hsa_circ_0087100/hsa-miR-6743-5p affects Th1 cell differentiation by regulating STAT1 in diabetic retinopathy.

Objective: To elucidate the role of the competitive endogenous RNA (ceRNA) network in immune infiltration of diabetic retinopathy (DR). Methods: We obtained differentially expressed (DE) circRNAs, miRNAs and mRNAs from the Gene Expression Omnibus database. Then, we identified immune infiltration by CIBERSORT and single-sample gene set enrichment analysis and discovered co-expression genes by weighted gene co-expression network analysis. Furthermore, STAT1-mediated Th1 differentiation was determined in DR cell models, DR patients and DR mouse models. Results: hsa_circ_0087100/hsa-miR-6743-5p/STAT1 was involved in immune infiltration of Th1 cells. Aberrant expression of the ceRNA network and STAT1-mediated Th1 differentiation was thus verified in vitro and in vivo. Conclusion: hsa_circ_0087100/hsa-miR-6743-5p/STAT1 may affect Th1 cell differentiation in DR.

Association of tumor budding with clinicopathological features and prognostic value in stage III-IV colorectal cancer.

BACKGROUND: Tumor budding (TB) has emerged as a promising independent prognostic biomarker in colorectal cancer (CRC). The prognostic role of TB has been extensively studied and currently affects clinical decision making in patients with stage I and II CRC. However, existing prognostic studies on TB in stage III CRC have been confined to small retrospective cohort studies. Consequently, this study investigated the correlation among TB categories, clinicopathological features, and prognosis in stage III-IV CRC to further enhance the precision and individualization of treatment through refined prognostic risk stratification. AIM: To analyze the relationship between TB categories and clinicopathological characteristics and assess their prognostic value in stage III-IV CRC to further refine the prognostic risk stratification of stage III-IV CRC. METHODS: The clinical data of 547 CRC patients were collected for this retrospective study. Infiltration at the front edge of the tumor buds was counted according to the 2016 International Tumor Budding Consensus Conference guidelines. RESULTS: Multivariate Cox proportional hazards regression analysis demonstrated that chemotherapy (P = 0.004), clinical stage IV (P < 0.001), ≥ 4 regional lymph node metastases (P = 0.004), left-sided colonic cancer (P = 0.040), and Bd 2-3 (P = 0.002) were independent prognostic factors in patients with stage III-IV CRC. Moreover, the density of tumor infiltrating lymphocytes was higher in Bd 1 than in Bd 2-3, both in the tumor stroma and its invasive margin. CONCLUSION: TB has an independent predictive prognostic value in patients with stage III-IV CRC. It is recommended to complete the TB report of stage III-IV CRC cases in the standardized pathological report to further refine risk stratification.

Heterogeneity of circulating CXCR5-PD-1hiTph cells in patients of type 2 and type 1 diabetes in Chinese population.

AIMS: Circulating peripheral helper T (Tph) cells are shown to promote the progression of autoimmune diseases. However, the role of Tph cells in inflammatory diseases such as type 2 diabetes mellitus (T2DM) and the differences between T2DM and autoimmune diabetes remain unclear. METHODS: We recruited 92 T2DM patients, 106 type 1 diabetes mellitus (T1DM) patients and 84 healthy control individuals. Peripheral blood mononucleated cells were isolated and examined by multicolor flow cytometry. We further evaluated the correlations between circulating Tph cells and clinical biochemical parameters, islet function, disease progression and islet autoantibodies. RESULTS: Circulating Tph cells were significantly higher in both T2DM and T1DM patients than in healthy control individuals. A significant positive correlation was observed between Tph cells and B cells in T1DM patients and overweight T2DM patients. Furthermore, Tph cells were negatively correlated with the area under the C-peptide curve (C-PAUC), and Tph cells were significantly positively correlated with fasting glucose and glycated hemoglobin levels in T2DM patients. However, no correlation was found between Tph cells and the above clinical indicators in T1DM patients. The frequency of Tph cells positively correlated with the titer of GAD autoantibodies and duration of disease in T1DM patients. In addition, we demonstrated that the frequency of Tph cells was decreased after rituximab therapy in T1DM patients. CONCLUSIONS: Circulating Tph cells are associated with blood glucose levels and islet function in T2DM patients. In T1DM patients, circulating Tph cells are associated with B cells and islet autoantibodies. This may suggest that Tph cells have different pathogenic mechanisms in the two types of diabetes. CLINICAL TRIAL INFORMATION: http://ClinicalTrials.gov NCT01280682 (registered July, 2010).

Identification and validation of RNA methylation-related alternative splicing gene signature for low-grade glioma to predict survival and immune landscapes.

BACKGROUND: Low-grade glioma (LGG) is a crucial pathological type of glioma. The present study aimed to explore multiple RNA methylation regulator-related AS events and investigate their prognostic values in LGG. METHODS: The prognostic model for low-grade glioma was established using the LASSO regression analysis. To validate prognostic value, we performed Kaplan-Maier survival analysis, ROC curves and nomograms. The ESTIMATE algorithm, the CIBERSORT algorithm and the ssGSEA algorithm were utilized to explore the role of the immune microenvironment in LGG. Subsequently, we then used GO, KEGG and GSEA enrichment analysis to explore the functional roles of these genes. In addition, we employed the GDSC database to screen potential chemotherapeutic agents. RESULTS: Eight RNA methylation related AS events were involved in construct a survival and prognosis model, which had good ability of independent prediction for patients with LGG. Patients in the high-risk group had shorter life expectancy and higher mortality, while patients in the low-risk group had a better prognosis. We constructed a nomogram which showed an excellent predictive performance for individual OS. The risk score exhibited a close correlation with some immune cells and expression of immune checkpoints. Patients in high-risk group were characterized by immunosuppressive microenvironment and poor response to immunotherapy, and were sensitive to more chemotherapeutic drugs. Pathway and functional enrichment analyses further confirmed that significant differences existed in immune landscape between the two subgroups. CONCLUSION: The prognostic RNA methylation-related alternative splicing signature constructed could constitute a promising prognostic biomarker, which could serve to optimize treatment regimens.

Rational Modulation of BODIPY Photosensitizers to Design Metal-Organic Framework-Based NIR Nanocomposites for High-Efficiency Photodynamic Therapy in a Hypoxic Environment.

Photodynamic therapy (PDT) is a promising noninvasive treatment that has drawn great attention. However, the hypoxic environment in tumors seriously limits the therapeutic effect of oxygen-dependent chemicals and PDT. Herein, a versatile nanocomposite DF-BODIPY@ZIF-8 with oxygen-generating ability was developed based on zeolitic imidazolate framework-8 (ZIF-8) by loading the near-infrared photosensitizer DF-BODIPY to overcome hypoxia-induced drug resistance in cancer therapy. ZIF-8 can catalyze the decomposition of hydrogen peroxide in tumors and increase the dissolved oxygen concentration, resulting in a significant improvement in PDT efficacy. Additionally, we found that enhancing the electronegativity of substituents can effectively reduce the energy level difference (ΔEst) between the minimum singlet state (S1) and the lowest triplet state (T1), leading to the enhancement of the singlet oxygen quantum yield. In vitro experiments suggested that DF-BODIPY@ZIF-8 indeed had a higher singlet oxygen quantum yield and better tumor cell phototoxicity than free DF-BODIPY. In vivo experiments also demonstrated that DF-BODIPY@ZIF-8 could effectively eliminate 4T1 tumors under light irradiation. Thus, we conclude that increasing the electronegativity of substituents and introducing a ZIF-8 material can effectively improve the singlet oxygen quantum yield and overcome the hypoxia limitations for high-efficiency PDT.

Additively manufactured macroporous chambers facilitate large volume soft tissue regeneration from adipose-derived extracellular matrix.

Breast tissue engineering is a promising alternative intervention for breast reconstruction. Due to their low immunogenicity and well-preserved adipogenic microenvironment, decellularized adipose tissue (DAT) can potentially regenerate adipose tissue in vivo. However, the volume of adipose tissue regenerated from DAT can hardly satisfy the demand for breast reconstruction. Tissue engineering chamber (TEC) is an effective technique for generation of large adipose tissue volumes. However, TEC applications necessitate reoperation to remove non-degradable plastic chambers and harvest autologous tissue flaps, which prolongs the operation time and causes potential damage to donor sites. We improved the TEC strategy by combining bioresorbable polycaprolactone (PCL) chambers and decellularized adipose tissues (DAT). A miniaturized porous PCL chamber was fabricated based on scaling differences between human and rabbit chests, and basic fibroblast growth factor (bFGF)-loaded DAT successfully prepared. In rabbit models, a highly vascularized adipose tissue that nearly filled up the PCL chamber (5 mL) was generated de novo from 0.5 mL bFGF-loaded DAT. The newly formed tissue had significantly high expressions of adipogenic genes, compared to the endogenous adipose tissue. The concept described here can be exploited for breast tissue engineering. STATEMENT OF SIGNIFICANCE: Decellularized adipose tissue (DAT), which provides infiltrated cells adipogenic microenvironment, can potentially regenerate adipose tissue in vivo. Nevertheless, the volume of regenerated adipose tissue is insufficient to repair large sized tissue defect. Tissue engineering chamber (TEC) could provide a protective space for in situ regeneration of large volume tissue. Herein, a new strategy by combining biodegradable polycaprolactone chambers and basic fibroblast growth factor-loaded decellularized adipose tissue is proposed. In rabbit model, newly formed adipose tissue regenerated from DAT successfully filled the dome shaped chamber with ten folds higher volume than DAT, which is proportionally similar to women breast. This work highlighted the importance of adipogenic microenvironment and protective space for adipose tissue regeneration.

Detection of Carboxylesterase 1 and Chlorpyrifos with ZIF-8 Metal-Organic Frameworks Using a Red Emission BODIPY-Based Probe.

In this work, a red emission fluorescent probe CBZ-BOD@zeolitic imidazolate framework-8 (ZIF-8) was fabricated based on metal-organic frameworks (MOFs) for detecting carboxylesterase 1 (CES1). The small molecule probe CBZ-BOD was first synthesized and then used to prepare the functionalized MOF material. ZIF-8 was chosen as an encapsulation shell to improve the detection properties of CBZ-BOD. Using this unique porous materials, ultrasensitive quantification of CES1 and chlorpyrifos was successfully realized. The low detection limit and high fluorescence quantum yield were calculated as 1.15 ng/mL and 0.65 for CBZ-BOD@ZIF-8, respectively. CBZ-BOD@ZIF-8 has good biocompatibility and was successfully applied to monitor the activity of CES1 in living cells. A molecular docking study was used to explore the binding of CES1 and CBZ-BOD, finding that CES1 can bind with the probe before and after hydrolysis. This type of materialized probe can inspire the development of fluorescent tools for further exploration of many pathological processes.

A minireview of viscosity-sensitive fluorescent probes: design and biological applications.

Microenvironment-related parameters like viscosity, polarity, and pH play important roles in controlling the physical or chemical behaviors of local molecules, which determine the physical or chemical behaviors of surrounding molecules. In general, changes of the internal microenvironment will usually lead to cellular malfunction or the occurrence of relevant diseases. In the last few decades, the field of chemicobiology has received great attention. Also, remarkable progress has been made in developing viscosity-sensitive fluorescent probes. These probes were particularly efficient for imaging viscosity in biomembranes as well as lighting up specific organelles, such as mitochondria and lysosome. Besides, there are some fluorescent probes that can be used to quantify intracellular viscosity when combined with fluorescence lifetime (FLIM) and ratiometric imaging under water-free conditions. In this review, we summarized the majority of viscosity-sensitive chemosensors that have been reported thus far.

Recent development of synthetic probes for detection of hypochlorous acid/hypochlorite.

Hypochlorous acid/hypochlorite (HOCl/OCl-), as one of the most important reactive oxygen species (ROS), plays an important role in various physiological and pathological processes. Nonproperly located or abnormal concentration of OCl-, however, is associated with many diseases. Thus, developing the fluorescent probe for detecting OCl- is of great significance. To this end, in last decade, many fluorescent probes have been developed and applied for detecting HOCl/OCl- in vitro and in vivo. Despite a great progress has achieved, the development and application of near-infrared fluorescent HOCl/OCl- probe still have some challenges. For example, highly specific and sensitive NIR fluorescent HOCl/OCl- probes applied in endogenous OCl- detection and subcellular organelle bioimaging. In this review, we summarized the representative cases of HOCl/OCl- probes with properties that mentioned above. The discussion contains design strategies, detection mechanisms, as well as applications in bioimaging.