A glutathione-sensitive drug delivery system based on carboxymethyl chitosan co-deliver Rose Bengal and oxymatrine for combined cancer treatment.

At present, monotherapy of tumor has not met the clinical needs, due to high doses, poor efficacy, and the emergence of drug resistance. Combination therapy can effectively solve these problems, which is a better option for tumor suppression. Based on this, we developed a novel glutathione-sensitive drug delivery nanoparticle system (OMT/CMCS-CYS-RB NPs) for oral cancer treatment. Briefly, carboxymethyl chitosan (CMCS) was used as a carrier to simultaneously load Rose Bengal (RB) and oxymatrine (OMT). The OMT/CMCS-CYS-RB NPs prepared by ion crosslinking were spheres with a stable structure. In addition, the nanoparticles can be excited in vitro to generate a large amount of singlet oxygen, which has a good photodynamic effect. In vitro anti-tumor activity study showed that the nanoparticles after the laser enhanced therapeutic efficacy on tumor cells compared with the free drug and exhibited well security. Furthermore, OMT/CMCS-CYS-RB NPs could inhibit the PI3K/AKT signaling pathway in oxidative stress, and realize tumor apoptosis through mitochondria-related pathways. In conclusion, this combination delivery system for delivering RB and OMT is a safe and effective strategy, which may provide a new avenue for the tumor treatment.

The Spouses of Stroke Patients Have a Similar Oral Microbiome to Their Partners with an Elevated Risk of Stroke.

Spousal members who share no genetic relatedness show similar oral microbiomes. Whether a shared microbiome increases the risk of cerebrovascular disease is challenging to investigate. The aim of this study was to compare the oral microbiota composition of poststroke patients, their partners, and controls and to compare the risk of stroke between partners of poststroke patients and controls. Forty-seven pairs of spouses and 34 control subjects were recruited for the study. Alcohol use, smoking, metabolic disease history, clinical test results, and oral health were documented. Oral microbiome samples were measured by 16S rRNA gene sequencing. The risk of stroke was measured by risk factor assessment (RFA) and the Framingham Stroke Profile (FSP). Poststroke patients and their partners exhibited higher alpha diversity than controls. Principal-coordinate analysis (PCoA) showed that poststroke patients share a more similar microbiota composition with their partners than controls. The differentially abundant microbial taxa among the 3 groups were identified by linear discriminant analysis effect size (LEfSe) analysis. The risk factor assessment indicated that partners of poststroke patients had a higher risk of stroke than controls. Spearman correlation analysis showed that Prevotellaceae was negatively associated with RFA. Lactobacillales was negatively associated with FSP, while Campilobacterota and [Eubacterium]_nodatum_group were positively associated with FSP. These results suggest that stroke risk may be transmissible between spouses through the oral microbiome, in which several bacteria might be involved in the pathogenesis of stroke.

Long-Term Pregnancy Outcomes of Patients with Diffuse Adenomyosis after Double-Flap Adenomyomectomy.

Although many studies show that patients with diffuse adenomyosis who underwent fertility-sparing surgery can have a successful pregnancy, their pregnancy outcomes are still controversial. The objective of this study was to determine long-term pregnancy outcomes and possible influencing factors after double-flap adenomyomectomy for patients with diffuse adenomyosis. A total of 137 patients with diffuse adenomyosis who underwent double-flap adenomyomectomy between January 2011 and December 2019 were studied, and correlations between pregnancy outcomes and clinical data, including age and junctional zone measured by magnetic resonance imaging (JZmax-A), were analyzed. The results show that 56 patients (40.9%, 56/137) had 62 pregnancies, including 35 natural pregnancies and 27 assisted reproduction pregnancies, after operation. A univariate regression analysis showed that the pregnancy outcomes were related to age at surgery, visual analog scale (VAS) score of preoperative dysmenorrhea, parity experience, length of infertility, and postoperative JZmax-A. A multivariate regression analysis showed that age at surgery, VAS score of preoperative dysmenorrhea, and postoperative JZmax-A were the independent indicators correlated with pregnancy outcomes. A receiver operating characteristic curve analysis showed that postoperative JZmax-A was the most valuable indicator for predicting pregnancy outcomes. Cumulative pregnancy rates during the first 3 years were 70.1% and 20.9% in the postoperative JZmax-A ≤ 8.5 mm and the postoperative JZmax-A > 8.5 mm groups, respectively. In conclusion, double-flap adenomyomectomy could improve fertility for diffuse adenomyosis, and postoperative JZmax-A might be a promising indicator for predicting pregnancy outcomes.

Glutathione-sensitive IPI-549 nanoparticles synergized with photodynamic Chlorin e6 for the treatment of breast cancer.

We combined phosphoinositol-3-kinin inhibitor IPI-549 and photodynamic Chlorin e6 (Ce6) on carboxymethyl chitosan to develop a novel drug delivery nanoparticle (NP) system (Ce6/CMCS-DSP-IPI549) and evaluate its glutathione (GSH) sensitivity and targeting ability for breast cancer treatment. The NPs were spherical with a uniform size of 218.8 nm, a stable structure over 7 days. The maximum encapsulation efficiency was 64.42%, and NPs drug loading was 8.05%. The NPs released drugs within tumor cells due to their high GSH concentration, while they maintained structural integrity in normal cells, which have low GSH concentration. The cumulative release rates of IPI-549 and Ce6 at 108 h were 70.67% and 40.35% (at GSH 10 mM) and 8.11% and 2.71% (at GSH 2µM), respectively. The NPs showed a strong inhibitory effect on 4T1 cells yet did not affect human umbilical vein endothelial cells (HUVECs). After irradiation by a 660 nm infrared laser for 72 h, the survival rate of 4T1 cells was 15.51%. Cellular uptake studies indicated that the NPs could accurately release drugs into tumor cells. In addition, the NPs had a good photodynamic effect and promoted the release of reactive oxygen species to damage tumor cells. Overall, the combination therapy of IPI-549 and Ce6 is safe and effective, and may provide a new avenue for the treatment of breast cancer.

Glycyrrhetinic acid remodels the tumor microenvironment and synergizes with doxorubicin for breast cancer treatment in a murine model.

We aimed to combine glycyrrhetinic acid with doxorubicin to prepare, characterize and evaluate a drug delivery nano-system with REDOX sensitivity for the treatment of breast cancer. M-DOX-GA NPs prepared by nano sedimentation were spherical, with a particle size of 181 nm. And the maximum encapsulation efficiency and drug loading in M-DOX-GA NPs were 89.28% and 18.22%, respectively. Cytotoxicity and cellular uptake experiments of nanoparticles to KC cells, Cal-27 cells and 4T1 cells were studied by the CCK-8 method. The result indicated that M-DOX-GA NPs could accurately release the drug into the tumor cells, thus achieving the targeted release of the drug. Comparing the survival rate of the above three cells, it was found that M-DOX-GA NPs had a good tumor selectivity and had a more significant therapeutic effect on breast cancer. A 4T1-bearing mouse model was established, and the tumor inhibition rate was 77.37% after injection of nanoparticle solution for 14 d. Normal tissue H&E stained sections and TUNEL assay were verified M-DOX-GA NPs have excellent tumor suppressive effect, and can efficiently reduce the toxic side effects on normal organisms, and effectively avoided 4T1 cells metastasis. Immunofluorescence detection and Western-blot analysis figured a decline in both CUGBP1 and α-SMA, which verifying the TME remodeling induced by glycyrrhetinic acid. Collectively, the combination of doxorubicin and glycyrrhetinic acid is an effective and safe strategy for remodeling fibrotic TME by improving the therapeutic outcome for breast cancer.

Tuning mPEG-PLA/vitamin E-TPGS-based mixed micelles for combined celecoxib/honokiol therapy for breast cancer.

This study aimed to develop, evaluate, and optimize the mPEG-PLA/vitamin E-TPGS mixed micelle drug delivery system to encapsulate celecoxib (CXB) and honokiol (HNK) for intravenous treatment of breast cancer. To this end, we formulated CXB-loaded mPEG-PLA/vitamin E-TPGS (PV-CXB) and HNK-loaded mPEG-PLA/vitamin E-TPGS (PV-HNK) mixed micelles and analyzed their characteristics. The 4T1 cell line was used for cytotoxicity determination and cellular uptake experiments, and for establishing a 4T1-bearing mouse model for histopathology, immunofluorescence, terminal deoxynucleotidyl transferase-mediated nick end labeling, and Western blot analysis. The synergistic effects of PV-CXB and PV-HNK combination therapy were investigated in vitro and in vivo using the coefficient of drug interaction values. The mean size of PV-CXB and PV-HNK prepared with optimal formulation was approximately 50 nm, with a spherical shape. PV-CXB and PV-HNK combination therapy exhibited cytotoxicity in 4T1 cells in vitro. However, the toxicity of PV-CXB and PV-HNK combination therapy was not apparent in normal tissues (heart, liver, spleen, lung, and kidney) in vivo and reduced the expression of collagen fibers in tumor tissues. Moreover, the combination therapy reduced the expression of tumor growth biomarkers (Foxp3, CD4, Gr-1, CD11b, CD31, Ki67, FoxM1, and VEGF). In addition, the tumor cell apoptosis rate reached 45.71 ± 0.62%. The combined treatment with PV-CXB and PV-HNK showed synergistic effect both in vitro and in vivo. Thus, the PV-CXB and PV-HNK drug delivery system could be used as a potential combination therapy for breast cancer .

Insight into the interactions between novel isoquinolin-1,3-dione derivatives and cyclin-dependent kinase 4 combining QSAR and molecular docking.

Several small-molecule CDK inhibitors have been identified, but none have been approved for clinical use in the past few years. A new series of 4-[(3-hydroxybenzylamino)-methylene]-4H-isoquinoline-1,3-diones were reported as highly potent and selective CDK4 inhibitors. In order to find more potent CDK4 inhibitors, the interactions between these novel isoquinoline-1,3-diones and cyclin-dependent kinase 4 was explored via in silico methodologies such as 3D-QSAR and docking on eighty-one compounds displaying potent selective activities against cyclin-dependent kinase 4. Internal and external cross-validation techniques were investigated as well as region focusing, bootstraping and leave-group-out. A training set of 66 compounds gave the satisfactory CoMFA model (q2 = 0.695, r2 = 0.947) and CoMSIA model (q2 = 0.641, r2 = 0.933). The remaining 15 compounds as a test set also gave good external predictive abilities with r2pred values of 0.875 and 0.769 for CoMFA and CoMSIA, respectively. The 3D-QSAR models generated here predicted that all five parameters are important for activity toward CDK4. Surflex-dock results, coincident with CoMFA/CoMSIA contour maps, gave the path for binding mode exploration between the inhibitors and CDK4 protein. Based on the QSAR and docking models, twenty new potent molecules have been designed and predicted better than the most active compound 12 in the literatures. The QSAR, docking and interactions analysis expand the structure-activity relationships of constrained isoquinoline-1,3-diones and contribute towards the development of more active CDK4 subtype-selective inhibitors.