Genetic estimation of causalities between educational attainment with common digestive tract diseases and the mediating pathways.

BACKGROUND: The association between education, intelligence, and cognition with digestive tract diseases has been established. However, the specific contribution of each factor in the pathogenesis of these diseases are still uncertain. METHOD: This study employed multivariable Mendelian randomization (MR) to assess the independent effects of education, intelligence, and cognition on gastrointestinal conditions in the FinnGen and UK Biobank European-ancestry populations. A two-step MR approach was employed to assess the mediating effects of the association. RESULTS: Meta-analysis of MR estimates from FinnGen and UK Biobank showed that 1- SD (4.2 years) higher education was causally associated with lower risks of gastroesophageal reflux (OR: 0.58; 95% CI: 0.50, 0.66), peptic ulcer (OR: 0.57; 95% CI: 0.47, 0.69), irritable bowel syndrome (OR: 0.70; 95% CI: 0.56, 0.87), diverticular disease (OR: 0.69; 95% CI: 0.61, 0.78), cholelithiasis (OR: 0.68; 95% CI: 0.59, 0.79) and acute pancreatitis (OR: 0.54; 95% CI: 0.41, 0.72), independently of intelligence and cognition. These causal associations were mediating by body mass index (3.7-22.3%), waist-to-hip ratio (8.3-11.9%), body fat percentage (4.1-39.8%), fasting insulin (1.4-5.5%) and major depression (6.0-12.4%). CONCLUSION: Our findings demonstrate a causal and independent association between education and six common digestive tract diseases. Additionally, our study highlights five mediators as crucial targets for preventing digestive tract diseases associated with lower education levels.

CDKL3 shapes immunosuppressive tumor microenvironment and initiates autophagy in esophageal cancer.

Background: CDKL3 has been associated with the prognosis of several tumors. However, the potential role of CDKL3 in immunotherapy and the tumor microenvironment (TME) in esophageal carcinoma (ESCA) remains unclear. Methods: In this study, Cox regression analysis was used to assess the predictive value of CDKL3 for ESCA outcomes. We systematically correlated CDKL3 with immunological features in the TME. The role of CDKL3 in predicting the efficacy of immunotherapy was also analyzed. Correlation analysis, Cox analysis and LASSO Cox regression were used to construct the CDKL3-related autophagy (CrA) risk score model. The relationship between CDKL3 expression and postoperative pathological complete response (pCR) rate in esophageal squamous cell carcinoma (ESCC) patients undergoing neoadjuvant chemoradiotherapy (nCRT) was evaluated using Immunohistochemical staining (IHC). The relationship between CDKL3 expression and autophagy induction was confirmed by immunofluorescence staining and western blot, and the effect of CDKL3 expression on macrophage polarization was verified by flow cytometry. Results: High expression of CDKL3 was found in ESCA and was associated with poor prognosis in ESCA. Moreover, CDKL3 expression was negatively correlated with tumor-infiltrating immune cells (TIICs), the integrality of the cancer immunity cycles, and anti-tumor signatures, while CDKL3 expression was positively correlated with suppressive TME-related chemokines and receptors, immune hyperprogressive genes, and suppressive immune checkpoint, resulting in immunosuppressive TME formation in ESCA. An analysis of immunotherapy cohorts of the ESCA and pan-cancer showed a better response to immunotherapy in tumor patients with lower CDKL3 levels. The CrA risk score model was constructed and validated to accurately predict the prognosis of ESCA. Notably, the CrA risk score of ESCA patients was significantly positively correlated with M2 macrophages. Furthermore, knockdown CDKL3 in KYSE150 cells could inhibit autophagy induction and M2 macrophage polarization. And, radiation could downregulate CDKL3 expression and autophagy induction, while ESCC patients with high CDKL3 expression had a significantly lower response rate after nCRT than those with low CDKL3 expression. Conclusion: CDKL3 may play an important role in anti-tumor immunity by regulating autophagy to promote the formation of immunosuppressive TME, thus playing a critical role in the prognosis of ESCA.

Kidney-tonifying blood-activating decoction delays ventricular remodeling in rats with chronic heart failure by regulating gut microbiota and metabolites and p38 mitogen-activated protein kinase/p65 nuclear factor kappa-B/aquaporin-4 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Myocardial infarction has likely contributed to the increased prevalence of heart failure(HF).As a result of ventricular remodeling and reduced cardiac function, colonic blood flow decreases, causing mucosal ischemia and hypoxia of the villous structure of the intestinal wall.This damage in gut barrier function increases bowel wall permeability, leading to fluid metabolism disorder,gut microbial dysbiosis, increased gut bacteria translocation into the circulatory system and increased circulating endotoxins, thus promoting a typical inflammatory state.Traditional Chinese Medicine plays a key role in the prevention and treatment of HF.Kidney-tonifying Blood-activating(KTBA) decoction has been proved for clinical treatment of chronic HF.However,the mechanism of KTBA decoction on chronic HF is still unclear. AIMS OF THE STUDY: The effect of KTBA decoction on gut microbiota and metabolites and p38MAPK/p65NF-κB/AQP4 signaling in rat colon was studied to investigate the mechanism that KTBA decoction delays ventricular remodeling and regulates water metabolism disorder in rats with HF after myocardial infarction based on the theory of "Kidney Storing Essence and Conducting Water". MATERIAL AND METHODS: In vivo,a rat model of HF after myocardial infarction was prepared by ligating the left anterior descending coronary artery combined with exhaustive swimming and starvation.The successful modeling rats were randomly divided into five groups:model group, tolvaptan group(gavaged 1.35mg/(kg•D) tolvaptan),KTBA decoction group(gavaged 15.75g/(kg•D) of KTBA decoction),KTBA decoction combined with SB203580(p38MAPK inhibitor) group(gavaged 15.75g/(kg•D) of KTBA decoction and intraperitoneally injected 1.5mg/(kg•D) of SB203580),and KTBA decoction combined with PDTC(p65NF-kB inhibitor) group(gavaged 15.75g/(kg•D) of KTBA decoction and intraperitoneally injected 120mg/(kg•D) of PDTC).The sham-operation group and model group were gavaged equal volume of normal saline.After 4 weeks of intervention with KTBA decoction,the effect of KTBA decoction on the cardiac structure and function of chronic HF model rats was observed by ultrasonic cardiogram.General state and cardiac index in rats were evaluated.Enzyme linked immunosorbent assay(ELISA) was used to measure N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration in rat serum.Hematoxylin and eosin(H&E) staining,and transmission electron microscope(TEM) were used to observe the morphology and ultrastructure of myocardial and colonic tissue,and myocardial fibrosis was measured by Masson's staining.Cardiac E-cadherin level was detected by Western blot.The mRNA expression and protein expression levels of p38MAPK,I-κBα, p65NF-κB,AQP4,Occludin and ZO-1 in colonic tissue were detected by reverse transcription-quantitative real-time polymerase chain reaction(RT-qPCR) and immunohistochemistry. Protein expression of p38MAPK, p-p38MAPK,I-κBα,p-I-κBα,p65NF-κB, p-p65NF-κB,AQP4,Occludin and ZO-1 in rat colon was detected using Western blot.Colonic microbiota and serum metabolites were respectively analyzed by amplicon sequencing and liquid chromatography-mass spectrometry.In vitro, CCD-841CoN cell was placed in the ischemic solution under hypoxic conditions (94%N2,5%CO2,and 1%O2) in a 37 °C incubator to establish an ischemia and hypoxia model.The CCD-841CoN cells were divided into 7 groups, namely blank group and model group with normal rat serum plus control siRNA, tolvaptan group with rat serum containing tolvaptan plus control siRNA, KTBA group with rat serum containing KTBA plus control siRNA, KTBA plus p38MAPK siRNA group, KTBA plus p65NF-κB siRNA group,and KTBA plus AQP4siRNA group.After 24h and 48h of intervention with KTBA decoction,RT-qPCR,immunofluorescence and Western blot was used to detect the mRNA expression and protein expression levels of p38MAPK,I-κBα,p65NF-κB,AQP4, Occludin and ZO-1 in CCD-841CoN cells. RESULTS: Compared with the model, KTBA decoction improved the general state, decraesed the serum NT-proBNP level,HW/BW ratio, LVIDd and LVIDs, increased E-cadherin level,EF and FS,reduced number of collagen fibers deposited in the myocardial interstitium,and recovered irregular arrangement of myofibril and swollen or vacuolated mitochondria with broken crista in myocardium.Moreover, KTBA decoction inhibited the expression of p38MAPK,I-κBα,and p65NF-κB and upregulated AQP4, Occludin and ZO-1 in colon tissues and CCD-841CoN cells.Additionally,p38siRNA or SB203580, p65siRNA or PDTC, and AQP4siRNA partially weakened the protective effects of KTBA in vitro and vivo.Notably,The LEfSe analysis results showed that there were six gut biomaker bacteria in model group, including Allobaculum, Bacillales,Turicibacter, Turicibacterales,Turicibacteraceae,and Bacilli. Besides, three gut biomaker bacteria containing Deltaproteobacteria, Desulfovibrionaceae,and Desulfovibrionales were enriched by KTBA treatment in chronic HF model.There were five differential metabolites, including L-Leucine,Pelargonic acid, Capsidiol,beta-Carotene,and L- Erythrulose, which can be regulated back in the same changed metabolic routes by the intervention of KTBA.L-Leucine had the positive correlation with Bacillales, Turicibacterales,Turicibacteraceae,and Turicibacter.L-Leucine significantly impacts Protein digestion and absorption, Mineral absorption,and Central carbon metabolism in cancer regulated by KTBA, which is involved in the expression of MAPK and tight junction in intestinal epithelial cells. CONCLUSIONS: KTBA decoction manipulates the expression of several key proteins in the p38MAPK/p65NF-κB/AQP4 signaling pathway, modulates gut microbiota and metabolites toward a more favorable profile, improves gut barrier function, delays cardiomyocyte hypertrophy and fibrosis,and improves cardiac function.

Microstructure and Mechanical Properties of Powder Metallurgy Superalloy Joints Welded by Inertia Friction Welding.

In recent years, for the structural characteristics and design requirements of the integral rotor and disc shaft of the integrated engine, the welding quality and mechanical properties of superalloy weldments have received increasing attention. In this paper, inertia friction welding (IFW) of FGH96 alloy was carried out using different welding parameters, and the homogeneous connection of FGH96 alloy hollow bars was successfully realized. The microstructure evolution, mechanical properties and fracture failure of the welded joints at room and high temperatures were investigated. The FGH96 alloy IFW joints were divided into the weld nugget zone (WNZ), the thermo-mechanically affected zone (TMAZ), the heat-affected zone (HAZ) and the base metal (BM), and there were significant differences in grain structure and distribution of the γ' phase in each of the characteristic zones. The microhardness and tensile properties of the IFW joints were investigated, and the results showed an "M"-shaped curve in the microhardness distribution, with the lowest point of hardness observed in the HAZ. The tensile test results indicated that the fracture position moved from the BM to the WNZ with the increase in temperature, the microstructure at the fracture changed significantly and the tensile strength decreased from 1512.0 MPa at room temperature to 1201.3 MPa at 750 °C. The difference in the mechanical properties of the joints was mainly attributed to the changes in the dissolution and precipitation of the γ' phase.

Preparation of smart magnetic fluids and application in sewage treatment: Copper adsorption, kinetic and isotherm study.

The effective removal of heavy metal ions from sewage remains a critical issue, and applying the operability of magnetic materials to large volume wastewater treatment has been a significant challenge. In this paper, metal ions adsorption induced aggregation strategy is proposed to solve this contradiction. The intelligent magnetic fluid designed in this study is a well-dispersed fluid state when treating sewage, and can efficiently adsorb heavy metal ions in wastewater with high adsorption capacity and ultra-fast adsorption kinetics. More importantly, after saturation of adsorption, the magnetic fluid will transform from a well-dispersed fluid state to an agglomeration state which is easy to precipitate and separate via external magnetic field. In a simple and effective way, the particles size of magnetic nanoparticles was precisely controlled by cellulose derivatives modification to obtain a stable magnetic fluid in water. The Freundlich model best described Cu2+ adsorption on magnetite nanoparticles, the correlation coefficients from the Cu2+ adsorption on the two magnetic fluids are 0.9554 and 0.9336, n are 1.868 and 2.117, revealing a favorable adsorption of Cu2+ onto magnetic fluids. The pseudo second-order model fitted the adsorption kinetic data better, the qe are 0.1948 and 0.1315 mmol/g and the R2 are 0.9999, indicating that the adsorption of Cu2+ onto the magnetic fluid was dominated by chemisorption. Moreover, the removal rate of Cu2+ in tap water and lake water was more than 97.1%, and the removal rate of large volume sewage was 81.7%. The synthetic magnetic fluid has high adsorption capacity, ultra-fast adsorption kinetics, reusability and easy separation, indicating its potential application for the removal of heavy metal ions from large-volume sewage.

Sensing and manipulating single lipid vesicles using dynamic DNA nanotechnology.

Natural and artificial lipid vesicles have been widely involved in nano-delivery, bio-analysis and diagnosis. For sensing and manipulating single lipid vesicles, dynamic DNA reactions were constructed inside or on the surface of lipid vesicles. In this review, we interpreted various ways of integrating lipid vesicles and dynamic DNA nanotechnology by summarizing the latest reports in bio-analysis and biomimetic cell research.

Synthesis of crown ether-based microporous organic networks: A new type of efficient adsorbents for chlorophenols.

Microporous organic networks (MONs) are a booming class of functional materials in elimination of environmental pollutants. However, the limit varieties of MONs still restrict their broad applications. Here we report the synthesis of a novel type of crown ether (CE)-based MONs via the coupling between brominated 18-crown-6 ether and different aromatic alkynyls. The constructed CE-based MONs integrates the good conjugation property of MONs and the inherent host-guest binding sites of CE, allowing the ultrafast and efficient adsorption and removal of a typical environmental priority pollutant 2,4,6-trichlorophenol (2,4,6-TCP). The hydrophobic CE-based MONs can also address the recovery challenge of unstable discrete CE in most organic and inorganic solvents. All CE-based MONs displayed fast adsorption kinetics (< 3 min) and large adsorption capacities (229.1-341.7 mg g-1) for 2,4,6-TCP. The CE-based MONs also gave stable adsorption capacities for 2,4,6-TCP in pH range of 4.0-6.0, NaCl concentration of 0-40 mg L-1, HA concentration of 0-30 mg L-1, or H2O2 ratio of < 5 %. Density functional theory calculation, Fourier transform infrared and X-ray photoelectron spectra evaluation revealed adsorption process involved hydrophobic, π-π and hydrogen bonding interactions. The CE-based MONs also showed favorable reusability and good adsorption for other toxic chlorophenols. This work highlights the potential of CE-based MONs in contaminants elimination.

Prognostic Profiling of the EMT-Associated and Immunity-Related LncRNAs in Lung Squamous Cell Carcinomas.

Lung squamous cell carcinoma (Lung SCC) is associated with metastatic disease, resulting in poor clinical prognosis and a low survival rate. The aberrant epithelial-mesenchymal transition (EMT) and long non-coding RNA (LncRNA) are critical attributors to tumor metastasis and invasiveness in Lung SCC. The present study divided lncRNAs into two subtypes, C1 and C2 (Cluster 1 and Cluster 2), according to the correlation of EMT activity within the public TCGA and GEO databases. Subsequently, the differential clinical characteristics, mutations, molecular pathways and immune cell deconvolution between C1 and C2 were evaluated. Lastly, we further identified three key lncRNAs (DNM3OS, MAGI2-AS3 and LINC01094) that were associated with EMT and, at the same time, prognostic for the clinical outcomes of Lung SCC patients. Our study may provide a new paradigm of metastasis-associated biomarkers for predicting the prognosis of Lung SCC.

An unusual case of subacute combined degeneration due to nitrous oxide abuse, which relapsed after bariatric surgery: A case report.

RATIONALE: Several studies have reported subacute combined degeneration (SCD) induced by nitrous oxide (N2O) abuse. However, few studies have reported that N2O-induced SCD recurred because of sleeve gastrectomy after neurological symptoms improved. PATIENT CONCERNS: We report the case of an 18-year-old woman who developed paresthesia, weakness in 4 limbs, and an unstable gait after frequent, excessive N2O inhalation. DIAGNOSIS: The patient was diagnosed as having SCD. INTERVENTIONS AND OUTCOMES: Nineteen days after intravenous mecobalamin and supplementation with other kinds of vitamin B, her weakness and paresthesia resolved. However, 7 months after discharge, the patient experienced recurrence following sleeve gastrectomy. Blood biochemistry revealed low vitamin B12 levels. After a 22-day treatment, similar to the first hospitalization, her residual numbness and unsteady gait improved. LESSONS: This case highlights that patients, especially those at high risk of vitamin B12 deficiency, undergoing sleeve gastrectomy require careful nutritional follow-up and routine monitoring of micronutrients such as vitamin B12 and homocysteine. Continuous vigilance is essential for patients with common and rare neurological complications.

Prognostic value of absolute lymphocyte count in patients with advanced esophageal cancer treated with immunotherapy: a retrospective analysis.

Background: Immunotherapy has become the standard of treatment for recurrent metastatic esophageal cancer (EC), and the value of efficacy predictive markers represented by programmed death-ligand 1 (PD-L1) is limited. The purpose of this study is to analyze the prognostic value of peripheral blood absolute lymphocyte count (ALC) at baseline in patients with recurrent metastatic EC treated with immunotherapy, and to further investigate the relationship between the minimal ALC value (Min ALC) and radiotherapy (RT) parameters. Methods: The main inclusion criteria were: histologically or imaging confirmed recurrent or metastatic EC; complete routine blood test data. A total of 105 patients were included in a single-center institution, 65 of whom had previously received RT. The optimal cut-off value for baseline lymphopenia was determined by the receiver operating characteristic (ROC) curve. The prognostic value of baseline phase lymphopenia for immunotherapy were determined by cox regression analysis and the associated factors affecting lymphopenia were explored by logistic regression analysis. Results: The cut-off value for baseline ALC predicting 1-year overall survival (OS) was 625 cells/µL. The OS was significantly lower in the lymphopenia group (ALC ≤625 cells/µL) than in the non-lymphopenia group (ALC >625 cells/µL) (median OS: 6 vs. 12 months, P=0.002). Multivariate analysis showed that pre-immunotherapy lymphopenia was an important factor influencing patient prognosis [hazard ratio (HR): 1.771, 95% confidence interval (CI): 1.051-2.985; P=0.032)] (adjusted for clinical factors including sex, age, tumor location, histology, degree of differentiation, distant metastasis, use of RT). Patients with a previous grade 4 (G4) Min ALC during RT were more likely to develop pre-immunotherapy lymphopenia following diagnosis of recurrent metastasis [odds ratio (OR): 10.809, 95% CI: 2.185-53.471; P=0.004]. Planning target volume (PTV) volume greater than 521.2 cm3 (OR: 19.981, 95% CI: 1.372-290.985; P=0.028) was an independent risk factor affecting the G4 Min ALC during RT. Conclusions: Lymphopenia is associated with a poorer immunotherapy prognosis in patients with recurrent metastatic EC and those with previous G4 Min ALC after RT. RT-related parameters, especially irradiation volume, can significantly affect lymphocyte counts.

Fluorescent nanomaterials combined with molecular imprinting polymer: synthesis, analytical applications, and challenges.

Fluorescent nanomaterials (FNMs) and molecular imprinted polymers (MIPs) have been widely used in analytical chemistry for determination. However, low selectivity of FNMs and low sensitivity of MIPs hinder their applications. Combining the merits of FNMs and MIPs, FNMs coated with MIPs (FNMs@MIPs) were proposed to solve those problems. Carbon dots, semiconductor quantum dots, noble metal nanoparticles, silica nanoparticles, and covalent-organic frameworks have been reported to be coated with MIPs. In order to overcome challenges for FNMs@MIPs, such as the lack of handy synthesis routes, incompatibility with aqueous solutions, heterogeneous size of particles, leakage of template molecules, the biocompatibility of FNMs@MIPs, and the inference between FNMs and MIPs, scientists proposed some solutions in recent years. We comprehensively review the newest advances of the FNMs@MIPs, and predict the direction of the future development. Graphical abstract.

Optimal Function Prediction of Key Aberrant Genes in Early-onset Preeclampsia Using a Modified Network-based Guilt by Association Method.

BACKGROUND: To predict the optimal functions of key aberrant genes in early-onset preeclampsia (EOPE) by using a modified network-based gene function inference method. METHODS: First, differentially expressed genes (DEGs) were extracted using linear models for microarray data (LIMMA) package. Then the Spearman's rank correlation coefficient was calculated to assess co-expressed strength of each interaction between DEGs, based on which the co-expressed genes network was constructed to vividly exhibit their interlinking relationship. Subsequently, Gene ontology (GO) annotations for EOPE were collected according to known confirmed database and DEGs. Ultimately, the multifunctionality algorithm was used to extend the "guilt by association" method based on the co-expressed network, and a 3-fold cross validation was operated to evaluate the accuracy of the algorithm. RESULTS: During the process, the GO terms, of which the area under the curve (AUC) over 0.7 were screened as the optimal gene functions for EOPE. Six functions including the ion binding and cellular response to stimulus were determined as the optimal gene functions. CONCLUSION: Such findings should help to better understand the pathogenesis of EOPE, so as to provide some references for clinical diagnosis and treatment in the future.

JTC-801 inhibits the proliferation and metastasis of ovarian cancer cell SKOV3 through inhibition of the PI3K - AKT signaling pathway.

Ovarian cancer (OC) is the commonest cause of gynaecological cancer-associated death because of the wide metastasis and frequent recidivation. JTC-801 is a new synthetic compound with the function of reversing pain and anxiety symptoms as a selective opioid receptor-like1 receptor (belonging to the G-protein-coupled receptor) antagonist. We investigated the role and possible mechanisms of JTC-801 in the cell growth and metastasis of OC. It was observed that JTC-801 inhibited the proliferation, invasion and migration of cancer in SKOV3 cells. The apoptosis rate of SKOV3 cells treated with JTC-801 was significantly increased (P<0.05), and the expression results of relevant apoptosis proteins (BCL2, BAX, Active Caspase-3) indicated the JTC-801 could induce the apoptosis of SKOV3. Further, the expression levels of phosphorylated AKT, phosphorylated mTOR, P70 and CyclinD1 in the PI3K/AKT signaling pathway were obviously reduced in the JTC-801 treated SKOV3 group. This suggests that JTC-801 exerts its anticancer effect through the PI3K/AKT signaling pathway. Our data also highlights the possibility of using JTC-801 as a novel therapeutic drug for OC treatment mean while it plays the analgesic effect.

Molecularly imprinted polymers for the detection of illegal drugs and additives: a review.

This review (with 154 refs.) describes the current status of using molecularly imprinted polymers in the extraction and quantitation of illicit drugs and additives. The review starts with an introduction into some synthesis methods (lump MIPs, spherical MIPs, surface imprinting) of MIPs using illicit drugs and additives as templates. The next section covers applications, with subsections on the detection of illegal additives in food, of doping in sports, and of illicit addictive drugs. A particular focus is directed towards current limitations and challenges, on the optimization of methods for preparation of MIPs, their applicability to aqueous samples, the leakage of template molecules, and the identification of the best balance between adsorption capacity and selectivity factor. At last, the need for convincing characterization methods, the lack of uniform parameters for defining selectivity, and the merits and demerits of MIPs prepared using nanomaterials are addressed. Strategies are suggested to solve existing problems, and future developments are discussed with respect to a more widespread use in relevant fields. Graphical abstract This review gives a comprehensive overview of the advances made in molecularly imprinting of polymers for use in the extraction and quantitation of illicit drugs and additives. Methods for syntheses, highlighted applications, limitations and current challenges are specifically addressed.

L-Carnitine Attenuates Cardiac Dysfunction by Ischemic Insults Through Akt Signaling Pathway.

We aim to investigate the cardioprotective effects of L-carnitine (LC) on cardiac function during ischemia and reperfusion (I/R) and contractile function of single cardiomyocyte. C57BL/6 J mice were randomly assigned to 5 groups: sham group; vehicle group, LC preconditioning group, LC preconditioning + LY294002 (a PI3K/Akt signaling pathway inhibitor) group (LC + LY), and LY294002 group (LY). The sham group was exposed to the open heart operation but not I/R, the other groups received 45 min ischemia/48 h reperfusion. At the end of reperfusion, echocardiography was performed on every mouse. In order to determine whether LC's cardioprotection could act directly at the level of cardiomyocytes, we also tested its effects on isolated cardiomyocytes under hypoxia condition. The expressions of p-PI3K, PI3K, Akt, p-Akt, Bax and Bcl-2 proteins were detected by immunoblotting. The results showed that LC preconditioning remarkably improved cardiac function after I/R, but the cardioprotective effect of LC was significantly weakened after the application of LY294002. We also found that LC could directly improve the contractile function of cardiomyocytes under hypoxia condition. The immunoblotting results showed that LC administration restrained myocardial apoptosis as evidenced by decreasing the level of Bax expression, increasing the levels of phosphorylation of Akt, PI3K, and Bcl-2 protein expression, but these were blocked by LYC94002. Thus, the cardioprotective effects of LC against myocardial ischemic damage and its effect on single cardiomyocyte under hypoxia may be associated with the PI3K/Akt signaling pathway.

The Binary System of Ibuprofen-Nicotinamide Under Nanoscale Confinement: From Cocrystal to Coamorphous State.

Coamorphous systems have gained success in stabilizing amorphous drugs and improving their solubility and dissolution. Here we proposed to confine a binary mixture of drug and coformer (CF) within nanopores to obtain a nanoconfined coamorphous (NCA) system. For proving feasibility of this proposal, a poorly water-soluble drug (ibuprofen) and a frequently used pharmaceutical CF (nicotinamide) were loaded into nanopores of mesoporous silica microspheres. The solid state of NCA system was characterized by differential scanning calorimetry, X-ray powder diffraction, infrared spectrum, and solid-state nuclear magnetic resonance. With large numbers of nanopores, mesoporous silica microspheres appear to be a feasible carrier to transform a cocrystal system into coamorphism by nanoscale confinement. Benefiting from both nanoscale confinement and CF, the NCA system of ibuprofen achieved synchronic increase in dissolution properties and physical stability. Consequently, the NCA strategy is effective in achieving coamorphous state and offers a promising alternative for formulating poorly water-soluble drugs.

Folic acid-functionalized drug delivery platform of resveratrol based on Pluronic 127/D-α-tocopheryl polyethylene glycol 1000 succinate mixed micelles.

A folic acid (FA)-functionalized drug vehicle platform based on Pluronic 127 (P127)/D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) mixed micelles was orchestrated for an effective delivery of the model drug resveratrol in order to address the problem of poor water solubility and rapid metabolism of resveratrol and improve its targeted accumulation at tumor site. The FA-decorated mixed micelles were prepared using thin-film hydration method and optimized by central composite design approach. The micelles were also characterized in terms of size and morphology, drug entrapment efficiency and in vitro release profile. In addition, the cytotoxicity and cell uptake of the micelles were evaluated in folate receptor-overexpressing MCF-7 cell line. In vivo pharmacokinetic and biodistribution studies were also performed. The average size of the micelles was ~20 nm with a spherical shape and high encapsulation efficiency (99.67%). The results of fluorescence microscopy confirmed the targeting capability of FA-conjugated micelles in MCF-7 cells. FA-modified micelles exhibited superior pharmacokinetics in comparison with that of solution. Further, the low accumulation of resveratrol-loaded FA micelles formulation in the heart and kidney avoided toxicity of these vital organs. It could be concluded that folate-modified P127/TPGS mixed micelles might serve as a potential delivery platform for resveratrol.

Facile large-scale preparation of mesoporous silica microspheres with the assistance of sucrose and their drug loading and releasing properties.

Mesoporous silica microspheres (MSMs) with a pore-size larger than 10nm and a large pore-volume have attracted considerable attention for their application in delivering poorly water-soluble drugs. Here we developed a simple method for large-scale synthesis of MSMs using sodium silicate as silica precursor. The novelty of this approach lies in the use of sucrose solution to achieve large size and volume of nanopores. The highest values of pore size and pore volume are 13.2 nm and 1.97 cm(3)/g, respectively. Importantly, the method is reliable and easily upscalable. The blank and drug-loaded MSMs were characterized by differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD). Ibuprofen and resveratrol were successfully loaded into the nanopores of MSMs in amorphous and nanocrystalline form and showed high drug-loadings and enhanced dissolution rates. This kind of MSMs appears to be a promising candidate as a new oral drug delivery vehicle providing a rapid drug release.

The histone demethylase PHF8 represses cardiac hypertrophy upon pressure overload.

BACKGROUND: Mammalian hearts undergo hypertrophy upon pressure overload to support increased workload. Sustained hypertrophy results in cardiac decompensation and subsequently heart failure. The mechanism that prevents the development of cardiac hypertrophy is still not fully understood. Here we elucidate the anti-hypertrophic role of the histone demethylase PHF8. METHODS AND RESULTS: PHF8 protein and mRNA levels were down-regulated in human failing hearts, mouse hypertrophic hearts and neonatal rat ventricle myocytes that underwent hypertrophy. Then we generated a cardiac-specific PHF8 transgenic mice, and found that PHF8 overexpression reversed cardiac dysfunction, hypertrophy and fibrosis upon pressure overload. In vivo evidence showed that PHF8 blocked protein synthesis and hypertrophic fetal genes expression. Furthermore, we found that PHF8 inhibited Akt-mTOR pathway in hypertrophic hearts and neonatal rat ventricle myocytes, and rapamycin treatment rescues the effects of PHF8 loss. CONCLUSION: These results indicate that PHF8 serves as an endogenous factor that the host uses to attenuate cardiac hypertrophy upon cardiac overload. Strategies based on its enhancement might be of benefit in the treatment of hypertrophic cardiomyopathy.