PTRF acts as an adipokine contributing to adipocyte dysfunctionality and ectopic lipid deposition

Adipose tissue (AT) expands under obesogenic conditions. Yet, when the growth exceeds a certain limit, AT becomes dysfunctional and surplus lipids start depositing ectopically. Polymerase I and transcription release factor (PTRF) has been proposed as a mechanism leading to a dysfunctional AT by decreasing the adipogenic potential of human adipocyte precursors. However, whether or not PTRF can be secreted by the adipocytes into the bloodstream is not yet known. For this work, PTRF presence was investigated in plasma. We also produced a recombinant PTRF (rPTRF) and examined its impact on the functional interactions between the adipocyte and the hepatocyte in vitro. We demonstrated that PTRF can be found in human plasma, and is at least in part, carried by exosomes. In vitro treatment with rPTRF increased the hypertrophy and senescence of 3T3-L1 adipocytes. In turn, those rPTRF-treated adipocytes increased lipid accumulation in hepatocytes. Lastly, we found a positive correlation between circulating PTRF and the concentration of PTRF in the visceral fat depot. All these findings point toward the presence of an enlarged and dysfunctional visceral adipose tissue which secretes PTRF. This circulating PTRF behaves as an adipokine and may partially contribute to the well-known detrimental effects of visceral fat accumulation

A comparative study of platelet-rich plasma, hydroxyapatite, demineralized bone matrix and autologous bone to promote bone regeneration after mandibular impacted third molar extraction.

Objectives: 1) to compare mandibular bone regeneration by applying autologous bone, platelet-rich plasma and two biomaterials (synthetic calcium hydroxyapatite, and demineralized bone matrix), and thus establish the potential benefits of these biomaterials in the regeneration of postextraction alveolar bone, 2) to identify wich of them accelerates more bone regeneration and 3) to determine whether there are differences in the postoperative period (pain, swelling, trismus, infection) depending on the material used. Study Design: It consists in a prospective, controlled (with a split- mouth design) and double blinded study. We use as a model an easily reproducible non-critical bone defect: the defect that remains after extraction of mandibular impacted third molar. The study design is based on the extraction of two mandibular impacted third molars in a patient during the same surgical procedure by the same surgeon. We assessed postoperative clinical data, and short, medium and long term neoformation of alveolar bone after extraction. We compared the two sockets (right and left), which had been grafted in a different way with the various elements mentioned above. In addition, we compared the postoperative inflammatory symptoms between groups. Results: The highest acceleration in bone formation was observed in groups in which we used autologous bone and demineralized bone matrix. There were no statistically significant differences between groups regarding pain, swelling, trismus and infection throughout the postoperative period. Conclusions: According to the results of our study, autologous bone persists as the gold standard material for bone regeneration. Among the assessed biomaterials, demineralized bone matrix has yielded the best results obtained. No significant differences in the postoperative (pain, swelling, trismus and infectious events) were observed, depending on the type of material used as a graft

Early life risk factors and their cumulative effects as predictors of overweight in Spanish children

Objectives: To explore early life risk factors of overweight/obesity at age 6 years and their cumulative effects on overweight/obesity at ages 2, 4 and 6 years. Methods: Altogether 1031 Spanish children were evaluated at birth and during a 6-year follow-up. Early life risk factors included: parental overweight/obesity, parental origin/ethnicity, maternal smoking during pregnancy, gestational weight gain, gestational age, birth weight, caesarean section, breastfeeding practices and rapid infant weight gain collected via hospital records. Cumulative effects were assessed by adding up those early risk factors that significantly increased the risk of overweight/obesity. We conducted binary logistic regression models. Results: Rapid infant weight gain (OR 2.29, 99% CI 1.54–3.42), maternal overweight/obesity (OR 1.93, 99% CI 1.27–2.92), paternal overweight/obesity (OR 2.17, 99% CI 1.44–3.28), Latin American/Roma origin (OR 3.20, 99% CI 1.60–6.39) and smoking during pregnancy (OR 1.61, 99% CI 1.01–2.59) remained significant after adjusting for confounders. A higher number of early life risk factors accumulated was associated with overweight/obesity at age 6 years but not at age 2 and 4 years. Conclusions: Rapid infant weight gain, parental overweight/obesity, maternal smoking and origin/ethnicity predict childhood overweight/obesity and present cumulative effects. Monitoring children with rapid weight gain and supporting a healthy parental weight are important for childhood obesity prevention

Contribution of Cytochrome P450 and ABCB1 Genetic Variability on Methadone Pharmacokinetics, Dose Requirements, and Response

Although the efficacy of methadone maintenance treatment (MMT) in opioid dependence disorder has been well established, the influence of methadone pharmacokinetics in dose requirement and clinical outcome remains controversial. The aim of this study is to analyze methadone dosage in responder and nonresponder patients considering pharmacogenetic and pharmacokinetic factors that may contribute to dosage adequacy. Opioid dependence patients (meeting Diagnostic and Statistical Manual of Mental Disorders, [4th Edition] criteria) from a MMT community program were recruited. Patients were clinically assessed and blood samples were obtained to determine plasma concentrations of (R,S)-, (R) and (S)- methadone and to study allelic variants of genes encoding CYP3A5, CYP2D6, CYP2B6, CYP2C9, CYP2C19, and P-glycoprotein. Responders and nonresponders were defined by illicit opioid consumption detected in random urinalysis. The final sample consisted in 105 opioid dependent patients of Caucasian origin. Responder patients received higher doses of methadone and have been included into treatment for a longer period. No differences were found in terms of genotype frequencies between groups. Only CYP2D6 metabolizing phenotype differences were found in outcome status, methadone dose requirements, and plasma concentrations, being higher in the ultrarapid metabolizers. No other differences were found between phenotype and responder status, methadone dose requirements, neither in methadone plasma concentrations. Pharmacokinetic factors could explain some but not all differences in MMT outcome and methadone dose requirements

Paracrine up-regulation of monocyte cyclooxygenase-2 by platelets: Role of transforming growth factor-beta1

To examine the role of platelets and platelet-derived products on cyclooxygenase-2 (Cox-2) induction in adherent monocytes and to address the signaling pathways involved. METHODS: Platelets and monocytes were obtained from peripheral blood of healthy donors. Adherent monocytes were co-cultured with autologous platelets or platelet releasates or exposed to mediators contained in platelet alpha-granules (either from platelet source or recombinant) for 4-24 h. Cox-2 protein and mRNA were determined by Western and RT-PCR analysis, respectively. Thromboxane B(2) (TxB(2)) and prostaglandin E(2) (PGE(2)) synthesis as index of Cox-2 activity, and levels of transforming growth factor-beta1 (TGF-beta1) in platelet releasates were measured by enzyme immunoassay (EIA). RESULTS: Activated platelets induce rapid and transient Cox-2 de novo synthesis in adherent monocytes. The effect is dependent upon the platelet number but not upon cell-cell contact. Platelet-induced Cox-2 was not affected by prevention of platelet TxA(2) synthesis or microparticle formation but was blunted by inhibition of platelet alpha-granule secretion. TGF-beta1, either platelet-derived or recombinant (rTGF-beta1), induced Cox-2 expression and activity in adherent monocytes at concentrations within the range of those detected in releasates from activated platelets; this effect was not shared by recombinant platelet-derived growth factor (rPDGF(BB)). The time course of Cox-2 induction by TGF-beta1 in monocytes was identical to that observed with platelet releasates. Moreover, TGF-beta1 receptor blockade completely abolished platelet-induced Cox-2 expression. p38 MAPK activation represents a common transduction pathway through which activated platelets and rTGF-beta1 induce Cox-2 in monocytes. CONCLUSION: These findings suggest that TGF-beta1 released by activated platelets has a pivotal role in Cox-2 induction in monocytes and further supports the key role of platelets in the inflammatory and reparative response

Paracrine up-regulation of monocyte cyclooxygenase-2 by platelets : role of TGF-beta1

Introduction. Cellular interactions between platelets and leukocytes provide a crucial mechanism for intercellular communication in thrombosis and inflammation. We have examined the role of platelets and platelet-derived products on cyclooxygenase-2 (Cox-2) induction in adherent monocytes and addressed the signaling pathways involved. Methods. Human monocytes were co-cultured with autologous platelets or platelet releasates or exposed to mediators contained in platelet alphagranules for 4-24 h. Cox-2 protein and mRNA were determined by Western and RT-PCR. Thromboxane B2 and prostaglandin E2 synthesis as index of Cox-2 activity, and levels of TGF-b1 in platelet releasates were measured by EIA. Results. Activated platelets induce rapid and transient Cox-2 de novo synthesis in adherent monocytes. The effect is dependent upon platelet number but not upon cell-cell contact. Platelet-induced Cox-2 was not affected by prevention of platelet TxA2 synthesis or microparticle formation but was blunted by inhibition of platelet alphagranule secretion. TGF-b1 induced Cox-2 expression and activity at concentrations within the range of those detected in releasates from activated platelets. The time course of monocyte Cox-2 induction by TGF-b1 was identical to that observed with platelet releasates. Moreover, TGF- b1 receptor blockade completely abolished platelet-induced Cox-2 expression. p38 MAPK activation represents a common transduction pathway through which activated platelets and rTGF-b1 induce Cox-2 in monocytes. Conclusions. Data suggest that TGF-b1 released by activated platelets is pivotal in Cox-2 induction in monocytes and further supports the key role of platelets in inflammatory and reparative response