Polypeptide N-Acetylgalactosaminyltransferase 14 (GALNT14) as a Chemosensitivity-Related Biomarker for Osteosarcoma.

Purpose: Osteosarcoma is the most common primary bone tumor. Polypeptide N-acetylgalactosaminyltransferase 14 (GALNT14), a member of the N-acetylgalactosaminyltransferase family, has been considered to be associated with various cancers. However, its role in osteosarcoma remains unknown. Here, we aimed to explore the expression and potential mechanism of GALNT14 in osteosarcoma through bioinformatics analysis and in vitro experiments. Methods: We investigated GALNT14 expression in osteosarcoma using GEO, the TIMER database, and clinical samples. Protein-protein interaction (PPI) network analysis on GALNT14 was performed by STRING. TARGET was used to identify differentially expressed genes (DEGs) between high and low GALNT14 expression. The correlation between GALNT14 and cuproptosis-related genes in osteosarcoma was analyzed by R language. The prognostic significance of GALNT14 was examined by Kaplan-Meier survival analysis. Additionally, we inhibited GALNT14 function in an osteosarcoma cell line by transfecting siRNA and subsequently explored the effect on drug sensitivity by CCK-8, clonogenic assay, and flow cytometry. Results: GALNT14 was significantly elevated in osteosarcoma tissue, osteosarcoma cell lines, and metastatic osteosarcoma. PPI analysis revealed that GALNT14 was associated with MUC7, MUC13, MUC5AC, C1GALT1, MUC15, MUC16, MUC1, MUC4, MUC21, and MUC17. In the high GALNT14 expression group, we discovered 81 upregulated DEGs and 73 downregulated DEGs. Functional enrichment analysis of DEGs showed significant enrichment in the Wnt, TGF-ß, Hippo, PI3K signaling pathways and cell adhesion molecules. Expression of cuproptosis-related genes was closely related in osteosarcoma, and GALNT14 expression was significantly positively correlated with FDX1, a key regulator of cuproptosis. Kaplan-Meier survival showed that GALNT14 was linked to poor overall survival and disease-free survival in osteosarcoma. In vitro experiments suggested that GALNT14 was associated with chemotherapy resistance in osteosarcoma. Conclusion: We identified a GALNT family gene, GALNT14, that was highly expressed in osteosarcoma. This gene was closely associated with metastasis, progression, cuproptosis-related genes, and chemosensitivity of osteosarcoma, and showed correlation with poor overall survival and disease-free survival in osteosarcoma.

Glutathione-modified graphene quantum dots as fluorescent probes for detecting organophosphorus pesticide residues in Radix Angelica Sinensis.

A novel fluorescent sensor was developed in this study based on glutathione-functionalized graphene quantum dots (GQDs@GSH) to detect organophosphorus pesticide residues in Radix Angelica Sinensis. GQDs@GSH was synthesized by a one-step pyrolysis method with a fluorescence quantum yield as high as 33.9% and its structure was characterized by transmission electron microscopy and X-ray photoelectron spectroscopy. GQDs@GSH exhibited excellent fluorescence property showing strong blue fluorescence under UV irradiation. The fluorescence of GQDs@GSH could be quenched by Fe3+ by electron transfer and the quenched fluorescence could be recovered due to the strong chelating and reducing ability of phytic acid (PA). Under the catalyzation of acetylcholinesterase (AChE) and choline oxidase (ChOx), acetylcholine (ACh) could be decomposed to H2O2, which could further oxidize Fe2+ to Fe3+ thus quenching the fluorescence of GQDs@GSH once again. Coumaphos, a kind of organophosphorus pesticide, could inhibit AChE activity, thus making the quenched fluorescence turn on again. Several parameters influencing the fluorescence response such as Fe3+, PA, ACh and coumaphos concentration, pH value and reaction time were optimized. Based on such a fluorescence "off-on-off-on" ngkmechanism, GQDs@GSH was successfully applied to the detection of coumaphos in Radix Angelica Sinensis. A good linear relationship between the fluorescence intensity and coumaphos concentration was obtained in the range of 0.1-10.0 µmol·L-1. By a standard addition method, the recoveries were measured to be 101.44-117.90% with RSDs lower than 1.98%. The biosensor system is simple, sensitive and accurate. It has a good application prospect in the detection of organophosphorus pesticide residues in traditional Chinese medicine and agricultural products, and also expanded the application scope for glutathione as a highly selective biological molecule.

SNX10 gene mutation in infantile malignant osteopetrosis: A case report and literature review. / SNX10åŸºå› çªå˜è‡´å©´å„¿æ¶æ€§çŸ³éª¨ç—‡1ä¾‹å¹¶æ–‡çŒ®å¤ä¹ .

A case of SNX10 gene mutation in a patient with infantile malignant osteopetrosis (IMO) was admitted to Department of Pediatrics, Third Xiangya Hospital, Central South University. The patient had the symptom of anemia, hepatosplenomegaly and growth retardation. The X-ray examination suggested extensive increase of bone density throughout the body, which was clinically diagnosed as IMO. The homozygous mutation of SNX10 gene c.61C>T was found via gene sequencing. We reviewed the relevant literatures and found that anemia, visual and hearing impairment, hepatosplenomegaly are the main clinical symptoms of IMO, SNX10 gene mutation is a rare cause of IMO, and hematopoietic stem cell transplantation is an effective treatment.

Lactate accelerates vascular calcification through NR4A1-regulated mitochondrial fission and BNIP3-related mitophagy.

Arterial media calcification is related to mitochondrial dysfunction. Protective mitophagy delays the progression of vascular calcification. We previously reported that lactate accelerates osteoblastic phenotype transition of VSMC through BNIP3-mediated mitophagy suppression. In this study, we investigated the specific links between lactate, mitochondrial homeostasis, and vascular calcification. Ex vivo, alizarin S red and von Kossa staining in addition to measurement of calcium content, RUNX2, and BMP-2 protein levels revealed that lactate accelerated arterial media calcification. We demonstrated that lactate induced mitochondrial fission and apoptosis in aortas, whereas mitophagy was suppressed. In VSMCs, lactate increased NR4A1 expression, leading to activation of DNA-PKcs and p53. Lactate induced Drp1 migration to the mitochondria and enhanced mitochondrial fission through NR4A1. Western blot analysis of LC3-II and p62 and mRFP-GFP-LC3 adenovirus detection showed that NR4A1 knockdown was involved in enhanced autophagy flux. Furthermore, NR4A1 inhibited BNIP3-related mitophagy, which was confirmed by TOMM20 and BNIP3 protein levels, and LC3-II co-localization with TOMM20. The excessive fission and deficient mitophagy damaged mitochondrial structure and impaired respiratory function, determined by mPTP opening rate, mitochondrial membrane potential, mitochondrial morphology under TEM, ATP production, and OCR, which was reversed by NR4A1 silencing. Mechanistically, lactate enhanced fission but halted mitophagy via activation of the NR4A1/DNA-PKcs/p53 pathway, evoking apoptosis, finally accelerating osteoblastic phenotype transition of VSMC and calcium deposition. This study suggests that the NR4A1/DNA-PKcs/p53 pathway is involved in the mechanism by which lactate accelerates vascular calcification, partly through excessive Drp-mediated mitochondrial fission and BNIP3-related mitophagy deficiency.

Investigation of the pharmacodynamic substances in dahuang zhechong pill that inhibit energy metabolism.

ETHNOPHARMACOLOGICAL RELEVANCE: Dahuang Zhechong pill (DHZCP) is a commonly used traditional Chinese medicine for the treatment of hepatocarcinoma. AIM OF THE STUDY: Previous studies have found that DHZCP can exert anti-hepatocarcinoma effects and reverse drug resistance by inhibiting energy metabolism. The goal of this study was to further explore the pharmacodynamic substances that inhibit energy metabolism. METHODS: The components of DHZCP absorbed into plasma were identified by UHPLC-Q-TOF-MS/MS. The Swiss and STITCH databases were used for target collection. The DAVID database was used for pathway enrichment analysis. Cytoscape software was used for network construction. The CCK-8 method detected cell viability. Chemiluminescence was used to detect ATP levels. RESULTS: A total of 89 components absorbed into plasma were identified by UHPLC-Q-TOF-MS/MS. Based on this, 24 potential pharmacodynamic substances were selected by network pharmacology. Among them, 11 components such as rhein can significantly inhibit ATP levels. CONCLUSIONS: Rhein, emodin, chrysophanol, hypoxanthine, baicalein, baicalin, wogonoside, acteoside, formononetin, isoliquiritigenin, and glycyrrhizic acid were the pharmacodynamic substances responsible for inhibition of energy metabolism of DHZCP.

Lactate accelerates calcification in VSMCs through suppression of BNIP3-mediated mitophagy.

Arterial media calcification is one of the major complications of diabetes mellitus, which is related to oxidative stress and apoptosis. Mitophagy is a special regulation of mitochondrial homeostasis and takes control of intracellular ROS generation and apoptotic pathways. High circulating levels of lactate usually accompanies diabetes. The potential link between lactate, mitophagy and vascular calcification is investigated in this study. Lactate treatment accelerated VSMC calcification, evaluated by measuring the calcium content, ALP activity, RUNX2, BMP-2 protein levels, and Alizarin red S staining. Lactate exposure caused excessive intracellular ROS generation and VSMC apoptosis. Lactate also impaired mitochondrial function, determined by mPTP opening rate, mitochondrial membrane potential and mitochondrial biogenesis markers. Western blot analysis of LC3-II and p62 and mRFP-GFP-LC3 adenovirus detection for autophagy flux revealed that lactate blocked autophagy flux. LC3-II co-staining with LAMP-1 and autophagosome quantification revealed lactate inhibited autophagy. Furthermore, lactate inhibited mitophagy, which was confirmed by TOMM20 and BNIP3 protein levels, LC3-II colocalization with BNIP3 and TEM assays. In addition, BNIP3-mediated mitophagy played a protective role against VSMC calcification in the presence of lactate. This study suggests that lactate accelerates osteoblastic phenotype transition of VSMC and calcium deposition partly through the BNIP3-mediated mitophagy deficiency induced oxidative stress and apoptosis.

Impact of smoking on all-cause mortality and cardiovascular events in patients after coronary revascularization with a percutaneous coronary intervention or coronary artery bypass graft: a systematic review and meta-analysis.

Although cigarette smoking is an independent risk factor for cardiovascular disease, inconsistent results have been published in the literature on its impacts on the cardiovascular health of patients after coronary revascularization with a percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG). We performed a comprehensive electronic database search through July 2018. Studies reporting the risk estimates of all-cause mortality and cardiovascular outcomes in patients after coronary revascularization with PCI or CABG on the basis of smoking status were selected. Multivariate-adjusted relative risks (RRs) and 95% confidence intervals (CIs) were pooled using random-effects models with inverse variance weighting. Data from 37 records including 126 901 participants were finally collected. Overall, the pooled RR (95% CI) associated with cigarette smoking was 1.26 (95% CI: 1.09-1.47) for all-cause mortality, 1.08 (95% CI: 0.92-1.28) for major adverse cardiovascular events, 0.96 (95% CI: 0.69-1.35) for cardiovascular mortality and 1.15 (95% CI: 0.81-1.64) for myocardial infarction. The increased risk of all-cause mortality was also observed in former smokers compared with those who had never smoked (RR: 1.19; 95% CI: 1.03-1.38). Furthermore, the negative effects of cigarette smoking on all-cause mortality were also observed in most subgroups. Cigarette smoking has been shown to increase the likelihood of all-cause mortality in patients after coronary revascularization with PCI or CABG. Smoking cessation is essential for PCI or CABG patients to manage their coronary artery disease.

Advanced glycation end products accelerate calcification in VSMCs through HIF-1α/PDK4 activation and suppress glucose metabolism.

Arterial media calcification is associated with diabetes mellitus. Previous studies have shown that advanced glycation end products (AGEs) are responsible for vascular smooth muscle cell (VSMC) calcification, but the underlying mechanisms remain unclear. Hypoxia-inducible factor-1α (HIF-1α), one of the major factors during hypoxia, and pyruvate dehydrogenase kinase 4 (PDK4), an important mitochondrial matrix enzyme in cellular metabolism shift, have been reported in VSMC calcification. The potential link among HIF-1α, PDK4, and AGEs-induced vascular calcification was investigated in this study. We observed that AGEs elevated HIF-1α and PDK4 expression levels in a dose-dependent manner and that maximal stimulation was attained at 24 h. Two important HIF-1α-regulated genes, vascular endothelial growth factor A (VEGFA) and glucose transporter 1 (GLUT-1), were significantly increased after AGEs exposure. Stabilization or nuclear translocation of HIF-1α increased PDK4 expression. PDK4 inhibition attenuated AGEs-induced VSMC calcification, which was evaluated by measuring the calcium content, alkaline phosphatase (ALP) activity and runt-related transcription factor 2 (RUNX2) expression levels and by Alizarin red S staining. In addition, the glucose consumption, lactate production, key enzymes of glucose metabolism and oxygen consumption rate (OCR) were decreased during AGEs-induced VSMC calcification. In conclusion, this study suggests that AGEs accelerate vascular calcification partly through the HIF-1α/PDK4 pathway and suppress glucose metabolism.

Involvement of brain-derived neurotrophic factor in exercise­induced cardioprotection of post-myocardial infarction rats.

Exercise induces a number of benefits, including angiogenesis in post­myocardial infarction (MI); however, the underlying mechanisms have not been fully clarified. Neurotrophic brain­derived neurotrophic factor (BDNF) serves a protective role in certain adult cardiac diseases through its specific receptor, BDNF/NT­3 growth factors receptor (TrkB). The present study explored the mechanisms by which exercise improves cardiac function, with a focus on the involvement of the BDNF/TrkB axis. MI rats were assigned to Sham, sedentary, exercise, exercise with K252a (a TrkB inhibitor), and exercise with NG­nitro­L­arginine methyl ester (L­NAME) groups. The exercise group was subjected to 8 weeks of treadmill running. The results demonstrated that the rats in the exercise group exhibited increased myocardial angiogenesis and improved cardiac function, which was attenuated by K252a. Exercise induced activation of the BDNF/TrkB axis in the ischaemic myocardium and increased serum BDNF levels were abated by exposure to L­NAME. Improvements in angiogenesis and left ventricular function exhibited a positive association, with changes in serum BDNF. In the in vitro experiments, human umbilical vein endothelial cells were exposed to shear stress (SS) of 12 dyn/cm2 to mimic the effects of exercise training on vascular tissue. An increased tube­forming capacity, and a nitric oxide (NO)­dependent prolonged activation of the BDNF/TrkB­full­length axis over 12 h, but not the TrkB­truncated axis, was observed. The SS­related angiogenic response was attenuated by TrkB inhibition. Overall, these results demonstrate that exercise confers certain aspects of its cardioprotective effects through the activation of the BDNF/TrkB axis in an NO­dependent manner, a process in which fluid­induced SS may serve a crucial role.

Association of genetic polymorphisms in vascular endothelial growth factor with susceptibility to coronary artery disease: a meta-analysis.

BACKGROUND: Single nucleotide polymorphisms (SNPs) located in the vascular endothelial growth factor (VEGF) gene may be correlated with the susceptibility to coronary artery disease (CAD) - although results have been controversial. The aim of this meta-analysis is to clarify the effects of VEGF -2578A/C (rs699947), -1154G/A (rs1570360), +405C/G (rs2010963), and + 936C/T (rs3025039) polymorphisms on CAD risk. METHODS: Pooled odds ratio (OR) and corresponding 95% confidence intervals (CIs) were calculated to estimate the strength of the association between VEGF gene polymorphisms and CAD risk. Fixed- or random-effects model was used depending on the heterogeneity between studies. RESULTS: In total, 13 eligible articles containing 29 studies were analysed. The pooled analysis indicated that the VEGF gene polymorphisms of rs699947, rs2010963, and rs3025039 were associated with an increased risk of CAD, whereas no significant associations were observed with the rs1570360 polymorphism. A subgroup analysis stratified by ethnicity revealed that the rs699947 and rs3025039 polymorphisms were associated with CAD risk in Asian populations. In addition, stratification by control source indicated an increased risk of CAD susceptibility with the rs699947 polymorphism for population-based studies of reduced heterogeneity. CONCLUSIONS: In summary, we concluded that the VEGF gene polymorphisms rs699947, rs2010963, and rs3025039 are correlated with an elevated CAD risk.

Comparative efficacy of pharmacological interventions for contrast-induced nephropathy prevention after coronary angiography: a network meta-analysis from randomized trials.

BACKGROUND: Contrast-induced nephropathy (CIN) is the major complication related to contrast media administration in patients after coronary angiography (CAG). However, inconsistent results have been published in the literature regarding the effects of pharmacological drugs on CIN prevention. We conducted a network meta-analysis to evaluate the relative efficacy of pharmacological interventions for the prevention of CIN. METHODS: We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from inception to July 2017. We included any randomized controlled trials of eleven pharmacological interventions that reported the prevention of CIN. RESULTS: We identified 3850 records through database searches, of which 107 studies comprising 21,450 participants were finally identified. Compared with intravenous saline, intravenous saline plus pharmacological drugs including statin [relative risk (RR) 0.57; 95% credibility interval (CrI) 0.39 to 0.83], N-acetylcysteine (NAC) (RR 0.84; 95% CrI, 0.71 to 0.98), vitamin and its analogues (RR 0.66; 95% CrI 0.45 to 0.97), brain natriuretic peptide (BNP) and its analogues (RR 0.46; 95% CrI 0.30 to 0.70), prostaglandin analogues (RR 0.37; 95% CrI 0.18 to 0.76), NAC plus sodium bicarbonate (SB) (RR 0.60; 95% CrI 0.39 to 0.90), and statin plus NAC (RR 0.39; 95% CrI 0.21 to 0.70), have helped to reduce the incidence of CIN in patients after CAG. The top four ranked treatments were statin plus NAC, BNP and its analogues, statin, and vitamin and its analogues, respectively. NAC plus intravenous saline was associated with lower incidence of short-term all-cause mortality than intravenous saline alone (RR 0.62; 95% CI, 0.40 to 0.96; P = 0.03). However, no evidence indicated that any of the pharmacological drugs were associated with a reduced requirement for dialysis and major adverse cardiac and cerebrovascular events (MACCE). CONCLUSIONS: Statin plus NAC plus intravenous saline seems to be the most effective treatment for the prevention of CIN in patients after CAG. NAC plus intravenous saline may have a protective role against short-term all-cause mortality. However, none of these drugs has effectively decreased the requirement for dialysis and MACCE.

Acetolactate Synthase-Inhibiting Gametocide Amidosulfuron Causes Chloroplast Destruction, Tissue Autophagy, and Elevation of Ethylene Release in Rapeseed.

Background: Acetolactate synthase (ALS)-inhibiting herbicides amidosulfuron (Hoestar) is an efficient gametocide that can induce male sterility in rapeseed (Brassica napus L.). We conducted an integrated study of cytological, transcriptomic, and physiological analysis to decipher the gametocidal effect of amidosulfuron. Results: In the first several days after exposure to amidosulfuron at a gametocidal dose of ca. 1 µg per plant, the plants showed the earliest symptoms including short retard of raceme elongation, slight chlorosis on leaf, and decrease of photosynthesis rate. Chloroplasts in leaf and anther epidermis, and tapetal plastids were deformed. Both tapetal cell and uni-nucleate microspore showed autophagic vacuoles and degenerated quickly. The amidosulfuron treatment caused reduction of photosynthetic rate and the contents of leaf chlorophyll, soluble sugar and pyruvate, as well as content alteration of several free amino acids in the treated plants. A comparison of transcriptomic profiling data of the young flower buds of the treated plants with the control identified 142 up-regulated and 201 down-regulated differential expression transcripts with functional annotations. Down-regulation of several interesting genes encoding PAIR1, SDS, PPD2, HFM1, CSTF77, A6, ALA6, UGE1, FLA20, A9, bHLH91, and putative cell wall protein LOC106368794, and up-regulation of autophagy-related protein ATG8A indicated functional abnormalities about cell cycle, cell wall formation, chloroplast structure, and tissue autophagy. Ethylene-responsive transcription factor RAP2-11-like was up-regulated in the flower buds and ethylene release rate was also elevated. The transcriptional regulation in the amidosulfuron-treated plants was in line with the cytological and physiological changes. Conclusions: The results suggested that metabolic decrease related to photosynthesis and energy supply are associated with male sterility induced by amidosulfuron. The results provide insights into the molecular mechanisms of gametocide-induced male sterility and expand the knowledge on the transcriptomic complexity of the plants exposure to sulfonylurea herbicide.