Redox-Responsive AIEgen Diselenide-Covalent Organic Framework Composites Targeting Hepatic Macrophages for Treatment of Drug-induced Liver Injury.

The escalating misuse of antipyretic and analgesic drugs, alongside the rising incidents of acute drug-induced liver injury, underscores the need for a precisely targeted drug delivery system. Herein, two isoreticular covalent organic frameworks (Se-COF and Se-BCOF) are developed by Schiff-base condensation of emissive tetraphenylethylene and diselenide-bridged monomers. Leveraging the specific affinity of macrophages for mannose, the first precise targeting of these COFs to liver macrophages is achieved. The correlation is also explored between the therapeutic effects of COFs and the NLRP3/ASC/Caspase-1 signaling pathway. Utilizing this innovative delivery vehicle, the synergistic delivery of matrine and berberine are accomplished, compounds extracted from traditional Chinese medicine. This approach not only demonstrated the synergistic effects of the drugs but also mitigated their toxicity. Notably, berberine, through phosphorylation of JNK and up-regulation of nuclear Nrf-2 and its downstream gene Mn-SOD expression, simultaneously countered excessive ROS and suppressed the activation of the NLRP3/ASC/Caspase-1 signaling pathway in injured liver tissues. This multifaceted approach proved highly effective in safeguarding against acute drug-induced liver injury, ultimately restoring liver health to normalcy. These findings present a novel and promising strategy for the treatment of acute drug-induced liver injury.

siRNA-induced CD44 knockdown suppresses the proliferation and invasion of colorectal cancer stem cells through inhibiting epithelial-mesenchymal transition.

CD44 has shown prognostic values and promising therapeutic potential in multiple human cancers; however, the effects of CD44 silencing on biological behaviors of cancer stem cells (CSCs) have not been fully understood in colorectal cancer. To examine the contribution of siRNA-induced knockdown of CD44 to the biological features of colorectal CSCs, colorectal CSCs HCT116-CSCs were generated, and CD44 was knocked down in HCT116-CSCs using siRNA. The proliferation, migration and invasion of HCT116-CSCs were measured, and apoptosis and cell-cycle analyses were performed. The sensitivity of HCT116-CSCs to oxaliplatin was tested, and xenograft tumor growth assay was performed to examine the role of CD44 in HCT116-CSCs tumorigenesis in vivo. In addition, the expression of epithelial-mesenchymal transition (EMT) markers E-cadherin, N-cadherin and vimentin was quantified. siRNA-induced knockdown of CD44 was found to inhibit the proliferation, migration and invasion, induce apoptosis, promote cell-cycle arrest at the G1/G0 phase and increase the sensitivity of HCT116-CSCs to oxaliplatin in HCT116-CSCs, and knockdown of CD44 suppressed in vivo tumorigenesis and intrapulmonary metastasis of HCT116-CSCs. Moreover, silencing CD44 resulted in EMT inhibition. Our findings demonstrate that siRNA-induced CD44 knockdown suppresses the proliferation, invasion and in vivo tumorigenesis and metastasis of colorectal CSCs by inhibiting EMT.

Exposure to air pollutants during pregnancy and after birth increases the risk of neonatal hyperbilirubinemia.

OBJECTIVES: Exposure to air pollution is associated with increased risks of several adverse conditions in newborns, such as preterm birth. Whether air pollution is associated with neonatal hyperbilirubinemia remains unclear. We aimed to develop and validate an air-quality-based model to better predict neonatal hyperbilirubinemia. METHODS: A multicenter, population-based cohort of neonates with a gestational age (GA) ≥35 weeks and birth weight ≥2000 g was enrolled in the study. The study was conducted in Shanghai, China, from July 2017 to December 2018. The daily average concentrations of particulate matter (PM) with aerodynamic diameters≤2.5 µm (PM2.5) and ≤10 µm (PM10), sulfur dioxide (SO2), nitrogen dioxide (NO2) and carbon monoxide (CO) were measured. Neonatal hyperbilirubinemia was diagnosed according to the American Academy of Pediatrics (AAP) guidelines by trained neonatologists. We used logistic least absolute shrinkage and selection operator (LASSO) regression to screen air pollutant indicators related to neonatal hyperbilirubinemia and build an air-quality signature for each patient. An air-quality-based nomogram was then established to predict the risk of neonatal hyperbilirubinemia. RESULTS: A total of 11196 neonates were evaluated. Prenatal PM10, CO and NO2 exposure and postpartum SO2 exposure were significantly associated with neonatal hyperbilirubinemia. The air-quality score was calculated according to the hyperbilirubinemia-related pollutants. The air-quality score of the hyperbilirubinemia group was significantly higher than that of the nonhyperbilirubinemia group (P < .01, odds ratio = 2.97). An air-quality-based logistic regression model was built and showed good discrimination (C-statistic of 0.675 [95% CI (confidence interval), 0.658 to 0.692]) and good calibration. Decision curve analysis showed that the air-quality-based model was better than the traditional clinical model in predicting neonatal hyperbilirubinemia. CONCLUSIONS: The findings of this study suggest that ambient air pollution exposure is associated with an increased risk of neonatal hyperbilirubinemia. Our results encourage further exploration of this possibility in future studies.

Tumor-derived covalent organic framework nanozymes for targeted chemo-photothermal combination therapy.

Covalent organic frameworks (COFs) have garnered enormous attention in anti-cancer therapy recently. However, the intrinsic drawbacks such as poor biocompatibility and low target-specificity greatly restrain the full clinical implementation of COF. Herein, we report a biomimetic multifunctional COF nanozyme, which consists of AIEgen-based COF (TPE-s COF) with encapsulated gold nanoparticles (Au NPs). The nanozyme was co-cultured with HepG2 cells until the cell membrane was fused with lipophilic TPE-s COF-Au@Cisplatin. By using the cryo-shocking method, we fabricated an inactivated form of the TPE-s COF-Au@Cisplatin nanozyme endocytosed in the HepG2 cell membrane (M@TPE-s COF-Au@Cisplatin), which lost their proliferative ability and pathogenicity. Upon laser irradiation, the M@TPE-s COF-Au@Cisplatin nanozymes cleaved, thereby releasing the TPE-s COF-Au nanozyme and Cisplatin to exert their photothermal and drug therapeutic effect. This work opens a new avenue to the synthesis of tumor-derived fluorescent TPE-s COF-Au nanozymes for highly efficient, synergetic, and targeted chemo-photothermal combination therapy of liver cancer.

Rat Bone Marrow-Derived Mesenchymal Stem Cells Promote the Migration and Invasion of Colorectal Cancer Stem Cells.

BACKGROUND: Colorectal cancer is one of the most common cancers and the second leading cause of cancer-related deaths worldwide. Targeting cancer stem cells (CSCs) may be a novel strategy for the treatment of colorectal cancer. Previous studies have shown that bone marrow-derived MSCs (BM-MSCs) promote tumor growth and metastasis. However, the role of rat BM-MSCs in the biological behaviors of colorectal CSCs remains unclear until now. MATERIALS AND METHODS: BM-MSCs were isolated from rats and characterized. CSCs were enriched from HCT116 cells using the microsphere culture method, and the microspheres incubated for at least 10 passages were termed HCT116-CSCs that were characterized. The effects of rat BM-MSCs on migration and invasion of HCT116-CSCs were examined using transwell migration and invasion assays and xenograft tumor growth assay. RESULTS: Rat BM-MSCs appeared typical stem cell morphology. Flow cytometry revealed positive CD29 and CD44 expression in rat BM-MSCs at passage 3, and rat BM-MSCs were found to differentiate into osteocytes following incubation in osteogenic induction medium. Microscopy, flow cytometric detection of stem cell surface markers, colony-formation assay and transwell migration and invasion assays characterized the successful preparation of HCT116-CSCs, and subcutaneous injection of HCT116-CSCs produced xenograft tumors in nude mice, while HE staining of the xenograft tumors displayed cancer specimen shapes. Transwell migration and invasion assays showed that rat BM-MSCs promoted the migration and invasion of HCT116-CSCs, and injection of rat BM-MSCs was found to promote the growth of the mouse xenograft tumor derived from HCT116-CSCs. CONCLUSION: Rat BM-MSCs promote the migration and invasion of colorectal CSCs, and colorectal CSCs may be a potential target for the therapy against colorectal cancer.

Variations in melatonin levels in preterm and term human breast milk during the first month after delivery.

The objectives of the present study were to examine the dynamic changes in breast milk melatonin throughout the course of lactation and to explore factors associated with changes in melatonin concentrations and rhythms in both preterm and term breast milk. Breast milk was collected sequentially at 03:00, 09:00, 15:00, and 21:00 in one day. Melatonin was analyzed in 392 breast milk samples from 98 healthy nursing mothers at 0 to 30 days postpartum. In both preterm and term breast milk, the melatonin concentration presented a circadian rhythm with the acrophase at around 03:00. Subgroup analysis showed the peak melatonin concentrations differed significantly across lactation stages, with the highest concentration in the colostrum, followed by transitional and mature breast milk. At 03:00, preterm breast milk had a higher concentration of melatonin than term breast milk in the colostrum (28.67 pg/mL vs. 25.31 pg/mL, p < 0.022), transitional breast milk (24.70 pg/mL vs. 22.55 pg/mL), and mature breast milk (22.37 pg/mL vs. 20.12 pg /mL). Further studies are warranted for their roles and significance on melatonin in breast milk in nutrition and metabolism of neonates.