miR-17-5p and miR-106a are involved in the balance between osteogenic and adipogenic differentiation of adipose-derived mesenchymal stem cells

AbstractMesenchymal stem cells (MSCs) can differentiate into several distinct cell types, including osteoblasts and adipocytes. The balance between osteogenic and adipogenic differentiation is disrupted in several osteogenic-related disorders, such as osteoporosis. So far, little is known about the molecular mechanisms that drive final lineage commitment of MSCs. In this study, we revealed that miR-17-5p and miR-106a have dual functions in the modulation of human adipose-derived mesenchymal stem cells (hADSCs) commitment by gain- and loss-of-function assays. They could promote adipogenesis and inhibit osteogenesis. Luciferase reporter assay, western blot and ELISA suggested BMP2 was a direct target of miR-17-5p and miR-106a. Downregulation of endogeneous BMP2 by RNA interference suppressed osteogenesis and increased adipogenesis, similar to the effect of miR-17-5p and miR-106a upregulation. Moreover, the inhibitory effects of miR-17-5p on osteogenic and adipogenic differentiation of hADSCs could be reversed by BMP2 RNA interference. In conclusion, miR-17-5p and miR-106a regulate osteogenic and adipogenic lineage commitment of hADSCs by directly targeting BMP2, and subsequently decreased osteogenic TAZ, MSX2 and Runx2, and increased adipogenic C/EBPα and PPARγ

Lessons learned from the blockade of immune checkpoints in cancer immunotherapy

Abstract The advent of immunotherapy, especially checkpoint inhibitor-based immunotherapy, has provided novel and powerful weapons against cancer. Because only a subset of cancer patients exhibit durable responses, further exploration of the mechanisms underlying the resistance to immunotherapy in the bulk of cancer patients is merited. Such efforts may help to identify which patients could benefit from immune checkpoint blockade. Given the existence of a great number of pathways by which cancer can escape immune surveillance, and the complexity of tumor-immune system interaction, development of various combination therapies, including those that combine with conventional therapies, would be necessary. In this review, we summarize the current understanding of the mechanisms by which resistance to checkpoint blockade immunotherapy occurs, and outline how actionable combination strategies may be derived to improve clinical outcomes for patients

A particle swarm optimization algorithm based on diversity-driven fusion of opposing phase selection strategies

Abstract Opposition-based learning (OBL) is often embedded in intelligent optimization algorithms to solve practical engineering and mathematical problems, but the combinatorial problems among different OBL variants are rarely studied. To this end, we propose a novel OBL variant based on the principle of optical imaging, which combines two novel types of quasi-opposite learning and extended opposite learning, called diversity-driven fused opposition learning (SQOBL). First, a density center based on a neighborhood model is proposed. Based on the rapid convergence of the centroid, combined the advantages of density and centroid to construct a double mean center (DMC) to replace the original center point in quasi-opposite learning based on the principle of refraction. Secondly, an extended opposite learning method based on optical refraction imaging is proposed. Diversity is then exploited to drive different opposing learning strategies at different stages of evolution, thus controlling the exploration and utilization of the algorithm. Finally, SQOBL was embedded in the PSO with eight others representative OBL variants to find the most optimal solution for a test suite. In addition, 8 novel intelligent optimization algorithms and the first three algorithms were selected to evaluate the performance of the latest CEC2022 benchmark test set and realistic constrained optimization problems. Experiments with 56 test functions and 3 real-world constraint optimization problems show that the proposed SQOBL has good integrative properties in CEC2015, CEC2017, CEC2020, and CEC2022 test suites

Adsorption Performance of La(III) and Y(III) on Orange Peel: Impact of Experimental Variables, Isotherms, and Kinetics

To alleviate the environmental problem associated with rare earth wastewater, this research applied waste orange peel (OP) for the adsorption of La(III) and Y(III) from aqueous solution. The adsorption properties of orange peel are characterized using scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR), and the participation of hydroxyl and other oxygen-containing groups that promote the physical-chemical interaction is verified. Batch adsorption results suggest that orange peel possesses a satisfactory adsorption performance for La(III) and Y(III). The optimal adsorption conditions were obtained at pH of 6, temperature of 40°C, appropriate dosage of 2 g/L and 3 g/L, contact time of 30 min, and initial ion concentration of 32 mg/L. Under the same condition, adsorption performance of La(III) is better than that of Y(III). The experimental data is well fitted by the Langmuir isotherm model with correlation coefficient R2>0.9 and the minimum standard error values. Equilibrium results show that Langmuir monolayer adsorption capacity of La(III) and Y(III) onto orange peel is up to 37.61 and 31.10 mg/g. The fitting results of kinetics prove that the adsorption process of La(III) and Y(III) follows the pseudosecond-order model. Thus, natural orange peel as a recyclable biosorbent has potential economic and applicative benefits to remove La(III) and Y(III) from aqueous solutions

Simultaneous determination of four Sudan dyes in rat blood by UFLCâMS/MS and its application to a pharmacokinetic study in rats

A rapid and sensitive method based on ultrafast liquid chromatographyâtandem mass spectrometry was developed and validated for simultaneous determination of Sudan I, Sudan II, Sudan III, and Sudan IV levels in rat whole blood. Cleanert C18 mixed-mode polymeric sorbent was used for effective solid-phase extraction cleanup. Separation was carried out on a reversed-phase C18 column (100 mmÃ2.1 mm, 1.8 μm) using 0.1% (v/v) formic acid in water/0.1% (v/v) formic acid in acetonitrile as the mobile phase in gradient elution. Quantification was performed by an electrospray ionization source in the positive multiple reaction monitoring mode using D5-Sudan I as the internal standard. Calibration curves showed good linearity between 0.2 and 20.0 μg/L, with correlation coefficients higher than 0.9990. The average recovery rates were between 93.05% and 114.98%. The intra- and inter-day relative standard deviations were within 6.2%. The lower limit of quantification was 0.2 μg/L. All the analytes were found to be stable in a series of stability studies. The proposed method was successfully applied to a pharmacokinetic study of four Sudan dyes after oral administration to rats. Keywords: Multiple reaction monitoring, Pharmacokinetics, Rat whole blood, Sudan dye, UFLCâMS/M

Fractal Design Boosts Extrusion-Based 3D Printing of Bone-Mimicking Radial-Gradient Scaffolds

Although extrusion-based three-dimensional (EB-3D) printing technique has been widely used in the complex fabrication of bone tissue-engineered scaffolds, a natural bone-like radial-gradient scaffold by this processing method is of huge challenge and still unmet. Inspired by a typical fractal structure of Koch snowflake, for the first time, a fractal-like porous scaffold with a controllable hierarchical gradient in the radial direction is presented via fractal design and then implemented by EB-3D printing. This radial-gradient structure successfully mimics the radially gradual decrease in porosity of natural bone from cancellous bone to cortical bone. First, we create a design-to-fabrication workflow with embedding the graded data on basis of fractal design into digital processing to instruct the extrusion process of fractal-like scaffolds. Further, by a combination of suitable extruded inks, a series of bone-mimicking scaffolds with a 3-iteration fractal-like structure are fabricated to demonstrate their superiority, including radial porosity, mechanical property, and permeability. This study showcases a robust strategy to overcome the limitations of conventional EB-3D printers for the design and fabrication of functionally graded scaffolds, showing great potential in bone tissue engineering

In Vitro Bioactivity Study of RGD-Coated Titanium Alloy Prothesis for Revision Total Hip Arthroplasty

Total hip arthroplasty (THA) is a common procedure for the treatment of end-stage hip joint disease, and the demand for revision THA will double by 2026. Ti6Al4V (Titanium, 6% Aluminum, and 4% Vanadium) is a kind of alloy commonly used to make hip prothesis. To promote the osseointegration between the prothesis and host bone is very important for the revision THA. The peptide Arg-Gly-Asp (RGD) could increase cell attachment and has been used in the vascular tissue engineering. In this study, we combined the RGD with Ti6Al4V alloy using the covalent cross-linking method to fabricate the functional Ti6Al4V alloy (FTA). The distribution of RGD oligopeptide on the FTA was even and homogeneous. The FTA scaffolds could promote mouse osteoblasts adhesion and spreading. Furthermore, the result of RT-qPCR indicated that the FTA scaffolds were more beneficial to osteogenesis, which may be due to the improvement of osteoblast adhesion by the RGD oligopeptide coated on FTA. Overall, the FTA scaffolds developed herein pave the road for designing and building more efficient prothesis for osseointegration between the host bone and prothesis in revision THA

Acute and Subacute Safety Evaluation of Black Tea Extract (Herbt Tea Essences) in Mice

Theabrownin (TB) is a heterogeneous biomacromolecule, extracted from tea, with many functional groups. Importantly, TB possesses diverse health benefits, such as antitumor activity and blood lipid-lowering effects. Presently, the content of TB in tea extract is relatively low. Here, we obtained a deep-processed black tea extract with a high content of TB (close to 80%), which was named Herbt Tea Essences (HTE). Currently, this study was designed to evaluate the biosafety of high-content TB products on mice. We implemented acute and subacute toxic experiments to assess its safety on organs, the serum biochemical and molecular levels. In the acute exposure study, we found that the median lethal dose (LD50) value of HTE was 21.68 g/kg (21.06–24.70 g/kg, greater than 5 g/kg), suggesting that HTE had a low acute toxicity. In the 28-day subacute exposure study, our results showed that no abnormal effects were observed in the 40 and 400 mg/kg/day HTE-treated groups. However, we observed slight nephrotoxicity in the 4000 mg/kg/day HTE-treated group. The HTE-induced nephrotoxic effect might involve the inflammatory response activation mediated by the nuclear transcription factor kappa-B (NF-κB) signaling pathway. This study would provide valuable data for the TB safety assessment and promote this natural biomacromolecule application in daily drinking