Drug-resistant exosome miR-99b-3p induces macrophage polarization and confers chemoresistance on sensitive cells by targeting PPP2CA.

The most frequent cancer in women to be diagnosed is breast cancer, and chemotherapy's ability to be effective is still significantly hampered by drug resistance. Tumor-derived exosomes play a significant role in drug resistance, immunological modulation, metastasis, and tumor proliferation. In this work, the differential miRNAs in the exosomes of drug-resistant and susceptible breast cancer cell lines were screened using miRNA-seq. It was demonstrated that drug-resistant human breast cancer cells and their exosomes expressed more miR-99b-3p than did susceptible cells and their exosomes. While drug-resistant cells' migration and paclitaxel resistance can be inhibited by driving down the expression of miR-99b-3p in those cells, exosomes containing miR-99b-3p from those cells can help susceptible cells migrate and become resistant. miR-99b-3p affects cell migration and paclitaxel resistance by targeting PPP2CA to promote AKT/mTOR phosphorylation. The drug-resistant cell exosome miR-99b-3p can be taken up by macrophages and affect the drug resistance and migration ability of sensitive cells by promoting the M2 polarization of macrophages. Downregulating miR-99b-3p has been shown in vivo to reverse macrophage M2 polarization, suppress tumor development, and prevent treatment resistance. The present study shows that drug-resistant cell exosomes miR-99b-3p can directly influence the migration, proliferation, and paclitaxel sensitivity of sensitive cells via PPP2CA. Additionally, the exosomes from drug-resistant cells can influence the polarization of macrophage M2 in the tumor microenvironment, which can also have an impact on the proliferation, migration, and paclitaxel sensitivity of sensitive cells.

Chemoselective [2 + 2]/[3 + 2] Photocycloaddition of 1,4-Dihydropyridines: Experimental and Theoretical Investigation.

The photocycloaddition of 1,4-dihydropyridines (1,4-DHPs) is a main approach to synthesize structurally complex compounds, which are important intermediates for the preparation of cage compounds, such as 3,9-diazatetraasterane, 3,6-diazatetraasterane, 3,9-diazatetracyclododecane, and 6,12-diazaterakishomocubanes. The acquisition of different cage compounds depended on the chemoselectivity, which is mainly caused by the reaction conditions and structural characteristics of 1,4-DHPs. This study aimed to investigate the effect of the structural characteristics on chemoselectivity in [2 + 2]/[3 + 2] photocycloaddition of 1,4-DHPs. The photocycloadditions were conducted on the 1,4-diaryl-1,4-dihydropyridine-3-carboxylic ester with steric hindrance groups at the C3 position or chirality at the C4 position irradiated by a 430 nm blue LED lamp. When the 1,4-DHPs contained high steric hindrance groups at the C3 position, [2 + 2] photocycloaddition was the main reaction, resulting in 3,9-diazatetraasteranes with a yield of 57%. Conversely, when the 1,4-DHPs were resolved to a chiral isomer, the main reaction was [3 + 2] photocycloaddition, producing 6,12-diazaterakishomocubanes with a yield of 87%. To investigate the chemoselectivity and understand the photocycloaddition of 1,4-DHPs, density functional theory (DFT) and time-dependent DFT (TDDFT) calculations were performed at the B3LYP-D3/def-SVP//M06-2X-D3/def2-TZVP level. The steric hindrance and excitation energy modulated by substituents at the C3 position and chiral carbon at the C4 position were crucial for the chemoselectivity in [2 + 2]/[3 + 2] photocycloaddition of 1,4-DHPs.

Glycolysis-based drug delivery nanosystems for therapeutic use in tumors and applications.

Tumor cells are able to use glycolysis to produce energy under hypoxic conditions, and even under aerobic conditions, they rely mainly on glycolysis for energy production, the Warburg effect. Conventional tumor therapeutic drugs are unidirectional, lacking in targeting and have limited therapeutic effect. The development of a large number of nanocarriers and targeted glycolysis for the treatment of tumors has been extensively investigated in order to improve the therapeutic efficacy. This paper reviews the research progress of nanocarriers based on targeting key glycolytic enzymes and related transporters, and combines nanocarrier systems with other therapeutic approaches to provide a new strategy for targeted glycolytic treatment of tumors, providing a theoretical reference for achieving efficient targeted treatment of tumors.

Characterization of Platelet-Associated Immunoglobulin by Flow Cytometry.

Measurement of platelet-associated imunoglobulin (PAIg) has frequently been applied for the diagnosis of idiopathic thrombocytopenic purpura (ITP) and other immune thrombocytopenias. In the present study, a flow cytometry (FCM) analysis has been used to detect and characterize PAIg in 47 patients with ITP and Evans' syndrome, 13 patients with non-immune thrombocytopenia, 10 patients with autoimmune hemolytic anemia (AIHA) whose platelet counts were in normal range, and 31 healthy volunteers. With FCM measurement, mean fluorescence intensity (MFI) of platelets from patients with ITP and Evans' syndrome (2.26 +/- 2.29) was significantly higher than those from non-immune thrombocytopenia (0.33 +/- 0.39), AIHA (0.17 +/- 0.07) and control subjects (0.25 +/- 0.15) (P < 0.01). Meanwhile, the percentage of positive platelets of patients with ITP and Evans' syndrome [(44.1 +/- 29.0)%] was also higher than those of non-immune thrombocytopenia [(17.5 +/- 9.4)%], AIHA [(10.7 +/- 7.5)%] and control subjects [(16.6 +/- 8.4)%] (P < 0.01). In addition, some peak shape abnormality appeared (double peaks and peak tail) in the histogram of fluorescence intensity (log) of 11 patients (23.4%) with ITP and Evans' syndrome either alone or accompanied with quantitative alteration of MFI and/or positive platelet percentage. In seven cases, the peak shape abnormality was the unique characteristic that could be detected and have never been seen in normal platelets. This phenotypic alteration perhaps reflects the existence of different platelet populations and could be of diagnostic value. Totally, the positive result of FCM measurement in patients with ITP and Evans' syndrome was 87.2%, slightly higher than 83.0% positive rate with ELISA method, without statistical difference. The correspondent rate of the results of these two analytical settings was 85.1%. This study shows that FCM assay is a rapid and sensitive method for the measurement of PAIg and seems to be suitable as a novel routine diagnostic technique of immune thrombocytopenia.