Drug-drug interaction between danshensu and irbesartan and its potential mechanism.

To uncover the effect of danshensu on irbesartan pharmacokinetics and its underlying mechanisms.To investigate the effect of danshensu on the pharmacokinetics of irbesartan, Sprague-Dawley rats (n = 6) were orally administered 30 mg/kg irbesartan alone (control group) or pre-treated with 160 mg/kg danshensu (experimental group). The effect of danshensu on the metabolic stability of irbesartan in RLMs was examined by LC-MS/MS method. The effect of danshensu on CYP2C9 activity was also determined.Danshensu markedly increased the AUC(0-t) (9573 ± 441 vs. 16157 ± 559 µg/L*h) and Cmax (821 ± 24 vs. 1231 ± 44 µg/L) of irbesartan. Danshensu prolonged the t1/2 (13.39 ± 0.98 vs. 16.04 ± 1.21 h) and decreased the clearance rate (2.27 ± 0.14 vs. 1.19 ± 0.10 L/h/kg) of irbesartan. Danshensu enhanced the metabolic stability of irbesartan in vitro with prolonged t1/2 (36.34 ± 11.68 vs. 48.62 ± 12.03 min) and reduced intrinsic clearance (38.14 ± 10.24 vs. 28.51 ± 9.06 µL/min/mg protein). Additionally, the IC50 value for CYP2C9 inhibition by danshensu was 35.74 µM.Danshensu enhanced systemic exposure of irbesartan by suppressing CYP2C9. The finding can also serve as a guidance for further investigation of danshensu-irbesartan interaction in clinical practice.

3D Lightweight Interconnected Melamine Foam Modified with Hollow CoFe2O4/MXene toward Efficient Microwave Absorption.

Considering the increasing severity of electromagnetic wave pollution, the development of high-performance low-filler-content microwave absorbers possessing wide frequency bands and strong absorption for practical applications is a demanding research hotspot. In this study, from the perspectives of the electromagnetic component coordination and structural design, a three-dimensional (3D) interconnected CoFe2O4/MXene-melamine foam (MF) was constructed via simple impregnation and a single freeze-drying step. By changing the absorber (CoFe2O4/MXene) concentration, the pore opening and electromagnetic properties of the 3D foams can be effectively adjusted. When the absorber concentration is sufficiently high to clog the internal pores, the microwave absorption is hindered. When the filler (CoFe2O4/MXene-MF) content is just ∼5.8 wt % (at a density of ∼33.3 mg cm-3), a minimum reflection loss (RLmin) of -72.1 dB is achieved at a matching thickness of 3.32 mm, and an effective absorption bandwidth (4.54 GHz) covering the whole X band is achieved at a thickness of 3 mm. CoFe2O4/MXene-MF, which possesses a 3D porous electromagnetic network structure, optimizes impedance matching and enhances multiple polarization relaxations and reflections/scattering, resulting in superior absorption capabilities. In particular, the continuous network structure ensures the uniform distribution of electromagnetic fields in the microstructure, achieving high absorption at low filler contents. This work provides a reference for subsequent 3D absorber concentration studies and a novel engineering strategy for preparing a low-filler-content, lightweight, and efficient electromagnetic wave absorber, which could be applied in the fields of radar security and information communications.

Mouse Embryonic Fibroblasts-Derived Extracellular Matrix Facilitates Expansion of Inner Ear-Derived Cells.

OBJECTIVE: Previous reports showed that mouse embryonic fibroblasts (MEFs) could support pluripotent stem cell selfrenewal and maintain their pluripotency. The goal of this study was to reveal whether the decellularized extracellular matrix derived from MEFs (MEF-ECM) is beneficial to promote the proliferation of inner ear-derived cells. MATERIALS AND METHODS: In this experimental study, we prepared a cell-free MEF-ECM through decellularization. Scanning electron microscope (SEM) and immunofluorescent staining were conducted for phenotype characterization. Organs of Corti were dissected from postnatal day 2 and the inner ear-derived cells were obtained. The identification of inner ear-derived cells was conducted by using reverse transcription-polymerase chain reaction (RT-PCR). Cell counting kit-8 (CCK-8) was used to evaluate the proliferation capability of inner ear-derived cells cultured on the MEFECM and tissue culture plate (TCP). RESULTS: The MEF-ECM was clearly observed after decellularization via SEM, and the immunofluorescence staining results revealed that MEF-ECM was composed of three proteins, including collagen I, fibronectin and laminin. Most importantly, the results of CCK-8 showed that compared with TCP, MEF-ECM could effectively facilitate the proliferation of inner ear-derived cells. CONCLUSION: The discovery of the potential of MEF-ECM in promoting inner ear-derived cell proliferation indicates that the decellularized matrix microenvironment may play a vital role in keeping proliferation ability of these cells. Our findings indicate that the use of MEF-ECM may serve as a novel approach for expanding inner ear-derived cells and potentially facilitating the clinical application of inner ear-derived cells for hearing loss in the future.

Urchin-like Fe3O4@C hollow spheres with core-shell structure: Controllable synthesis and microwave absorption.

The steadily increasing use of microwave stealth materials in aerospace flying vehicles needs the development of lightweight absorbers with low density and high thermal stability for printing or spraying. In that regard, the structural designability of typical microwave absorbers made of Fe3O4 seems to be a significant roadmap. In this work, a hollow spherical structure with a uniform carbon shell around the urchin-like Fe3O4 core (Fe3O4@C) was produced via a two-step hydrothermal method and annealing. The Fe3O4@C absorber exhibited a strong minimum reflection loss (RLmin) of -73.5 dB at the matching thickness of 3.23 mm. The maximum effective absorption bandwidth (EABmax) was 4.78 GHz at 4.55 mm. The proposed urchin-like core-shell structure was shown to provide good impedance matching and electromagnetic loss ability due to the synergistic effect of Fe3O4 and C. In particular, the urchin-like structure increases the heterogeneous interfaces and effectively improves their polarization and relaxation. On the other hand, it reduces the density of the absorber and enhances multiple scattering attenuations of electromagnetic waves (EMWs). Therefore, the findings of the present study open up prospects for the design of high-efficiency lightweight microwave absorbers with specialized structures.

Chicken utricle stromal cell-derived decellularized extracellular matrix coated nanofibrous scaffolds promote auditory cell production.

Stem cell therapy has a broad future in treating sensorineural hearing loss in mammals. But how to produce sufficient functional auditory cells including hair cells, supporting cells as well as spiral ganglion neurons from potential stem cells is the bottleneck. In this study, we aimed to simulate inner ear development microenvironment to induce inner ear stem cells to differentiate into auditory cells. The different mass ratios of poly-l-lactic acid/gelatin (PLLA/Gel) scaffolds were fabricated by electrospinning technology to mimic the structure of the native cochlear sensory epithelium. The chicken utricle stromal cells were isolated and cultured, and then seeded on the PLLA/Gel scaffolds. The chicken utricle stromal cell-derived decellularized extracellular matrix (U-dECM)-coated PLLA/Gel bioactive nanofiber scaffolds (U-dECM/PLLA/Gel) were prepared by decellularization. The U-dECM/PLLA/Gel scaffolds were used for culture of inner ear stem cells, and the effects of the modified scaffolds on the differentiation of inner ear stem cells were analyzed by RT-PCR and immunofluorescent staining. The results showed that U-dECM/PLLA/Gel scaffolds possessed good biomechanical properties can significantly promote the differentiation of inner ear stem cells and make them differentiate into auditory cells. Collectively, these findings indicated that U-dECM-coated biomimetic nanomaterials may be a promising strategy for auditory cell production.

COVID-19 in pulmonary critically ill patients: metagenomic identification of fungi and characterization of pathogenic microorganisms.

Background: Fungal co-infection is prevalent in critically ill patients with COVID-19. The conventional approach applied to fungal identification has relatively low sensitivity and is time-consuming. The metagenomic next-generation sequencing (mNGS) technology can simultaneously detect a variety of microorganisms, and is increasingly being used for the rapid detection and diagnosis of pathogens. Methods: In this single-center retrospective study, we described the clinical presentation and outcomes of COVID-19 and mNGS positive for fungi in pulmonary critically ill patients during the outbreak of Omicron infection from December 2022 to January 2023. Results: Among 43 COVID-19 patients with acute respiratory distress syndrome (ARDS) on a single intensive care unit (ICU), 10 were reported to be fungal positive using the mNGS test. The number of pathogenic microorganisms detected by mNGS was significantly higher than that via traditional methods, especially in the detection of fungi and viruses. Aspergillus infection was dominant, and most of these patients also had concurrent bacterial or viral infections. Probable or possible COVID-19-associated pulmonary aspergillosis (CAPA) was diagnosed in all 10 patients, and the prognosis was poor. Conclusion: Patients with COVID-19 may be at increased risk of developing fungal infections as well as concurrent bacterial or viral infections, and mNGS can be a powerful tool in identifying these infections. Clinicians should be aware of the increased risk of fungal infections in COVID-19 patients, particularly those who have underlying immunocompromising conditions, and should monitor for early signs of infection.

MG132 protects against lung injury following brain death in rats.

Brain death (BD) results in injury to organs and induces lung donor dysfunction. Since the 20S proteasome abnormality is associated with a variety of diseases, the present study investigated whether it was involved in lung injury following BD in rats, and the effects of the proteasome inhibitor MG132 on lung injury was also assessed. Rats were assigned to a BD group or a control sham group. The BD group of rats were sacrificed at different time points after BD. Administration of MG132 was performed intraperitoneally 30 min before BD. Arterial blood was drawn to measure the oxygenation index [partial artery pressure of oxygen (PaO2)/fractional concentration of inspired oxygen (FiO2)]. The right lung was used for staining with hematoxylin and eosin, immunohistochemistry, immunofluorescence, western blotting and RT-qPCR analysis. The left lung was used to measure the wet and dry weights. Rat alveolar macrophages (NR8383) were treated with MG132 and hypoxia/reoxygenation (H/R) and used for western blotting and flow cytometry. The PaO2/FiO2 ratio decreased after BD; the wet/dry weight ratio, histological lung injury score and protein expression of 20S proteasome ß1 and inducible nitric oxide synthase (iNOS) gradually increased in rats after BD. Colocalization in the immunofluorescence between 20S proteasome ß1 and iNOS was observed. MG132 treatment increased the PaO2/FiO2 ratio and decreased the wet/dry weight ratio, histological lung injury score and protein expression of 20S proteasome ß1 and iNOS in rats after BD. MG132 was revealed to increase NR8383 apoptosis after H/R and to upregulate the protein expression levels of p-JNK and cleaved-caspase 3. Overall, the proteasome inhibitor MG132 could effectively reduce lung injury, which may be associated with its ability to inhibit the expression of the proteasome and promote the apoptosis of alveolar macrophages.

Comprehensive Exploration of M2 Macrophages and Its Related Genes for Predicting Clinical Outcomes and Drug Sensitivity in Lung Squamous Cell Carcinoma.

Background: M2 macrophages play an important role in cancers. However, the role of M2 macrophages has not been clarified in lung squamous cell carcinoma. Methods: All the open-accessed data were downloaded from The Cancer Genome Atlas database. All the analysis was performed in the R software. The CIBERSORT algorithm was utilized to quantify the immune cell infiltration in the tumor microenvironment. LASSO regression and multivariate Cox regression analysis were carried out for the creation of the prognostic model. Pathway enrichment analysis was performed using the single sample Gene Set Enrichment Analysis (ssGSEA) and clueGO algorithm. Results: In our study, we comprehensively explored the role of M2 macrophages and its related genes in LUSC patients. We found that the patients with high M2 macrophage infiltration tend to have a worse prognosis. Also, some oncogenetic pathways were activated in the patients with high M2 macrophage infiltration. Further, a prognosis model based on six M2 macrophage-related genes was established, including TRIM58, VIPR2, CTNNA3, KIAA0408, CLEC4G, and MATN4, which showed a good prognosis prediction efficiency in both training and validation cohort. Pathway enrichment analysis showed that the pathway of allograft rejection, bile acid metabolism, coagulation, inflammatory response, IL6/JAK/STAT3 signaling, hedgehog signaling, peroxisome, and myogenesis were significantly activated in the high-risk patients. Based on the results of an investigation of immune infiltration, risk score was found to have a positive correlation with M2 macrophages and resting CD4+ memory T cells, but a negative correlation with follicular helper T cells, M1 macrophages, and Tregs. In addition, we discovered that patients in high-risk groups may respond better to immunotherapy than individuals in lower-risk groups. However, low-risk patients might be more sensitive to cisplatin. Conclusions: Our model is a powerful tool to predict LUSC patient prognosis and could indicate the sensitivity of immunotherapy and chemotherapy.

FDA Warning Letters: A Retrospective Analysis of Letters Issued to Pharmaceutical Companies from 2010-2020.

Purpose: To launch a pharmaceutical product in the US market, approval from the FDA is required. Pharmaceutical companies undergo FDA pre-approval inspection (PAI for small molecule products) or pre-license approval (PLI for biological products) at their manufacturing sites (including contract development and manufacturing organization, testing laboratories, and packaging labelling facilities) prior to approval. After the products are approved by the FDA, surveillance inspections are performed by the FDA which are risk based as which company and which site will be inspected. The present study examines the causes of warning letters issued by the Center for Drug Evaluation and Research (CDER), FDA to the pharmaceutical companies after post-approval inspections. Methods: Warning letters issued from the time period 2010 to 2020 were obtained from the FDA website, and information about date of issuance, company, and type of violations was extracted for the study. Results: Poor compliance to CGMP and misbranding were the most common reasons for the warning letters. Detailed analysis of CGMP warning letters elucidated three major types of violations, namely deficiencies in process validation, documentation practices (data integrity), and quality control corresponding to 26%, 21%, and 15% warning letters, respectively. Conclusion: Review of the analysed letters demonstrates that the FDA's major concern is over CGMP compliance. To avoid these warning letters, pharmaceutical manufacturers need to improve their quality compliance and focus on creating effective quality management systems that govern the entire manufacturing process, quality control, employee training, and documentation practice. Companies should develop an internal compliance check list and also be ready for corrective measures as and when required. Supplementary Information: The online version contains supplementary material available at 10.1007/s12247-022-09678-2.

Associations of cadmium exposure with risk of metabolic syndrome and its individual components: a meta-analysis.

Data directly associating cadmium (Cd) with metabolic syndrome (MetS) are sparse and inconsistent. We aimed to quantitatively assess the association of Cd exposure with risk of MetS and its individual components. Literature searching was performed in PubMed, EMBASE, and MEDLINE-OVID through September, 2021. Weighted odds ratios (ORs) for MetS and its components were pooled by comparing the highest to the lowest category of Cd exposure using random-effects models. Eleven (10 from Asia and 1 from the US) cross-sectional studies (33,887 participants and 7176 cases) were identified. Overall, Cd exposure was not associated with risk of MetS [OR: 1.08, 95% confidence interval (CI): 0.92, 1.28]. However, the association became significant when pooling Asian studies (OR: 1.18, 95% CI: 1.02, 1.35), and it was more pronounced with Cd measured in blood (OR: 1.24, 95% CI: 1.05, 1.45). Additionally, Cd exposure was significantly associated with reduced HDL-cholesterol (OR: 1.27, 95% CI: 1.05, 1.54) and elevated triglyceride (OR: 1.17, 95% CI: 1.05, 1.30), but not other components. This meta-analysis indicates that Cd exposure is associated with risk of MetS among Asian populations, which is mainly explained by Cd's association with dyslipidemia. Further studies are needed to better understand the mechanism of action.

Magnesium intake is inversely associated with risk of non-alcoholic fatty liver disease among American adults.

PURPOSE: Human data are limited linking magnesium (Mg) intake to the risk of non-alcoholic fatty liver disease (NAFLD). We aimed to examine the association between Mg intake and the risk of NAFLD among young adults in the US with a 25-year follow-up. METHODS: This study included 2685 participants from the Coronary Artery Risk Development in Young Adult (CARDIA) study. Diet and dietary supplements were assessed at baseline (1985-1986) and exam years 7 and 20 using an interview-based dietary history. NAFLD, defined as liver attenuation ≤ 51 Hounsfield Units excluding secondary causes of liver fat accumulation, was identified by non-contrast-computed tomography scanning at exam year 25. Multivariable-adjusted logistic regression model was used to examine the associations between cumulative average total intake of Mg (dietary plus supplemental) and NAFLD odds. RESULTS: A total of 629 NAFLD cases were documented. After adjustment for potential confounders, an inverse association between total Mg intake and NAFLD odds was observed. Compared to participants in the lowest quintile of total Mg intake, the odds of NAFLD was 55% lower among individuals in the highest quintile [multivariable-adjusted odds ratio (OR) = 0.45, 95% confidence interval (CI) (0.23, 0.85), p for trend = 0.03]. Consistently, whole-grain consumption, a major dietary source of Mg, was inversely associated with NAFLD odds (p for trend = 0.02). CONCLUSIONS: This study suggests that higher cumulative intake of Mg throughout adulthood is associated with lower odds of NAFLD in midlife. Future studies are needed to establish a possible causal relationship.

Cadmium Exposure in Young Adulthood Is Associated with Risk of Nonalcoholic Fatty Liver Disease in Midlife.

BACKGROUND: Studies have suggested that cadmium (Cd) may be involved in the etiology of nonalcoholic fatty liver disease (NAFLD), but available data in human is sparse. AIMS: We aimed to examine Cd exposure in young adulthood in relation to prevalent NAFLD in midlife among American adults. METHODS: This study included 2446 participants from the Coronary Artery Risk Development in Young Adults study with toenail Cd measurement at exam year 2 (baseline) and computed tomography quantification of liver fat at exam year 25. Toenail Cd concentrations were considered as a reliable marker of long-term exposure. NAFLD was defined if liver attenuation < 51 Hounsfield units after excluding other possible causes of liver fat. Multivariable-adjusted logistic regression models were used to estimate the odds ratio of NAFLD by Cd exposure. RESULTS: Median toenail Cd concentration was 8.2 ppb (inter-quartile range 4.3-18.6 ppb). After 23 years from baseline, 580 participants with prevalent NAFLD (24% prevalence) in midlife were identified. Compared with individuals in the lowest quartile, those in the highest quartile of toenail Cd had a significantly higher odds of NAFLD (OR: 1.43, 95% CI: 1.02, 1.99, P for trend: 0.04) after adjustment for demographics, socioeconomics, major lifestyle factors, and baseline levels of body mass index, lipids, and fasting insulin. The association was not significantly modified by race, sex, BMI, or smoking status at baseline. CONCLUSIONS: Toenail Cd concentration was associated with a higher odds of prevalent NAFLD23 years later in life in this cohort of US general population.

Osteoblast-derived extracellular matrix coated PLLA/silk fibroin composite nanofibers promote osteogenic differentiation of bone mesenchymal stem cells.

Poly-L-lactic acid (PLLA) is one of the most commonly used synthetic materials for regenerative medicine, and silk fibroin (SF) is a natural protein with excellent biocompatibility. Combination of PLLA and SF in a proper proportion by electrospinning may generate composite nanofibers that could meet the requirements of scaffolding in bone tissue engineering. The application of PLLA/SF nanofibrous scaffold for osteogenesis is well established in vitro and in vivo. However, PLLA/SF nanofibrous scaffold does not have an ideal ability to promote cell adhesion, proliferation, and differentiation. Extracellular matrix (ECM) plays a critical role in modulating cellular behavior. However, the role of combination of natural ECM with nanofibrous scaffold in regulating osteogenic differentiation is unclear. In this study, we aimed to develop a novel composite PLLA/SF nanofibrous scaffold coated with osteoblast-derived extracellular matrix (O-ECM/PLLA/SF) and analyze the effects of the modified scaffold on osteogenic differentiation of BMSCs. The surface structural features and compositions of the O-ECM/PLLA/SF scaffold were characterized by SEM and immunofluorescence staining. The capacities of the O-ECM/PLLA/SF scaffold to induce osteogenic differentiation of BMSCs were investigated by alkaline phosphatase (ALP) and alizarin red staining (ARS). The results showed BMSCs cultured on O-ECM/PLLA/SF scaffold significantly increased osteogenic differentiation compared with cells cultured individually on a scaffold or O-ECM. Collectively, these findings indicate that O-ECM-coated nanofibrous scaffold can be a promising strategy for osteogenic differentiation of BMSCs, opening a new possibility of utilizing composite scaffolds for bone tissue engineering.

Attapulgite-MXene Hybrids with Ti3C2Tx Lamellae Surface Modified by Attapulgite as a Mechanical Reinforcement for Epoxy Composites.

As a member of two-dimensional (2D) materials, MXene is an ideal reinforcement phase for modified polymers due to its large number of polar functional groups on the surface. However, it is still relatively difficult to modify any functional groups on the surface of MXene at present, which limits its application in enhancing some polymers. Herein, one-dimensional (1D) attapulgite (ATP) nanomaterials were introduced onto the surface of MXene to form ATP-MXene hybrids, which successfully improved the mechanical properties of the epoxy composites. ATP with appropriate content can increase the surface roughness of the MXene lamellae to obtain better interface interaction. Therefore, remarkable enhancement on the mechanical property was achieved by adding M02A025 (0.2 wt % MXene and 0.25 wt % ATP), which is the optimum composition in the hybrids for composite mechanical properties. Compared to neat epoxy, the tensile strength, flexural strength and critical stress intensity factor (KIC) of M02A025/epoxy are increased by 88%, 57%, and 195%, respectively, showing a high application prospect.

Self-driven microstructural evolution of Au@Pd core-shell nanoparticles for greatly enhanced catalytic performance during methanol electrooxidation.

The lack of direct insight into the microstructural evolution of catalytic materials under electrochemical polarization has inhibited the development of heterogeneous catalysts. By investigating a typical Au@Pd core-shell nanostructure, the present study discloses the microstructural evolution of heterogeneous catalytic materials during the methanol electrooxidation reaction (MOR). The electrocatalytic activity of the as-prepared Au@Pd_core-shell nanoparticles continuously increased during the first 100 successive voltammetry cycles of the MOR. Microstructural characterization studies revealed that during the MOR, an Au/Pd mixed bimetallic shell was formed by the self-driven microstructural evolution of the Au@Pd_core-shell nanoparticles. Both the experimental and calculation results indicated that the Au/Pd mixed bimetallic shell reduced the binding strength of OH- and CO on the catalyst surface. The exposed Au atoms in the shell region also produced large-scale reactive ˙OH radicals that facilitated the oxidative removal of the adsorbed carbonaceous species from the adjacent Pd active sites.

Stable and active Pt colloid preparation by modified citrate reduction and a mechanism analysis of inorganic additives.

Ultra-small and monodispersed Pt nanoparticles (NPs) have been successfully synthesized in polymer electrolyte membrane fuel cells. The process normally involves the use of capping agents, organic species, templates, and substrates and is thus complex. Hence, obtaining Pt NPs with a clean surface is challenging. In this study, a method for preparing stable and highly dispersed Pt NPs with clean surfaces is proposed. The method involves the use of a modified Na3C6H5O7 reduction process assisted by NaNO3 stabilization. The specific complexations of NO2- ions possibly alter the reaction kinetics and lower the growth rate of Pt NPs by retarding the reduction reaction. The optimized Pt/carbon nanotube (CNT) catalysts exhibit high mass activity and moderate activity decay after 10,000 times of potential cycling compared with commercially available Pt/C catalysts. Then, membrane electrode assemblies based on the resultant catalysts are characterized. The cell performance of 744 mW cm-2 (maximum power density) is achieved after the optimized Pt/CNT catalysts are used in carbon black.

Fabrication of superparamagnetic nano-silica@ quercetin-encapsulated PLGA nanocomposite: Potential application for cardiovascular diseases.

Cardiovascular malady (CVM) isn't just the essential driver of death in created western nations, yet additionally, its sickness load is expanding in China. Oxidative pressure initiated free radicals assume a basic job in cell forms involved in atherosclerosis and numerous other heart illnesses. Quercetin (QC) is cancer prevention agents medicate which is demonstrated that successfully secures against CVMs. Encapsulations of medications in polymeric materials are generally utilized in creating continued and controllable medication discharge, or to keep away from the debasement of non-discharged medications. In this present work, a novel arrangement of polymeric superparamagnetic nano-silica (SiN)@poly(lactic-co-glycolic acid) (PLGA) (SiN@PLGA) stacked with QC was created by means of lyophilization method so as to improve poor watery solvency and steadiness of the medication with the point of preventing atherosclerosis. The aftereffects of SEM investigation and the checking, TEM affirmed the manufacture of the circular nanocomposite, smooth surface, and thin size dispersion. The discharge profile of QC from the particles was explored by deciding the medication sum discharged at explicit interims for by iridescence. The data got from this investigation encourages the structure and manufacture of nanocomposite as conceivable conveyance frameworks for epitome, assurance and controlled arrival of the flavonoid QC which is expecting to secure against CVMs.

Conditioned Medium Enhances Osteogenic Differentiation of Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells.

Background: Recent studies have shown that induced pluripotent stem cells (iPSCs) could be differentiated into mesenchymal stem cells (MSCs) with notable advantages over iPSCs per se. In order to promote the application of iPSC-MSCs for osteoregenerative medicine, the present study aimed to assess the ability of murine iPSC-MSCs to differentiate into osteoblast phenotype. Methods: Osteogenic differentiation medium, blending mouse osteoblast-conditioned medium (CM) with basic medium (BM) at ratio 3:7, 5:5 and 7:3, were administered to iPSC-MSCs, respectively. After 14 days, differentiation was evaluated by lineage-specific morphology, histological stain, quantitative reverse transcription-polymerase chain reaction and immunostaining. Results: The osteogenesis-related genes, alp, runx2, col1 and ocn expressions suggest that culture medium consisting of CM:BM at the ratio of 3:7 enhanced the osteogenic differentiation more than other concentrations that were tested. In addition, the alkaline phosphatase activity and osteogenic marker Runx2 expression demonstrate that the combination of CM and BM significantly enhanced the osteogenic differentiation of iPSC-MSCs. Conclusion: In summary, this study has shown that osteoblast-derived CM can dramatically enhance osteogenic differentiation of iPSC-MSCs toward osteoblasts. Results from this work will contribute to optimize the osteogenic induction conditions of iPSC-MSCs and will assist in the potential application of iPSC-MSCs for bone tissue engineering.

MKP1 overexpression reduces TNF-α-induced cardiac injury via suppressing mitochondrial fragmentation and inhibiting the JNK-MIEF1 pathways.

Mitochondrial stress has been acknowledged as the pathogenesis for tumor necrosis factor-α (TNF-α)-induced septic cardiomyopathy. Recently, MAP kinase phosphatase 1 (MKP1) downregulation and mitochondrial fragmentation modulate the mitochondrial stress via multiple molecular mechanisms. Thereby, the goal of our current work is to figure out the functional role of mitochondrial fragmentation in TNF-α-induced septic cardiomyopathy. Our results exhibited that MKP1 expression was significantly repressed in hearts treated by TNF-α. Overexpression of MKP1 sustained cardiac function and attenuated cardiomyocytes death in TNF-α-treated hearts. At the molecular levels, decreased MKP1 induced mitochondrial stress, as indicated by mitochondrial calcium overloading, mitochondrial oxidative stress, mitochondrial antioxidant downregulation, mitochondrial membrane potential reduction, mitochondrial bioenergetics suppression, mitochondrial proapoptotic factors liberation, and caspase-9 apoptotic pathway activation. To the end, we illustrated that MKP1-modulated mitochondrial stress via mitochondrial fragmentation; reactivation of mitochondrial fragmentation abolished the protective effect of MKP1 overexpression on mitochondrial function. Further, MKP1 affected mitochondrial division in a mechanism through the JNK-MIEF1 axis. Blockade of JNK pathway abolished the regulatory actions of MKP1 on mitochondrial division. Altogether, our results identify MKP1 as a novel cardioprotective factor in TNF-α-related septic cardiomyopathy via affecting mitochondrial division by the way of JNK-MIEF1 signaling pathway. Therefore, MKP1 expression, mitochondrial fragmentation modification, and JNK-MIEF1 pathway modulation may be considered as potential therapeutic targets for the treatment of cardiac injury induced by sepsis.

Influence of 24-diamino-5-phenylthiazole on neomycin ototoxicity in cultured organ of Corti explants.

Hair cells do not undergo spontaneous regeneration when they are damaged in the mammalian organ of Corti, leading to irreversible hearing loss. Previous studies have shown that 24-diamino-5-phenylthiazole (DAPT), an inhibitor of Notch signaling, plays a major role in inner ear development. However, whether DAPT influences antibiotic-induced hair cell damage remains uncertain. The present study aimed to investigate whether DAPT exerts protective or regenerative effects on neomycin-damaged hair cells. A histological analysis was carried out to assess the number and morphological changes of hair cells in cultured organ of Corti explants. Our results showed that in-vitro treatment with DAPT induced extra hair cells, whereas no newly generated supporting cells were found. We also found that DAPT was effective for preventing hair cell loss when cotreatment with neomycin was performed, suggesting that DAPT exerted protective effects on neomycin ototoxicity. In addition, DAPT treatment for 2-4 days following neomycin damage induced supernumerary hair cells. These findings indicate that inhibition of Notch signaling is a possible strategy for the treatment of hair cell loss caused by aminoglycoside antibiotics.