Emerging Strategies to Overcome Current CAR-T Therapy Dilemmas - Exosomes Derived from CAR-T Cells.

Adoptive T cells immunotherapy, specifically chimeric antigen receptor T cells (CAR-T), has shown promising therapeutic efficacy in the treatment of hematologic malignancies. As extensive research on CAR-T therapies has been conducted, various challenges have emerged that significantly hampered their clinical application, including tumor recurrence, CAR-T cell exhaustion, and cytokine release syndrome (CRS). To overcome the hurdles of CAR-T therapy in clinical treatment, cell-free emerging therapies based on exosomes derived from CAR-T cells have been developed as an effective and promising alternative approach. In this review, we present CAR-T cell-based therapies for the treatment of tumors, including the features and benefits of CAR-T therapies, the limitations that exist in this field, and the measures taken to overcome them. Furthermore, we discuss the notable benefits of utilizing exosomes released from CAR-T cells in tumor treatment and anticipate potential issues in clinical trials. Lastly, drawing from previous research on exosomes from CAR-T cells and the characteristics of exosomes, we propose strategies to overcome these restrictions. Additionally, the review discusses the plight in large-scale preparation of exosome and provides potential solutions for future clinical applications.

Synthesis of compounds based on the active domain of cabotegravir and their application in inhibiting tumor cells activity.

Structural modification based on existing drugs, which ensures the safety of marketed drugs, is an essential approach in developing new drugs. In this study, we modified the structure of cabotegravir by introducing the front alkyne on the core structure through chemical reaction, resulting in the synthesis of 9 compounds resembling 1,2,3-triazoles. The potential of these new cabotegravir derivatives as tumor suppressors in gastrointestinal tumors was investigated. Based on the MTT experiment, most compounds showed a reduction in the viability of KYSE30 and HCT116 cells. Notably, derivatives 5b and 5h exhibited the most significant inhibitory effects. To further explore the effects of derivatives 5b and 5h on gastrointestinal tumors, KYSE30 cells were chosen as a representative cell line. Both derivatives can effectively curtail the migration and invasion capabilities of KYSE30 cells and induce apoptosis in a dose-dependent manner. We further demonstrated these derivatives induce cell apoptosis in KYSE30 cells by inhibiting the expression of Stat3 protein and Smad2/3 protein. Based on the above results, we suggest they show promise in developing drugs for esophageal squamous cell carcinoma.

The changed multiscale structures of tight nut (Cyperus esculentus) starch decide its modified physicochemical properties: The effects of non-thermal and thermal treatments.

Non-thermal dielectric barrier discharge plasma (DBDP) and four thermal treatments, including baking (BT), high pressure cooking (HPC), radio frequency (RF) and microwave (MW) were applied to modify the structural and physicochemical properties of Cyperus esculentus starch (CES). The results showed that the thermal treatments remarkably disordered the crystalline structures of CES through weakening the double-helix conformation of amylopectin, while DBDP caused much more gentle influence on the starch structures than them. Specifically, MW induced the high-frequency displacement of polar molecules and intensive collisions between starch and water molecules, causing the largest stretching and swelling extents of amylopectin, resulting in the highest pasting and rheological viscosity of CES in four thermal treatments. As DBDP did not favor the aggregation of amylopectin chains, the deaggregated starch chains promoted the hydration effects with water molecules, boosting the final pasting viscosity, apparent rheological viscosity, freeze-thaw stability and digestion velocity of CES. Besides, the gelatinization-retrogradation process in the thermal treatments regulated starch digestion velocity and produced type III resistant starch in CES. Conclusively, the modified physicochemical properties of CES resulted from the altered molecular structures of starch by the applied treatments.

Electrochemical Micro-Immunosensor of Cubic AuPt Dendritic Nanocrystals/Ti3C2-MXenes for Exosomes Detection.

Exosomes are extracellular vesicles that exist in body circulation as intercellular message transmitters. Although the potential of tumor-derived exosomes for non-invasive cancer diagnosis is promising, the rapid detection and effective capture of exosomes remains challenging. Herein, a portable electrochemical aptasensor of cubic AuPt dendritic nanocrystals (AuPt DNs)/Ti3C2 assisted in signal amplification, and aptamer CD63 modified graphene oxide (GO) was immobilized on a screen-printed carbon electrode (SPCE) as the substrate materials for the direct capture and detection of colorectal carcinoma exosomes. Cubic AuPt DNs/Ti3C2 was synthesized according to a simple hydrothermal procedure, and the AuPt DNs/Ti3C2-Apt hybrid demonstrated an efficient recognition of exosomes. Under optimal conditions, a detection limit of down to 20 exosomes µL-1 was achieved with the linear range from 100 exosomes µL-1 to 5.0 × 105 exosomes µL-1. The proposed immunosensor could be suitable for the analysis of exosomes and has clinical value in the early diagnosis of cancer.

"Targeting Design" of Nanoparticles in Tumor Therapy.

Tumor-targeted therapy based on nanoparticles is a popular research direction in the biomedical field. After decades of research and development, both the passive targeting ability of the inherent properties of NPs and the active targeting based on ligand receptor interaction have gained deeper understanding. Unfortunately, most targeted delivery strategies are still in the preclinical trial stage, so it is necessary to further study the biological fate of particles in vivo and the interaction mechanism with tumors. This article reviews different targeted delivery strategies based on NPs, and focuses on the physical and chemical properties of NPs (size, morphology, surface and intrinsic properties), ligands (binding number/force, activity and species) and receptors (endocytosis, distribution and recycling) and other factors that affect particle targeting. The limitations and solutions of these factors are further discussed, and a variety of new targeting schemes are introduced, hoping to provide guidance for future targeting design and achieve the purpose of rapid transformation of targeted particles into clinical application.

α-Amylase inhibition of a certain dietary polyphenol is predominantly affected by the concentration of α-1, 4-glucosidic bonds in starchy and artificial substrates.

To elucidate why the inhibitory activity of one same polyphenol against α-amylase varies in different works. Seven starchy and three artificial substrates, and a polyphenolic competitive inhibitor, tannic acid (TA) were applied to study the enzyme inhibition in different digestion systems. The results showed that the IC50 values of TA were similar for all starches at the same starch concentration, although there existed difference in starch physiochemical properties, like branching degree, amylose chain distribution, viscosity, and digestion rate. However, the IC50 values significantly decreased with the substrate concentration decreasing, regardless of substrate types. Notably, TA had a similar competitive inhibition constant (Kic) for all the starches, despite the difference in substrate concentration, indicating that the fixed constant unconditionally describes the inhibitor-enzyme binding property. In the TA/amylase/starch system, the physical adsorption of TA with starch was much weaker than the specific binding of TA with α-amylase that was driven by hydrogen bondings and π-stackings. Therefore, it was the substrate, i.e., α-1,4-glucosidic bond concentration, rather than the existing matrix of the bonds, that predominantly affected the inhibitory activity of a polyphenol, because of the competitive action between α-1,4-glucosidic bond and the polyphenol regarding binding with the enzyme.

Network pharmacology approach to evaluate the therapeutic effects of mulberry leaf components for obesity.

Obesity is a chronic condition that has become a serious public health challenge globally due to the association with a high incidence of complications. Mulberry leaf is one of the most commonly used medicinal and herbal medicines that has been reported to ameliorate obesity and hyperlipidemia. However, the mechanism remains unclear. In the present study, a network pharmacology approach was used to explore the potential mechanism underlying the effects of mulberry leaf extract on obesity. First, the potential targets of mulberry leaf and obesity were predicted using SwissTargetPrediction, Online Mendelian Inheritance in Man, GeneCards and Comparative Toxicogenomics Database databases, which were then used to construct the protein-protein interaction networks. Gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyzes were performed using R version 3.6.3. Finally, results of this network analysis were verified by using the mulberry leaf extract to treat high-fat diet-induced obese mice. In total, 24 target genes associated with obesity that could potentially be affected by mulberry leaf treatment were predicted by network pharmacology, using which top seven related pathways were determined by KEGG enrichment analysis. Triglyceride (TG) and total cholesterol (TC) levels in mice serum were detected using TG and TC assay kits. Hepatic fat accumulation was detected by H&E staining whereas liver lipid droplets were detected by Oil red O staining in mice tissues. The expression of IL-1ß, NF-κB inhibitor α, inducible nitric oxide synthase, AMP-activated protein kinase (AMPK), sterol regulatory element-binding proteins and fatty acid synthase in the visceral white adipose tissues of mice was analyzed by western blotting. The expression of TNF-α, peroxisome proliferator activated receptor (PPAR)D, PPARG, fatty acid amide hydrolase (FAAH) and hydroxysteroid 11-ß dehydrogenase 1 (HSD11B1) in the visceral white adipose tissues of mice was detected by reverse transcription-quantitative PCR. Mulberry leaf extract was found to reduce fat accumulation and hepatic lipid droplet formation. Mulberry leaf also alleviated inflammation and lipogenesis whilst promoting lipid catabolism and fatty acid oxidation by promoting the AMPK signaling pathway. The possible anti-obesity effects of mulberry leaf on the mice may be due to the downregulation of TNF-α, PPARD and PPARG and the upregulation of FAAH and HSD11B1. These results were consistent with the GO enrichment analysis and suggested that mulberry leaf may regulate lipid metabolism and catabolism, fatty acid metabolism and biosynthesis and the inflammatory response to reduce obesity.