Emerging evidence suggests that osteoarthritis is associated with high cholesterol levels in some osteoarthritis patients. However, the specific mechanism under this metabolic osteoarthritis ...phenotype remains unclear. We find that cholesterol metabolism-related gene, LRP3 (low-density lipoprotein receptor-related protein 3) is significantly reduced in high-cholesterol diet mouse's cartilage. By using Lrp3
mice in vivo and LRP3 lentiviral-transduced chondrocytes in vitro, we identify that LRP3 positively regulate chondrocyte extracellular matrix metabolism, and its deficiency aggravate the degeneration of cartilage. Regardless of diet, LRP3 overexpression in cartilage attenuate anterior cruciate ligament transection induced osteoarthritis progression in rats and Lrp3 knockout-induced osteoarthritis progression in mice. LRP3 knockdown upregulate syndecan-4 by activating the Ras signaling pathway. We identify syndecan-4 as a downstream molecular target of LRP3 in osteoarthritis pathogenesis. These findings suggest that cholesterol-LRP3- syndecan-4 axis plays critical roles in osteoarthritis development, and LRP3 gene therapy may provide a therapeutic regimen for osteoarthritis treatment.
Behavioral research has established that humans implicitly tend to hold a positive view toward themselves. In this study, we employed the event-related potential (ERP) technique to explore neural ...manifestations of positive implicit self-esteem using the Go/Nogo association task (GNAT). Participants generated a response (Go) or withheld a response (Nogo) to self or others words and good or bad attributes. Behavioral data showed that participants responded faster to the self paired with good than the self paired with bad, whereas the opposite proved true for others, reflecting the positive nature of implicit self-esteem. ERP results showed an augmented N200 over the frontal areas in Nogo responses relative to Go responses. Moreover, the positive implicit self-positivity bias delayed the onset time of the N200 wave difference between Nogo and Go trials, suggesting that positive implicit self-esteem is manifested on neural activity about 270 ms after the presentation of self-relevant stimuli. These findings provide neural evidence for the positivity and automaticity of implicit self-esteem.
Pregnancy is associated with metabolic changes to accommodate the mother and her growing fetus. The microbiome has been shown to modulate host metabolism of endogenous and exogenous substances. ...However, the combined effects of pregnancy and the microbiome on host metabolism have not been investigated. The objective of this study was to investigate how the microbiome affects overall hepatic metabolic processes during pregnancy. We assessed these changes within 4 groups of C57BL/6 mice: conventional non-pregnant, conventional pregnant, germ-free non-pregnant, and germ-free pregnant mice. We performed RNA-seq analysis on liver tissues and LC-MS/MS analysis of the plasma to assess the effects of pregnancy and the microbiome on hepatic transcriptome and untargeted plasma metabolome to describe metabolic changes as results of both pregnancy and lack of microbiome. By integrating transcriptomics and metabolomics data, we identified eight metabolic pathways that were significantly enriched for differentially expressed genes associated with pregnancy in both conventional and germ-free mice. Notably, of the eight pathways, 4 pathways (retinol metabolism, arachidonic acid metabolism, linoleic acid metabolism, and steroid hormone biosynthesis) which are all critical for normal pregnancy and fetal development were affected by the germ-free status in pregnant mice, but not at all in non-pregnant mice, indicating that the alterations in these four pathways caused by the lack of microbiome are unique for pregnancy. These results provide novel insight into the role of the microbiome in modulating host metabolic processes critical for maternal health and fetal development during pregnancy.
Recent work has shown that recognizing point symbols is an essential task in the field of map digitization. For the identification of symbols, it is generally necessary to compare the symbols with a ...specific criterion and find the most similar one with each known symbol one by one. Most of the works can only identify a single symbol, a small number of works are to deal with multiple symbols simultaneously with a low recognition accuracy. Given the two deficiencies, this paper proposes a deep transfer learning architecture, where the task is to learn a symbol classifier with AlexNet. For the insufficient dataset, we develop a method for transfer learning that uses a MNIST dataset to pretrain the model, which makes up for the problem of small training dataset and enhances the generalization of the model. Before the recognition process, preprocessing the point symbols in the map to coarse screening out the areas suspected of point symbols. We show a significant improvement over using point symbol images to keep a high performance in being able to deal with many more categories of symbols simultaneously.
The expansion and intensification of human activities have resulted in excessive nitrogen (N) in rivers, causing worldwide concern. To effectively manage agricultural non-point source pollution and ...ensure a safe drinking water supply in watersheds, it is crucial to trace and quantify the primary sources and spatial distribution patterns of N. In response to the challenge of unclear sources and agricultural non-point source pollution, this study utilised the Bayesian isotope mixing model and Soil and Water Assessment Toolmodel to identify the dominant nitrate sources and transformation processes. These models were employed to quantify N retention by the mainstream and tributaries in the Bai River Basin, which directly impacts the safety of drinking water in Beijing. Total N (TN) concentrations in the Yunzhou Reservoir (4.22 ± 0.04 mg.L˗1) and Miyun Reservoir (2.88 ± 0.62 mg.L˗1) inlets in autumn and winter were V class (2 mg.L˗1) category as per GB 3838–2002 standards. This implies higher risks of eutrophication and algal blooms exceeding the standards at individual points and seasons in the Bai River. Fertilisers were the main nitrate source in the Bai River Basin, contributing 44.6% during the dry season and 62.9% during the wet season, suggesting that nitrate is more susceptible to leaching and runoff during rainy periods. Rainfall was not a major contributor, with only 3.2% and 2.9% originating from the Hebei and Beijing areas of the Bai River, respectively. Annually, the Bai River Basin exports loads of approximately 629.3 t.a˗1 of TN and 433.7 t.a˗1 of organic N (Org-N) from the Bai River Basin land to the river. The TN and Org-N loads at the final destination in the Miyun Reservoir were 521.3 t.a˗1 and 100.3 t.a˗1, respectively. Of the exported TN and Org-N, 17.16% and 76.87%, respectively, were retained in the river network. Consequently, N transformation occurred in the Bai River, with nitrification–denitrification being particularly dominant. Nitrification was more evident in the nitrate-enriched river.
•Pollution risks persist in the Bai River during certain seasons.•Nitrification is more evident in the nitrate-enriched river.•Mainstream had a significant retention effect on the Organic N in the Bai River•Fertiliser is the dominant source of nitrate in the Bai River Basin
Acute respiratory distress syndrome (ARDS) is a complex cascade that develops from acute lung injury (ALI). Ginseng can be used to treat ALI/ARDS. Studies have shown that some of ingredients in ...ginseng had anti-inflammation, antioxidative, and immune regulation effects and can protect alveolar epithelial cells in mice. However, the potential targets, biological processes, and pathways related to ginseng against ALI/ARDS have not been investigated systematically. We employed network pharmacology, molecular docking, and animal experiments to explore the therapeutic effects and underlying mechanism of action of ginseng against ALI/ARDS. We identified 25 compounds using ultrahigh-performance liquid chromatography Q-Orbitrap mass spectrometry and their 410 putative targets through database analyses. Sixty-nine of them were considered to be key targets of ginseng against ALI/ARDS according to overlapping with ALI/ARDS-related targets and further screening in a protein-protein interaction (PPI) network. The phosphatidylinositol 3-kinase-protein kinase B (PI3K-AkT) and mitogen-activated protein kinase (MAPK) pathways were recognized to have critical roles for ginseng in ALI/ARDS treatment. Signal transducer and activator of transcription (STAT) 3, vascular endothelial growth factor A (VEGFA), fibroblast growth factor (FGF) 2, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), MAPK1, and interleukin (IL) 2 were the top six nodes identified by analyses of a compound-target-pathway network. Molecular docking showed that most of the ingredients in ginseng could combine well with the six nodes. Ginseng could reduce the pathologic damage, neutrophil aggregation, proinflammatory factors, and pulmonary edema in vivo and inhibit the PI3K-Akt signaling pathway and MAPK signaling pathway through downregulating expressions of STAT3, VEGFA, FGF2, PIK3CA, MAPK1, and IL2. Our study provides a theoretical basis for ginseng treatment of ALI/ARDS.
Recent evidence from our laboratory suggests that impeding ER stress–GSK3α/β signaling attenuates the progression and development of atherosclerosis in mouse model systems. The objective of this ...study was to determine if the tissue-specific genetic ablation of GSK3α/β could promote the regression of established atherosclerotic plaques. Five-week-old low-density lipoprotein receptor knockout (Ldlr−/−) mice were fed a high-fat diet for 16 weeks to promote atherosclerotic lesion formation. Mice were then injected with tamoxifen to induce macrophage-specific GSK3α/β deletion, and switched to standard diet for 12 weeks. All mice were sacrificed at 33 weeks of age and atherosclerosis was quantified and characterized. Female mice with induced macrophage-specific GSK3α deficiency, but not GSK3β deficiency, had reduced plaque volume (~25%) and necrosis (~40%) in the aortic sinus, compared to baseline mice. Atherosclerosis was also significantly reduced (~60%) in the descending aorta. Macrophage-specific GSK3α-deficient mice showed indications of increased plaque stability and reduced inflammation in plaques, as well as increased CCR7 and ABCA1 expression in lesional macrophages, consistent with regressive plaques. These results suggest that GSK3α ablation promotes atherosclerotic plaque regression and identify GSK3α as a potential target for the development of new therapies to treat existing atherosclerotic lesions in patients with cardiovascular disease.
Display omitted
•JBB, a formula containing ten edible herbs that against alcoholic liver injury.•JBB alleviates inflammation, oxidative stress, and apoptosis.•JBB regulates NFκB, KEAP1, and HIF1 ...pathways.
Alcoholic liver disease (ALD) is a liver injury caused by chronic or binge alcohol consumption. Jiubanban (JBB) is a 10-edible-herb- formula. The current study investigated the protective effects and mechanisms of JBB against chronic alcoholic liver injury. The results showed that JBB significantly alleviated chronic alcoholic liver injury caused by chronic-binge alcohol consumption. JBB accelerated ethanol metabolism and had a protective effect on both acute and chronic alcoholic liver injury. By modulating the NFκB, KEAP1, and HIF1 pathways, JBB was shown to reduce the production of cytokines (IL-6 and TNFα), enhanced the activity of anti-oxidative enzymes (SOD and GSH-px), reduced associated products (ROS and MDA), reversing inflammation, oxidative stress, and apoptosis. The study findings suggest that this functional herbal food combination may be a risk-free therapeutic strategy for treating ALD.
Esophageal cancer, a leading cause of cancer death worldwide, is associated with abnormal activation of the AKT signaling pathway. Xanthohumol, a prenylated flavonoid tested in clinical trials, is ...reported to exert anti‐diabetes, anti‐inflammation and anticancer activities. However, the mechanisms underlying its chemopreventive or chemotherapeutic effects remain elusive. In the present study, we found that xanthohumol directly targeted AKT1/2 in esophageal squamous cell carcinoma (ESCC). Xanthohumol significantly inhibited the AKT kinase activity in an ATP competitive manner, which was confirmed in binding and computational docking models. KYSE70, 450 and 510 ESCC cell lines highly express AKT and knockdown of AKT1/2 suppressed proliferation of these cells. Treatment with xanthohumol inhibited ESCC cell growth and induced apoptosis and cell cycle arrest at the G1 phase. Xanthohumol also decreased expression of cyclin D1 and increased the levels of cleaved caspase‐3, ‐7 and ‐PARP as well as Bax, Bims and cytochrome c in ESCC cells by downregulating AKT signaling targets, including glycogen synthase kinase 3 beta (GSK3β), mammalian target of rapamycin, and ribosomal protein S6 (S6K). Furthermore, xanthohumol decreased tumor volume and weight in patient‐derived xenografts (PDXs) that highly expressed AKT, but had no effect on PDXs that exhibited low expression of AKT in vivo. Kinase array results showed that xanthohumol treatment decreased phosphorylated p27 expression in both ESCC cell lines and PDX models. Taken together, our data suggest that the inhibition of ESCC tumor growth with xanthohumol is caused by targeting AKT. These results provide good evidence for translation toward clinical trials with xanthohumol.
What's new?
Esophageal squamous cell carcinoma (ESCC) is among the most common and deadliest forms of esophageal malignancy. Chemotherapy remains the mainstay of treatment, even though many ESCC patients experience disease progression despite therapy. Here, the authors investigated a novel agent for ESCC, the prenylated flavonoid xanthohumol. In ESCC cells, xanthohumol was found to directly target AKT kinase, inhibiting AKT activity, suppressing cell proliferation, and inducing apoptosis. In a patient‐derived xenograft mouse model, xanthohumol reduced tumor volume specifically in high AKT‐expressing tumors, with little effect on low AKT tumors. The data suggest that AKT targeting is a promising therapeutic strategy in ESCC.
It is usually believed that differentiated thyroid cancer is less likely to have distant metastases and rarely occurs secondary to hyperthyroidism. In our case report, we describe a patient diagnosed ...with thyroid fetal adenoma in 2002 who subsequently presented with a painful lump in her right rib. Through puncture biopsy, the mass was considered as metastatic follicular thyroid carcinoma, and then she appeared to have hyperthyroidism. The results of SPECT examination and other tests suggested that the hyperthyroidism was secondary to the thyroid cancer. The patient further underwent total thyroidectomy, and the pathology did not find any follicular thyroid foci. In this article, we analyze and discuss this case and review the relevant literature.
PDF
