in Chinese Han population.

BACKGROUND: CAD (Coronary Artery Disease) is a complex disease that influenced by various environmental and genetic factors. Previous studies have found many single nucleotide polymorphisms (SNPs) associated with the risk of CAD occurrence. However, the results are inconsistent. In this study, we aim to investigate genetic etiology in Chinese Han population by analysis of 7 SNPs in lipid metabolism pathway that previously has been reported to be associated with CAD. METHODS: A total of 631 samples were used in this study, including 435 CAD cases and 196 normal healthy controls. SNP genotyping were conducted via multiplex PCR amplifying followed by NGS (next-generation sequencing). RESULTS: Rs662799 in APOA5 (Apolipoprotein A5) gene was associated with CAD in Chinese Han population (Odds-ratio = 1.374, P-value = 0.03). No significant association was observed between the rest of SNPs and CAD. Stratified association analysis revealed rs5882 was associated with CAD in non-hypertension group (Odds-ratio = 1.593, P-value = 0.023). Rs1800588 was associated with CAD in smoking group (Odds-ratio = 1.603, P-value = 0.035). CONCLUSION: The minor allele of rs662799 was the risk factor of CAD occurrences in Chinese Han population.

Predictive Value of Serum Albumin Level for the Prognosis of Severe Sepsis Without Exogenous Human Albumin Administration: A Prospective Cohort Study.

BACKGROUND:: The prognostic significance of serum albumin levels in patients with sepsis has previously been reported; however, these studies have not excluded the potential confounding effect of exogenous albumin administration. In this study, we investigate the predictive value of serum albumin for the prognosis of severe sepsis without the interference of exogenous albumin administration. METHODS:: A prospective cohort study was conducted from April to November 2014 in the internal and surgical intensive care units of a tertiary care hospital. During the study period, due to a supply shortage, patients were not treated with human albumin. Serum albumin levels were measured, and laboratory and clinical data were collected at the onset of severe sepsis. Prognostic factors were analyzed using receiver operating characteristic curve and multivariate Cox proportional hazard regression analysis. Survival was assessed by Kaplan-Meier method. RESULTS:: One hundred sixteen patients were included in the study. The overall 28-day mortality was 26.7%. The most common infection sources were lower respiratory tract, abdomen/pelvis, and bloodstream. Compared to patients who survived, those who died had lower serum albumin levels and higher Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores. Receiver operating characteristic curves demonstrate that albumin level is a strong predictor of 28-day mortality, and the optimal cutoff value maximizing sensitivity and specificity is 29.2 g/L. Through multivariate Cox regression analysis, low serum albumin levels (<29.2 g/L) and APACHE II scores are identified as independent risk factors for mortality. Patients with lower serum albumin levels more often had abdominal/pelvic sources of infection, acute kidney or liver injury, septic shock, and higher APACHE II and SOFA scores. The 28-day survival rate was lower for patients with serum albumin below 29.2 g/L than for patients with serum albumin at or above this level. CONCLUSION:: Having excluded potential confounding effect of exogenous albumin administration, low serum albumin levels are associated with an increased risk of death in patients with severe sepsis.

Association of Interleukin-6 Genetic Polymorphisms and Environment Factors Interactions with Coronary Artery Disease in a Chinese Han Population.

OBJECTIVES: To investigate the influence of IL-6 single nucleotide polymorphisms (SNPs), additional gene-gene and gene-environment interactions on coronary artery disease (CAD) risk. METHODS: A total of 751 participants (429 CAD patients and 322 controls) were recruited in this study. Logistic regression analysis was conducted to evaluate the association of IL-6 SNPs with CAD risk and generalized multifactor dimensionality reduction (GMDR) was performed to investigate the best interaction combinations for gene-gene and gene-environment interactions. RESULTS: CAD risk is significantly higher in carriers of C allele of the rs1800795 polymorphism than those with GG genotype (CC + CG versus GG, adjusted OR (95%CI) = 2.07 (1.56-2.86), p < 0.001). GMDR analysis revealed rs1800795 was significantly interacted with tobacco smoking and alcohol drinking in two-locus model (p < 0.0010). Current smokers with CC or CG of rs1800795 genotype have the highest CAD risk, OR (95%CI) = 3.22 (2.45-3.94) and current drinkers with CC or CG of rs1800795 genotype have the highest CAD risk, OR (95%CI) = 3.17 (2.20-4.24). CONCLUSION: The C allele of rs1800795 within IL-6 gene promoter, rs1800795-tobacco smoking and rs1800795-alcohol drinking interaction were all associated with increased CAD risk.

Efficiency and safety of bivalirudin in patients undergoing emergency percutaneous coronary intervention via radial access: A subgroup analysis from the bivalirudin in acute myocardial infarction versus heparin and GPI plus heparin trial.

OBJECTIVES: To explore the efficiency and safety of bivalirudin in patients undergoing emergency percutaneous coronary intervention via radial access. BACKGROUND: Bivalirudin reduces bleeding risks over heparin in patients undergoing PCI. However, bleeding advantages of bivalirudin in patients undergoing transradial intervention is uncertain. METHODS: In the BRIGHT trial, 1,723 patients underwent emergency PCI via radial access, with 576 patients in the bivalirudin arm, 576 in the heparin arm and 571 in the heparin plus tirofiban arm. The primary outcome was 30-day net adverse clinical event (NACE), defined as a composite of major cardiac and cerebral events or any bleeding. RESULTS: 30-day NACE occurred in 5.7% with bivalirudin, 7.8% with heparin alone (vs. bivalirudin, P = 0.159), and 10.3% with heparin plus tifofiban (vs. bivalirudin, P = 0.004). The 30-day bleeding rate was 0.9% for bivalirudin, 2.3% for heparin (vs. bivalirudin, P = 0.057), and 5.8% for heparin plus tirofiban (vs. bivalirudin, P < 0.001). Major cardiac and cerebral events (4.9 vs. 5.7 vs. 4.6%, P = 0.899), stent thrombosis (0.5 vs. 0.5 vs. 0.7%, P = 0.899) and acquired thrombocytopenia (0.2 vs. 0.5 vs. 0.9%, P = 0.257) at 30 days were similar among three arms. The interaction test for PCI access and randomized treatment showed no significance on all bleeding (P > 0.05). CONCLUSIONS: The bleeding benefit of bivalirudin was independent of artery access. Bivalirudin lead to statistical reduction on bleeding risks in comparison to heparin plus tirofiban, and only small numerical difference in comparison to heparin, with comparable risks of ischemic events and stent thrombosis in patients with acute myocardial infarction (AMI) undergoing emergency transradial PCI. © 2016 Wiley Periodicals, Inc.

Transplantation of EPCs overexpressing PDGFR-ß promotes vascular repair in the early phase after vascular injury.

BACKGROUND: Endothelial progenitor cells (EPCs) play important roles in the regeneration of the vascular endothelial cells (ECs). Platelet-derived growth factor receptor (PDGFR)-ß is known to contribute to proliferation, migration, and angiogenesis of EPCs, this study aims to investigate effects of transplantation of EPCs overexpressing PDGFR-ß on vascular regeneration. METHODS: We transplanted genetically modified EPCs overexpressing PDGFR-ß into a mouse model with carotid artery injury. After 3 days of EPCs transplantation, the enhanced green fluorescent protein (EGFP)-expressing cells were found at the injury site and the lining of the lumen by laser scanning confocal microscope (LSCM). At 4, 7, and 14 days of the carotid artery injury, reendothelialization was evaluated by Evans Blue staining. Neointima formation was evaluated at day 14 with hematoxylin and eosin (HE) staining by calculating the neointimal area, medial area, and neointimal/media (NI/M) ratio. Intimal cell apoptosis was evaluated using TUNEL assay. Then we tested whether PDGF-BB-induced VSMC migration and PDGF-BB's function in reducing VSMC apoptosis can be attenuated by EPCs overexpressing PDGFR-ß in a transwell co-culture system. RESULTS: Our results showed that EPCs overexpressing PDGFR-ß accelerates reendothelialization and mitigates neointimal formation at 14 days after injury. Moreover, we found that there is great possibility that EPCs overexpressing PDGFR-ß enhanc VSMC apoptosis and suppress VSMC migration by competitive consumption of PDGF-BB in the early phase after carotid artery injury in mice. CONCLUSIONS: We report the first in vivo and in vitro evidence that transplantation of genetically modified EPC can have a combined effect of both amplifying the reendothelialization capacity of EPCs and inhibiting neointima formation so as to facilitate better inhibition of adverse remodeling after vascular injury.

Comparative ultrastructure analysis of radiation-induced radioresistant laryngeal cancer hep-2 cell line.

Radioresistance is one of the main reasons for the failure of radiotherapy in laryngeal cancer. However, the mechanisms of radioresistance of tumor cells have remained elusive. This study was conducted to identify the ultrastructural changes of radiation-induced radioresistant laryngeal cancer hep-2 cell line. First, a radioresistant hep-2R cell line was generated after prolonged exposure to γ-rays for 60 Gy (6 Gy/day, 2 days/week) and was confirmed by clonogenic assay. Next, the ultrastructural differences between hep-2R cells and hep-2 cells were compared by transmission electron microscopy. Finally, the results showed that hep-2R cells showed significant resistance to radiation compared with parental hep-2 cells. Increased cell nucleus atypia, more rough endoplasmic reticulum and less mitochondria were observed in hep-2R cells. The amount of microvilli of hep-2R was similar to hep-2 cell. In summary, these ultrastructural differences revealed the morphological mechanism that hep-2R cells had stronger radioresistance than hep-2 cells.

Association between the duration of smoking cessation and α-Klotho levels in the US middle-aged and elderly population.

Background: α-Klotho is a molecule associated with aging and several diseases. Previous studies have reported decreased levels of serum α-Klotho (SαKl) in smokers compared to never smokers. Interestingly, we also found the SαKl level could partly recover in those who quit smoking. The objective of this study was to investigate SαKl levels in the US population who quit smoking for a certain period. Methods: A total of 9268 participants, ranging in age from 40 to 79 years were enrolled in this cross-sectional study, 37.04 % were identified as former smoker. Data from the NHANES conducted between 2007 and 2016 were utilized for analysis. The association between the period of smoking cessation and SαKl levels was evaluated through multivariate linear regression models. Additionally, a detailed analysis stratified by key clinical factors was performed. Results: The mean level of SαKl among the former smoker was 827.41 pg/mL. After full adjustment, the SαKl level increased over time after smoking cessation, with an increase of 1.20 pg/ml per year of abstinence (P = 0.005). The linear correlation persists regardless of the duration of the smoking habit before quitting. In the stratified analysis, a positive correlation was observed between duration of smoking cessation and SαKl levels in individuals aged 60-79 years, females, normal weight individuals, those involved in moderate or vigorous physical activity, and those with a history of cancer (all P<0.05). Conclusion: This study showed a positive association between the duration of smoking cessation and SαKl levels in former smokers. Prolonged abstinence may contribute to increased SαKl levels which may protect people against aging-related diseases.

ox-LDL-Induced Endothelial Progenitor Cell Oxidative Stress via p38/Keap1/Nrf2 Pathway.

BACKGROUND: Nrf2 which was recently reported to regulate the antioxidant genes and cellular redox regulators was highly expressed in EPCs. However, its role in ox-LDL-induced EPC oxidative stress and apoptosis has not been fully illustrated. METHODS: EPCs isolated from human peripheral blood mononuclear cells were treated with different concentrations of ox-LDL, Keap1 siRNA, and a specific p38 MAPK inhibitor SB203580 and then used to assay the cytoplasmic Nrf2, nuclear Nrf2, NAD(P) H:quinone oxidoreductase 1 (NQO1) and Bax/Bcl-2 levels with Western blot, NQO1 mRNA levels with RT-PCR, ROS levels with H2DCF-DA, loss/disruption of mitochondrial membrane potential with JC-1, apoptosis with Annexin V and PI, migration with transwell chambers, and tube formation with Matrigel. RESULTS: ox-LDL decreased the nuclear Nrf2/Histone H3 to cytoplasmic Nrf2/GAPDH ratio, NQO1 mRNA, and protein levels. ox-LDL enhanced ROS production, induced the loss of membrane potential, and increased the cell shrinkage, pyknotic nuclei, and apoptosis of EPCs. Keap1 siRNA increased Nrf2 nuclear translocation, NQO1 mRNA transcription, and protein expression and prevented ROS generation and formation of JC-1 monomers. ox-LDL increased the activation of p38. SB203580 significantly eliminated ox-LDL induced inhibition of Nrf2 nuclear translocation, depression of NQO1 mRNA transcription, generation of ROS, and formation of JC-1 monomers in EPCs. Keap1 siRNA decreased the Bax/Bcl-2 ratio which was increased by ox-LDL in EPCs. ox-LDL decreased EPC migration and tube formation. Keap1 siRNA preserved the migration and tube formation of EPCs. CONCLUSION: ox-LDL activated EPCs p38/Keap1/Nrf2 pathway and induced oxidative stress, dysfunction, and apoptosis of EPCs.

The thrombodynamic ratio as a predictor of 28-day mortality in sepsis patients.

BACKGROUND: The thrombodynamic ratio (TDR) as a composite thromboelastography (TEG) parameter, has been proven to be valuable in multiple diseases. However, the association between TDR and mortality in sepsis has not been studied. METHODS: One hundred forty-one patients were enrolled in this retrospectively study. TEG was performed immediately at admission. Two cox proportional hazards models were developed for the prediction of 28-day mortality. The C statistic, continuous net reclassification index (cNRI) and integrated discriminatory index (IDI) were calculated to compare the discrimination performance of clinical models with and without the TDR value. The integrated calibration index (ICI) and E50 were calculated to compare the calibration. RESULTS: Patients with lower TDR were more likely to have organ impairments and increased 28-day mortality. The TDR value improved discrimination performance in both Model 1 (C statistic, 0.745 vs 0.735; cNRI 19.4%, p = 0.044; IDI 5.6%, p = 0.012) and Model 2 (C statistic, 0.761 vs 0.751; IDI, 5.1%, p = 0.012). Compared to the calibration curve of Model 1 without TDR, addition of TDR displayed better calibration (ICI, 0.023; E50, 0.021). CONCLUSION: TDR value significantly predicts 28-day mortality in patients with sepsis and could improve the discrimination and calibration performance of clinical prediction models.