Methylation induced DNA base-pairing damage is one of the major causes of cancer. O6-alkylguanine-DNA alkyltransferase (AGT) is considered a demethylation agent of the methylated DNA. Structural investigations with thermodynamic properties of the AGT-DNA complex are still lacking. In this report, we modeled two catalytic states of AGT-DNA interactions and an AGT-DNA covalent complex and explored structural features using molecular dynamics (MD) simulations. We utilized the umbrella sampling method to investigate the changes in the free energy of the interactions in two different AGT-DNA catalytic states, one with methylated GUA in DNA and the other with methylated CYS145 in AGT. These non-covalent complexes represent the pre- and post-repair complexes. Therefore, our study encompasses the process of recognition, complex formation, and separation of the AGT and the damaged (methylated) DNA base. We believe that the use of parameters for the amino acid and nucleotide modifications and for the protein-DNA covalent bond will allow investigations of the DNA repair mechanism as well as the exploration of cancer therapeutics targeting the AGT-DNA complexes at various functional states as well as explorations via stabilization of the complex.
Sevoflurane (SEV) is a typical volatile anaesthetic and has an antitumour activity in various cancer cells. Here, we were curious whether SEV has tumour-suppressive effects in neuroblastoma (NB).
NB cell lines (K-N-SH and SK-N-AS) were treated with SEV (1%, 2% and 4%). Cell Counting Kit-8 (CCK8) and Transwell assays were conducted to examine cell proliferation and invasion, respectively. The apoptosis was verified by flow cytometry, and the yes-associated protein 1 (YAP1), Bax, Bcl2 and cleaved caspase3 levels were detected by western blotting. Quantitative real-time PCR (qRT-PCR) was conducted to monitor the miR-144-3p level in SEV-treated NB cells. The targeted relationship between miR-144-3p and YAP1 was predicted by bioinformatics and testified by the dual-luciferase reporter assay.
SEV mitigated NB cell proliferation and invasion and strengthened apoptosis dose-dependently. SEV upregulated miR-144-3p. Moreover, the miR-144-3p inhibitor transfection significantly reduced the tumour-suppressive effect of SEV on NB cells. Furthermore, the dual-luciferase reporter assay confirmed that miR-144-3p targeted YAP1 and overexpressing YAP1 partially weakened the inhibitive effects of miR-144-3p on NB cells.
SEV abated NB cell proliferation and invasion and accelerated apoptosis through the miR-144-3p/YAP1 axis.
SEV abated NB cell proliferation and invasion and accelerated apoptosis through the miR-144-3p/YAP1 axis.Ewing-like adamantinoma (EAD) is a rare bone tumor. It remains unclear whether EAD belongs to adamantinoma, Ewing sarcoma (ES), or an independent category. Herein, we present a case of femoral sarcoma previously diagnosed as EAD in a 26-year-old woman. We observed amplified EWSR1 and NFATC2 fusion signals using fluorescence in situ hybridization. Prompted by its unique radiological features, we reviewed the current literature on skeletal EWSR1-NFATC2 sarcoma (ENS) and EAD. Navitoclax purchase In addition to the similar histological features, we found that both ENS and EAD displayed similar characteristic radiological features, such as the tendency to occur in the diaphysis of long bones, cortical expansion and buttressing-type thickening, and bone surface involvement with saucer-like erosion without cortical destruction. We believe that these unique radiological features were related to its indolent behavior. Altogether, it is possible that previously reported EAD cases may be neither ES nor the classic adamantinoma but ENS. Further studies are needed to clarify the relationship between EAD and ENS.Ligustilide exerts potential neuroprotective effects against various cerebral ischaemic insults and neurodegenerative disorders. However, the function and mechanisms of LIG-mediated hippocampal neural stem cells (H-NSCs) activation as well as cognitive recovery in the context of post-operative cognitive dysfunction (POCD) remain elusive and need to be explored. Mice were subjected to transient global cerebral ischaemia and reperfusion (tGCI/R) injury and treated with LIG (80 mg/kg) or vehicle for 1 month. Morris water maze test and western blot were employed to assess cognitive function. Nissl staining and immunofluorescence (IF) staining were used to detect H-NSCs proliferation and neurogenesis in hippocampus. Subsequently, primary H-NSCs were treated with LIG, and the level of H-NSCs proliferation and neuronal-differentiation was examined by IF staining for Edu and β-Tubulin III. The protein levels of ERK1/2, β-catenin, NICD, TLR4, Akt and FoxO1 were examined using western blotting. Finally, pretreatment with the ERK agonist SCH772984 was performed to observe the change in ERK expression. LIG treatment promoted H-NSCs proliferation and neurogenesis, increased the number of neurons in the hippocampal subfields, and ultimately reversed cognitive impairment in tGCI/R injury. Furthermore, LIG also promoted primary H-NSCs proliferation and neuronal-differentiation, as well as ERK1/2 phosphorylation. Pretreatment with SCH772984 effectively reversed the ability of LIG to induce ERK1/2 phosphorylation and promote H-NSCs proliferation and neuronal-differentiation. LIG can promote cognitive recovery after tGCI/R injury by activating ERK1/2 in H-NSCs to promote their proliferation and neurogenesis in the hippocampus. Therefore, LIG has potential for use in the prevention and/or treatment of POCD.
Current research suggests an association between antibiotic use in early life and later obesity. Less is known about prenatal antibiotic exposure and foetal growth. We investigated the association between prenatal antibiotic exposure and birth weight.
Data from the Danish National Birth Cohort were linked to the Danish National Medical Birth Registry. Exposure was self-reported antibiotic use in pregnancy. Outcome was registered birth weight. Multivariable linear regression models were adjusted for confounders defined a priori.
A total of 63 300 mother-child dyads from 1996 to 2002 were included. Overall, prenatal antibiotic exposure was not associated with birth weight (-8.90 g, 95%CI -19.5- +1.64 g, p=0.10). Findings were similar for those born term and preterm. Antibiotic exposure in second to third trimester, compared to no exposure, was associated with lower birth weight (-12.6g, 95%CI -24.1 to -1.1g, p=0.03). In sex-stratified analyses, there were no observed associations between antibiotics and birth weight.Navitoclax purchase
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