Introduction
Glucose tolerance is often impaired in pulmonary tuberculosis (TB) patients. We aimed to explore the relationship between computed tomography (CT) findings of TB and blood glucose levels ...in diabetes mellitus (DM) patients.
Methods
763 diabetes mellitus patients with pulmonary tuberculosis (DMTB) from March 2015 to March 2018 were selected and their clinical data were retrospectively evaluated. CT appearance of DMTB was reviewed and compared according to blood glucose levels and CT scores. TB scores were calculated according to the combination of typical and atypical CT appearance. The relationship between blood glucose levels and CT scores was analyzed via Pearson correlation coefficient.
Results
TB lesions mainly occurred in the left lung and the lower lobes in the DMTB patients. Nodules and cavities are the main typical complications in these DMTB patients, and especially the number and size of cavities predominantly contribute to CT scan scores. The size of cavities (diameters (cm), median (95% CI of median)) was 0.72 (0.66–0.77), 1.20 (1.09–1.28), and 3.45 (2.92–3.94) from the low-, middle- and high-CT-score groups, respectively. The patients with high CT scores had a higher level of fasting plasma glucose (mean 13.48 mM, 95% CI of median 12.56–14.44 mM) than the patients in the low-CT-score (mean 8.73 mM, 95% CI of median 8.49–9.36 mM) and middle-CT-score groups (mean 10.16 mM, 95% CI of median 9.89–10.49 mM) (
P
< 0.0001). CT scores have a consistent relationship with the levels of blood glucose (rho = 0.60,
P
< 0.0001).
Conclusions
CT appearance stands for the severity of tuberculosis and is closely associated with blood glucose levels in diabetic TB patients.
Seat belt detection in intelligent transportation systems is an important research area, but the current algorithms for such systems are not very well developed. Existing methods are mostly based on ...edge detection and the Hough transform. However, there are many kinds of vehicles and background environments, which produce many possible edges; thus, these methods often produce false positives. We therefore propose a seat belt detection algorithm for complex road backgrounds based on multi-scale feature extraction using deep learning. We first extract multi-scale features from the regions of the labeled vehicle, windshield, and seat belt to train the detection models using convolution neural network (CNN). Then the coarse candidates of the vehicle, windshield, and seat belt in the test image are detected. For the accurate detection results, a post-processing is employed by using the detection scores as well as the relative positions of these vehicle components to train a classification model through support vector machine (SVM). Finally, we perform a fine mapping and identification process using this classification model on the seat belt region. This method performed well when applied to a database of images collected by road surveillance cameras.
Ubiquitin specific protease 7 (USP7) is one of the deubiquitinating enzymes (DUB) that erases ubiquitin and protects substrate protein from degradation. Full activity of USP7 requires the C-terminal ...Ub-like domains fold back onto the catalytic domain, allowing the remodeling of the active site to a catalytically competent state by the C-terminal peptide. Until now, numerous proteins have been identified as substrates of USP7, which play a key role in cell cycle, DNA repair, chromatin remodeling, and epigenetic regulation. Aberrant activation or overexpression of USP7 may promote oncogenesis and viral disease, making it a target for therapeutic intervention. Currently, several synthetic small molecules have been identified as inhibitors of USP7, and applied in the treatment of diverse diseases. Hence, USP7 may be a promising therapeutic target for the treatment of cancer.
Obesity is a high risk factor for colorectal cancer (CRC). The contribution of underlying epigenetic mechanisms to CRC and the precise targets of epigenetic alterations during cancer development are ...largely unknown. Several types of epigenetic processes have been described, including DNA methylation, histone modification, and microRNA expression. To investigate the relationship between obesity and CRC, we studied both obese and CRC patients, focusing on genome-wide peripheral blood DNA methylation alterations. Our results show abnormal distributions of overlapping differentially methylated regions (DMRs) such as hypermethylated CpG islands, which may account for epigenetic instability driving cancer initiation in obesity patients. Furthermore, functional analysis suggests that altered DNA methylation of extracellular (e.g., O-glycan processing) and intracellular components contribute to activation of oncogenes (e.g. KRAS and SCL2A1) and suppression of tumor suppressors (e.g. ARHGEF4, EPHB2 and SOCS3), leading to increased oncogenic potency. Our study demonstrates how DNA methylation changes in obesity contribute to CRC development, providing direct evidence of an association between obesity and CRC. It also reveals the diagnostic potential of using DNA methylation as an early risk evaluation to detect patients with high risk for CRC.
The mammalian Phospholipase D MitoPLD facilitates mitochondrial fusion by generating the signaling lipid phosphatidic acid (PA). The
Drosophila MitoPLD homolog Zucchini (Zuc), a proposed cytoplasmic ...nuclease, is required for piRNA generation, a critical event in germline development. We show that Zuc localizes to mitochondria and has MitoPLD-like activity. Conversely,
MitoPLD
−/− mice exhibit the meiotic arrest, DNA damage, and male sterility characteristic of mice lacking piRNAs. The primary function of MitoPLD seems to be the generation of mitochondrial-surface PA. This PA in turn recruits the phosphatase Lipin 1, which converts PA to diacylglycerol and promotes mitochondrial fission, suggesting a mechanism for mitochondrial morphology homeostasis. MitoPLD and Lipin 1 have opposing effects on mitochondria length and on intermitochondrial cement (nuage), a structure found between aggregated mitochondria that is implicated in piRNA generation. We propose that mitochondrial-surface PA generated by MitoPLD/Zuc recruits or activates nuage components critical for piRNA production.
► MitoPLD/Zuc generate the lipid phosphatidic acid (PA) on the mitochondrial surface ► This PA recruits the phosphatase Lipin 1, which converts the PA to diacylglycerol ► MitoPLD and Lipin 1 exert opposing effects on mitochondria and on germline nuage ►
MitoPLD
−/− spermatocytes exhibit disaggregated mitochondria and meiotic arrest
Ischemic/reperfusion (I/R) injury is the primary cause of acute kidney injury (AKI). Gastrin, a gastrointestinal hormone, is involved in the regulation of kidney function of sodium excretion. ...However, whether gastrin has an effect on kidney I/R injury is unknown. Here we show that cholecystokinin B receptor (CCKBR), the gastrin receptor, was significantly up-regulated in I/R-injured mouse kidneys. While pre-administration of gastrin ameliorated I/R-induced renal pathological damage, as reflected by the levels of serum creatinine and blood urea nitrogen, hematoxylin and eosin staining and periodic acid-Schiff staining. The protective effect could be ascribed to the reduced apoptosis for gastrin reduced tubular cell apoptosis both
and
.
studies also showed gastrin preserved the viability of hypoxia/reoxygenation (H/R)-treated human kidney 2 (HK-2) cells and reduced the lactate dehydrogenase release, which were blocked by CI-988, a specific CCKBR antagonist. Mechanistically, the PI3K/Akt/Bad pathway participates in the pathological process, because gastrin treatment increased phosphorylation of PI3K, Akt and Bad. While in the presence of wortmannin (1 μM), a PI3K inhibitor, the gastrin-induced phosphorylation of Akt after H/R treatment was blocked. Additionally, wortmannin and Akt inhibitor VIII blocked the protective effect of gastrin on viability of HK-2 cells subjected to H/R treatment. These studies reveals that gastrin attenuates kidney I/R injury via a PI3K/Akt/Bad-mediated anti-apoptosis signaling. Thus, gastrin can be considered as a promising drug candidate to prevent AKI.
KDM5B (also known as PLU-1 and JARID1B) is 2-oxoglutarate and Fe2+ dependent oxygenase that acts as a histone H3K4 demethylase, which is a key participant in inhibiting the expression of tumor ...suppressors as a drug target. Here, we present the discovery of pyrazole derivatives compound 5 by structure-based virtual screening and biochemical screening with IC50 of 9.320 μM against KDM5B, and its subsequent optimization to give 1-(4-methoxyphenyl)-N-(2-methyl-2-morpholinopropyl)-3-phenyl-1H-pyrazole-4-carboxamide (27 ab), a potent KDM5B inhibitor with IC50 of 0.0244 μM. In MKN45 cells, compound 27 ab can bind and stabilize KDM5B and induce the accumulation of H3K4me2/3, bona fide substrates of KDM5B, while keep the amount of H3K4me1, H3K9me2/3 and H3K27me2 without change. Further biological study also indicated that compound 27 ab is a potent cellular active KDM5B inhibitor that can inhibit MKN45 cell proliferation, wound healing and migration. In sum, our finding gives a novel structure for the discovery of KDM5B inhibitor and targeting KDM5B may be a new therapeutic strategy for gastric cancer treatment.
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•Pyrazole derivatives were discovered as novel KDM5B inhibitors.•35 compounds were synthesized and studied on their KDM5B inhibitory activities for SARs.•Compound 27 ab is a potent and cellular active KDM5B inhibitor that can inhibit MKN45 cell proliferation and migration.
Extracellular vesicles (EVs) carry signals within or at their limiting membranes, providing a mechanism by which cells can exchange more complex information than what was previously thought. In ...addition to mRNAs and microRNAs, there are DNA fragments in EVs. Solexa sequencing indicated the presence of at least 16434 genomic DNA (gDNA) fragments in the EVs from human plasma. Immunofluorescence study showed direct evidence that acridine orange-stained EV DNAs could be transferred into the cells and localize to and inside the nuclear membrane. However, whether the transferred EV DNAs are functional or not is not clear. We found that EV gDNAs could be homologously or heterologously transferred from donor cells to recipient cells, and increase gDNA-coding mRNA, protein expression, and function (e.g. AT1 receptor). An endogenous promoter of the AT1 receptor, NF-κB, could be recruited to the transferred DNAs in the nucleus, and increase the transcription of AT1 receptor in the recipient cells. Moreover, the transferred EV gDNAs have pathophysiological significance. BCR/ABL hybrid gene, involved in the pathogenesis of chronic myeloid leukemia, could be transferred from K562 EVs to HEK293 cells or neutrophils. Our present study shows that the gDNAs transferred from EVs to cells have physiological significance, not only to increase the gDNA-coding mRNA and protein levels, but also to influence function in recipient cells.
This study aimed to delineate the diagnostic significance of miR-182-5p by investigating its influence on myocardial apoptosis and function, employing both in vivo and in vitro myocardial infarction ...models.
A rat myocardial infarction model was established. Myocardial infarction area was detected using the 2,3,5-chlorotriphenyltetrazolium (TTC) method, myocardial enzyme spectrums were measured using enzyme-linked immunosorbent assay (ELISA), myocardial structure was detected by hematoxylin and eosin (HE) staining, myocardial apoptosis was detected using the TUNEL method, and expression levels of miR-182-5p and apoptosis-related molecules were detected using real-time fluorescence quantitative PCR (qPCR) and Western blot. miR-182-5p mimics and inhibitor were transfected into rat H9C2 cardiomyocytes and mouse HL-1 cardiomyocytes to establish a hypoxia model. Cardiomyocyte viability was detected using the CCK-8 method, expression levels of apoptosis-related indicators were detected using Western blot, and caspase-3/7 activity was detected using a caspase-3/7 activity detection kit. AAV9 adeno-associated virus was used to construct an miR-182-5p overexpression virus, which was injected into mice through the tail vein to create a mouse myocardial infarction model. TTC, ELISA, HE staining, echocardiography, real-time fluorescence qPCR, and Western blot methods were used to detect the effects of AAV9-miR-182-5p on myocardial injury, myocardial function, and myocardial apoptosis levels in myocardial infarction.
The rat model displayed reduced miR-182-5p expression concurrent with an increase in apoptosis. The in vitro H9C2 and HL-1 hypoxia models revealed that miR-182-5p augmented the hypoxia-induced decrease in myocardial cell viability, suppressed Bcl-2 expression, and increased Bax, Bnip3, and caspase-3/7 activity levels. The injection of AAV9-miR-182-5p significantly exacerbated myocardial tissue damage, impaired myocardial function, and enhanced apoptosis.
miR-182-5p escalates myocardial injury during myocardial infarction by fostering apoptosis. Interventions that aim to reduce miR-182-5p levels might be crucial in halting the progression of myocardial infarction.
Curcumin exerts beneficial effects on cardiovascular diseases, including hypertension. However, its mechanisms are unknown. We propose that curcumin prevents the development of hypertension by ...regulating AT1 receptor (AT1R) expression in arteries. The present study examined how curcumin regulates AT1R expression in vascular smooth muscle cells and investigated the physiological significance of this regulation in angiotensin (Ang) II-induced hypertension. The results showed that curcumin decreased AT1R expression in a concentration- and time-dependent manner in vascular smooth muscle cells. Using luciferase reporters with an entire AT1 or a mutant AT1R in A10 cells, the AT1R promoter activity was inhibited by 10(-6 )M curcumin, and the proximal element (from -61 to +25 bp) of the AT1R promoter was crucial for curcumin-induced AT1R down-regulation. An electrophoretic mobility shift assay showed that curcumin decreased specificity protein 1 (SP1) binding with the AT1R promoter in A10 cells. Curcumin treatment reduced Ang II-induced hypertension in C57Bl/6J mice, which was accompanied by lower AT1R expression in the arteries and decreased Ang II-mediated vasoconstriction in the mesenteric artery. These findings indicate that curcumin down-regulates AT1R expression in A10 cells by affecting SP1/AT1R DNA binding, thus reducing AT1R-mediated vasoconstriction and subsequently prevents the development of hypertension in an Ang II-induced hypertensive model.
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