Acute lung injury (ALI) induced by sepsis is characterized by an inflammatory process related to the up‐regulation of inflammatory cytokines and chemokines. In the present study, we explored the role ...of circC3P1 in sepsis‐induced ALI in vitro and in vivo. The caecal ligation and puncture (CLP)‐induced sepsis model was established through CLP surgery. Forty adult male C57BL/6 mice were randomly assigned into sham, CLP, CLP + vector and CLP + circC3P1 (each n = 10). Primary murine pulmonary microvascular endothelial cells (MPVECs) were transfected with circC3P1 or empty vector 24 hours prior to LPS treatment via Lipofectamine 2000. The expressions of circC3P1, tumour necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6) and IL‐1β were evaluated after 6‐h LPS treatment. Cell apoptosis was evaluated via flow cytometry. The CLP group demonstrated pulmonary morphological abnormalities, increased concentrations of TNF‐α, IL‐6 and IL‐1β in the lung tissue, compared with the sham group. MPVECs treated with LPS significantly elevated TNF‐α, IL‐6 and IL‐1β levels and increased cell apoptosis than that in the control group. The circC3P1 overexpression in sepsis‐induced ALI mice attenuated pulmonary injury, inflammation and apoptosis. Besides, circC3P1 revealed anti‐inflammatory and anti‐apoptotic effect in MPVEC‐treated LPS. CircC3P1 overexpression reduced cell apoptosis and pro‐inflammatory cytokines levels via down‐regulating miR‐21. CircC3P1 attenuated pro‐inflammatory cytokine production and cell apoptosis in ALI induced by sepsis through modulating miR‐21, indicating that circC3P1 is a promising therapeutic biomarker for sepsis‐induced ALI.
Vascular integrity helps maintain brain microenvironment homeostasis, which is critical for the normal development and function of the central nervous system. It is known that neural cells can ...regulate brain vascular integrity. However, due to the high complexity of neurovascular interactions involved, understanding of the neural regulation of brain vascular integrity is still rudimentary. Using intact zebrafish larvae and cultured rodent brain cells, we find that neurons transfer miR-132, a highly conserved and neuron-enriched microRNA, via secreting exosomes to endothelial cells (ECs) to maintain brain vascular integrity. Following translocation to ECs through exosome internalization, miR-132 regulates the expression of vascular endothelial cadherin (VE-cadherin), an important adherens junction protein, by directly targeting eukaryotic elongation factor 2 kinase (eef2k). Disruption of neuronal miR-132 expression or exosome secretion, or overexpression of vascular eef2k impairs VE-cadherin expression and brain vascular integrity. Our study indicates that miR-132 acts as an intercellular signal mediating neural regulation of the brain vascular integrity and suggests that the neuronal exosome is a novel avenue for neurovascular communication.
Enzyme‐prodrug therapies have shown unique advantages in efficiency, selectivity, and specificity of in vivo prodrug activation. However, precise spatiotemporal control of both the enzyme and its ...substrate at the target site, preservation of enzyme activity, and in situ substrate depletion due to low prodrug delivery efficiency continue to be great challenges. Here, we propose a novel core–shell reactor partitioning enzyme and prodrug by ZIF‐8, which integrates an enzyme with its substrate and increases the drug loading capacity (DLC) using a prodrug as the building ligand to form a Zn‐prodrug shell. Cytochrome P450 (CYP450) is immobilized in ZIF‐8, and the antitumor drug dacarbazine (DTIC) is coordinated and deposited in its outer layer with a high DLC of 43.6±0.8 %. With this configuration, a much higher prodrug conversion efficiency of CYP450 (36.5±1.5 %) and lower IC50 value (26.3±2.6 μg/mL) are measured for B16‐F10 cells with a higher NADPH concentration than those of L02 cells and HUVECs. With the tumor targeting ability of hyaluronic acid, this core–shell enzyme reactor shows a high tumor suppression rate of 96.6±1.9 % and provides a simple and versatile strategy for enabling in vivo biocatalysis to be more efficient, selective, and safer.
A novel core–shell reactor partitioning CYP450 and prodrug by ZIF‐8 is proposed to improve the efficacy, selectivity, and safety of enzyme‐prodrug therapy. Here, cytochrome P450 (CYP450) is immobilized in ZIF‐8, and the antitumor drug dacarbazine (DTIC) is coordinated and deposited in its outer layer, leading to a high drug loading capacity of 43.6±0.8 %. This reactor exhibits NADPH‐sensitive in situ prodrug activation specificity in tumor cells, which achieves high prodrug conversion efficiency of 36.5±1.5 %.
Ultrathin nanosheets of two-dimensional covalent organic frameworks covered a quartz nanopipette and then acted as a nanopore device for single-molecule DNA sensing. Our results showed that a single ...DNA homopolymer as short as 6 bases could be detected. The dwell times of 30-mer DNA homopolymers were obviously longer than the times of 10- or 6-mer ones. For different bases, poly(dA)6 showed the slowest transport speed (∼595 μs/base) compared with cytosine (∼355 μs/base) in poly(dC)6 and thymine (∼220 μs/base) in poly(dT)6. Such translocation speeds are the slowest ever reported in two-dimensional material-based nanopores. Poly(dA)6 also showed the biggest current blockade (94.74 pA) compared with poly(dC)6 (79.54 pA) and poly(dT)6 (71.41 pA). However, the present difference in blockade current was not big enough to distinguish the four DNA bases. Our study exhibits the shortest single DNA molecules that can be detected by COF nanopores at the present stage and lights the way for DNA sequencing based on solid-state nanopores.
Microfluidic paper-based analytical devices (μPADs) for detection of hydrogen peroxide and glucose have been developed. The analytical performance of colorimetric detection using the conventional ...starch-iodine color reaction has been significantly improved by using gelatin as the surface modifier which retains the enzyme activity in the dry filter paper strip, improves antioxidability, as well as decreases the strong background signal. Under optimal conditions, the color intensities show a good linear relationship with glucose concentration ranging from 0.5 to 5 mM and hydrogen peroxide concentration from 0.5 to 6 mM, with the detection limit of 0.05 mM and 0.1 mM, respectively. In addition, the accuracy of colorimetric sensor has been successfully assessed in detecting glucose from real human serum samples and recovery value ranges from 95.7% to 97%, which are approaching to the glucose oxidase endpoint. The new colorimetric assay exhibits high sensitivity, good selectivity, acceptable stability and reproducibility. The present approach is promising for monitoring glucose for point of care diagnostic applications, especially in regions with resource-limited settings.
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•A facile and sensitive colorimetric assay was proposed based on μPADs coupled with starch-iodide-gelatin system.•The gelatin can provide biocompatible microenvironment and improve the analytical performance of colorimetric methods.•The accuracy of colorimetric sensor was successfully assessed to detect the glucose in the real serum samples.•This colorimetric assay is used to monitor glucose for point of care diagnostic applications.
Inflammatory bowel disease (IBD) is a persistent and chronic disease that is characterized by destructive gastrointestinal (GI) inflammation. Researchers are trying to identify and develop new and ...more effective treatments with no side effects. Acute and chronic mouse models of IBD were established using dextran sulfate sodium (DSS) solution. To evaluate the efficacy and mechanism, umbilical cord mesenchymal stem cells (UCMSCs) were obtained from Kunming (KM) mice and humans. In the chronic IBD study, the survival rates of the normal control, model, mouse UCMSC (mUCMSC) and human UCMSC (hUCMSC) groups were 100%, 40%, 86.7%, and 100%, respectively. The histopathological scores of the normal control, intraperitoneal injection, intravenous treatment, and model groups were 0.5 ± 0.30, 5.9 ± 1.10, 8.7 ± 1.39, and 8.8 ± 1.33 (p = 0.021). UCMSCs promoted the expression of the intestinal tight junction protein occludin, downregulated the protein expression of the autophagy marker LC3A/B in colon tissue, and upregulated the expression of VEGF-A and VEGFR-1 at the injured site. This study provides an experimental model for elucidating the therapeutic effects of UCMSCs in IBD. We provide a theoretical basis and method for the clinical treatment of IBD using UCMSCs.
Megakaryoblastic leukemia 1 (MKL1) was closely related to the pathogenesis of various human malignant cancers. MiR34a was reported to be closely related to cancer cell proliferation. Forkhead box ...protein 3 (FOXP3) was a transcription factor that played a different role in different cancer types. CDK6 was involved in cell cycle progression and was upregulated in several types of cancers. The present study investigated the effects of MKL1/miR34a/FOXP3 axis on cell proliferation in MGC803 gastric cancer cells. Our results demonstrated that overexpression of MKL1 promoted proliferation of MGC80‐3 cells, MKL1 directly binding to the promoter of CDK6 to increase its expression. Knockdown of FOXP3 promoted proliferation of MGC80‐3 cells and MKL1 inhibited the expression of FOXP3 via miR‐34a. The finding can contribute to elucidating the regulatory mechanism involved in the cell cycle progression of gastric cancer cells and may aid in screening potential gene targets for the biological therapy of gastric cancer.
Overexpression of megakaryoblastic leukemia 1 (MKL1) promoted proliferation of MGC80‐3 cells, MKL1 inhibited the expression of forkhead box protein 3 (FOXP3) via miR‐34a.
Breast cancer is the most common type of invasive cancer in females and metastasis is one of the major causes of breast cancer-associated mortality. Following detachment from the primary site, ...disseminated tumor cells (DTCs) enter the bloodstream and establish secondary colonies during the metastatic process. An increasing amount of studies have elucidated the importance of Notch signaling in breast cancer metastasis; therefore, the present review focuses on the mechanisms by which Notch contributes to the occurrence of breast cancer DTCs, increases their motility, establishes interactions with the tumor microenvironment, protects DTCs from host surveillance and finally facilitates secondary colonization. Identification of the underlying mechanisms of Notch-associated breast cancer metastasis will provide additional insights that may contribute towards the development of novel Notch-targeted therapeutic strategies, which may aid in reducing metastasis, culminating in an improved patient prognosis.
Thyroid cancer remains the most common endocrine malignancy worldwide, and its incidence has steadily increased over the past four years. Papillary Thyroid Cancer (PTC) is the most common ...differentiated thyroid cancer, accounting for 80–85% of all thyroid cancers. Mitochondrial proteins (MRPs) are an important part of the structural and functional integrity of the mitochondrial ribosomal complex. It has been reported that MRPL9 is highly expressed in liver cancer and promotes cell proliferation and migration, but it has not been reported in PTC. In the present study we found that MRPL9 was highly expressed in PTC tissues and cell lines, and lentivirus-mediated overexpression of MRPL9 promoted the proliferation and migration ability of PTC cells, whereas knockdown of MRPL9 had the opposite effect. The interaction between MRPL9 and GGCT (γ-glutamylcyclotransferase) was found by immunofluorescence and co-immunoprecipitation experiments (Co-IP). In addition, GGCT is highly expressed in PTC tissues and cell lines, and knockdown of GGCT/MRPL9 in vivo inhibited the growth of subcutaneous xenografts in nude mice and inhibited the formation of lung metastases. Mechanistically, we found that knockdown of GGCT/MRPL9 inhibited the MAPK/ERK signaling pathway. In conclusion, our study found that the interaction of GGCT and MRPL9 modulates the MAPK/ERK pathway, affecting the proliferation and migration of PTC cells. Therefore, GGCT/MRPL9 may serve as a potential biomarker for PTC monitoring and PTC treatment.
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