Deregulated cellular metabolism is a hallmark of tumors. Cancer cells increase glucose and glutamine flux to provide energy needs and macromolecular synthesis demands. Several studies have been ...focused on the importance of glycolysis and pentose phosphate pathway. However, a neglected but very important branch of glucose metabolism is the hexosamine biosynthesis pathway (HBP). The HBP is a branch of the glucose metabolic pathway that consumes ∼2–5% of the total glucose, generating UDP-GlcNAc as the end product. UDP-GlcNAc is the donor substrate used in multiple glycosylation reactions. Thus, HBP links the altered metabolism with aberrant glycosylation providing a mechanism for cancer cells to sense and respond to microenvironment changes. Here, we investigate the changes of glucose metabolism during epithelial mesenchymal transition (EMT) and the role of O-GlcNAcylation in this process. We show that A549 cells increase glucose uptake during EMT, but instead of increasing the glycolysis and pentose phosphate pathway, the glucose is shunted through the HBP. The activation of HBP induces an aberrant cell surface glycosylation and O-GlcNAcylation. The cell surface glycans display an increase of sialylation α2–6, poly-LacNAc, and fucosylation, all known epitopes found in different tumor models. In addition, modulation of O-GlcNAc levels was demonstrated to be important during the EMT process. Taken together, our results indicate that EMT is an applicable model to study metabolic and glycophenotype changes during carcinogenesis, suggesting that cell glycosylation senses metabolic changes and modulates cell plasticity.
Growing evidences indicate that aberrant glycosylation can modulate tumor cell invasion and metastasis. The process termed "epithelial-mesenchymal transition" (EMT) provides a basic experimental ...model to shed light on this complex process. The EMT involves a striking decline in epithelial markers, accompanied by enhanced expression of mesenchymal markers, culminating in cell morphology change and increased cell motility. Few recent studies have established the participation glycosylation during EMT. Studies now come into knowledge brought to light the involvement of a site-specific O-glycosylation in the IIICS domain of human oncofetal fibronectin (onfFN) during the EMT process. Herein we show that high glucose induces EMT in A549 cells as demonstrated by TGF-β secretion, cell morphology changes, increased cellular motility and the emergence of mesenchymal markers. The hyperglycemic conditions increased onfFN protein levels, promoted an up regulation of mRNA levels for ppGalNAc-T6 and FN IIICS domain, which contain the hexapeptide (VTHPGY) required for onfFN biosynthesis. Glucose effect involves hexosamine (HBP) biosynthetic pathway as overexpression of glutamine: fructose-6-phosphate amidotransferase increases mesenchymal markers, onfFN levels and mRNA levels for FN IIICS domain. In summary, our results demonstrate, for the first time that the metabolism of glucose through HBP promotes O-glycosylation of the oncofetal form of FN during EMT modulating tumorogenesis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hypertensive individuals are at greater risk for developing chronic kidney disease (CKD). Reducing proteinuria has been suggested as a possible therapeutic approach to treat CKD. However, the ...mechanisms underlying the development of proteinuria in hypertensive conditions are incompletely understood. Cardiac and vascular dysfunction is associated with changes in the O-GlcNAcylation pathway in hypertensive models. We hypothesized that O-GlcNAcylation is also involved in renal damage, especially development of proteinuria, associated with hypertension. Using the spontaneously hypertensive rat (SHR) model, we observed higher renal cortex O-GlcNAcylation, glutamine–fructose aminotransferase (GFAT), and O-GlcNAc transferase (OGT) protein expression, which positively correlated with proteinuria. Interestingly, this was observed in hypertensive, but not pre-hypertensive, rats. Pharmacological inhibition of GFAT decreased renal cortex O-GlcNAcylation, proteinuria, and albuminuria in SHR. Using a proximal tubule cell line, we observed that increased O-GlcNAcylation reduced megalin surface expression and albumin endocytosis in vitro, and the effects were correlated in vivo. Moreover, megalin is O-GlcNAcylated both in vitro and in vivo. In conclusion, our results demonstrate a new mechanism involved in hypertension-associated proteinuria.
Background and Aim:
Talc poudrage has been used since many years for sclerosing chronic pleural effusion. Several reports have shown good results managing chronic seromas after breast, vascular, and ...incisional hernia surgeries. The purpose of this study is to determine the utility of talc seromadesis for the management of chronic seromas after incisional hernia surgery
Materials and Methods:
Multicentric prospective observational study including patients diagnosed of chronic seromas after incisional hernia surgery. Under local anesthesia and ultrasonographic control, two percutaneous trocars were placed in the seroma, washing the seroma cavity with 0.9% saline solution and aspirating the remaining liquid. A sample of 4 g of talcum powder was introduced in the seroma cavity, and a 15-F drain was left in place. Patients were followed each week during at least 4 weeks after drainage removal.
Results:
Between January 2013 and December 2016, a total of six patients were enrolled in the study. Talc poudrage was performed without any complications. Drains were pulled out in a mean time of 3 (range: 2–4) weeks. One case of the chronic seromas was efficiently sclerosed with talc without recurrence in time. In three cases, the seroma recurred, and the final solution was surgical decortication of the seroma. In the other two cases, seroma also recurred and were managed with instillation of ethanol and iodine povidone.
Conclusion:
In our experience, the management of chronic seromas after incisional hernia repair with talc seromadesis is ineffective and is associated with a high rate of seroma recurrence.
In this randomized, multicenter, controlled, double‐blind, sequential trial, 381 patients undergoing primary total knee replacement were randomly assigned to receive subcutaneous injections of either ...3500 IU anti‐factor Xa of bemiparin sodium, first dose 6 h after surgery, or 40 mg of enoxaparin, first dose 12 h before surgery, followed by daily doses for 10 ± 2 days, for the prophylaxis of venous thromboembolism. The primary efficacy endpoint was venous thromboembolism up to postoperative day 10 ± 2, defined as deep vein thrombosis detected by mandatory bilateral venography, documented symptomatic deep vein thrombosis and/or documented symptomatic pulmonary embolism. The primary safety endpoint was major bleeding. Eighty‐seven percent of all randomized patients (333 of 381 patients) were evaluable for efficacy. The incidence of venous thromboembolism was 32.1% (53 of 165 patients) in the bemiparin group and 36.9% (62 of 168 patients) in the enoxaparin group. The absolute risk difference was 4.8% in favor of bemiparin 95% confidence interval (CI), −15.1% to 5.6%; non‐inferiority P‐value: 0.02; superiority P‐value: 0.36. The incidence of proximal deep vein thrombosis was 1.8% (three of 165 patients) in the bemiparin group and 4.2% (seven of 168 patients) in the enoxaparin group. Major bleeding occurred in six patients (three in each group). There were no deaths during the study. This trial shows that bemiparin started postoperatively is as effective and safe as enoxaparin started preoperatively in the prevention of venous thromboembolism in patients undergoing total knee replacement.
•MCLEA with highest enzymatic activity at low temperatures near to 37 °C.•MCLEA with a high enzyme loading efficiency of 90%.•Magnetic nanoparticles enhanced activity of cross-linked cellulase ...aggregates.•High values of frequency and AMF amplitude decrease MCLEA activity.•Frequency have more significant effects on MCLEA activity than the AMF amplitude.
A magnetic cross-linked enzyme aggregate (MCLEA) of cellulases and a non-magnetic analogue (CLEA) were synthesized and further investigated. The obtained MCLEA and CLEA showed a high enzyme loading efficiency of 90% and 88%, respectively. However, the MCLEA presented an activity 33% higher than the CLEA one, suggesting a catalytic enhancement effect as a result of magnetic nanoparticle presence in cross-linked cellulase aggregates structure. In addition, MCLEA shows an unusual behavior with highest enzymatic activity at low temperatures near to 37 °C. Lastly, a full factorial design (2x2) with two variables at two levels, frequency (203–420 kHz) and amplitude (3–6 kA m−1), was used in order to better investigate the effects of an alternating magnetic field (AMF) on MCLEA activity. AMF application decreased MCLEA activity, particularly in the highest values of frequency and amplitude, when compared to condition field free. In addition, frequency implied in more significant effects on MCLEA activity when compared to AMF amplitude.
Summary
Although a growing body of evidence demonstrates that altered mtDNA content (mtDNAc) has clinical implications in several types of solid tumours, its prognostic relevance in acute ...promyelocytic leukaemia (APL) patients remains largely unknown. Here, we show that patients with higher‐than‐normal mtDNAc had better outcomes regardless of tumour burden. These results were more evident in patients with low‐risk of relapse. The multivariate Cox proportional hazard model demonstrated that high mtDNAc was independently associated with a decreased cumulative incidence of relapse. Altogether, our data highlights the possible role of mitochondrial metabolism in APL patients treated with ATRA.
Obsessive-compulsive disorder (OCD) is a psychiatric disorder characterized by obsessions and/or compulsions. Different striatal subregions belonging to the cortico-striato-thalamic circuitry (CSTC) ...play an important role in the pathophysiology of OCD. The transcriptomes of 3 separate striatal areas (putamen (PT), caudate nucleus (CN) and accumbens nucleus (NAC)) from postmortem brain tissue were compared between 6 OCD and 8 control cases. In addition to network connectivity deregulation, different biological processes are specific to each striatum region according to the tripartite model of the striatum and contribute in various ways to OCD pathophysiology. Specifically, regulation of neurotransmitter levels and presynaptic processes involved in chemical synaptic transmission were shared between NAC and PT. The Gene Ontology terms cellular response to chemical stimulus, response to external stimulus, response to organic substance, regulation of synaptic plasticity, and modulation of synaptic transmission were shared between CN and PT. Most genes harboring common and/or rare variants previously associated with OCD that were differentially expressed or part of a least preserved coexpression module in our study also suggest striatum subregion specificity. At the transcriptional level, our study supports differences in the 3 circuit CSTC model associated with OCD.
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