Stroke is the second leading cause of death worldwide and the leading cause of long-term disability that seriously endangers health and quality of human life. Tissue-type fibrinogen activator is ...currently the only drug approved by FDA for the treatment of ischemic stroke. Neuroprotection is theoretically a common strategy for the treatment of both ischemic and hemorrhagic stroke; therefore, the development of neuroprotective agent has been the focus of research. However, no ideal neuroprotective drug is clinically available. Phosphoglycerate kinase-1 (PGK1) activator has the effect of inhibiting apoptosis and protecting tissue damage, and therefore could be a potential neuroprotective agent. To obtain effective PGK1 activators, we virtually screened a large chemical database and their evaluated the efficacy by the
oxidative stress model, PGK1 enzymatic activity assay, and oxygen-glucose stripping reperfusion (OGD/R) model. The results showed that compounds 7979989, Z112553128 and AK-693/21087020 are potential PGK1 activators with protective effects against PQ-induced oxidative stress in the
model and could effectively ameliorate apoptosis induced by OGD/R-induced neuronal cell injury. Additionally, compounds 7979989 and Z112553128 are effective in alleviating LPS-induced cellular inflammation. This study indicated that these compounds are promising lead compounds that provide theoretical and material basis to the neuroprotective drug discovery.
‘Homotherapy for heteropathy’ is a theory by which different diseases with similar pathogenesis can be treated with one Chinese formula. We aimed to explore the key components and core targets of ...Weijing decoction (WJD) in treating various lung diseases, namely, pneumonia, chronic obstructive pulmonary disease (COPD), acute lung injury (ALI), pulmonary fibrosis, pulmonary tuberculosis and non-small cell lung cancer (NSCLC), via network pharmacology, molecular docking and some experiments.
This is the first study on the mechanism of WJD in treating various lung diseases by ‘homotherapy for heteropathy’. This study is helpful for the transformation of TCM formula and development of new drugs.
Active components and therapeutic targets of WJD were obtained via TCMSP and UniProt databases. Targets of the six pulmonary diseases were harvested from the GeneCards TTD, DisGeNet, UniProt and OMIM databases. Drug-disease intersection targets, corresponding Venn diagrams, herb-component-target networks and protein–protein interaction networks were established. Furthermore, GO biological function and KEGG enrichment analysis were completed. Moreover, the binding activity between main compounds and core targets was measured through molecular docking. Finally, the xenograft NSCLC mouse model was established. Immune responses were evaluated by flow cytometry and mRNA expression levels of critical targets were measured by real-time PCR.
JUN, CASP3 and PTGS2 were the most critical targets in six pulmonary diseases. The active compounds beta-sitosterol, tricin and stigmasterol stably bound to many active sites on target proteins. WJD had extensive pharmacological regulation, involving pathways related to cancer, inflammation, infection, hypoxia, immunity and so on.
Effects of WJD against various lung diseases involve lots of compounds, targets and pathways. These findings will facilitate further research as well as clinical application of WJD.
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A simple and effective photochemical method was developed for cross-linking of polymer gate dielectrics. Laborious synthetic processes for functionalizing polymer dielectrics with ...photo-cross-linkable groups were avoided. The photo-cross-linker, BBP-4, was added into host polymers by simple solution blending process, which was capable of abstracting hydrogen atoms from polymers containing active C―H groups upon exposure to ultraviolet (UV) radiation. The cross-linking can be completed with a relatively long wavelength UV light (365 nm). The approach has been applied to methacrylate and styrenic polymers such as commercial poly(methylmethacrylate) (PMMA), poly(
iso
-butylmethacrylate) (P
i
BMA) and poly(4-methylstyrene) (PMS). The cross-linked networks enhanced dielectric properties and solvent resistance of the thin films. The bottom-gate organic field-effect transistors (OFETs) through all solution processes on plastic substrate were fabricated. The OFET devices showed low voltage operation and steep subthreshold swing at relatively small gate dielectric capacitance.
Abstract
Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer. In the development and progression of LUAD, epigenetic aberration plays a crucial role. However, the ...function of RNA N6-methyladenosine (m
6
A) modifications in the LUAD progression is unknown. The m6A regulator modification patterns in 955 LUAD samples were analyzed comprehensively. Patterns were systematically correlated with the tumor microenvironment (TME) cell-infiltration characteristics. Using principal component analysis algorithms, the m6Ascore was generated to quantify m
6
A modification patterns in individual tumors. Then, their values for predicting prognoses and therapeutic response in LUAD patients were assessed. Three distinct m
6
A modification patterns in LUAD were identified. Among them, the prognosis of m6Acluster C was the best, while the prognosis of m
6
Acluster A was the worst. Interestingly, the characterization of TME cell infiltration and biological behavior differed among the three patterns. To evaluate m
6
A modification patterns within individual tumors, an m
6
Ascore signature was constructed. The results showed that the high m
6
Ascore group was associated with a better prognosis; tumor somatic mutations and tumor microenvironment differed significantly between the high- and low- m
6
Ascore groups. Furthermore, in the cohort with anti-CTLA-4 treatment alone, patients with a high m
6
Ascore had higher ICI scores, which indicated significant therapeutic advantage and clinical benefits.
P21-activated kinase 4 (PAK4) involves in cell proliferation in cancer and mutually regulates with p53, a molecule is demonstrated to control cell autophagy by mammalian target of rapamycin ...(mTOR)/protein kinase B (AKT) signaling. Since the signaling exhibits an association with PAK family members in cell autophagy, it implies that PAK4-relevant proliferation may be impacted by autophagy via p53 with a lack of evidence in cancer cells.
In this research, transient and stable PAK4-knockdown human hepatocarcinoma cell lines (HepG2) were constructed by transfection of PAK4-RNA interference (RNAi) plasmid and lentivirus containing PAK4-RNAi plasmid, respectively. We investigated cell proliferation using methyl thiazolyl tetrazolium (MTT) and Cell Counting Kit 8 (CCK8) assays, cell cycle by flow cytometry (FCM) and cell autophagy by monodansylcadaverine (MDC) staining and autophagic biomarker's expression, and detected the expressions of p53, mTOR, phosphorylated-AKT (p-AKT) and AKT by immunofluorescence and western blot to explore the mechanism.
We successfully constructed transient and stable PAK4-knockdown HepG2 cell lines, and detected dysfunction of the cells' proliferation. An increased expression of p53, as a molecule of cell-cycle-surveillance on G1/S phase, was demonstrated in the cells although the cell cycle blocked at G2/M. And then, we detected increased autophagosome and autophagic biomarker LC3-II, and decreased expressions in p-AKT and mTOR.
The proliferation is reduced in PAK4-knockdown HepG2 cells, which is relative to not only cell cycle arrest but also cell autophagy, and p53/mTOR/p-AKT signaling involves in the cell progress. The findings provide a new mechanism on PAK4 block in cancer therapy.
Circulating endothelial progenitor cells (EPCs) may be a biomarker for vascular function and cardiovascular risk in patients with coronary artery disease (CAD). Dimethylarginine ...dimethylaminohydrolase 2 (DDAH2) regulates the function of EPCs. This study aimed to examine whether hypermethylation of DDAH2 promoter contributes to impaired function of EPCs in CAD patients.
Peripheral blood mono-nuclear cells from 25 CAD patients and 15 healthy volunteers were collected and differentiated into EPCs. EPCs were tested for their adhesive capability. DDAH2 mRNA expression was analyzed by real-time PCR, and the methylation of DDAH2 promoter was detected by bisulfite genomic sequencing.
DDAH2 promoter in EPCs from CAD patients was hypermethylated and the methylation level was negatively correlated to DDAH2 mRNA level and adhesion function of EPCs. Homocysteine impaired the adhesion function of EPCs, accompanied by lower DDAH2 expression and higher methylation level of DDAH2 promoter, compared to controls. These effects of homocysteine were reversed by pretreatment with Aza, an inhibitor of DNA methyltransferase.
Hypermethylation in DDAH2 promoter is positively correlated to the dysfunction of EPCs in CAD patients. Homocysteine disrupts EPCs function via inducing the hypermethylation of DDAH2 promoter, suggesting a key role of epigenetic mechanism in the progression of atherosclerosis.
Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), is emerging as a key contributor for endothelial dysfunction and its effects on endothelium are not yet ...completely defined. The aim of this study was to investigate ADMA-induced apoptosis and its mechanisms in human umbilical vein endothelial cells (HUVECs). Apoptosis was evaluated by in situ terminal uridine nick end labeling (TUNEL) assay and DNA fragmentation analysis. Caspase-3 activity was measured using a colorimetric protease assay kit. Activations of mitogen-activated protein kinases (MAPKs) were characterized by Western blot and immunofluorescence. Intracellular oxidant production was measured using H
2DCF-DA, an oxidant-sensitive fluorescent indicator. ADMA (3–30 μM) induced apoptosis of HUVECs in a dose- and time-dependent manner. Caspase-3 was activated during apoptosis and its specific inhibitor DEVD-CHO significantly attenuated ADMA-induced apoptosis. Phosphorylation of p38 MAPK was induced by ADMA, and p38 MAPK specific inhibitor SB203580 concentration-dependently prevented ADMA-induced caspase-3 activation and cell apoptosis. ADMA increased intracellular oxidant production, which was significantly suppressed by intracellular antioxidant PDTC,
l-arginine or antisense endothelial NOS mRNA. They also markedly prevented ADMA-induced phosphorylation of p38 MAPK and cell apoptosis. In conclusion, our present results demonstrate that ADMA induces apoptosis of endothelial cell via elevation of intracellular oxidant production, which involves p38 MAPK/caspase-3-dependent signaling pathway.
Several randomized clinical trials (RCTs) investigated the effects of the manual placental removal on hemorrhage or other hemorrhage-related complications compared with the spontaneous placental ...removal during cesarean section (CS), while the results remained controversial and were inconsistent. The purpose of this meta-analysis was to quantify the pooled effects of the methods of placental removal on hemorrhage during CS.
A systematic literature search was conducted using PubMed, EMBASE, Web of Science, and Google Scholar. Heterogeneity was tested by
statistics and Q-statistic. The random-effects model or fixed-effects model were used to calculate the pooled effect for the included studies according to heterogeneity. And the term of standardized mean difference (SMD) with 95% confidence intervals (CI) was pooled and estimated the effects across all studies.
A total of nine RCTs were included in this meta-analysis. Compared with spontaneous group, manual placental removal increased the amount of hemorrhage (
= 0.53, 95% CI 0.12, 0.94;
= 2.54,
= 0.011) and increased the risk of endometritis (
= 1.84, 95% CI 1.31, 2.58;
= 3.52,
< 0.0001). In contrast, there was no significant difference concerning the operating time (
= -0.30, 95% CI -0.85, 0.24;
= 1.09,
= 0.276), the length of hospital stays (
= 0.11, 95% CI -0.08, 0.30;
= 1.11,
= 0.265), and blood transfusion requirement (
= 1.36, 95% CI 0.91, 2.04; Z = 1.52,
= 0.129), respectively.
Comparing with spontaneous placental removal, manual placental removal appeared to be less positive effect during CS. Because of the limitations of this meta-analysis, more high-quality RCTs are needed to confirm our findings.
To investigate whether there are aberrant acetylation modifications in global histone and monocyte chemoattractant protein-1 (MCP-1) promoter in monocytes from patients with coronary artery disease ...(CAD) and demonstrate the potential mechanisms.
CD14+ monocytes were isolated from 13 patients with CAD and 18 confirmed non-CAD controls using magnetic beads. Global histone H3/H4 acetylation and H3K4/H3K27 tri-methylation levels were measured with enzyme-linked immunosorbent assay. Quantitative real time-PCR was performed to detect the mRNA expression levels of MCP-1 and enzymes involved in histone modification processes. Histone modification levels in MCP-1 promoter were assessed by ChIP-qPCR assay.
Our results showed a markedly lower global histone H3 acetylation level in monocytes from CAD patients. Global H3K27 tri-methylation level was significantly increased in monocytes from CAD patients. Furthermore, the mRNA expression levels of epigenetic modification enzymes HDAC3, SIRT1, P300, JMJD3 and SUV39H1 were decreased significantly in monocytes from CAD patients, while HDAC7 mRNA expression level was markedly increased. MCP-1 mRNA expression level was increased histone H3/H4 acetylation levels in MCP-1 promoter were markedly increased in monocytes of CAD patients.
Aberrant histone modifications, including acetylation and tri-methylation, were found both in global histone and specific MCP-1 gene locos in monocytes from patients with CAD. Aberrant epigenetic modification enzymes expressions may be the regulatory mechanism responsible for aberrant histone modifications.
The dorsal anterior cingulate cortex (dACC) plays a critical role in cognitive control over different domains of tasks. The dACC activities uniformly represent task-generic intensities of control ...signals across different tasks. However, it remains unclear whether the dACC activities could also encode task identities of control signals across different tasks. If so, how the two types of control information are coherently organized in the dACC? Decision uncertainty is an internally-generated control signal by retrospective monitoring, namely, metacognition, even with no external feedback. We here investigated neural representations of decision uncertainty accompanying three decision-making tasks in the domains of perception, rule-based inference, and memory using trial-by-trial univariate and multivariate analyses on functional magnetic resonance imaging (fMRI) data acquired on human male and female healthy subjects. Our results demonstrated that the dACC represented decision uncertainty commonly across the three decision-making tasks. Further, the multivariate fMRI analyses revealed a mosaic form of neural representations of decision uncertainty across tasks in the dACC. The identity and intensity information was separately represented in two dissociable components, the high-dimensional pattern and the scalar magnitude, of the dACC multivoxel fMRI activities. Lastly, a follow-up behavioral experiment confirmed that this mosaic form of neural representations of parallelly existing decision uncertainty across different tasks should lead to mutual interferences more on the intensity, but less on the identity of control signals. Thus, our findings suggest that the dACC with the mosaic form of neural representations could provide task-generic and task-specific metacognitive control signals to guide appropriate control on different decision-making tasks.
Metacognition is a form of cognitive control using internally generated decision uncertainty to guide behavior adjustment with no needs of external feedback. Decision uncertainty as a generalizable control signal is commonly encoded in the human dorsal anterior cingulate cortex (dACC) accompanying different decision-making tasks. It remains unknown whether or not the task-specific control information is represented in the dACC. We here revealed that multivoxel functional magnetic resonance imaging (fMRI) activities associated with decision uncertainty in the dACC concurrently represented the identity and intensity information. The mixtures of neural representations of decision uncertainty across different tasks should cause specific interferences on each other. Hence, the neural representations of control signals in the human dACC should be task-generic and task-specific.
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