m6A methylation of RNF43 inhibits the progression of endometriosis through regulating oxidative phosphorylation via NDUFS1.

Oxidative phosphorylation is becoming increasingly important in the induction and development of endometriosis. Recently, it has been reported that ring finger protein 43 (RNF43) is involved in the process of oxidative phosphorylation, but the mechanism remains unclear. Our investigation is to delve into the roles of RNF43 in endometriosis and elucidate the related mechanisms. We found RNF43 was downregulated in ectopic endometrial tissue and primary ectopic endometrial stromal cells (ECESCs). Knockdown of RNF43 enhanced cell viability and migration by activating oxidative phosphorylation in eutopic endometrial stromal cells (EUESCs), while overexpression of RNF43 led to the opposite results. Moreover, RNF43 reinforced the ubiquitination and degradation of NADH dehydrogenase Fe-S protein 1 (NDUFS1) by interacting with it. Likewise to RNF43 overexpression, NDUFS1 silencing inhibited cell viability, migration, and oxidative phosphorylation in ECESCs. NDUFS1 was a downstream target of RNF43, mediating its biological role in endometriosis. Interestingly, the expression and stability of RNF43 mRNA were regulated by the Methyltransferase-like 3 (METTL3)/IGF2BP2 m6A modification axis. The results of rat experiments showed decreased RNF43 expression and increased NDUFS1 expression in endometriosis rats, which was enhanced by METTL3 inhibition. Those observations indicated that m6A methylation-mediated RNF43 negatively affects viability and migration of endometrial stromal cells through regulating oxidative phosphorylation via NDUFS1. The discovery of METTL3/RNF43/NDUFS1 axis suggested promising therapeutic targets for endometriosis.

Enhanced anti-glioma efficacy of biodegradable periodic mesoporous organosilica nanoparticles through target delivery of chemotherapeutics.

Glioma is the most common malignant tumor of the brain and enhancing the efficacy of chemotherapy in glioma is critical for improving patients' prognosis. In this study, a glioma-targeting drug delivery system is constructed using biodegradable periodic mesoporous organosilica nanoparticles (PMO) that are modified with lactoferrin (Lf) ligands. The obtained PMO is doped with thioether groups and can be degraded in the high concentration of glutathione in tumor cells. The surface area and pore volume of PMO are 772 cm2/g and 0.98 cm3/g, respectively and the loading capacity of doxorubicin (Dox) is as high as 20%. The results of the confocal laser scanning microscope show that the uptake of PMO-Lf@Dox by C6 cells is higher than PMO@Dox. The quantitative analysis of the flow cytometer further demonstrates that more PMO-Lf@Dox enter C6 cells, indicating that the modification of lactoferrin can significantly increase the uptake of C6 cells. Finally, the therapeutic efficacy results show that Lf-modified PMO enhances the inhibitory effect of Dox on C6 cells when incubated for 24 h and 72 h. In summary, this lactoferrin receptor-mediated PMO drug carrier with biodegradability in glutathione in tumor cells can be used to enhance drug delivery into glioma without long-term accumulation in vivo. In this study, a glioma-targeting drug delivery system is constructed using periodic mesoporous organosilica nanoparticles (PMO) that modified with lactoferrin (Lf) ligands. This lactoferrin receptor-mediated PMO drug carrier can be used to enhance drug delivery into brain glioma.

Cross-cultural adaptation and validation of the geriatric 8 screening tool in Chinese hospitalized older adults with cancer.

OBJECTIVES: To translate, cross-culturally adapt, and validate the Geriatric 8 (G8) questionnaire in Chinese hospitalized older adults with cancer. METHODS: The Chinese version of the G8 (C-G8) was produced following Brislin's guidelines. The psychometric properties of the C-G8 were evaluated among 296 eligible patients. RESULTS: The content validity index of the C-G8 was 0.8∼1 at the item level and 0.975 at the scale level. The C-G8 identified more frail individuals among these older (>75 years) participants compared to their younger (65∼75 years) counterparts (frailty prevalence: 87.1% vs. 70.9%, P=0.010). The convergent validity of the C-G8 was tested by correlating it with the FRAIL scale (r=-0.592, P<0.001). The C-G8 had a lower internal consistency (Cronbach's α coefficient=0.501) but higher test-retest reliability and inter-rater reliability (intraclass correlation coefficient=0.913 and 0.993, respectively, P<0.001). CONCLUSIONS: The C-G8 questionnaire presented acceptable validity and reliability and could be used in Chinese hospitalized older adults with cancer.

Simultaneous glutamine metabolism and PD-L1 inhibition to enhance suppression of triple-negative breast cancer.

Blockade of programmed cell death 1 ligand (PD-L1) has been used to treat triple-negative breast cancer (TNBC), and various strategies are under investigation to improve the treatment response rate. Inhibition of glutamine metabolism can reduce the massive consumption of glutamine by tumor cells and meet the demand for glutamine by lymphocytes in tumors, thereby improving the anti-tumor effect on the PD-L1 blockade therapy. Here, molybdenum disulfide (MoS2) was employed to simultaneously deliver anti-PDL1 antibody (aPDL1) and V9302 to boost the anti-tumor immune response in TNBC cells. The characterization results show that MoS2 has a dispersed lamellar structure with a size of about 181 nm and a size of 232 nm after poly (L-lysine) (PLL) modification, with high stability and biocompatibility. The loading capacity of aPDL1 and V9302 are 3.84% and 24.76%, respectively. V9302 loaded MoS2 (MoS2-V9302) can effectively kill 4T1 cells and significantly reduce glutamine uptake of tumor cells. It slightly increases CD8+ cells in the tumor and promotes CD8+ cells from the tumor edge into the tumor core. In vivo studies demonstrate that the combination of aPDL1 and V9302 (MoS2-aPDL1-V9302) can strongly inhibit the growth of TNBC 4T1 tumors. Interestingly, after the treatment of MoS2-aPDL1-V9302, glutamine levels in tumor interstitial fluid increased. Subsequently, subtypes of cytotoxic T cells (CD8+) in the tumors were analyzed according to two markers of T cell activation, CD69, and CD25, and the results reveal a marked increase in the proportion of activated T cells. The levels of cytokines in the corresponding tumor interstitial fluid are also significantly increased. Additionally, during the treatment, the body weights of the mice remain stable, the main indicators of liver and kidney function in the blood do not increase significantly, and there are no obvious lesions in the main organs, indicating low systemic toxicity. In conclusion, our study provides new insights into glutamine metabolism in the tumor microenvironment affects immune checkpoint blockade therapy in TNBC, and highlights the potential clinical implications of combining glutamine metabolism inhibition with immune checkpoint blockade in the treatment of TNBC.

Dye-loaded mesoporous polydopamine nanoparticles for multimodal tumor theranostics with enhanced immunogenic cell death.

BACKGROUND: Tumor phototherapy especially photodynamic therapy (PDT) or photothermal therapy (PTT), has been considered as an attractive strategy to elicit significant immunogenic cell death (ICD) at an optimal tumor retention of PDT/PTT agents. Heptamethine cyanine dye (IR-780), a promising PDT/PTT agent, which can be used for near-infrared (NIR) fluorescence/photoacoustic (PA) imaging guided tumor phototherapy, however, the strong hydrophobicity, short circulation time, and potential toxicity in vivo hinder its biomedical applications. To address this challenge, we developed mesoporous polydopamine nanoparticles (MPDA) with excellent biocompatibility, PTT efficacy, and PA imaging ability, facilitating an efficient loading and protection of hydrophobic IR-780. RESULTS: The IR-780 loaded MPDA (IR-780@MPDA) exhibited high loading capacity of IR-780 (49.7 wt%), good physiological solubility and stability, and reduced toxicity. In vivo NIR fluorescence and PA imaging revealed high tumor accumulation of IR-780@MPDA. Furthermore, the combined PDT/PTT of IR-780@MPDA could induce ICD, triggered immunotherapeutic response to breast tumor by the activation of cytotoxic T cells, resulting in significant suppression of tumor growth in vivo. CONCLUSION: This study demonstrated that the as-developed compact and biocompatible platform could induce combined PDT/PTT and accelerate immune activation via excellent tumor accumulation ability, offering multimodal tumor theranostics with negligible systemic toxicity.

Chlorin e6-Biotin Conjugates for Tumor-Targeting Photodynamic Therapy.

To improve the tumor-targeting efficacy of photodynamic therapy, biotin was conjugated with chlorin e6 to develop a new tumor-targeting photosensitizer, Ce6-biotin. The Ce6-biotin had good water solubility and low aggregation. The singlet-oxygen generation rate of Ce6-biotin was slightly increased compared to Ce6. Flow cytometry and confocal laser scanning microscopy results confirmed Ce6-biotin had higher binding affinity toward biotin-receptor-positive HeLa human cervical carcinoma cells than its precursor, Ce6. Due to the BR-targeting ability of Ce6-biotin, it exhibited stronger cytotoxicity to HeLa cells upon laser irradiation. The IC50 against HeLa cells of Ce6-biotin and Ce6 were 1.28 µM and 2.31 µM, respectively. Furthermore, both Ce6-biotin and Ce6 showed minimal dark toxicity. The selectively enhanced therapeutic efficacy and low dark toxicity suggest that Ce6-biotin is a promising PS for BR-positive-tumor-targeting photodynamic therapy.

Deformable Hollow Periodic Mesoporous Organosilica Nanocapsules for Significantly Improved Cellular Uptake.

Mesoporous solids have been widely used in various biomedical areas such as drug delivery and tumor therapy. Although deformability has been recognized as a prime important characteristic influencing cellular uptake, the synthesis of deformable mesoporous solids is still a great challenge. Herein, deformable thioether-, benzene-, and ethane-bridged hollow periodic mesoporous organosilica (HPMO) nanocapsules have successfully been synthesized for the first time by a preferential etching approach. The prepared HPMO nanocapsules possess uniform diameters (240-310 nm), high surface areas (up to 878 m2·g-1), well-defined mesopores (2.6-3.2 nm), and large pore volumes (0.33-0.75 m3·g-1). Most importantly, the HPMO nanocapsules simultaneously have large hollow cavities (164-270 nm), thin shell thicknesses (20-38 nm), and abundant organic moiety in the shells, which endow a lower Young's modulus (EY) of 3.95 MPa than that of solid PMO nanoparticles (251 MPa). The HPMOs with low EY are intrinsically flexible and deformable in the solution, which has been well-characterized by liquid cell electron microscopy. More interestingly, it is found that the deformable HPMOs can easily enter into human breast cancer MCF-7 cells via a spherical-to-oval morphology change, resulting in a 26-fold enhancement in cellular uptake (43.1% cells internalized with nanocapsules versus 1.65% cells with solid counterparts). The deformable HPMO nanocapsules were further loaded with anticancer drug doxorubicin (DOX), which shows high killing effects for MCF-7 cells, demonstrating the promise for biomedical applications.

Facile Synthesis of Yolk-Shell-Structured Triple-Hybridized Periodic Mesoporous Organosilica Nanoparticles for Biomedicine.

The synthesis of mesoporous nanoparticles with controllable structure and organic groups is important for their applications. In this work, yolk-shell-structured periodic mesoporous organosilica (PMO) nanoparticles simultaneously incorporated with ethane-, thioether-, and benzene-bridged moieties are successfully synthesized. The preparation of the triple-hybridized PMOs is via a cetyltrimethylammonium bromide-directed sol-gel process using mixed bridged silsesquioxanes as precursors and a following hydrothermal treatment. The yolk-shell-structured triple-hybridized PMO nanoparticles have large surface area (320 m(2) g(-1) ), ordered mesochannels (2.5 nm), large pore volume (0.59 cm(3) g(-1) ), uniform and controllable diameter (88-380 nm), core size (22-110 nm), and shell thickness (13-45 nm). In vitro cytotoxicity, hemolysis assay, and histological studies demonstrate that the yolk-shell-structured triple-hybridized PMO nanoparticles have excellent biocompatibility. Moreover, the organic groups in the triple-hybridized PMOs endow them with an ability for covalent connection of near-infrared fluorescence dyes, a high hydrophobic drug loading capacity, and a glutathione-responsive drug release property, which make them promising candidates for applications in bioimaging and drug delivery.

Metabolomics-Based Screening of Biofilm-Inhibitory Compounds against Pseudomonas aeruginosa from Burdock Leaf.

Screening of anti-biofilm compounds from the burdock leaf based on metabolomics is reported here. The crystal violet assay indicated 34% ethanol elution fraction of burdock leaf could completely inhibit biofilm formation of Pseudomonas aeruginosa at 1 mg·mL(-1). Then, the chemical composition of burdock leaf fraction was analyzed by ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) and 11 active compounds (chlorogenic acid, caffeic acid, p-coumaric acid, quercetin, ursolic acid, rutin, cynarin, luteolin, crocin, benzoic acid, and Tenacissoside I) were identified. Lastly, UPLC-MS analysis was employed to obtain the metabolic fingerprints of burdock leaf fractions before and after inhibiting the biofilm of Pseudomonas aeruginosa. The metabolic fingerprints were transformed to data, analyzed with PLS-DA (partial least squares discriminant analysis) and the peaks whose area was significantly changed were found out. Thus, 81 compounds were screened as potential anti-biofilm ingredients. Among them, rutin, ursolic acid, caffeic acid, p-coumaric acid and quercetin were identified and confirmed as the main anti-biofilm compounds in burdock leaf. The study provided basic anti-biofilm profile data for the compounds in burdock leaf, as well as provided a convenient method for fast screening of anti-biofilm compounds from natural plants.

Double-layer hollow mesoporous silica nanoparticles for ultrasound-guided photodynamic treatment.

Cervical carcinoma persists as a major global public health burden. While conventional therapeutic modalities inevitably cause ablation of adjacent non-tumorous tissues, photodynamic therapy (PDT) offers a targeted cytotoxic strategy through a photosensitizing agent (PS). However, the hydrophobicity and lack of selective accumulation of promising PS compounds such as zinc(II) phthalocyanine (ZnPc) impedes their clinical translation as standalone agents. The present study sought to incorporate ZnPc within double-layer hollow mesoporous silica nanoparticles (DHMSN) as nanocarriers to enhance aqueous dispersibility and tumor specificity. Owing to their compartmentalized design, the hollow mesoporous silica nanoparticles (HMSN) demonstrated enhanced ultrasonic imaging contrast. Combined with the vaporization of the perfluorocarbon perfluoropentane (PFP), the HMSN-encapsulated ZnPc enabled real-time ultrasound monitoring of PDT treatment.In vivo, the innate thermal energy induced vaporization of the DHMSN-carried PFP to significantly amplify ultrasound signals from the tumor site. Results demonstrated biocompatibility, efficient PFP microbubble generation, and robust photocatalytic activity. Collectively, this investigation establishes ultrasound-guided PDT utilizing multi-layer HMSN as a targeted therapeutic strategy for cervical malignancies with mitigated toxicity.