Tectoridin alleviates caerulein-induced severe acute pancreatitis by targeting ERK2 to promote macrophage M2 polarization.

Severe acute pancreatitis (SAP) is an inflammatory disease of the pancreas with a high mortality rate. Macrophages play a crucial role in the pathogenesis of pancreatitis. Tectoridin (Tec) is a highly active isoflavone with anti-inflammatory pharmacological activity. However, the role of Tec in the SAP process is not known. The purpose of this study was to investigate the therapeutic effect and potential mechanism of Tec on SAP. To establish SAP mice by intraperitoneal injection of caerulein and Lipopolysaccharide (LPS), the role of Tec in the course of SAP was investigated based on histopathology, biochemical indicators of amylase and lipase and inflammatory factors. The relationship between Tec and macrophage polarization was verified by immunofluorescence, real-time quantitative PCR and Western blot analysis. We then further predicted the possible targets and signal pathways of action of Tec by network pharmacology and molecular docking, and validated them by in vivo and in vitro. In this study, we demonstrated that Tec significantly reduced pancreatic injury in SAP mice, and decreased serum levels of amylase and lipase. The immunofluorescence and Western blot analysis showed that Tec promoted macrophage M2 polarization. Network pharmacology and molecular docking predicted that Tec may target ERK2 for the treatment of SAP, and in vivo and in vitro experiments proved that Tec inhibited the ERK MAPK signal pathway. In summary, Tec can target ERK2, promote macrophage M2 polarization and attenuate pancreatic injury, Tec may be a potential drug for the treatment of SAP.

Ethanol responsive lnc171 promotes migration and invasion of HCC cells via mir-873-5p/ZEB1 axis.

BACKGROUNDS: Long nonconding RNAs (lncRNAs) have been found to be a vital regulatory factor in the development process of human cancer, and could regarded as diagnostic or prognostic biomarkers for human cancers. Here, we aim to confirm the expression and molecular mechanism of RP11-171K16.5 (lnc171) in hepatocellular carcinoma (HCC). METHODS: Screening of differentially expressed lncRNAs by RNA sequencing. Expression level of gene was studied by quantitative real-time PCR (qRT-PCR). The effects of lnc171, mir-873-5p, and ethanol on migration and invasion activity of cells were studied used transwell assay, and luciferase reporter assay was used to confirm the binding site. RESULTS: RNA sequencing showed that lnc171 was markedly up-regulated in HCC. siRNA-mediated knockdown of lnc171 repressed the migration and invasion ability of HCC cells. Bioinformatic analysis, dual luciferase reporter assay, and qRT-PCR indicated that lnc171 interacted with mir-873-5p in HCC cells, and Zin-finger E-box binding homeobox (ZEB1) was a downstream target gene of mir-873-5p. In addition, lnc171 could enhance migration and invasion ability of HCC cells by up-regulating ZEB1 via sponging mir-873-5p. More interestingly, ethanol stimulation could up-regulate the increase of lnc171, thereby regulating the expression of competing endogenous RNA (ceRNA) network factors which lnc171 participated in HCC cells. CONCLUSIONS: Our date demonstrates that lnc171 was a responsive factor of ethanol, and plays a vital role in development of HCC via binding of mir-873-5p.

Causal associations between gut microbiota and sepsis: A two-sample Mendelian randomization study.

BACKGROUND: Targeting the gut microbiota may become a new therapeutic to prevent and treat sepsis. Nonetheless, the causal relationship between specific intestinal flora and sepsis is still unclear. METHODS: A two-sample Mendelian randomization study was performed using the summary statistics of gut microbiota from the largest available genome-wide association study (n = 18,340). The summary statistics of sepsis were obtained from the UK Biobank (n = 486,484). Inverse-variance weighted, weighted median and MR-Egger were used to examine the causal association between gut microbiota and sepsis. Cochrane's Q test, MR-Egger intercept test, MR-PRESSO Global test and Rucker's Q'-test were used for sensitivity analyses. The leave-one method was used for testing the stability of MR results, and Bonferroni-corrected was used to test the strength of the causal relationship between exposure and outcome. RESULTS: Nine intestinal microflora were found causally associated with sepsis, and 11 intestinal microflora were causally associated with 28-day death in sepsis. Among them, Order Victivallales had a strong causality with lower risk of sepsis (OR = 0.86, 95% CI: 0.78-0.94, p = .00165) and lower 28-day mortality of sepsis (OR = 0.68, 95% CI: 0.53-0.87, p = .00179) after Bonferroni-corrected test. No pleiotropy was detected. CONCLUSIONS: Through the two-sample MR analysis, we identified the specific intestinal flora that had a causal relationship with the risk and prognosis of sepsis at the level of gene prediction, which may provide helpful biomarkers for early disease diagnosis and potential therapeutic targets for sepsis.

Vasorin contributes to lung injury via FABP4-mediated inflammation.

BACKGROUND: Lung injury caused by pulmonary inflammation is one of the main manifestations of respiratory diseases. Vasorin (VASN) is a cell-surface glycoprotein encoded by the VASN gene and is expressed in the lungs of developing mouse foetuses. Previous research has revealed that VASN is associated with many diseases. However, its exact function in the lungs and the underlying mechanism remain poorly understood. METHODS AND RESULTS: To investigate the molecular mechanisms involved in lung disease caused by VASN deficiency, a VASN gene knockout (VASN-/-) model was established. The pathological changes in the lungs of VASN-/- mice were similar to those in a lung injury experimental mouse model. We further analysed the transcriptomes of the lungs of VASN-/- mice and wild-type mice. Genes in twenty-four signalling pathways were enriched in the lungs of VASN-/- mice, among which PPAR signalling pathway genes (3 genes, FABP4, Plin1, AdipoQ, were upregulated, while apoA5 was downregulated) were found to be closely related to lung injury. The most significantly changed lung injury-related gene, FABP4, was selected for further verification. The mRNA and protein levels of FABP4 were significantly increased in the lungs of VASN-/- mice, as were the mRNA and protein levels of the inflammatory factors IL-6, TNF-α and IL-1ß. CONCLUSIONS: We believe that these data provide molecular evidence for the regulatory role of VASN in inflammation in the context of lung injury.

[Simultaneous determination of content of eight components in Caesalpinia decapetala by UPLC-MS/MS].

The present study established the ultra-high performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS) method for simultaneous determination of the content of eight major active components in Caesalpinia decapetala and performed the quality evaluation of C. decapetala from different habitats with the chemical pattern recognition. The analysis was carried out on a Waters BEH C_(18) column(2.1 mm×100 mm, 1.7 µm) at 40 ℃, with the mobile phase of water containing 0.1% formic acid(A) and acetonitrile containing 0.1% formic acid under gradient elution, the flow rate of 0.3 mL·min~(-1), and the injection volume of 1 µL. The electrospray ionization(ESI) source in the negative mode and multiple reaction monitoring(MRM) were used for MS quantitative analysis. The content results were analyzed by the hierarchical cluster analysis(HCA) and principal component analysis(PCA) for the evaluation of the quality difference. Eight components showed good linear relationships within their respective concentration ranges(r>0.999), with the average recoveries of 96.85%-103.4% and RSD of 0.52%-2.8%. The analysis results showed that the quality of samples from different batches was different. The samples were classified into three clusters by HCA and PCA. The method is simple, sensitive, accurate, and efficient, and can be used for the quality evaluation of C. decapetala.

[Pharmacokinetics of three index components of Periploca forrestii in rats by microdialysis combined with UPLC-MS/MS].

The present study established a UPLC-MS/MS method for the content determination of Periploca forrestii microdialysis samples and investigated the pharmacokinetics of three index components of P. forrestii in rats. The effects of flow rate and concentration of perfusate on the recovery rate were investigated by the concentration difference method(increment method and decrement method). The microdialysis samples at different time points were collected, and the concentrations of three index components were determined by UPLC-MS/MS. The actual drug concentrations were corrected with the in vivo recovery rate, and the pharmacokinetic parameters were calculated by WinNonlin 8.2. In the in vitro recovery test, the recovery rate measured by the increment method and the decrement method was inversely proportional to the flow rate and independent of the concentration. The pharmacokinetic parameter AUC_(0-t) values of 3-O-caffeoyl quinic acid, 4-O-caffeoyl quinic acid, and 5-O-caffeoyl quinic acid were(23 911.23±5 679.67),(16 688.43±3 448.45), and(9 677.02±1 606.74) min·µg·L~(-1), respectively. C_(max) values were(170.66±58.02),(121.61±48.14), and(69.69±18.23) µg·L~(-1), respectively. The UPLC-MS/MS method has the advantages of specificity, rapidity, high sensitivity, and accurate quantification. It can simultaneously determine the concentration of 3-O-caffeoyl quinic acid and other two index components in microdialysis samples and is suitable for the pharmacokinetics study of the three index components of P. forrestii in normal rats.

Preparation of an anti-NEK2 monoclonal antibody and its application in liver cancer.

BACKGROUND: Never in mitosis gene-A (NIMA)-related expressed kinase 2 (NEK2) is a serine/threonine protein kinase regulated by the cell cycle. The purpose of this study was to obtain NEK2 protein to prepare an anti-NEK2 monoclonal antibody (mAb) and explore the application of the anti-NEK2 mAb of therapeutic and diagnostic in hepatocellular carcinoma (HCC). RESULTS: The NEK2 gene sequence was cloned from the normal liver cell line HL7702, and the full-length NEK2 gene sequence was cloned into the prokaryotic expression vector pET30a and transformed into Escherichia coli BL21 (DE3) cells. The recombinant fusion protein was obtained under optimized conditions and injected in BALB/c mice to prepare an anti-NEK2 mAb. By screening, we obtained a stable hybridoma cell line named 3A3 that could stably secrete anti-NEK2 mAb. Anti-NEK2 3A3 mAb was purified from ascites fluid. The isotype was IgG1, and the affinity constant (Kaff) was 6.0 × 108 L/mol. Western blot, indirect enzyme-linked immunosorbent assay (iELISA), immunofluorescence and immunocytochemical analyses showed that the mAb could specifically recognize the NEK2 protein. MTT assays showed that the mAb 3A3 could inhibit the proliferation of HCC cells. KEGG pathway analysis showed that NEK2 might affected pathways of the cell cycle. Moreover, NEK2-related genes were mainly enriched in the S and G2 phases and might act as tumor-promoting genes by regulating the S/G2 phase transition of HCC cells. CONCLUSIONS: An anti-NEK2 mAb with high potency, high affinity and high specificity was prepared by prokaryotic expression system in this study and may be used in the establishment of ELISA detection kits and targeted treatment of liver cancer.

The microbiological diagnostic performance of metagenomic next-generation sequencing in patients with sepsis.

BACKGROUND: In this study, we aimed to perform a comprehensive analysis on the metagenomic next-generation sequencing for the etiological diagnosis of septic patients, and further to establish optimal read values for detecting common pathogens. METHODS: In this single-center retrospective study, septic patients who underwent pathogen detection by both microbial culture and metagenomic next-generation sequencing in the intensive care unit of the Second People's Hospital of Shenzhen from June 24, 2015, to October 20, 2019, were included. RESULTS: A total of 193 patients with 305 detected specimens were included in the final analysis. The results of metagenomic next-generation sequencing showed significantly higher positive rates in samples from disparate loci, including blood, bronchoalveolar lavage fluid, and cerebrospinal fluid, as well as in the determination of various pathogens. The optimal diagnostic reads were 2893, 1825.5, and 892.5 for Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae, respectively. CONCLUSIONS: The metagenomic next-generation sequencing is capable of identifying multiple pathogens in specimens from septic patients, and shows significantly higher positive rates than culture-based diagnostics. The optimal diagnostic reads for frequently detected microbes might be useful for the clinical application of metagenomic next-generation sequencing in terms of timely and accurately determining etiological pathogens for suspected and confirmed cases of sepsis due to well-performed data interpretation.

RNA sequencing of plasma exosomes revealed novel functional long noncoding RNAs in hepatocellular carcinoma.

Exosomal long noncoding RNA (lncRNA) has been found to be associated with the development of cancers. However, the expression characteristics and the biological roles of exosomal lncRNAs in hepatocellular carcinoma (HCC) remain unknown. Here, by RNA sequencing, we found 9440 mRNAs and 8572 lncRNAs were differentially expressed (DE-) in plasma exosomes between HCC patients and healthy controls. Exosomal DE-lncRNAs displayed higher expression levels and tissue specificity, lower expression variability and splicing efficiency than DE-mRNAs. Six candidate DE-lncRNAs (fold change 6 or more, P ≤ .01) were high in HCC cells and cell exosomes. The knockdown of these candidate DE-lncRNAs significantly affected the migration, proliferation, and apoptosis in HCC cells. In particular, a novel DE-lncRNA, RP11-85G21.1 (lnc85), promoted HCC cellular proliferation and migration by targeted binding and regulating of miR-324-5p. More importantly, the level of serum lnc85 was highly expressed in both Alpha-fetoprotein (AFP)-positive and AFP-negative HCC patients and allowed distinguishing AFP-negative HCC from healthy control and liver cirrhosis (area under the receiver operating characteristic curve, 0.869; sensitivity, 80.0%; specificity, 76.5%) with high accuracy. Our finding offers a new insight into the association between the dysregulation of exosomal lncRNA and HCC, suggesting that lnc85 could be a potential biomarker of HCC.

Bound state and non-Markovian dynamics of a quantum emitter around a surface plasmonic nanostructure.

A bound state between a quantum emitter (QE) and surface plasmon polaritons (SPPs) can be formed, where the excited QE will not relax completely to its ground state and is partially stabilized in its excited state after a long time. We develop some theoretical methods for investigating this problem and show how to form such a bound state and its effect on the non-Markovian decay dynamics. We put forward an efficient numerical approach for calculating the analytical part of the self-energy for frequency below the lower energy threshold. We also propose an efficient formalism for obtaining the long-time value of the excited-state population without calculating the eigenfrequency of the bound state or performing a time evolution of the system, in which the probability amplitude for the excited state in the steady limit is equal to one minus the integral of the evolution spectrum over the positive frequency range. With the above two quantities obtained, we show that the non-Markovian decay dynamics of an initially excited QE can be efficiently obtained by the method based on the Green's function expression for the evolution operator when a bound state exists. A general criterion for identifying the existence of a bound state is presented. The performances of the above methods are numerically demonstrated for a QE located around a metal nanosphere and in a gap plasmonic nanocavity. Numerical results show that these methods work well and the QE becomes partially stabilized in its excited state at a long time for the transition dipole moment beyond its critical value. In addition, it is also found that this critical value is heavily dependent on the distance between the QE and the metal surface, but nearly independent on the size of the nanosphere or the rod. Our methods can be utilized to understand the suppressed decay dynamics for a QE in an open quantum system and provide a general picture on how to form such a bound state.

[Pulmonary ventilation function parameters of children aged 5-14 years in Kunming, China: a comparative analysis of measured values versus predicted values based on Zapletal equation].

OBJECTIVE: To study the percentage of the measured values of the main pulmonary ventilation function parameters in their predicted values based on Zapletal equation among healthy children aged 5-14 years in Kunming, China, and to provide a basis for accurate judgment of pulmonary ventilation function in clinical practice. METHODS: A total of 702 healthy children aged 5-14 years (352 boys and 350 girls) from Kunming were enrolled. The Jaeger spirometer was used to measure the nine indices:forced vital capacity (FVC), forced expiratory volume in one second (FEV1), ratio of forced expiratory volume in one second to forced vital capacity (FEV1/FVC), maximal mid-expiratory flow (MMEF), forced expiratory flow at 25% of forced vital capacity (FEF25), forced expiratory flow at 50% of forced vital capacity (FEF50), forced expiratory flow at 75% of forced vital capacity (FEF75), peak expiratory flow (PEF), and maximal voluntary ventilation (MVV). The values obtained from the Zapletal equation of predicted values provided by the spirometer were used as the predicted values of children, and the percentage of measured values in predicted values was calculated. RESULTS: In the 702 children, the percentages of the measured values of the main pulmonary ventilation function parameters PEF, FVC, FEV1, FEV1/FVC, and MVV in their predicted values fluctuated from 102% to 114%, 94% to 108%, 98% to 113%, 98% to 107%, and 141% to 183% respectively. As for the main airway velocity parameters, the percentages of the measured values of FEF25, FEF50, FEF75, and MMEF in their predicted values fluctuated from 98% to 116%, 85% to 102%, 71% to 98%, and 83% to 100% respectively. The percentages of the measured values of PEF, FVC, FEV1, FEV1/FVC, MVV, FEF25, FEF50, FEF75, and MMEF in their predicted values had the lower limits of normal of 88.2%, 88.4%, 92.0%, 94.4%, 118.5%, 82.9%, 70.0%, 62.1%, and 70.1% respectively. CONCLUSIONS: There are differences between pulmonary ventilation function parameter levels and normal values provided by Zapletal equation in healthy children aged 5-14 years in Kunming. As for the pulmonary ventilation function parameters of PEF, FVC, FEV, FEV1/FVC, MVV, FEF25, FEF50, FEF75, and MMEF in these children, the lower limits of normal of measured values in predicted values may be determined as 88.2%, 88.4%, 92.0%, 94.4%, 118.5%, 82.9%, 70.0%, 62.1%, and 70.1% respectively.

Effects of transtheoretical model-based intervention on the self-management of patients with an ostomy: A randomised controlled trial.

AIMS AND OBJECTIVES: To determine the effect of a transtheoretical model (TTM)-based intervention on patients with an ostomy and provide patient-centred, accessible assistance and dynamic education to improve patient self-management. BACKGROUND: Proper self-management may promote the rehabilitation of patients with an ostomy. TTM-based interventions have resulted in positive health behavioural changes. DESIGN: Randomised controlled trial performed according to the CONSORT guidelines. SUBJECT AND SETTING: The sample comprised 55 men and 37 women (24-77 years old, mean ± SD = 52.8 ± 11.13 years). The study settings included three tertiary hospitals in Changsha, Hunan, China. METHODS: The 92 patients, recruited from August 2012 to March 2013, were randomised into a control group and an intervention group. Randomisation was done by using a block randomisation list with a block size of 4. Self-management behaviours were assessed at the baseline, 2 days before discharge and after 1, 3 and 6 months of follow-up. The chi-squared test, independent sample t test and repeated measures analysis of variance were used to analyse the data. RESULTS: Patients in the intervention group were more likely to be at the action and maintenance stages compared with those in the control group. We also observed significant improvements in the self-management ability in the process of change, the decisional balance and self-efficacy in the intervention group compared with those in the control group after four intervention sessions and up to 6 months of follow-up. No serious intervention-related adverse events were observed. CONCLUSIONS: The TTM-based intervention had positive effects on self-management behaviours of patients with an ostomy. RELEVANCE TO CLINICAL PRACTICE: The TTM-based intervention had positive effects on self-management behaviours of patients with an ostomy and may provide a reference for health providers to develop behaviour promotion programmes to improve the self-management of patients with an ostomy.

Zinc finger protein 467 regulates Wnt signaling by modulating the expression of sclerostin in adipose derived stem cells.

Osteoporosis is a metabolic disease in which a disruption of the balance between bone formation by osteoblasts and bone resorption by osteoclasts leads to the progressive deterioration of bone density and quality. Tissue engineering approaches to the treatment of osteoporosis depend on the identification of factors that promote the differentiation of progenitor cells towards an osteoblastic phenotype. In the present study, we expanded on prior findings on the role of zinc finger protein 467 (Zfp467) in the osteoblastic differentiation of adipose-derived stem cells (ADSCs) and explored the underlying mechanisms. We showed that Zfp467 binds to and regulates the expression of the SOST gene, which encodes a secreted glycoprotein named sclerostin (Sost) that is expressed exclusively by osteocytes and functions as a negative regulator of bone formation through the modulation of Wnt signaling. Overexpression of Zfp467 in ADSCs inhibited Wnt signaling by promoting binding of Sost to the Wnt coreceptors LRP5/6 and disrupting Wnt induced Frizzled-LRP6 complex formation, and siRNA mediated Sost silencing reversed the inhibition of Wnt signaling by Zfp467 in ADSCs. Our results indicate that Zfp467 regulates the differentiation of ADSCs via a mechanism involving Sost-mediated inhibition of Wnt signaling, suggesting potential therapeutic targets for the treatment of osteoporosis.

A quadruple-strategy of modification on carbon nitride boosts oxygen reduction for high performance photocatalytic hydrogen peroxide production.

This paper reports a quadruple-strategy for material design, simultaneously applying morphology control, group modification, defect engineering and alkali metal doping to the design of catalysts, and successfully constructing irregular clusters of carbon nitride (pMNK-CN) with excellent photogenerated carrier separation performance and structural stability. The pMNK-CN is an irregular flower cluster-like morphology with a nanosheet structure on the surface, and the repolymerization process of the prepolymer in the microvoid of the metal salt gives it an open pore structure. With the help of essential characterization, it was confirmed that the heptazine unit in the backbone underwent partial decomposition due to the etching of metal salts at high temperatures, reducing the overall polymerization and introducing cyano and nitrogen vacancies. Meanwhile, the potassium ion embedded in the lattice can induce the growth of ordered structures and thus improve the short-range order. The pMNK-CN possesses a hydrogen peroxide production efficiency of 240.0 µmol·g-1·h-1 in pure water, which is 31 times higher than that of bulk carbon nitride. And the apparent quantum efficiencies of pMNK-CN in the 380 and 420 nm bands are 17.5 % and 14.8 % in the presence of isopropanol. The effects of each modification strategies on the electronic structure of carbon nitride were investigated using First-Principles, and it was demonstrated that the multiple modification strategies synergistically enhanced the optical absorption, photogenerated charge separation efficiency, and lowered the reaction energy barrier, thus greatly contributing to the oxygen reduction to hydrogen peroxide performance.

Harmine ameliorates CCl4-induced acute liver injury through suppression of autophagy and inflammation.

CCl4-induced acute liver injury (ALI) is characterized by heightened autophagy, inflammation, and oxidative damage. Accumulating evidence suggests that harmine exerts beneficial effects in countering CCl4-induced ALI by mitigating inflammation and oxidative stress. However, the impact of autophagy on CCl4-induced ALI and the protective role of harmine remain unclear. This study aimed to investigate the potential protective effects of harmine against CCl4-induced ALI in mice by suppressing autophagy and inflammation. Male Kunming mice were orally administered harmine or bifendate for seven days. Subsequently, one hour after the final administration, the model group and treatment groups were intraperitoneally injected with CCl4 to induce ALI. The findings revealed that harmine significantly reduced the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in serum, and ameliorated the liver histopathological changes induced by CCl4. Furthermore, harmine diminished the levels of TNF-α and IL-6, restored the levels of glutathione (GSH) and superoxide dismutase (SOD), and suppressed the production of nitric oxide (NO) and malondialdehyde (MDA) in the liver. Mechanistically, harmine down-regulated LC3B II/I, p38 MAPK, TLR4, and NF-κB levels, while upregulating p62, Bcl-2, Beclin1, ULK1, and p-mTOR expression. In conclusion, harmine mitigated CCl4-induced ALI by inhibiting autophagy and inflammation through the p38 MAPK/mTOR autophagy pathway, the Bcl-2/Beclin1 pathway, and the TLR4/NF-κB pathway.

(-)-Epicatechin gallate prevented atherosclerosis by reducing abnormal proliferation of VSMCs and oxidative stress of AML 12 cells.

(-)-Epicatechin gallate (ECG) is beneficial to the treatment of cardiovascular diseases (CVDs), especially atherosclerosis (AS) through antioxidant stress, but there is a lack of detailed mechanism research. In this study, the therapeutic target of ECG was determined by crossing the drug target and disease target of CVDs and AS. The combination ability of ECG with important targets was verified by Discovery Studio software. The abnormal proliferation of vascular smooth muscle cells (VSMCs) induced by Ang-II and the oxidative damage of AML 12 induced by H2O2 were established to verify the reliability of ECG intervention on the target protein. A total of 120 ECG targets for the treatment of CVDs-AS were predicted by network pharmacology. The results of molecular docking showed that ECG has strong binding force with VEGFA, MMP-9, CASP3 and MMP-2 domains. In vitro experiments confirmed that ECG significantly reduced the expression of VEGFA, MMP-9, CASP3 and MMP-2 in Ang-II-induced VSMCs, and also blocked the abnormal proliferation, oxidative stress and inflammatory reaction of VSMCs by inhibiting the phosphorylation of PI3K signaling pathway. At the same time, ECG also interfered with H2O2-induced oxidative damage of AML 12 cells, decreased the expression of ROS and MDA and cell foaming, and increased the activities of antioxidant enzymes such as SOD, thus playing a protective role.

ß-Cyclodextrin and Hyaluronic Acid-Modified Targeted Nanodelivery System for Atherosclerosis Prevention.

Natural products have been widely recognized in clinical treatment because of their low toxicity and high activity. It is worth paying attention to modifying the biopolymer into nanostructures to give natural active ingredients additional targeting effects. In this study, based on the multifunctional modification of ß-cyclodextrin (ß-CD), a nanoplatform encapsulating the unstable drug (-)-epicatechin gallate (ECG) was designed to deliver to atherosclerotic plaques. Acetalization cyclodextrin (PH-CD), which responds to low-pH environments, and hyaluronic acid cyclodextrin, which targets the CD44 receptor on macrophage membranes, were synthesized from ß-CD and hyaluronic acid using acetalization and transesterification, respectively. The resulting dual-carrier nanoparticles (Double-NPs) loaded with ECG were prepared using a solvent evaporation method. The Double-NPs effectively scavenged reactive oxygen species, promoted macrophage migration, inhibited macrophage apoptosis, and suppressed abnormal proliferation and migration of vascular smooth muscle cells. Furthermore, the Double-NPs actively accumulated in atherosclerotic plaques in ApoE-/- mice fed with a high-fat diet, leading to a reduced plaque area, inflammatory infiltration, and plaque instability. Our findings demonstrate that the newly developed ECG nanopreparation represents an effective and safe nanotherapy for diseases such as atherosclerosis.

Elevations in presepsin, PCT, hs-CRP, and IL-6 levels predict mortality among septic patients in ICU.

BACKGROUND: Aim to investigate the predictive value of changes in presepsin (PSEP), procalcitonin (PCT), high-sensitivity C-reactive protein (hsCRP), and interleukin-6 (IL-6) levels to for mortality in septic patients in intensive care unit (ICU). METHOD: This study enrolled septic patients between November 2020 and December 2021. Levels of PSEP, PCT, hsCRP, and IL-6 were measured on 1st (PSEP_0, PCT_0, hsCRP_0, IL-6_0) and 3rd day (PSEP_3, PCT_3, hsCRP_3, IL-6_3). Follow-up was performed on days 3, 7, 14, 21, and 28 after enrollment. The outcome was all-cause death. RESULTS: The study included 119 participants, and the mortality was 18.5%. In univariable Cox proportional-hazards regression (Cox) analysis, △PSEP (= PSEP_3- PSEP_0) > 211.49 pg/ml (hazard ratio (HR) 2.70, 95% confidence interval (CI) 1.17-6.22), △PCT (= PCT_3- PCT_0) > -0.13 ng/ml (HR 7.31, 95% CI 2.68-19.80), △hsCRP (= hsCRP_3- hsCRP_0) > -19.29 mg/L (HR 6.89, 95% CI 1.61-29.40), and △IL-6 (= IL-6_3- IL-6_0) > 1.00 pg/ml (HR 3.13, 95% CI 1.35-7.24) indicated an increased risk of mortality. The composite concordance index for alterations in all four distinct biomarkers was highest (concordance index 0.83, 95% CI 0.76-0.91), suggesting the optimal performance of this panel in mortality prediction. In decision curve analysis, compared with the APACHE Ⅱ and SOFA scores, the combination of the four biomarkers had a larger net benefit. Interestingly, IL-6 was predominantly produced by monocytes upon LPS stimulation in PBMCs. CONCLUSIONS: △PSEP, △PCT, △hsCRP, and △IL-6 are reliable biomarkers for predicting mortality in septic patients in ICU, and their combination has the best performance.

Flagellin/TLR5 responses induce mucus hypersecretion by activating EGFR via an epithelial cell signaling cascades.

Mucus hypersecretion is an important manifestation in patients with chronic inflammatory airway diseases. Excessive production of mucin leads to airway mucus obstruction and contributes to morbidity and mortality in these diseases. The molecular mechanisms underlying mucin overproduction, however, still remain largely unknown. Here, we report that the bacterium Pseudomonas aeruginosa (P. aeruginosa), an important human respiratory pathogen, induced MUC5AC mucin expression via an epithelial cell signaling cascade in human airway epithelial cells. The flagellin purified from P. aeruginosa up-regulated MUC5AC expression by activating its receptor Toll-like receptor 5 (TLR5) in 16HBE cells. This effect was inhibited by NADPH oxidase inhibitor (DPI), small interfering RNA of dual oxidase 2 (Duox2) and reactive oxygen species (ROS) scavengers (nPG and DMSO). Flagellin induced TGF-α release, and stimulated phosphorylated epidermal growth factor receptor (EGFR) and MUC5AC overproduction. These effects were prevented by EGFR and TGF-α neutralizing antibodies, metalloprotease inhibitors (GM6001 and TNF-α protease inhibitor-1) and specific knockdown of TNF-α-converting enzyme (TACE) with TACE siRNA. These findings may bring new insights into the molecular pathogenesis of P. aeruginosa infections and lead to novel therapeutic intervention for mucin overproduction in patients with P. aeruginosa infections.

Increased hsa-miR-100-5p Expression Improves Hepatocellular Carcinoma Prognosis in the Asian Population with PLK1 Variant rs27770A>G.

Hepatocellular carcinoma (HCC) has the highest incidence and mortality in the Asian population, and race is an independent risk factor affecting survival time in liver cancer. Micro RNAs (miRNAs) are remarkably dysregulated in HCC and closely associated with HCC prognosis. Recent studies show that genetic variability between ethnic groups may result in differences in the specificity of HCC miRNA biomarkers. Here, we reveal a high expression level of hsa-miR-100-5p, an HCC prognosis-related miRNA, which improves HCC prognosis in the Asian Population with Polo-like kinase 1 (PLK1) variant rs27770A>G. In this study, we discovered that hsa-miR-100-5p was downregulated in various HCC cell lines. While mimics transient transfection and mouse liver cancer model confirmed the interaction between hsa-miR-100-5p and PLK1, a stratified analysis based on the Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) data suggest both low hsa-miR-100-5p expression level and high PLK1 expression level associated with poor HCC prognosis, especially in the Asian population. According to the 1000 Genomes Project database, the SNP rs27770 located in 3'UTR of PLK1 had a significantly higher G allele frequency in the East Asian population. Bioinformatics analysis suggested that rs27770 A>G affects PLK1 mRNA secondary structure and alters the hsa-miR-100-5p/PLK1 interaction by forming an additional seedless binding site. This racial variation caused PLK1 to be more vulnerable to hsa-miR-100-5p inhibition, resulting in hsa-miR-100-5p being more favorable for HCC prognosis in the Asian population.