Congenital scoliosis is a common type of vertebral malformation. Genetic susceptibility has been implicated in congenital scoliosis.
We evaluated 161 Han Chinese persons with sporadic congenital ...scoliosis, 166 Han Chinese controls, and 2 pedigrees, family members of which had a 16p11.2 deletion, using comparative genomic hybridization, quantitative polymerase-chain-reaction analysis, and DNA sequencing. We carried out tests of replication using an additional series of 76 Han Chinese persons with congenital scoliosis and a multicenter series of 42 persons with 16p11.2 deletions.
We identified a total of 17 heterozygous TBX6 null mutations in the 161 persons with sporadic congenital scoliosis (11%); we did not observe any null mutations in TBX6 in 166 controls (P<3.8×10(-6)). These null alleles include copy-number variants (12 instances of a 16p11.2 deletion affecting TBX6) and single-nucleotide variants (1 nonsense and 4 frame-shift mutations). However, the discordant intrafamilial phenotypes of 16p11.2 deletion carriers suggest that heterozygous TBX6 null mutation is insufficient to cause congenital scoliosis. We went on to identify a common TBX6 haplotype as the second risk allele in all 17 carriers of TBX6 null mutations (P<1.1×10(-6)). Replication studies involving additional persons with congenital scoliosis who carried a deletion affecting TBX6 confirmed this compound inheritance model. In vitro functional assays suggested that the risk haplotype is a hypomorphic allele. Hemivertebrae are characteristic of TBX6-associated congenital scoliosis.
Compound inheritance of a rare null mutation and a hypomorphic allele of TBX6 accounted for up to 11% of congenital scoliosis cases in the series that we analyzed. (Funded by the National Basic Research Program of China and others.).
This paper introduces the in vitro test method of hypoglycemic components in food‐grade natural products. The specific steps and results of the experimental methods were introduced in detail, ...including enzyme inhibition test, inhibition kinetics test, multispectral analysis, cell screening model test, molecular docking, and molecular dynamics test. Through the above series of tests, we can judge whether the components in natural products have a lowering effect on blood glucose and analyze the mechanism of action.
This study was conducted to investigate the effect of subpressure on the bond strength of resin to zirconia ceramic. The subpressure would create a pressure gradient which could clean out the bubbles ...in the adhesives or bonding interface.
Twenty-eight pre-sintered zirconia discs were fabricated. Half of them were polished (group P, n = 14), and the rest were sandblasted (group S, n = 14). After sintered,the surface roughness of the zirconia discs was measured. Then, they were randomly divided into two subgroups (n = 7). The groups were named as follows: PC: P + no additional treatments; PP: P + 0.04 MPa after application of adhesives; SC: S + no additional treatments; and SP: S + 0.04 MPa after application of adhesives. Resin columns were bonded to the zirconia specimens to determine shear bond strength (SBS). The bonding interfaces were observed and the fracture modes were evaluated. Statistical analysis was performed on all data.
The surface roughness of group S was significantly higher than that of group P (P<0.05). The SBS values were PC = 13.48 ± 0.7 MPa, PP = 15.22 ± 0.8 MPa, SC = 17.23 ± 0.7 MPa and SP = 21.68 ± 1.4 MPa. There were significant differences among the groups (P<0.05). Scanning electron microscopy (SEM) results showed that the adhesives of group SP and PP were closer and denser to the zirconia ceramic than that of group PC and SC. The proportion of the mixed fracture mode significantly increased after adding subpressure (P< 0.05).
Subpressure can improve the shear bond strength of resin to zirconia ceramics and increase micro-infiltration between the adhesives and the zirconia ceramics, especially on the rough surfaces.
Intrahepatic cholestasis is a common condition of many liver diseases with few therapies. Yinchenzhufu decoction (YCZFD) is a representative traditional Chinese herbal formula used for treating ...jaundice and liver disease.
To investigate the hepatoprotective effect of YCZFD against cholestatic liver injury and reveal its potential mechanism.
Mice with alpha-naphthyl isothiocyanate (ANIT)-induced intrahepatic cholestasis were orally administered YCZFD at doses of 3, 6, and 12g crude drug/kg for 2 weeks followed by subsequent analyses. A serum metabolomics study was then performed to explore the different metabolites influenced by YCZFD using ultra-high-performance liquid chromatography coupled with linear ion trap-Orbitrap hybrid mass spectrometry (UPLC-LTQ-Orbitrap-MS/MS).The levels of individual bile acids in the serum, liver, and bile were determined by UPLC-MS/MS. The expression of metabolic enzymes, transporters, inflammatory factors, and cytokeratin-19 (CK-19) was determined by real-time PCR, western blotting, and immunohistochemistry.
YCZFD administration decreased the serum biochemical indexes and ameliorated pathological damage, such as hepatic necrosis and inflammatory cell infiltration. Serum metabolomics revealed that the metabolites influenced by YCZFD were mainly associated with bile acid metabolism and inflammation. YCZFD administration effectively ameliorated the disordered bile acid homeostasis. The bile acid transporter, multidrug-resistance associated protein 2 (Mrp2), and the metabolic enzyme, cytochrome P450 2b10 (Cyp2b10), were upregulated in the YCZFD intervention group compared to those in the ANIT-induced group. YCZFD administration also significantly inhibited nuclear factor-κB (NF-κB) and its phosphorylation and decreased the expression of proinflammatory cytokines including tumor necrosis factor-α, interleukin-1β, and intercellular adhesion molecule-1 in ANIT-induced cholestatic mice. Additionally, the level of CK-19 was lower in the YCZFD intervention group than in the ANIT-induced cholestatic mice.
YCZFD administration ameliorated disordered bile acid homeostasis, inhibited NF-κB pathway-mediated inflammation, and protected the liver from bile duct injury. Therefore, YCZFD exerted a protective effect against cholestatic liver injury.
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Normal high-density lipoprotein (nHDL) in normal, healthy subjects is able to promote angiogenesis, but the mechanism remains incompletely understood. HDL from patients with coronary artery disease ...may undergo a variety of oxidative modifications, rendering it dysfunctional; whether the angiogenic effect is mitigated by such dysfunctional HDL (dHDL) is unknown. We hypothesized that dHDL compromises angiogenesis. The angiogenic effects of nHDL and dHDL were assessed using endothelial cell culture, endothelial sprouts from cardiac tissue from C57BL/6 mice, zebrafish model for vascular growth and a model of impaired vascular growth in hypercholesterolemic low-density lipoprotein receptor null(LDLr-/-)mice. MiRNA microarray and proteomic analyses were used to determine the mechanisms. Lipid hydroperoxides were greater in dHDL than in nHDL. While nHDL stimulated angiogenesis, dHDL attenuated these responses. Protein and miRNA profiles in endothelial cells differed between nHDL and dHDL treatments. Moreover, nHDL suppressed miR-24-3p expression to increase vinculin expression resulting in nitric oxide (NO) production, whereas dHDL delivered miR-24-3p to inhibit vinculin expression leading to superoxide anion (O2•-) generation via scavenger receptor class B type 1. Vinculin was required for endothelial nitric oxide synthase (eNOS) expression and activation and modulated the PI3K/AKT/eNOS and ERK1/2 signaling pathways to regulate nHDL- and VEGF-induced angiogenesis. Vinculin overexpression or miR-24-3p inhibition reversed dHDL-impaired angiogenesis. The expressions of vinculin and eNOS and angiogenesis were decreased, but the expression of miR-24-3p and lipid hydroperoxides in HDL were increased in the ischemic lower limbs of hypercholesterolemic LDLr-/- mice. Overexpression of vinculin or miR-24-3p antagomir restored the impaired-angiogenesis in ischemic hypercholesterolemic LDLr-/- mice. Collectively, nHDL stimulated vinculin and eNOS expression to increase NO production by suppressing miR-24-3p to induce angiogenesis, whereas dHDL inhibited vinculin and eNOS expression to enhance O2•- generation by delivering miR-24-3p to impair angiogenesis, and that vinculin and miR-24-3p may be therapeutic targets for dHDL-impaired angiogenesis.
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•nHDL and dHDL regulated angiogenesis differently via alterations in vinculin expression.•nHDL suppressed miR-24-3p to increase vinculin expression to stimulate NO production.•dHDL delivered miR-24-3p to inhibit vinculin expression to enhance O2.•- generation.•Vinculin and miR-24-3p may be therapeutic targets for dHDL-impaired angiogenesis.•Cell-free assay may be used to measure the oxidative levels of HDL.
In the context of secondary forest succession, aboveground-belowground interactions are known to affect the dynamics and functional structure of plant communities. However, the links between soil ...microbial communities, soil abiotic properties, plant functional traits in the case of semi-arid and arid ecosystems, are unclear. In this study, we investigated the changes in soil microbial species diversity and community composition, and the corresponding effects of soil abiotic properties and plant functional traits, during a ≥150-year secondary forest succession on the Loess Plateau, which represents a typical semi-arid ecosystem in China. Plant community fragments were assigned to six successional stages: 1-4, 4-8, 8-15, 15-50, 50-100, and 100-150 years after abandonment. Bacterial and fungal communities were analyzed by high-throughput sequencing of the V4 hypervariable region of the 16S rRNA gene and the internal transcribed spacer (ITS2) region of the rRNA operon, respectively. A multivariate variation-partitioning approach was used to estimate the contributions of soil properties and plant traits to the observed microbial community composition. We found considerable differences in bacterial and fungal community compositions between the early (S1-S3) and later (S4-S6) successional stages. In total, 18 and 12 unique families were, respectively, obtained for bacteria and fungi, as indicators of microbial community succession across the six stages. Bacterial alpha diversity was positively correlated with plant species alpha diversity, while fungal diversity was negatively correlated with plant species diversity. Certain fungal and bacterial taxa appeared to be associated with the occurrence of dominant plant species at different successional stages. Soil properties (pH, total N, total C, NH
-N, NO
-N, and PO
-P concentrations) and plant traits explained 63.80% and 56.68% of total variance in bacterial and fungal community compositions, respectively. These results indicate that soil microbial communities are coupled with plant communities via the mediation of microbial species diversity and community composition over a long-term secondary forest succession in the semi-arid ecosystem. The bacterial and fungal communities show distinct patterns in response to plant community succession, according to both soil abiotic properties and plant functional traits.
Colorectal cancer (CRC) is one of highly prevalent cancer. Immunotherapy with immune checkpoint inhibitors (ICIs) has dramatically changed the landscape of treatment for many advanced cancers, but ...CRC still exhibits suboptimal response to immunotherapy. The gut microbiota can affect both anti-tumor and pro-tumor immune responses, and further modulate the efficacy of cancer immunotherapy, particularly in the context of therapy with ICIs. Therefore, a deeper understanding of how the gut microbiota modulates immune responses is crucial to improve the outcomes of CRC patients receiving immunotherapy and to overcome resistance in nonresponders. The present review aims to describe the relationship between the gut microbiota, CRC, and antitumor immune responses, with a particular focus on key studies and recent findings on the effect of the gut microbiota on the antitumor immune activity. We also discuss the potential mechanisms by which the gut microbiota influences host antitumor immune responses as well as the prospective role of intestinal flora in CRC treatment. Furthermore, the therapeutic potential and limitations of different modulation strategies for the gut microbiota are also discussed. These insights may facilitate to better comprehend the interplay between the gut microbiota and the antitumor immune responses of CRC patients and provide new research pathways to enhance immunotherapy efficacy and expand the patient population that could be benefited by immunotherapy.
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•Gut microbiota (GM) shapes antitumor immune responses, affecting cancer immunotherapy, especially ICIs treatment.•Some beneficial or deleterious bacterial species have been reported to enhance or disrupt antitumor immunity in CRC.•GM complexly interacts with antitumor immunity via antigen cross-reactivity, pattern recognition receptors, and metabolites.•Modulating microbiota holds promise for enhancing ICIs efficacy, but current related clinical evidence is lacking in CRC.•Future research should identify precise GM manipulation methods to enhance CRC immunotherapy efficacy.
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.
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.
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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.
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