Causal relationships between peripheral immune cells and Alzheimer's disease: a two-sample Mendelian randomization study.

OBJECTIVE: Previous research suggests that peripheral immune cells may play a role in the development of Alzheimer's disease (AD). Our study aims to determine if the composition of peripheral immune cells directly contributes to the occurrence of AD. METHODS: We utilized a two-sample Mendelian randomization (MR) approach to examine the association between peripheral immune cells and AD.The primary analysis method used was the inverse variance weighted (IVW) method, and we also conducted analyses using MR Egger, weighted median, simple mode, and weighted mode methods to ensure the accuracy of the results.Heterogeneity and horizontal pleiotropy were evaluated using Cochran's Q statistics and the MR Egger intercept, respectively. RESULTS: The study found a significant correlation between increased IgD + CD24- AC cells (Odds Ratio [OR] = 1.03, 95% Confidence Interval [CI] = 1.01-1.06, P = 0.0172), increased CD4 + %leukocyte (OR = 1.08, 95% CI = 1.02-1.14, P = 0.0086), and increased CD4 + CD8dim AC cells (OR = 1.06, 95% CI = 1.01-1.11, P = 0.0218), with an increased susceptibility to AD. Conversely, an increase in EM DN (CD4-CD8-) %T cells (OR = 0.95, 95% CI = 0.92-0.99, P = 0.0164) and an increase in DN (CD4-CD8-) AC cells (OR = 0.93, 95% CI = 0.88-0.99, P = 0.0145) were associated with a protective effect against AD. CONCLUSION: Our findings establish a causal link between peripheral immune cells and AD. This study is the first to examine the relationship between peripheral immune cells and AD using MR, offering valuable insights for early diagnosis and treatment decisions.

Early initiation of norepinephrine in patients with septic shock: A propensity score-based analysis.

BACKGROUND: The use of vasopressors is vital in septic shock. However, the optimal timing of treatment remains unclear. Therefore, we aimed to explore the impact of early norepinephrine initiation on the survival of patients with septic shock. METHODS: We selected 4253 patients from the Medical Information Mart for Intensive Care IV database between 2008 and 2019. The primary outcome was 28-day mortality. Propensity score matching (PSM) was applied to minimize between-group imbalances, and a restricted mean survival time was used to quantify the beneficial impact of early norepinephrine treatment on survival. Sensitivity analyses were conducted to test the robustness of the study results in multiple cohorts. RESULTS: In the PSM cohort, 2862 patients were equally assigned to early (receiving norepinephrine within the first 3 h) and delayed (> 3 h) norepinephrine initiation groups. Patients in the early norepinephrine initiation group received significantly less fluid therapy (0 vs. 79 mL/kg), had lower 28-day mortality (30.0% vs. 37.8%), longer survival days (21.89 vs. 20.37 days), shorter duration of intensive care unit (4.9 vs. 7.2 days) and hospital stays (12.4 vs. 13.6 days), shorter duration of supportive norepinephrine and invasive mechanical ventilation, lower incidence of organ failure progression (64.4% vs. 79.2%) within 24 h after shock onset, and higher mean arterial pressure within 6 and 24 h after shock onset than patients in the delayed norepinephrine initiation group (p < 0.05). CONCLUSIONS: Norepinephrine initiation within the first 3 h, regardless of preload dependency, was associated with longer survival time and shorter duration of supportive norepinephrine and invasive mechanical ventilation and may delay or partially reverse rapid onset organ failure.

Hypothermia alleviated LPS-induced acute lung injury in Rat models through TLR2/MyD88 pathway.

Acute lung injury (ALI) is a common clinical syndrome in ICU departments with high mortality. The pathology of ALI is still not clear and there is no specific and efficient treatment against ALI. In this study, we established ALI rat model through lipopolysaccharide administration. We found that hypothermia therapy led to significant improvement in oxygenation index, edema formation and pathological score, demonstrating that hypothermia is beneficial to the recovery of lung function and alleviation of lung injury. Besides, hypothermia resulted in a decrease in plasminogen activator inhibitor-1(PAI-1) concentration, showing the inflammation was partially inhibited. This was also confirmed by a decrease in TNF-α mRNA and protein level in hypothermia group. The effect of hypothermia was mediated by TLR2/MyD88 signaling, which led to the alteration in NF-κB p65 level. Collectively, this study indicated that hypothermia therapy was potentially an efficient therapy against ALI.

Anti-inflammatory effect of dexmedetomidine combined with hypothermia on acute respiratory distress syndrome in rats.

BACKGROUND: To investigate the protective effect of combination of dexmedetomidine and hypothermia on lipopolysaccharide (LPS) induced acute respiratory distress syndrome in rats. METHODS: Fifty male Wistar rats were randomly divided into five groups, with 10 rats in each group. The acute respiratory distress syndrome model was reproduced by LPS injected into the right external jugular vein (L group); only saline was injected into the right external jugular vein for control group (C group). In hypothermia group (T group), the body temperature was lowered to 32.5°C-33.0°C after 1 h of LPS injection, and 10 rats were sacrificed at 8 h. Group dexmedetomidine (D group) and dexmedetomidine combined with hypothermia group (DT group) received intraperitoneal dexmedetomidine 30 min before LPS was injected. The arterial blood gas was determined in all the groups before and 8 h after instillation of saline or LPS, and the oxygenation index (PaO2/FiO2) was calculated. The pro-inflammatory cytokines TNF-alpha (TNF-α) and interleukin- 6 (IL-6) levels were determined by enzyme-linked immunosorbent assay. The expression of inflammatory signaling proteins in bronchial alveolar lavage fluid was determined by Western blot. RESULTS: Compared with group L, TNF-α and IL-6 levels in serum of rats were significantly lower (P < 0.05), the expression of toll-like receptors 4 and phosphorylated c-Jun N-terminal kinase was significantly lower (P < 0.05), and the p-Akt level was significantly higher (P < 0.05). Moreover, the dexmedetomidine combined with hypothermia treated was superior to the single method. CONCLUSIONS: The combination of dexmedetomidine and hypothermia could alleviate acute lung injury in rats.

Effect of mild hypothermia on the expression of toll-like receptor 2 in lung tissues with experimental acute lung injury.

OBJECTIVE AND DESIGN: Our study aimed to determine the effect of mild hypothermia (MHT) on the expression of toll-like receptor 2 (TLR2) in lung tissue with acute lung injury. The animals were randomly divided into control, model and mild hypothermia groups. METHODS: A total of 40 rats was used in the study. Acute lung injury was induced by lipopolysaccharide and MHT was maintained at 32.5∼33.0 °C using body surface ice-bag placement combined with animal thermostat system. The ratio of PaO2/FiO2 was recorded. The mRNA and protein expressions of TLR2 were measured by real-time polymerase chain reaction and western blotting respectively. Moreover, enzyme linked immunosorbent assay were used for the quantification of TNF-α. RESULTS: The ratio of PaO2/FiO2 was increased by MHT. TLR2 and TNF-α were increased in the rat lung 1h and 8h in the rats with acute lung injury while they were significantly decreased by MHT. Histological examination revealed that MHT alleviated the degree of inflammation. CONCLUSION: Our study suggested that MHT might improve the lung function by inhibiting the inflammation via down-regulating the expressions of TLR2 in the acute injury lung tissues.

Novel application of nanomedicine for the treatment of acute lung injury: a literature review.

Nanoparticles have attracted extensive attention due to their high degree of cell targeting, biocompatibility, controllable biological activity, and outstanding pharmacokinetics. Changing the size, morphology, and surface chemical groups of nanoparticles can increase the biological distribution of agents to achieve precise tissue targeting and optimize therapeutic effects. Examples of their use include nanoparticles designed for increasing antigen-specific immune responses, developing vaccines, and treating inflammatory diseases. Nanoparticles show the potential to become a new generation of therapeutic agents for regulating inflammation. Recently, many nanomaterials with targeted properties have been developed to treat acute lung injury/acute respiratory distress syndrome (ALI/ARDS). In this review, we provide a brief explanation of the pathological mechanism underlying ALI/ARDS and a systematic overview of the latest technology and research progress in nanomedicine treatments of ALI, including improved nanocarriers, nanozymes, and nanovaccines for the targeted treatment of lung injury. Ultimately, these nanomedicines will be used for the clinical treatment of ALI/ARDS.

[Effect of mild hypothermia on macrophage polarization in lipopolysaccharide-induced acute lung injury mice].

OBJECTIVE: To investigate the effect of mild hypothermia on macrophage polarization in lipopolysaccharide (LPS)-induced acute lung injury (ALI) mice and to clarify its role in lung injury. METHODS: According to a random number table method, 18 male C57BL/6 mice were divided into sham operation group (Sham group), ALI normothermic model group (NT group) and ALI mild hypothermia treatment group (HT group), with 6 mice in each group. The ALI model in mice was established by the method of tracheal instillation of LPS, and temperature control was administered at 1 hour after surgery. The anus temperature in NT group was kept at 36-38?centigrade, while the anus temperature in HT group was kept at 32-34?centigrade. The target anus temperature in both groups were maintained for 6 hours and then slowly rewarmed to 36-38 centigrade. The Sham group was infused with an equal amount of physiological saline through the trachea without temperature control. After 24 hours of modeling, serum was collected and mice were sacrificed to obtain lung tissue. Pathological changes in lung tissue were observed under light microscopy and semi-quantitative lung injury score was performed. Enzyme linked immunosorbent assay (ELISA) was used to detect the serum levels of interleukins (IL-1ß, IL-10). Real-time quantitative polymerase chain reaction (RT-qPCR) was used to test the indicators of macrophage polarization, such as the mRNA expressions of CD86, IL-6, CD206 and arginase 1 (Arg1) in the lung tissue. The protein expression of M1 macrophage marker inducible nitric oxide synthase (iNOS) and M2 macrophage marker Arg1 were detected by Western blotting. RESULTS: Compared with the Sham group, the NT group appeared significant pulmonary hemorrhage and edema, thickened lung septum, inflammatory cell infiltration, and lung injury score was significantly increased; serum IL-1ß level was significantly elevated; IL-10 level was increased without statistical significance; the expressions of CD86 mRNA, IL-6 mRNA and iNOS protein were significantly elevated, and CD206 mRNA was significantly decreased; the mRNA and protein expressions of Arg1 decreased, but there were no significant differences. Compared with the NT group, the pathological injury of lung tissue in HT group was significantly reduced, and the lung injury score was significantly decreased (4.78±0.96 vs. 8.56±1.98, P < 0.01); serum IL-1ß level was decreased (ng/L: 13.52±1.95 vs. 27.18±3.87, P < 0.01), and IL-10 level was significantly increased (ng/L: 42.59±15.79 vs. 14.62±4.47, P < 0.01); IL-6 mRNA expression was decreased in lung tissue (2-ΔΔCt: 3.37±0.92 vs. 10.04±0.91, P < 0.05), the expression of M1 macrophage markers CD86 mRNA and iNOS protein were significantly decreased [CD86 mRNA (2-ΔΔCt): 0.52±0.16 vs. 1.95±0.33, iNOS protein (iNOS/ß-actin): 0.57±0.19 vs. 1.11±0.27, both P < 0.05], the expression of M2 macrophage markers CD206 mRNA, Arg1 mRNA and Arg1 protein were significantly increased [CD206 mRNA (2-ΔΔCt): 3.99±0.17 vs. 0.34±0.17, Arg1 mRNA (2-ΔΔCt): 2.33±0.73 vs. 0.94±0.23, Arg1 protein (Arg1/ß-actin): 0.96±0.09 vs. 0.31±0.11, all P < 0.05]. CONCLUSIONS: Mild hypothermia can alleviate the inflammatory response and protect lung tissue in ALI mice, which may be related to the inhibition of M1 macrophage polarization and promotion of M2 macrophage polarization.

Genetic Prediction of Causal Relationships between Osteoporosis and Sepsis: Evidence from Mendelian Randomization with two-sample Designs.

BACKGROUND: Recent observational studies have suggested that osteoporosis may be a risk factor for sepsis. To mitigate confounding factors and establish the causal relationship between sepsis and osteoporosis, we conducted a two-sample Mendelian randomization analysis using publicly available summary statistics. METHODS: Utilizing summary data from FinnGen Biobank, we employed a two-sample Mendelian randomization (MR) analysis to predict the causal relationship between osteoporosis and sepsis. The MR analysis primarily utilized the inverse variance weighted (IVW) method, supplemented by MR-Egger, weighted median, weighted mode, and simple mode analyses, with Bayesian weighted MR (BWMR) analysis employed for result validation. Sensitivity analyses included MR-PRESSO, "leave-one-out" analysis, MR-Egger regression, and Cochran's Q test. RESULTS: In the European population, an increase of one standard deviation in osteoporosis was associated with an 11% increased risk of sepsis, with an odds ratio (OR) of 1.11 (95% CI, 1.06 - 1.16; p = 3.75E-06). BWMR yielded an OR of 1.11 (95% CI, 1.06 - 1.67; p = 1.21E-05), suggesting osteoporosis as a risk factor for sepsis. Conversely, an increase of one standard deviation in sepsis was associated with a 26% increased risk of osteoporosis, with an OR of 1.26 (95% CI, 1.11 - 1.16; p = 0.45E-03). BWMR yielded an OR of 1.26 (95% CI, 1.09 - 1.45; p = 1.45E-03), supporting sepsis as a risk factor for osteoporosis. CONCLUSION: There is a association between osteoporosis and sepsis, with osteoporosis may serving as a risk factor for the development of sepsis, while sepsis may also promote the progression of osteoporosis.

Mild Hypothermia Alleviates CLP-induced Multiple Organ Dysfunction by Mitigating Pyroptosis Through the TLR4/NF-κB/NLRP3 Signaling Pathway.

BACKGROUND: Multiple organ failure secondary to severe sepsis leads to increased morbidity and mortality and is often accompanied by inflammation and immune system dysfunction. Mild hypothermia has been shown to have anti-inflammatory properties, but whether it can exert a protective effect in cases of multiple organ failure remains unclear. Thus, in this study, we investigated the protective effect of mild hypothermia on septic multiple organ failure and the underlying mechanism for this effect. METHOD: Sepsis was induced through the cecal ligation and puncture (CLP) method. Rats were then housed at normal (36-38°C) or mild hypothermic (32-34°C) temperature for 10 h. RESULTS: CLP-induced effects on inflammatory cytokines and biochemical markers in serum were reversed by mild hypothermia. The pathological injury score and the expressions of pyroptosis markers, including TLR4, MyD88 and NF-κB signaling molecules, showed a similar trend. Moreover, 3 d survival of CLP rats was improved by mild hypothermia. CONCLUSIONS: Mild hypothermia alleviated CLP-induced organ failure and the downstream effects on pyroptosis, probably through the TLR4/NF-κB/NLRP3 signaling pathway.

[Evaluation of extravascular lung water index in critically ill patients based on lung ultrasound radiomics analysis combined with machine learning].

OBJECTIVE: To explore lung ultrasound radiomics features which related to extravascular lung water index (EVLWI), and to predict EVLWI in critically ill patients based on lung ultrasound radiomics combined with machine learning and validate its effectiveness. METHODS: A retrospective case-control study was conducted. The lung ultrasound videos and pulse indicated continuous cardiac output (PiCCO) monitoring results of critically ill patients admitted to the department of critical care medicine of the First Affiliated Hospital of Guangxi Medical University from November 2021 to October 2022 were collected, and randomly divided into training set and validation set at 8:2. The corresponding images from lung ultrasound videos were obtained to extract radiomics features. The EVLWI measured by PiCCO was regarded as the "gold standard", and the radiomics features of training set was filtered through statistical analysis and LASSO algorithm. Eight machine learning models were trained using filtered radiomics features including random forest (RF), extreme gradient boost (XGBoost), decision tree (DT), Naive Bayes (NB), multi-layer perceptron (MLP), K-nearest neighbor (KNN), support vector machine (SVM), and Logistic regression (LR). Receiver operator characteristic curve (ROC curve) was plotted to evaluate the predictive performance of models on EVLWI in the validation set. RESULTS: A total of 151 samples from 30 patients were enrolled (including 906 lung ultrasound videos and 151 PiCCO monitoring results), 120 in the training set, and 31 in the validation set. There were no statistically significant differences in main baseline data including gender, age, body mass index (BMI), mean arterial pressure (MAP), central venous pressure (CVP), heart rate (HR), cardiac index (CI), cardiac function index (CFI), stroke volume index (SVI), global end diastolic volume index (GEDVI), systemic vascular resistance index (SVRI), pulmonary vascular permeability index (PVPI) and EVLWI. The overall EVLWI range in 151 PiCCO monitoring results was 3.7-25.6 mL/kg. Layered analysis showed that both datasets had EVLWI in the 7-15 mL/kg interval, and there was no statistically significant difference in EVLWI distribution. Two radiomics features were selected by using LASSO algorithm, namely grayscale non-uniformity (weight was -0.006 464) and complexity (weight was -0.167 583), and they were used for modeling. ROC curve analysis showed that the MLP model had better predictive performance. The area under the ROC curve (AUC) of the prediction validation set EVLWI was higher than that of RF, XGBoost, DT, KNN, LR, SVM, NB models (0.682 vs. 0.658, 0.657, 0.614, 0.608, 0.596, 0.557, 0.472). CONCLUSIONS: The gray level non-uniformity and complexity of lung ultrasound were the most correlated radiomics features with EVLWI monitored by PiCCO. The MLP model based on gray level non-uniformity and complexity of lung ultrasound can be used for semi-quantitative prediction of EVLWI in critically ill patients.

Intravenous high-dose vitamin C monotherapy for sepsis and septic shock: A meta-analysis of randomized controlled trials.

BACKGROUND: Vitamin C has been used as an adjuvant in the treatment of sepsis and septic shock; however, its role remains controversial. This study aimed to assess the effectiveness of intravenous high-dose vitamin C in sepsis and septic shock patients by meta-analysis. METHODS: The PubMed, Embase, and Cochrane Library electronic databases were searched to identify relevant studies. The primary outcome was defined as the short-term all-cause mortality rate. Secondary outcomes included duration of vasoactive drug use, intensive care unit length of stay, sequential organ failure assessment scores up to 96 hours after treatment and 90-day mortality. Review Manager version 5.4 was used to perform the meta-analysis. Relative risk and mean differences (MD) with 95% confidence intervals were determined using fixed- or random-effects models. RESULTS: Eight randomized controlled trials (RCTs) comprising 1394 patients were eligible for assessment. Overall, the pooled results showed that high-dose vitamin C decreased short-term all-cause mortality in patients with sepsis, but no significant differences were observed in patients with septic shock. Additionally, high-dose vitamin C was associated with decreased duration of vasoactive drug use in patients with sepsis, but not in patients with septic shock. However, it did not significantly affect the duration of intensive care unit stay in RCTs of patients with sepsis and septic shock. Additionally, it did not significantly affect sequential organ failure assessment scores 96 hours post-treatment or 90-day mortality. CONCLUSION: These results suggest that intravenous high-dose vitamin C may improve outcomes in patients with sepsis, but do not benefit patients with septic shock. Further RCTs and other studies should be conducted to determine whether vitamin C should be recommended as an adjunctive sepsis treatment.

[Value of creatinine clearance rate estimated based on serum cystatin C in patients with acute kidney injury].

OBJECTIVE: To investigate diagnostic value of creatinine clearance rate (CCr) based on serum cystatin C (SCys C) in acute kidney injury (AKI), and whether it could predict the need for renal replacement therapy (RRT). METHODS: The patients enrolled with the length of intensive care unit (ICU) stay over 3 days were collected from August 2010 to May 2011. According to the diagnosis of AKI during the ICU stay, patients were divided into the AKI group (n=21) and non-AKI group (n=30). After patients were admitted, the level of SCys C and creatinine (SCr) were measured so as to count CCr based on SCys C (SCys C-CCr) or on SCr (SCr-CCr) respectively, meanwhile urine volume and acute physiology and chronic health evaluation II (APACHE II) score were monitored. The value of CCr counted by SCys C and SCr on predict AKI and the correlations between RRT were compared. RESULTS: SCr-CCr and SCys C-CCr in AKI group both were significantly lower than non-AKI group all the way through on admission, and 2 days and 1 day before AKI diagnosed and the day AKI diagnosed. The level of SCys C-CCr on 2 days prior to AKI diagnosed was significantly lower than the day admitted (70.6±8.4 ml×min(-1)×1.73 m(-2) vs. 114.8±15.8 ml×min(-1)×1.73 m(-2), P<0.01), whereas the level of SCr-CCr were not significantly changed (76.4±19.3 ml×min(-1)×1.73 m(-2) vs. 78.7±22.1 ml×min(-1)×1.73 m(-2), P>0.05). Receptor operative curve (ROC) analysis indicated that SCys C-CCr could predict AKI earlier than SCr-CCr, as the area under curve (AUC) of SCys C-CCr and SCr-CCr on 2 days prior to AKI diagnosed were 0.859 and 0.664, respectively, and the sensitivity were 90.5% and 47.6%, the specificity were 76.2% and 81.0%. In AKI group 6 patients were treated with RRT, the AKI patients receiving RRT had significantly higher APACHE II score on admission (29.6±4.5 vs. 17.0±5.6, P<0.05) and less urine volume within 24 hours (740±465 ml vs. 1780±1230 ml, P<0.05) than patients not received RRT, however, SCys C-CCr has no significant difference between the sub-group (50.4±11.2 ml×min(-1)×1.73 m(-2) vs. 53.0±8.4 ml×min(-1)×1.73 m(-2), P>0.05). SCys C-CCr did not predict the need of RRT on the day to diagnose AKI (AUC=0.65). CONCLUSIONS: The sensitivity of SCys C-CCr were high, but its specificity not. The SCys C-CCr may be helpful for excluding diagnose of AKI in high risk patients. However, it could not predict the need for renal replacement therapy on the day AKI diagnosed.

Dexmedetomidine Attenuates LPS-Stimulated Alveolar Type II Cells' Injury through Upregulation of miR-140-3p and Partial Suppression of PD-L1 Involving Inactivating JNK-Bnip3 Pathway.

Dexmedetomidine (DEX), which is reported to be a newly discovered, novel α-2 adrenoceptor agonist, is known to exhibit anti-inflammatory properties in several diseases. DEX regulates inflammation-related signaling pathways and genes through interactions with several miRNAs. This study verified that expression levels of miR-140-3p were diminished when alveolar type II cells were exposed to LPS. However, the levels of miR-140-3p were confirmed as showing an increase with DEX treatment. These observations revealed that the expression of miR-140-3p was related to the beneficial effects that accompanied the DEX treatment of LPS-induced ALI. In addition, PD-1/PD-L1 expression increased extensively when RLE-6TN cells were induced by LPS. The increased expression was reduced after treatment with DEX. Thus, it appears that the PD-L1 expression was targeted directly by miR-140-3p, resulting in the partial repression of PD-L1 levels, which involved the inhibition of p-JNK and Bnip3 expression. Therefore, DEX was shown to inhibit the PD-L1 expression by promoting partially increased miR-140-3p levels in RLE-6TN cells. DEX also inactivated the JNK-Bnip3 pathway, resulting in the inhibition of inflammation and alleviating alveolar type II cell injury.

Molecular mechanism analysis of m6A modification-related lncRNA-miRNA-mRNA network in regulating autophagy in acute pancreatitis.

This study aims to explore the molecular mechanism of N6-methyladenosine (m6A) modification-related long noncoding RNA (lncRNA)-microRNA (miRNA)-messenger RNA (mRNA) network in regulating autophagy and affecting the occurrence and development of acute pancreatitis (AP). RNA-seq datasets related to AP were obtained from Gene Expression Omnibus (GEO) database and merged after batch effect removal. lncRNAs significantly related to m6A in AP, namely candidate lncRNA, were screened by correlation analysis and differential expression analysis. In addition, candidate autophagy genes were screened through the multiple databases. Furthermore, the key pathways for autophagy to play a role in AP were determined by functional enrichment analysis. Finally, we predicted the miRNAs binding to genes and lncRNAs through TargetScan, miRDB and DIANA TOOLS databases and constructed two types of lncRNA-miRNA-mRNA regulatory networks mediated by upregulated and downregulated lncRNAs in AP. Nine lncRNAs related to m6A were differentially expressed in AP, and 21 candidate autophagy genes were obtained. Phosphoinositide 3-kinase (PI3K)-Akt signaling pathway and Forkhead box O (FoxO) signaling pathway might be the key pathways for autophagy to play a role in AP. Finally, we constructed a lncRNA-miRNA-mRNA regulatory network. An upregulated lncRNA competitively binds to 13 miRNAs to regulate 6 autophagy genes, and a lncRNA-miRNA-mRNA regulatory network in which 2 downregulated lncRNAs competitively bind to 7 miRNAs to regulate 2 autophagy genes. m6A modification-related lncRNA Pvt1, lncRNA Meg3 and lncRNA AW112010 may mediate the lncRNA-miRNA-mRNA network, thereby regulating autophagy to affect the development of AP.

An Oxidative Stress-Related Genes Signature for Predicting Survival in Bladder Cancer: Based on TCGA Database and Bioinformatics.

Background: Oxidative stress (OS) responses have been linked to oncogenesis and tumor progression and have recently been regarded as a potential strategy for tumor therapy. However, OS-related therapeutic targets have not been identified to date in the bladder cancer (BC). Methods: The mRNA expression and clinical data of BC were downloaded from the public database. Prognostic risk score signature was constructed using LASSO Cox regression analysis. External validation was performed in GSE15307 cohort. ESTIMATE, CIBERSORT, and ssGSEA algorithm were used to analyze immune cell infiltration and immune microenvironment. Next, functional enrichment analysis was performed to elucidate the mechanism underlying the signature. Additionally, we performed a nomogram to forecast the survival rate of individual BC patients. Results: An OS-related genes (OSRGs) signature was constructed. Overall survival was lower in the high-risk group than in the low-risk group, according to survival analyses. The area under the curve (AUC) of ROC curves further validated the prognostic signature's strong prediction performance in these two cohorts. The risk score was verified as an independent risk factor for BC by independent prognostic analysis. Moreover, as compared to TNM stage alone, a nomogram that integrated the risk score with TNM stage showed a much superior predictive value. Immune infiltration and tumor microenvironment studies indicated that immune cells and functions may play a significant role in carcinogenesis and development. The levels of expression of prognostic genes were shown to be substantially linked with drug sensitivity. Conclusion: We developed a novel OSRGs signature for predicting overall survival and impacting the immune status in patients with BC. New nomogram can help clinicians predict the survival rate of BC patients. These findings shed new light on the potential usage of OSRGs signature in BC patients.

Shenfu Injection Protects Brain Injury in Rats with Cardiac Arrest through Nogo/NgR Pathway.

The effect of Shenfu injection on brain injury after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) along with the underlying mechanism of axonal regeneration was explored. CA/CPR model in rats was established for subsequent experiments. A total of 160 rats were randomly divided into sham group, model group, conventional western medicine (CWM) group, Shenfu group, and antagonist group (n = 32 per group). After 3 hours, 24 hours, 3 days, and 7 days of drug administration, the modified Neurological Severity Score tests were performed. The ultrastructure of the brain and hippocampus was observed by electron microscopy. Real-time quantitative polymerase chain reaction (PCR), western blotting, and immunohistochemistry were used to detect Nogo receptor (NgR) expression in the hippocampus and cerebral cortex, and Nogo-NgR expression in CA/CPR model. Neurological deficits in the model group were severe at 3 hours, 24 hours, 3 days, and 7 days after the recovery of natural circulation, whereas the neurological deficits in CWM, antagonist, and Shenfu group were relatively mild. The ultrastructure of neuronal cells in Shenfu group had relatively complete cell membranes and more vesicles than those in the model group. The results of PCR and western blotting showed lower messenger ribonucleic acid and protein expression of NgR in Shenfu group than the model group and CWM group. Immunohistochemical examination indicated a reduction of Nogo-NgR expression in Shenfu group and antagonist group. Our results suggested that Shenfu injection reduced brain injury by attenuating Nogo-NgR signaling pathway and promoting axonal regeneration.

[Effects of hypothermia on the concentration of surfactant protein A during endotoxin induced acute lung injury in rats].

OBJECTIVE: To investigate the effect of hypothermia (HT) on the concentration of surfactant protein A (SP-A) during lipopolysaccharide (LPS) induced acute lung injury (ALI) in rats. METHODS: Forty male Wistar rats were randomly divided into three groups. The ALI model was reproduced by LPS intratracheal instillation; only saline was instilled intratracheally for control group. Rats in both model group and control group were sacrificed respectively at 1 hour and 8 hours (each n=8). In HT group the body temperature was lowered to 32.5-33.0 centigrade 1 hour after LPS instillation, and 8 rats were sacrificed at 8 hours. The arterial blood gas was determined in all the groups before and 1 hour and 8 hours after instillation of saline or LPS, and the oxygenation index (PaO(2)/FiO(2)) was calculated. The concentration of SP-A in bronchoalveolar lavage fluid (BALF) was determined by enzyme linked immunosorbent assay. The morphological changes in lung tissue of rats were observed under light microscope. RESULTS: At 1 hour after intratracheal instillation of LPS, the PaO(2)/FiO(2) of each group reached the diagnostic criterion of ALI. Compared with control 1 hour group, the SP-A (µg/L) in BALF of model 1 hour group was decreased (53.27±1.95 vs. 74.81±6.55, P<0.01); the SP-A in model 8 hour group and HT 8 hour group (4.35±2.76 and 51.36±2.33) was both obviously decreased compared with control 8 hour group (70.81±5.01, both P<0.01). Compared with model 8 hour group, the SP-A of HT 8 hour group was obviously increased (P<0.01). Results of light microscopic examination, it was revealed that the alveolar structure of control 1 hour group and control 8 hour group was almost normal. Inflammatory response in lung tissues in model 8 hour group was found to be most serious; compared with model 8 hour group, inflammatory response in lung tissues in model 1 hour group and HT 8 hour group was reduced in certain degree. CONCLUSION: A certain extent of HT may reduce lung injury of early endotoxin induced ALI rats by delaying lowering of alveolar SP-A levels.

[Research progress on the mechanism of two-component systems in regulating carbapenem resistance of Klebsiella pneumoniae].

Carbapenem-resistant Klebsiella pneumoniae (CRKP) leads to high mortality of infected patients. How to deal with CRKP is an urgent problem in clinical practice, and it is imperative to carry out researchon carbapenem resistance mechanism of CRKP. The two-component systems (TCSs) areassociated with the development of drug resistance in a variety of bacteria, and TCSs were expected to be important therapeutic targets for CRKP. Therefore, this article reviewed the mechanisms of TCSs in the regulation of CRKP from the following several aspects: common mechanisms of carbapenem resistance of CRKP, research progress in drug resistance of TCSs, relationships between Klebsiella pneumoniae and TCSs, and so on. It may provide some research ideas for future research and the references for clinical diagnosis and treatment.

Novel noncoding RNAs biomarkers in acute respiratory distress syndrome.

Introduction: Acute respiratory distress syndrome (ARDS) is a very common condition associated with critically ill patients, which causes substantial morbidity and mortality. Currently, there is no effective clinical ARDS treatment strategy. Novel targets that effectively treat ARDS need to be found.Areas covered: Data sources were published articles through June 2019 in PubMed using the following keywords: 'acute respiratory distress syndrome,' 'miRNAs,' 'lncRNAs,' and 'biomarkers.' The selection of studies focused on in cellular model, animal model, and clinical studies of ARDS.Expert commentary: Accumulated evidence revealed that some specific miRNAs and lncRNAs could regulate the signaling pathways of the pathophysiology by targeting specific molecule in ARDS. The differentially expressed miRNAs exert a crucial role in apoptosis of neutrophil, antigen-presenting cells and lung epithelial cell, and the dysfunction of mitochondrial. Recently, the influence of lncRNAs upon miRNA function is also rapidly emerging. In some cases, lncRNA MALAT1 target TLR4 to mediate the p38 MAPK and NF-κB signaling pathway in ARDS rat model. In other cases, lncRNA CASC2 was found to act as a ceRNA of miR-144-3p which directly targeted AQP1 in LPS-induced A549 cell. In addition, other miRNA-lncRNA regulatory patterns in ARDS and novel biomarkers still require deeper research.

[The effect of mild hypothermia on interleukin-3 expression in septic mice].

OBJECTIVE: To investigate whether or not mild hypothermia can inhibit the expression and release of interleukin-3 (IL-3) in septic mice and whether it has a protective effect on septic mice. METHODS: According to random number table method, 120 male C57BL/6 mice were divided into sham operation group (Sham group), sepsis normal temperature group (NT group) and sepsis mild hypothermia group (HT group), with 40 mice in each group. The acute septic mice model was established by cecal ligation and puncture (CLP) method. In the HT group, body temperature decreased to 32-34 centigrade at 1 hour after CLP and was maintained for 8 hours, followed by rewarming slowly to 36-38 centigrade. In the NT group, mice were resuscitated after CLP and body temperature was maintained at 36-38 centigrade throughout the experimental periods, while in Sham group, the cecum was not ligated or punctured and resuscitated routinely. The average arterial pressure (MAP) of 20 mice in each group was monitored for 12 hours after CLP, and the survival time was observed for 4 days. The serum of remaining mice was collected at 12 hours after CLP, and the mice were killed for organ tissues. The serum levels of IL-3, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were determined by enzyme linked immunosorbent assay (ELISA). Western blotting was used to detect IL-3 protein expression in spleen and lung tissues. The pathological changes of lung and liver tissues were observed under microscope and the semi-quantitative scoring was performed. RESULTS: MAP of NT group and HT group decreased after CLP with the prolongation of time. MAP (mmHg, 1 mmHg = 0.133 kPa) of HT group at 10 hours and 12 hours after CLP were significantly higher than those of NT group (10 hours: 74.4±12.4 vs. 62.9±7.2, 12 hours: 68.4±3.7 vs. 57.5±9.6, both P < 0.01). Compared with Sham group, serum levels of IL-3, IL-6 and TNF-α in NT group and HT group were significantly increased at 12 hours after CLP [IL-3 (ng/L): 2.21±0.87, 0.18±0.04 vs. 0, IL-6 (ng/L): 51.22±18.65, 24.68±6.20 vs. 1.36±0.34, TNF-α (ng/L): 101.43±38.60, 72.15±25.12 vs. 14.49±5.17, all P < 0.01]. IL-3 protein expressions of spleen and lung tissues in NT group and HT group were significantly increased compared to those in Sham group (IL-3/ß-actin: spleen tissue 0.200±0.039, 0.135±0.023 vs. 0.090±0.023, lung tissue 0.085±0.009, 0.056±0.009 vs. 0.039±0.005, all P < 0.01). The serum levels of IL-3, IL-6 and TNF-α were significantly lower in HT group than those in the NT group [IL-3 (ng/L): 0.18±0.04 vs. 2.21±0.87, IL-6 (ng/L): 24.68±6.20 vs. 51.22±18.65, TNF-α (ng/L): 72.15±25.12 vs. 101.43±38.60, all P < 0.01]. The expressions of IL-3 protein in HT group were significantly lower than those in NT group (IL-3/ß-actin: spleen tissue 0.135±0.023 vs. 0.200±0.039, lung tissue 0.056±0.009 vs. 0.085±0.009, both P < 0.01). The lung tissue injury and liver tissue injury scores in HT group were significantly lower than those in NT group (lung tissue injury score: 4.00±1.41 vs. 6.67±2.16, P = 0.03, liver tissue injury score: 3.83±1.47 vs. 7.17±2.14, P = 0.01). Compared to NT group, the 4-day survival rate of HT group was significantly improved (50% vs. 30%, P < 0.01). CONCLUSIONS: Mild hypothermia can significantly inhibit the expression and release of IL-3 in septic mice, attenuate organ injury, and protecte septic mice.