Background
DL‐3‐n‐butylphthalide (NBP) has been approved to be effective in improving cognitive deficits. The aim of the current study was to determine whether NBP protects against cognitive deficits ...in a rat model of vascular dementia (VD) induced by chronic cerebral hypoperfusion (CCH) by regulating the sonic hedgehog (Shh)/patched1 (Ptch1) pathway and endoplasmic reticulum stress (ERS)‐related markers.
Methods
Adult male Sprague‐Dawley rats were subjected to permanent bilateral occlusion of the common carotid arteries (2VO) to established the model of VD. These rats were randomly divided into five groups: sham, model, NBP30 (30 mg/kg), NBP
60 (60 mg/kg), and NBP
120 (120 mg/kg) groups. The Morris water maze test was used to assess for cognitive function at 4 weeks after operation.
Results
NBP significantly alleviated spatial learning and memory impairment, and inhibited the loss of neurons in the CA1 region of the hippocampus. Western blot analysis and real‐time quantitative polymerase chain reaction analysis revealed that plasticity‐related synaptic markers and the Shh/Ptch1 pathway significantly increased in the NBP treated groups, while ERS‐related markers decreased.
Conclusion
The results of the current study prove that the Shh/Ptch1 pathway plays an essential role in the model of VD. NBP had protective effects on cognitive impairment induced by CCH. This mechanism was associated with ERS and the Shh/Ptch1 pathway. Meanwhile, the Shh/Ptch1 pathway and ERS may interact with each other.
Autophagy is a conserved catabolic process characterized by degradation and recycling of cytosolic components or organelles through a lysosome-dependent pathway. It has a complex and close ...relationship to drug resistance in breast cancer. MicroRNAs (miRNAs) are small noncoding molecules that can influence numerous cellular processes including autophagy, through the posttranscriptional regulation of gene expression. Autophagy is regulated by many proteins and pathways, some of which in turn have been found to be regulated by miRNAs. These miRNAs may affect the drug resistance of breast cancer. Drug resistance is the main cause of distant recurrence, metastasis and death in breast cancer patients. In this review, we summarize the causative relationship between autophagy and drug resistance of breast cancer. The roles of autophagy-related proteins and pathways and their associated miRNAs in drug resistance of breast cancer are also discussed.
As a widespread application in underground metal mines, cementitious tailings backfill (CTB) has a significant implication for recycling dangerous process tailings and enhancing the safety of mining ...voids. The pore structure of CTB that is liable on the features and proportions of tailings and binders is correlated to its mechanical characteristics (i.e., elastic modulus, uniaxial compressive strength). This study deals with the influence of curing conditions such as temperature (20–50 °C), stress (0–540 kPa), and time (3–28 days) on mechanical and pore structure characteristics of CTB. Fill samples were prepared in a stable solid dosage and cement/water ratio of 76% and 1/6, respectively, and put into cylindrical molds (D × H: 50 × 100 mm). A new lab instrument with adjustable curing conditions was adopted for fills. A PC-controlled mechanical press and Hg intrusion porosimetry were applied to assess CTB's strength and pore structure properties. Results suggest that, with advancing curing temperature/stress, the strength and elastic modulus of CTB show a rising trend, while its growth rates show a falling trend. CTB's porosity shows a declining trend, and it exists a good linear correlation between fill's strength and apparent porosity. CTB's strength essentially depends on the volume of medium (1–10 μm) and micro (0.01–1 μm) pores. As a result, several practical equations for CTB specimens are established, which consider types of tailings and admixtures.
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•Evolution law between elastic modulus and strength for CTB specimens is analyzed.•Pore characteristics of fills exposed to diverse curing conditions is obtained.•Relationship between filling strength and pore properties is investigated.
Magnesium (Mg) is both an essential macro-element and a known catalyst, and it plays a vital role in various physiological activities and mechanisms in relation to chronic kidney disease (CKD). ...However, epidemiological evidence involving this is limited and not entirely consistent. This study aims to explore the association of serum Mg concentrations with the risk of CKD among general Chinese adults.
A total of 8,277 Chinese adults were included in the wave of 2009 from the China Health and Nutrition Survey (CHNS). The primary outcome was the risk of CKD, which was defined as the estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m
. Multivariable logistic regression model was used to examine the relationship of serum Mg concentrations with the risk of CKD.
Included were 8,277 individuals, with an overall CKD prevalence of 11.8% (n = 977). Compared with the first quartile of serum Mg, the multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for participants in the second, third, and fourth quartiles of serum Mg were 0.74 (0.58, 0.93), 0.87 (0.69, 1.11) and 1.29 (1.03, 1.61), respectively. Similar results were observed in our several sensitivity analyses. Restricted cubic spline analysis demonstrated a nonlinear (similar "J"-shaped) association between serum Mg concentrations and the risk of CKD (P
<0.001), with a threshold at around a serum Mg value of 2.2 mg/dL.
Our results suggested a similar "J"-shaped association between serum Mg concentration and the risk of CKD among Chinese adults. Further large prospective studies are needed to verify these findings.
Osteosarcoma is the most common primary malignant bone tumor in children and adolescents. Many patients with osteosarcoma readily develop resistance to chemotherapy and have an extremely dismal ...prognosis. Dioscin, a saponin, is known to exhibit potent anticancer activities and induce cellular death of a variety of cancer types. However, the inhibitory effect of dioscin on osteosarcoma cells and its underlying mechanisms have not been fully elucidated. We investigated the responses of human U2-OS and MG63 osteosarcoma cells to dioscin with regard to proliferation, apoptosis, migration, and invasion, and studied the effect of dioscin on MAPK-related proteins by western blot analysis assays. Dioscin inhibited osteosarcoma cell proliferation, migration, and invasion. Moreover, it induced osteosarcoma cell apoptosis via reactive oxygen species (ROS)-dependent apoptotic signaling. N-acetylcysteine, a reactive oxygen species inhibitor, suppressed dioscin-induced apoptosis, indicating that ROS play an essential role in dioscin-induced apoptosis. Western blot analysis assays showed that p38 MAPK was upregulated after dioscin treatment, and that dioscin induced apoptosis by upregulating ROS-mediated p38 MAPK signaling. Our study suggests that dioscin possesses antitumor activities against human osteosarcoma cells, inhibits osteosarcoma cell proliferation, migration and invasion, and induces osteosarcoma cell apoptosis through upregulating ROS-mediated p38 MAPK signaling. This study may provide a new therapeutic strategy and potential clinical applications for the treatment of osteosarcoma.
Purple sweet potato color (PSPC), a class of naturally occurring anthocyanins, exhibits beneficial effects on metabolic syndrome. Sustained inflammation plays a crucial role in the pathogenesis of ...metabolic syndrome. Here we explored the effects of PSPC on high-fat diet (HFD)-induced hepatic inflammation and the mechanisms underlying these effects. Mice were divided into four groups: Control group, HFD group, HFD + PSPC group, and PSPC group. PSPC was administered by daily oral gavage at doses of 700 mg/kg/day for 20 weeks. Nicotinamide riboside (NR) was used to increase NAD⁺ levels. Our results showed that PSPC effectively ameliorated obesity and liver injuries in HFD-fed mice. Moreover, PSPC notably blocked hepatic oxidative stress in HFD-treated mice. Furthermore, PSPC dramatically restored NAD⁺ level to abate endoplasmic reticulum stress (ER stress) in HFD-treated mouse livers, which was confirmed by NR treatment. Consequently, PSPC remarkably suppressed the nuclear factor-κB (NF-κB) p65 nuclear translocation and nucleotide oligomerization domain protein1/2 (NOD1/2) signaling in HFD-treated mouse livers. Thereby, PSPC markedly diminished the NLR family, pyrin domain containing 3 (NLRP3) inflammasome activation, ultimately lowering the expressions of inflammation-related genes in HFD-treated mouse livers. In summary, PSPC protected against HFD-induced hepatic inflammation by boosting NAD⁺ level to inhibit NLRP3 inflammasome activation.
2,2′,4,4′-Tetrabromodiphenyl ether (BDE-47) is associated with various adverse human health effects; however, the knowledge of its toxicity is still very limited. Mitochondrial injury has been ...observed in liver cells exposed to BDE-47 in vitro. Mitophagy impairment causes the accumulation of dysfunctional mitochondria, contributing to the pathological mechanisms of liver injury. The aim of this study was to investigate whether BDE-47 impairs mitophagy to trigger mitochondrial dysfunction-related liver injury and the underlying mechanisms. This study revealed that BDE-47 elicited mitochondrial dysfunction and related oxidative liver injury by impairing mitophagy. Moreover, our results showed that NAD+ insufficiency is responsible for BDE-47-mediated mitophagy defect and mitochondrial dysfunction in mouse livers, which was associated with suppression of Sirt3/FoxO3a/PINK1 signaling. Furthermore, our results indicated a potential role of miR-34a-5p in the hepatotoxicity of BDE-47. Mechanistically, BDE-47 dramatically upregulated miR-34a-5p expression in mouse livers. The data from AAV-sponge-mediated miR-34a-5p inhibition suggested that miR-34a-5p diminished NAD+ level by directly targeting NAMPT expression in BDE-47-treated mouse livers, which was confirmed by luciferase reporter assay. Consequently, miR-34a-5p markedly abated Sirt3/FoxO3a/PINK1 signaling-mediated mitophagy to promote mitochondrial dysfunction in BDE-47-treated mouse livers. The present study provided in vivo evidence to reveal a potential mechanism for BDE-47-induced mitochondrial dysfunction and related liver injury and indicated that miR-34a-5p-mediated mitophagy impairment might be a therapeutic target for BDE-47 toxicity.
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•BDE-47 impairs mitophagy to elicit mitochondrial dysfunction-related hepatotoxicity.•Impaired NAD+/Sirt3/parkin signaling contributes to BDE-47-mediated mitophagy defect.•Elevated miR-34a-5p by BDE-47 causes NAD+ insufficiency by targeting NAMPT expression.•MiR-34a-5p promotes BDE-47-induced mitophagy defect by abating Sirt3/parkin signaling.•MiR-34a-5p-induced mitophagy defect may be an intervention target for BDE-47 toxicity.
BDE-47 impairs mitophagy to elicit mitochondrial dysfunction-related liver injury by promoting miR-34a-5p-mediated inhibition of NAD+/Sirt3/parkin signaling.
Sesamin (Ses), one of the major lignans in sesame seeds and oil, has been reported to have many benefits and medicinal properties. However, its protective effects against nickel (Ni)-induced injury ...in liver have not been clarified. The aim of the present study was to investigate the effects of sesamin on hepatic oxidative DNA injury and apoptosis in mice exposed to nickel. Kunming mice were exposed to nickel sulfate with or without sesamin coadministration for 20 days. The data showed that sesamin significantly prevented nickel-induced hepatotoxicity in a dose-dependent manner, indicated by both diagnostic indicators of liver damage (serum aminotransferase activities) and histopathological analysis. Moreover, nickel-induced profound elevation of reactive oxygen species (ROS) production and oxidative stress, as evidenced by an increase of the lipid peroxidation level and depletion of the intracellular reduced glutathione (GSH) level in liver, were suppressed by treatment with sesamin. Sesamin also restored the activities of antioxidant enzymes (T-SOD, CAT, and GPx) and decreased 8-hydroxy-2-deoxyguanosine (8-OHdG) levels in nickel-treated mice. Furthermore, a TUNEL assay showed that nickel-induced apoptosis in mouse liver was significantly inhibited by sesamin. Exploration of the underlying mechanisms of sesamin action revealed that activities of caspase-3 were markedly inhibited by the treatment of sesamin in the liver of nickel-treated mice. Sesamin increased expression levels of phosphoinositide-3-kinase (PI3K) and phosphorylated protein kinase B (PBK/Akt) in liver, which in turn inactivated pro-apoptotic signaling events, restoring the balance between pro- and anti-apoptotic Bcl-2 proteins in the liver of nickel-treated mice. In conclusion, these results suggested that the inhibition of nickel-induced apoptosis by sesamin is due at least in part to its antioxidant activity and its ability to modulate the PI3K-Akt signaling pathway.
Purpose
To establish and validate two predictive radiomics models for preoperative prediction of lymph node metastases (LNMs) and tumor deposits (TDs) respectively in rectal cancer (RC) patients.
...Methods
A total of 139 RC patients (98 in the training cohort and 41 in the validation cohort) were enrolled in the present study. High-resolution magnetic resonance images (HRMRI) were retrieved for tumor segmentation and feature extraction. HRMRI findings of RC were assessed by three experienced radiologists. Two radiomics nomograms were established by integrating the clinical risk factors, HRMRI findings and radiomics signature.
Results
The predictive nomogram of LNMs showed good predictive performance (area under the curve AUC, 0.90; 95% confidence interval CI 0.83–0.96) which was better than clinico-radiological (AUC, 0.83; 95% CI 0.74–0.93; Delong test,
p
= 0.017) or radiomics signature-only model (AUC, 0.77; 95% CI 0.67–0.86; Delong test,
p
= 0.003) in training cohort. Application of the nomogram in the validation cohort still exhibited good performance (AUC, 0.87; 95% CI 0.76–0.98). The accuracy, sensitivity and specificity of the combined model in predicting LNMs was 0.86,0.79 and 0.91 in training cohort and 0.83,0.85 and 0.82 in validation cohort. As for TDs, the predictive efficacy of the nomogram (AUC, 0.82; 95% CI 0.71–0.93) was not significantly higher than radiomics signature-only model (AUC, 0.80; 95% CI 0.69–0.92; Delong test,
p
= 0.71). Radiomics signature-only model was adopted to predict TDs with accuracy=0.76, sensitivity=0.72 and specificity=0.94 in training cohort and 0.68, 0.62 and 0.97 in validation cohort.
Conclusion
HRMRI-based radiomics models could be helpful for the prediction of LNMs and TDs preoperatively in RC patients.
Alternarin A (1), a rearranged drimane meroterpenoid characterized by a thioglycerate moiety, was isolated together with two known analogues from the coral-associated fungi Alternaria sp. ZH-15. Its ...structure was determined based on spectroscopic analysis, modified Mosher’s method, and TDDFT/ECD calculations. In a primary cultured cortical neuronal network, compound 1 effectively inhibited the activity of spontaneous synchronous Ca2+ oscillations and 4-aminopyridine induced epileptic discharges in the low micromolar concentration range.
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