Amino acid metabolism dysregulation associated with inflammation and insulin resistance in HIV-infected individuals with metabolic disorders.

Amino acid metabolic profile, particularly its association with clinical characteristics, remains unclear in patients with human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS) combined with metabolic disorders. In this study, we performed targeted metabolomic analyses on 64 patients with HIV/AIDS and 21 healthy controls. Twenty-four amino acids and selected intermediate metabolites in the serum were quantitatively detected using high-performance liquid chromatography-tandem mass spectrometry, and characteristic changes and metabolic pathways were analyzed in HIV-infected patients with different degrees of abnormal glucose and lipid metabolism. Spearman's partial correlation was used to analyze the association between amino acids, biochemical parameters, and inflammatory cytokines. The results showed that the main metabolic pathways of the eighteen differential metabolites involved were arginine biosynthesis and metabolism, methionine cycle, and tryptophan metabolism. Fourteen differential amino acid metabolites were positively correlated with nine inflammatory cytokines, including TNF-α, C-reactive protein, IL-1ß, and galectin-3 (FDR < 0.1). Kynurenine, ornithine, and homocysteine were positively correlated with fasting blood glucose and insulin resistance index (FDR < 0.1). Our study revealed a multi-pathway imbalance in amino acid metabolism in patients with HIV/AIDS, which was significantly correlated with inflammation and insulin resistance.

Molecularly Imprinted Polymers with Enzymatic Properties Reduce Cytokine Release Syndrome.

A core-shell molecularly imprinted polymer nanoparticle with biological enzyme functional characteristics was developed by oxidative polymerization of template protein and polydopamine on the surface of protease-copper phosphate hybrid nanoflowers by molecular imprinting technology and enzyme immobilization technology. The obtained molecularly imprinted polymer showed specific binding characteristics with the template protein. It recognized and enriched the target molecules through the surface molecularly imprinted sites of the shell structure. In addition, the bound target molecules were further degraded into fragments by nanozymes with biological enzyme characteristics in the core. In this study, molecular imprinting technology and biotechnology were combined to obtain bifunctional molecularly imprinted polymer nanoparticles that can not only enrich template molecules but also degrade them into fragments. Herein, we selected interleukin 6 (IL-6), the target molecule of cytokine release syndrome (CRS), as a template molecule, and reported a molecularly imprinted polymer with degrading enzyme properties that can rapidly reduce IL-6 levels in vivo, including a molecularly imprinted layer that can recognize and bind IL-6 and nanozymes that can degrade IL-6 and deactivate it. It is used to clear the excessive secretion of IL-6 in CRS and reduce the level of IL-6 in the body to achieve the purpose of adjuvant treatment of CRS.

Exenatide-loaded inside-porous poly(lactic-co-glycolic acid) microspheres as a long-acting drug delivery system with improved release characteristics.

The glucagon-like peptide-1 receptor agonist exenatide (EXT) is an effective treatment for type 2 diabetes. However, this peptide has a short biological half-life and the delayed release characteristic of current formulations limit its clinical application. Herein, we prepared EXT-loaded inside-porous poly(d,l-lactic-co-glycolic acid (PLGA) microspheres with outside layers (EXT-PMS) using a W1/O/W2 emulsion method with a microfluidic technique and its fabrication and formulation conditions were systematically investigated. In vitro dissolution experiments showed that the PLGA concentration, proportion of drug and oil phase, and the number and size of pores strongly affected the release behaviors of EXT-PMS. In vitro, the optimized EXT-PMS with large internal pores exhibited rapid and stable release without a lag phase. In a rat model, subcutaneous administration of the product yielded plasma concentrations of EXT that was sustained for 30 days with low burst and no delayed-release effect. The preparation of inside-porous microspheres is lighting up the development of long-acting drug delivery systems for other drugs with favorable release characteristics.

Development of a Highly Water-Soluble Lycopene Cyclodextrin Ternary Formulation by the Integrated Experimental and Modeling Techniques.

Lycopene, the aliphatic hydrocarbon carotenoid with abundant bioactivities, has instability, extremely poor water solubility, and low oral bioavailability. The study aimed to develop a highly water-soluble and practical lycopene formulation to improve the oral bioavailability and efficiency of lycopene. Environment-friendly hot-melt extrusion (HME) technique was applied to fabricate lycopene-cyclodextrin-polyethylene glycol 6000 (PEG 6000) ternary systems, which possessed highly aqueous solubility (897.665 µg mL-1), almost 32-fold higher than that of the reported lycopene binary inclusion (27.1 ± 3.2 µg mL-1). The dissolution rate was significantly accelerated compared to pure lycopene. The molecular mechanism was further investigated by the integrated experimental and modeling tools. Molecular dynamics (MD) simulation revealed lycopene molecule was wrapped within the aggregates of hydroxypropyl-beta-cyclodextrin (HP-ß-CD) and PEG 6000 through extensive hydrogen bond interactions, which was experimentally validated by DSC, XRD, and FTIR spectrum analysis. The third component PEG 6000 facilitated the process of HME and augmented hydrogen bond interactions with HP-ß-CD. Moreover, lycopene inclusions exhibited significant antitumor activity via inhibiting cell proliferation and inducing apoptosis. The pharmacokinetic studies showed the relative bioavailability of lycopene ternary preparation was up to 313.08% and the Cmax was 4.9-fold higher than that of the marketed tablet. In conclusion, the lycopene cyclodextrin ternary formulation developed by the modified HME techniques is suitable for industrial production, while PEG 6000 plays a vital part in the multicomponent systems to increase solubility, dissolution rate, and oral bioavailability of lycopene. The combination of experimental and computational tools is able to benefit the development of multicomponent formulations accurately and effectively.