miR-194-5p and NEAT1 have been reported to be associated with multiple malignancies, but their roles in acute myeloid leukemia (AML) remains not fully understood.
Bone marrow samples were collected ...for monocyte separation. qRT-PCR assay was performed to investigate the expression patterns of NEAT1 and miR-194-5p in AML. CCK-8, soft agar colony formation, flow cytometry and transwell assays were employed to explore the biological functions of NEAT1 or miR-194-5p. Methylation PCR was performed to monitor the methylation of NEAT1. Luciferase reporter assay was subjected to verify the relationship between miR-194-5p and DNMT3A. Immunofluorescence and western blotting were performed to detect the alterations of protein expression.
NEAT1 and miR-194-5p were both down-regulated in AML. Overexpression of either NEAT1 or miR-194-5p repressed proliferation, induced apoptosis and restrained migration and invasion of AML cells. There was a negative correlation between NEAT1 and DNMT3A in AML. Knockdown of DNMT3A dramatically decreased the methylation of NEAT1. Moreover, DNMT3A was identified as a downstream target of miR-194-5p. Furthermore, down-regulation of DNMT3A rescued the impacts on the malignant phenotypes of NEAT1 inhibition by miR-194-5p inhibitor.
Altogether, down-regulation of NEAT1 mediated by miR-194-5p/DNMT3A axis promotes AML progression, which might provide therapeutic targets in AML treatment.
Previous report showed that a variety of icotinib derivatives bearing different 1,2,3-triazole moieties, which could be readily prepared
via
copper (I)-catalyzed cycloaddition (CuAAC) reaction ...between icotinib and different azides, exhibited interesting activity against different lung cancer cell lines such as H460, H1975, H1299, A549 or PC-9. To further expand the application scope of the compounds and to validate the function of triazole groups in drug design, the anti-cancer activity of these compounds against esophageal squamous carcinoma (ESCC) cells was tested herein. Preliminary MTT experiments suggested that these compounds were active against different ESCC cell lines such as KYSE70, KYSE410, or KYSE450 as well as their drug-resistant ones. Especially, compound 3l showed interesting anticancer activity against these cell lines. The mode of action was studied
via
molecular docking, SPR experiments and other biochemical studies, and 3l exhibited higher binding potential to wild-type EGFR than icotinib did.
In vivo
anticancer study showed that 3l could inhibit tumor growth of cell-line-derived xenografts in ESCC. Study also suggested that 3l was a potent inhibitor for EGFR-TK pathway. Combining these results, 3l represents a promising lead compound for the design of anti-cancer drugs against ESCC.
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•β-cyclodextrin-based nanosponges (CDNSs) were synthesized for the delivery of crocetin (CRT).•The molar ratio of β-CD and crosslinker affected the solubilization efficiency of ...β-CDNSs.•The loading of β-CDNSs greatly improved the aqueous solubility of CRT.•The cytotoxicity against tumor cells and antioxidant activity of CRT were enhanced by CDNSs loading.
Crocetin (CRT) is a natural carotenoid compound with promising health benefits but its use is restricted because of the poor aqueous solubility. Therefore, cyclodextrin-based nanosponges (CDNSs), a kind of water-soluble supramolecular macrocyclic polymer, was employed to load CRT for improving the solubility. The β-CDNSs with different molar ratio of β-CD and crosslinker were synthesized and β-CDNS 1:8 was chosen. The loading capacity (LC) and complexation efficiency (CE) of prepared CRT-loaded β-CDNS were about 17.92% and 94.64%. The formation of inclusion and non-inclusion structure of CRT-loaded β-CDNS was confirmed by different techniques. The surface properties and dispersibility were also studied. Besides, the water solubility of CRT was significantly increased to 7.27 μg/mL. The antioxidant activity of CRT was enhanced. The in vitro cytotoxicity of CRT for normal cells was reduced and for tumor cells was increased through the loading of β-CDNS. In summary, this work demonstrated β-CDNS could be used for the delivery of CRT and promote the application of CRT in many fields.
This study aimed to investigate the effects of subpressure on the bond properties of total-etching adhesive to dentin. Thirty-six caries-free premolars were sectioned parallel to the occlusal plane ...and randomly divided into four groups (n = 9): a control group (C, no treatment) and three subpressure groups, which were treated under 0.8, 0.6 or 0.4 bar after applying adhesives, named S
, S
and S
, respectively. Afterward, resin was bonded to the dentin surface, and 27 beams (1.0 mm × 1.0 mm) of each group were sectioned. One was selected to observe the bonding interface from each group by SEM. Each group was divided into two subgroups (n = 13): 24 hours of water storage (I) and 10,000 thermocycling (A). The microtensile bond strength (μTBS), failure modes and nanoleakage expression were evaluated. SEM results showed that the subpressure groups had longer and denser resin tags. The μTBS of the subpressure groups was higher than that of the control group (p < 0.05). The subpressure groups were dominated by mixed failure, whereas main interfacial failure appeared in group C. The subpressure groups showed less silver deposition than the control group (p < 0.05). The subpressure technique may remarkably improve bonding strength and decrease nanoleakage on total-etching bonding.
Epithelial-mesenchymal transition (EMT) is one of the important regulators of metastasis in advanced hepatocellular carcinoma (HCC). Blocking the Notch signaling pathway and then reversing the EMT ...process is a hot spot in clinical tumor research. Here, we aimed to investigate the effect and underlying mechanisms of ADAM-17 (a key cleavage enzyme of Notch pathway) inhibitor ZLDI-8 we found before on the metastasis of hepatocellular carcinoma in vitro and in vivo.
The cell viability of HCC cells was evaluated by MTT and colony formation assays. Migration and invasion were assessed respectively with wound healing and transwell assays. The expression and location of proteins were detected by western blot and immunofluorescence, respectively. The effects of ZLDI-8 on metastasis of liver cancer in vivo were investigated in a tail vein injection model.
In the present work, ZLDI-8 significantly inhibited proliferation, migration, invasion and EMT phenotype of highly aggressive MHCC97-H and LM3 cells. Moreover, ZLDI-8 could inhibit the migration and invasion of HepG2 and Bel7402 cells induced by TGF-β1. ZLDI-8 suppressed the protein expression of interstitial markers and increased that of epithelial markers. Meanwhile, ZLDI-8 decreased the expression of proteins in the Notch signaling pathway. Finally, ZLDI-8 blocks metastasis in the lung metastasis model in vivo.
ZLDI-8 suppressed the metastasis of hepatocellular carcinoma, which was associated with reversing the EMT process and regulating Notch signaling pathway. The study laid the foundation for the discovery of drugs that reverse EMT to inhibit advanced HCC metastasis.
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•ZLDI-8 inhibits migration, invasion and EMT phenotype of HCC cell lines.•ZLDI-8 inhibits the notch pathway and regulates EMT-related proteins.•ZLDI-8 is expected to be an effective agent in the treatment of advanced HCC.
In the present investigation, a series of dihydrotriazine derivatives-bearing 5-aryloxypyrazole moieties were synthesized and their structures were confirmed by different spectral tools. The ...biological evaluation in vitro revealed that some of the target compounds exerted good antibacterial and antifungal activity in comparison with the reference drugs. Among these novel hybrids, compound
10d
showed the most potent activity with minimum inhibitory concentration values (MIC) of 0.5 µg/mL against
S. aureus
4220, MRSA 3506 and
E. coli
1924 strain. The cytotoxic activity of the compounds
6d
,
6m
,
10d
and
10g
was assessed in MCF-7 and HeLa cells. Growth kinetics study showed significant inhibition of bacterial growth when treated with different conc. of
10d
. In vitro enzyme study implied that compound
10d
exerted its antibacterial activity through DHFR inhibition. Moreover, significant inhibition of biofilm formation was observed in bacterial cells treated with MIC conc. of
10d
as visualized by SEM micrographs.
Graphic abstract
Twenty-nine target compounds were designed, synthesized and evaluated in terms of their antibacterial and antifungal activities.
As a common complication of diabetes, the pathogenesis of diabetic peripheral neuropathy (DPN) is closely related to high glucose but has not been clarified. Exosomes can mediate crosstalk between ...Schwann cells (SC) and neurons in the peripheral nerve. Herein, we found that miR-21 in serum exosomes from DPN rats was decreased. SC proliferation was inhibited, cell apoptosis was increased, and the expression of miR-21 in cells and exosomes was downregulated when cultured in high glucose. Increasing miR-21 expression reversed these changes, while knockdown of miR-21 led to the opposite results. When co-cultured with exosomes derived from SC exposed to high glucose, neurite outgrowth was inhibited. On the contrary, neurite outgrowth was accelerated when incubated with exosomes rich in miR-21. We further demonstrated that the SC-derived exosomal miR-21 participates in neurite outgrowth probably through the AKT signaling pathway. Thus, SC-derived exosomal miR-21 contributes to high glucose regulation of neurite outgrowth.
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•The miR-21 was decreased in serum exosomes and sciatic nerve of DPN rats•High glucose inhibited SC viability and downregulated the expression of miR-21•Exosomes derived from SC cultured in high glucose inhibited the neurite outgrowth•SC-derived exosomes rich in miR-21 accelerated the neurite outgrowth of neuron
Biological sciences; Neuroscience; Molecular neuroscience; Diabetology
Intrahepatic cholestasis (IC) is a common syndrome that affects the liver, with treatment options being limited. Huangqi decoction (HQD), a classic herbal medicine, has shown protective effects ...against IC. In this study, isobaric tags for relative and absolute quantification-based quantitative proteomics was performed to investigate the potential mechanism of action of HQD on α-naphthylisothiocyanate (ANIT)-induced IC, resulting in 2796 quantified proteins across all samples, including 270 differentially expressed proteins under HQD treatment. Fuzzy c-means clustering analysis of these 270 proteins assigned the proinflammatory proteins, such as LCN2, SAA1, FGG, FGA, and FGB, to Cluster 1 (upregulated by ANIT, and downregulated by HQD). Functional bioinformatics and protein–protein interaction network analyses indicated that these proinflammatory proteins were involved in the STAT3 signaling pathway. Further real-time PCR and Western blot experiments confirmed that the expression of these proteins was consistent with the proteomic results. Moreover, HQD treatment decreased the phosphorylation of STAT3, induced by ANIT. Western blot experiments revealed that HQD treatment decreased phosphorylation of NF-κB and downregulated the expression of the inflammatory gene IL-6 and therefore inhibited the IL-6/STAT3 signaling pathway. In summary, the present study suggested that HQD may ameliorate acute cholestatic liver injury via inhibition of the NF-κB/IL-6/STAT3 signaling pathway.
γ-secretase is an aspartyl protease that cleaves multiple substrates within their transmembrane domains. γ- secretase processes the amyloid precursor protein (APP) to generate β-amyloid (Aβ) peptides ...associated with Alzheimer's disease. Here, we show that APP possesses a substrate inhibitory domain (ASID) that negatively modulates γ-secretase activity for Aβ production by binding to an allosteric site within the γ-secretase complex. Alteration of this ASID by deletion or mutation, as is seen with the Flemish mutation (A21G), reduces its inhibitory potency and promotes Aβ production. Notably, peptides derived from ASID show selective inhibition of γ-secretase activity for Aβ production over Notch1 processing. Therefore, this mode of regulation represents an unprecedented mechanism for modulating γ-secretase, providing insight into the molecular basis of Alzheimer's disease pathogenesis and a potential strategy for the development of therapeutics.
The new surgical procedure of full-endoscopic interlaminar lumbar discectomy (FILD) has achieved favorable effects in the treatment of lumbar disc herniation (LDH). Along with the wide range of ...applications of FILD, a series of complications related to the operation has gradually emerged.
To describe the types, incidences, and characteristics of complications following FILD and to explore preventative and treatment measures.
Retrospective, observational study.
A spine center affiliated with a large general hospital.
In total, 479 patients with LDH underwent FILDs that were performed by a single experienced spine surgeon between January 2010 and April 2013. Data concerning the complications were recorded.
All 479 cases successfully underwent the procedure. A total of 482 procedures were completed. The mean follow-up time was 44.3 months with a range of 24 to 60 months. The average patient age was 47.8 years with a range of 16 to 76 years. Twenty-nine (6.0%) related complications emerged, including 3 cases (0.6%) of incomplete decompression in which the symptoms gradually decreased following 3 - 6 weeks of conservative treatment, 2 cases (0.4%) of nerve root injury in which the patients recovered well following 1 - 3 months of neurotrophic drug and functional exercise treatment, 15 cases (3.1%) of paresthesia that gradually improved following 1 - 8 weeks of rehabilitation exercises and treatment with mecobalamin and pregabalin, and 9 cases of recurrent herniation (1.9%). The latter condition was controlled in 4 cases with a conservative method, and 5 of these cases underwent reoperations that included 3 traditional open surgeries and 2 FILDs. Furthermore, the complication rate for the first 100 cases was 18%. This rate decreased to 2.9% for cases 101 - 479. The incidence of L4-5 herniation (8.2%) was significantly greater than that of L5-S1 (4.5%).
This is a retrospective study, and some bias exists due to the single-center study design.
FILD is a surgical approach that has a low complication rate. Incomplete decompression, nerve root injury, paresthesia, and recurrent herniation were observed in our study. Some effective measures can prevent and reduce the incidence of the complications including strict indications for surgery, a thorough action plan, and a high level of surgical skill. Key words: Complication, lumbar disc herniation, lumbar discectomy, endoscopic, inter-laminar discectomy, minimally invasive spine surgery.
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