Multicomponent deoxyribozymes (MNAzymes) have great potential in gene therapy, but their ability to recognize disease tissue and further achieve synergistic gene regulation has rarely been studied. ...Herein, Arginylglycylaspartic acid (RGD)-modified Distearyl acylphosphatidyl ethanolamine (DSPE)-polyethylene glycol (PEG) (DSPE-PEG-RGD) micelle is prepared with a DSPE hydrophobic core to load the photothermal therapy (PTT) dye IR780 and the calcium efflux pump inhibitor curcumin. Then, the MNAzyme is distributed into the hydrophilic PEG layer and sealed with calcium phosphate through biomineralization. Moreover, RGD is attached to the outer tail of PEG for tumor targeting. The constructed nanomachine can release MNAzyme and the cofactor Ca
under acidic conditions and self-assemble into an active mode to cleave heat shock protein (HSP) mRNA by consuming the oncogene miRNA-21. Silencing miRNA-21 enhances the expression of the tumor suppressor gene PTEN, leading to PTT sensitization. Meanwhile, curcumin maintains high intracellular Ca
to further suppress HSP-chaperone ATP by disrupting mitochondrial Ca
homeostasis. Therefore, pancreatic cancer is triple-sensitized to IR780-mediated PTT. The in vitro and in vivo results show that the MNAzyme-based nanomachine can strongly regulate HSP and PTEN expression and lead to significant pancreatic tumor inhibition under laser irradiation.
As an emerging technology relevant to materials science, 3D printing technology simplifies material production process, shortens the preparation cycle, and provides a broader space for disease ...treatment. This review introduces the latest development in 3D printing, the goal is showing summary of the preparation and the utilization of this technology. We first describe the familiar biological ink for 3d printing. Then, we focus on different applications, including drug delivery, tumor modeling, and organ printing. Later, we described the application of this technology in some disciplines, including neurosurgery, gastrointestinal surgery, and orthopedics. Finally, the recent challenges and prospects of 3D printing are presented.
Exosomes play a critical role in intercellular communication since they contain signalling molecules and genetic materials. During tumorigenesis, tumour-derived exosomes have been demonstrated to ...promote tumour angiogenesis and metastasis. However, how the exosomes facilitate tumour metastasis is not clear. Here we explored the effect of HeLa cell-derived exosomes (Exo
HeLa
) on endothelial tight junctions (TJ) and the related mechanisms. After human umbilical vein endothelial cells (HUVEC) were treated with Exo
HeLa
, TJ proteins zonula occludens-1 (ZO-1) and Claudin-5 in HUVEC were significantly reduced as compared with that treated with exosomes from human cervical epithelial cells, while mRNA levels of ZO-1 and Claudin-5 remained unchanged. Consequently, permeability of endothelial monolayer was increased after the treatment with Exo
HeLa
. Injection of Exo
HeLa
into mice also increased vascular permeability and tumour metastasis in vivo. Neither knocking down of Dicer nor use of inhibitors of microRNAs targeting at mRNAs of ZO-1 and Claudin-5 could block the inhibitory effect of Exo
HeLa
on ZO-1 and Claudin-5. The expression of genes involved in endoplasmic reticulum (ER) stress was significantly increased in HUVECs after treated with Exo
HeLa
. Inhibition of ER stress by knocking down protein kinase RNA-like endoplasmic reticulum kinase prevented the down-regulation of ZO-1 and Claudin-5 by Exo
HeLa
. Our study found that HeLa cell-derived exosomes promote metastasis by triggering ER stress in endothelial cells and break down endothelial integrity. Such effect of exosomes is microRNA-independent.
The treatment of diabetic wounds remains a great challenge for medical community. Here, we present a novel structural color supramolecular hydrogel patch for diabetic wound treatment. This hydrogel ...patch was created by using N-acryloyl glycinamide (NAGA) and 1-vinyl-1,2,4-triazole (VTZ) mixed supramolecular hydrogel as the inverse opal scaffold, and temperature responsive poly(N-isopropylacrylamide) (PNIPAM) hydrogel loaded with vascular endothelial cell growth factor (VEGF) as a filler. Supramolecular hydrogel renders hydrogel patch with superior mechanical properties, in which NAGA and VTZ also provide self-healing and antibacterial properties, respectively. Besides, as the existence of PNIPAM, the hydrogel patch was endowed with thermal-responsiveness property, which could release actives in response to temperature stimulus. Given these excellent performances, we have demonstrated that the supramolecular hydrogel patch could significantly enhance the wound healing process in diabetes rats by downregulating the expression of inflammatory factors, promoting collagen deposition and angiogenesis. Attractively, due to responsive optical property of inverse opal scaffold, the hydrogel patch could display color-sensing behavior that was suitable for the wound monitoring and management as well as guidance of clinical treatment. These distinctive features indicate that the presented hydrogel patches have huge potential values in biomedical fields.
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•Inverse opal scaffolds generated from self-healing supramolecular hydrogel.•Hydrogel patches exerted antibacterial and anti-inflammatory effect in a drug-free way.•Hydrogel patches with thermal-responsive delivery system for delivery of treatments.•Hydrogel patches exhibited color-sensing property in response to temperature variations.•Hydrogel patches promoted re-epithelialization and vascularisation of granulation tissue in diabetic wounds.
The seismic stability analysis of a slope is a complex process influenced by earthquake action characteristics and soil mechanical properties. This paper presents a novel seismic slope stability ...analysis method using the relative residual displacement increment method in combination with the strength reduction method (SRM) and the actual deformation characteristics of the slope. By calculating the relative displacement of the key point inside the landslide mass and the reference point outside the landslide mass after each reduction, the safety factor of the slope is determined by the strength reduction factor (SRF) corresponding to the maximum absolute value of the relative residual displacement increment that appears after a continuous plastic penetration zone. The method eliminates interference caused by significant displacement fluctuations of key points under earthquake action and reduces the subjective error that can occur when manually identifying displacement mutation points. The proposed method is validated by dynamic calculations of homogeneous and layered soil slopes and compared with three other criteria: applicability, accuracy, and stability.
Building structural type information is the foundation for seismic risk assessment and management since it reflects the behavior of buildings under seismic load. However, in earthquake-prone regions, ...most of this information is out-of-date or nonexistent. This paper proposes a deep learning-based method for automatically identifying building structural types from unmanned aerial vehicle (UAV) oblique images. The method consists of four steps: (1) collect facades of buildings with different structural types by web crawler technology as a sample set; (2) construct a convolutional neural network with a facade prior knowledge attention branch and train the model using the sample set; (3) extract building facades from UAV oblique images based on the georeferencing results of feature points as the test set; (4) identify building structural types by inputting the test set into the trained model. Three cases have been selected to verify the feasibility and applicability of the method. The average recall rate of 85% and the average F1 score of 83% have been achieved in areas with regular building distribution. This method integrates multidisciplinary knowledge to provide a solution for rapid collection of building vulnerability information, and expands the role of oblique photography data in urban management and disaster prevention planning.
Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by the loss of immune tolerance. Lupus nephritis (LN) is still a major cause of the morbidity and mortality of SLE. ...In clinical practice, diagnosis, and therapy of SLE is complicated and challenging due to lack of ideal biomarkers. Exosomes could be detected from numerous kinds of biological fluids and their specific contents are considered as hallmarks of autoimmune diseases. The exosomal miRNA profiles of SLE/LN patients significantly differ from those of the healthy controls making them as attractive biomarkers for renal injury. Exosomes are considered as optimal delivery vehicles owing to their higher stable, minimal toxicity, lower immunogenicity features and specific target effects. Endogenous miRNAs can be functionally transferred by exosomes from donor cells to recipient cells, displaying their immunomodulatory effects. In addition, it has been confirmed that exosomal miRNAs could directly interact with Toll-like receptors (TLRs) signaling pathways to regulate NF-κB activation and the secretion of inflammatory cytokines. The present Review mainly focuses on the immunomodulatory effects of exosomal-miRNAs, the complex interplay between exosomes, miRNAs and TLR signaling pathways, and how the exosomal-miRNAs can become non-invasive diagnostic molecules and potential therapeutic strategies for the management of SLE.
Gastric cancer (GC) is a prevalent form of malignancy characterized by significant heterogeneity. The development of a specific prediction model is of utmost importance to improve therapy ...alternatives. The presence of H. pylori can elicit pyroptosis, a notable carcinogenic process. Furthermore, the administration of chemotherapeutic drugs is often employed as a therapeutic approach to addressing this condition. In the present investigation, it was observed that there were variations in the production of 17 pyroptosis-regulating proteins between stomach tissue with tumor development and GC cells. The predictive relevance of each gene associated with pyroptosis was assessed using the cohort from the cancer genome atlas (TCGA). The least absolute shrinkage and selection operator (LASSO) was utilized to enhance the outcomes of the regression approach. Patients with gastric cancer GC in the cohort from the TCGA were categorized into low-risk or high-risk groups based on their gene expression profiles. Patients with a low risk of gastric cancer had a higher likelihood of survival compared to persons classified as high risk (P<0.0001). A subset of patients diagnosed with GC from a Genes Expression Omnibus (GEO) cohort was stratified according to their overall survival (OS) duration. The statistical analysis revealed a higher significance level (P=0.0063) regarding OS time among low-risk individuals. The study revealed that the GC risk score emerged as a significant independent prognostic factor for OS in patients diagnosed with GC. The results of Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) research revealed that genes associated with a high-risk group had significantly elevated levels of immune system-related activity. Furthermore, it was found that the state of immunity was diminished within this particular group. The relationship between the immune response to cancer and pyroptosis genes is highly interconnected, suggesting that these genes have the potential to serve as prognostic indicators for GC.
Emerging evidence shows that periodontal disease (PD) may increase the risk of Coronavirus disease 2019 (COVID-19) complications. Here, we undertook a two-sample Mendelian randomization (MR) study, ...and investigated for the first time the possible causal impact of PD on host susceptibility to COVID-19 and its severity.
Summary statistics of COVID-19 susceptibility and severity were retrieved from the COVID-19 Host Genetics Initiative and used as outcomes. Single nucleotide polymorphisms associated with PD in Genome-wide association study were included as exposure. Inverse-variance weighted (IVW) method was employed as the main approach to analyze the causal relationships between PD and COVID-19. Three additional methods were adopted, allowing the existence of horizontal pleiotropy, including MR-Egger regression, weighted median and weighted mode methods. Comprehensive sensitivity analyses were also conducted for estimating the robustness of the identified associations.
The MR estimates showed that PD was significantly associated with significantly higher susceptibility to COVID-19 using IVW (OR = 1.024, P = 0.017, 95% CI 1.004-1.045) and weighted median method (OR = 1.029, P = 0.024, 95% CI 1.003-1.055). Furthermore, it revealed that PD was significantly linked to COVID-19 severity based on the comparison of hospitalization versus population controls (IVW, OR = 1.025, P = 0.039, 95% CI 1.001-1.049; weighted median, OR = 1.030, P = 0.027, 95% CI 1.003-1.058). No such association was observed in the cohort of highly severe cases confirmed versus those not hospitalized due to COVID-19.
We provide evidence on the possible causality of PD accounting for the susceptibility and severity of COVID-19, highlighting the importance of oral/periodontal healthcare for general wellbeing during the pandemic and beyond.
Cancer therapy is moving beyond traditional chemotherapy to include epigenetic approaches. KDM6 demethylases are dynamic regulation of gene expression by histone demethylation in response to diverse ...stimuli, and thus their dysregulation has been observed in various cancers. In this review, we first briefly introduce structural features of KDM6 subfamily, and then discuss the regulation of KDM6, which involves the coordinated control between cellular metabolism (intrinsic regulators) and tumor microenvironment (extrinsic stimuli). We further describe the aberrant functions of KDM6 in human cancers, acting as either a tumor suppressor or an oncoprotein in a context-dependent manner. Finally, we propose potential therapy of KDM6 enzymes based on their structural features, epigenetics, and immunomodulatory mechanisms, providing novel insights for prevention and treatment of cancers.
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