The corticotrophin-releasing factor/urocortin system regulates white fat browning in mice through paracrine mechanisms

Objectives: The corticotrophin-releasing factor (CRF)/urocortin system is expressed in the adipose tissue of mammals, but its functional role in this tissue remains unknown. Methods: Pharmacological manipulation of the activity of CRF receptors, CRF1 and CRF2, was performed in 3T3L1 white pre-adipocytes and T37i brown pre-adipocytes during in vitro differentiation. The expression of genes of the CRF/urocortin system and of markers of white and brown adipocytes was evaluated along with mitochondrial biogenesis and cellular oxygen consumption. Metabolic evaluation of corticosterone-deficient or supplemented Crhr1-null (Crhr1−/−) mice and their wild-type controls was performed along with gene expression analysis carried out in white (WAT) and brown (BAT) adipose tissues. Results: Peptides of the CRF/urocortin system and their cognate receptors were expressed in both pre-adipocyte cell lines. In vitro pharmacological studies showed an inhibition of the expression of the CRF2 pathway by the constitutive activity of the CRF1 pathway. Pharmacological activation of CRF2 and, to a lesser extent, inhibition of CRF1 signaling induced molecular and functional changes indicating transdifferentiation of white pre-adipocytes and differentiation of brown pre-adipocytes. Crhr1−/− mice showed increased expression of CRF2 and its agonist Urocortin 2 in adipocytes that was associated to brown conversion of WAT and activation of BAT. Crhr1−/− mice were resistant to diet-induced obesity and glucose intolerance. Restoring physiological circulating corticosterone levels abrogated molecular changes in adipocytes and the favorable phenotype of Crhr1−/− mice. Conclusions: Our findings suggest the importance of the CRF2 pathway in the control of adipocyte plasticity. Increased CRF2 activity in adipocytes induces browning of WAT, differentiation of BAT and is associated with a favorable metabolic phenotype in mice lacking CRF1. Circulating corticosterone represses CRF2 activity in adipocytes and may thus regulate adipocyte physiology through the modulation of the local CRF/urocortin system. Targeting CRF receptor signaling specifically in the adipose tissue may represent a novel approach to tackle obesity

Identification and Characterization of Novel Perivascular Adventitial Cells in the Whole Mount Mesenteric Branch Artery Using Immunofluorescent Staining and Scanning Confocal Microscopy Imaging

A novel perivascular adventitial cell termed, adventitial neuronal somata (ANNIES) expressing the neural cell adhesion molecule (NCAM) and the vasodilator neuropeptide, calcitonin gene-related peptide (CGRP), exists in the adult rat mesenteric branch artery (MBA) in situ. In addition, we have previously shown that ANNIES coexpress CGRP and NCAM. We now show that ANNIES express the neurite growth marker, growth associated protein-43(Gap-43), palladin, and the calcium sensing receptor (CaSR), that senses changes in extracellular Ca(2+) and participates in vasodilator mechanisms. Thus, a previously characterized vasodilator, calcium sensing autocrine/paracrine system, exists in the perivascular adventitia associated with neural-vascular interface. Images of the whole mount MBA segments were analyzed under scanning confocal microscopy. Confocal analysis showed that the Gap-43, CaSR, and palladin were present in ANNIES about 37 ± 4%, 94 ± 6%, and 80 ± 10% respectively, comparable to CGRP (100%). Immunoblots from MBA confirmed the presence of Gap-43 (48 kD), NCAM (120 and 140 kD), and palladin (90–92 and 140 kD). In summary, CGRP, and NCAM-containing neural cells in the perivascular adventitia also express palladin and CaSR, and coexpress Gap-43 which may participate in response to stress/injury and vasodilator mechanisms as part of a perivascular sensory neural network

Climate fluctuations during the Holocene in NW Iberia: high and low latitude linkages

International audienceHigh resolution benthic foraminiferal oxygen and carbon stable isotopes (?18O, ?13C) from core EUGC-3B are used here to infer rapid climatic changes for the last 8500 yr in the Ría de Muros (NW Iberian Margin). Benthic foraminiferal ?18O and ?13C potentially register migrations in the position of the hydrographic front formed between two different intermediate water masses: Eastern North Atlantic Central Water of subpolar origin (ENACWsp), and subtropical origin (ENACWsp). The isotopic records have been compared with two well established North Atlantic marine Holocene paleoceanographic records from low (Sea Surface Temperatures anomalies off Cape Blanc, NW Africa) and high latitudes (Hematite Stained Grains percentage, subpolar North Atlantic). This comparison clearly demonstrates that there is a strong link between high- and low-latitude climatic perturbations at centennial-millennial time scales during the Holocene. Spectral analyses also points at a pole-to-equator propagation of the so-called 1500 yr cycles. Our results demonstrate that during the Holocene, the NW Iberian Margin has undergone a series of cold episodes which are likely triggered at high latitudes in the North Atlantic and are rapidly propagated towards lower latitudes. Conceivably, the propagation of these rapid climatic changes involves a shift of atmospheric and oceanic circulatory systems and so a migration of the hydrographical fronts and water masses all along the North Atlantic area

Complications and treatment errors in periodontal therapy in medically compromised patients

Patients who are medically compromised may be at an increased risk of complications and treatment errors following periodontal therapy. A review of the evidence on the topic is presented, in relation to the type of complication reported, of periodontal treatment, and of patients' medical status. Further, a framework for risk assessment and appropriate treatment modifications is introduced, with the aim of facilitating the management of patients with existing comorbidities and reducing the incidence of treatment complications

Acidosis tubular renal como presentación clínica de Síndrome de Sjögren: reporte de caso

Presentamos el caso clínico de una mujer en la quinta década de la vida, de nacionalidad argentina, que acudió a la guardia de clínica médica de un hospital de tercer nivel por cuadro de mialgias y paresia en las cuatro extremidades, de inicio agudo, progresivo, con dificultad para la movilización de miembros superiores, bipedestación y marcha. Se constató hipocalemia severa, acidosis metabólica, pH urinario alcalino, brecha aniónica urinaria positiva (excreción de amonio), hipocitraturia e hipercalciuria, por lo que se diagnosticó Acidosis Tubular Renal (ATR) tipo I; además se evidenció elevación de creatinkinasa (CK) e insuficiencia renal aguda que corrigió con la reposición de líquidos. Al interrogatorio dirigido, la paciente refirió síndrome seco asociado a artralgias, de varios años de evolución, por lo que se realizaron estudios complementarios que apoyaron el diagnóstico de Síndrome de Sjögren

Prilog istraživanju promjena na škrgama zebrice (Danio rerio) prilikom izloženosti dioksinu

This study determined cell changes in the gills of zebrafish (Danio rerio, Hamilton, 1822) as a result of a dietary supply of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). 50 zebrafish were divided into five groups, one control group and four experimental ones. The experimental groups were supplied 10, 40, 100 and 270 ng/day/fish TCDD, respectively. Structural, ultrastructural and morphometric studies of the fish gill were carried out, indicating that, in low concentrations, fish gills presented hyperemia with progressive erosion of the endothelium of the capillaries resulting in edema and microhaemorrhages. In the non-respiratory gill, in those groups with low concentrations, it could be observed that the chloride cells presented hypertrophy as a result of dilatation of the intracellular canal and swelling of the microvilli, losing their activity in the degradation of chemical substances (according to some authors) in those groups with a higher concentration. Mucous cells presented hyperplasia and hypertrophy. The sensory buds were not directly affected, but, due to the presence of interstitial edema, swelling of the supporting cells occurred without the involvement of the neurosensory cells. We concluded that dioxins affect the gills to a greater or lesser extent depending on their concentration in the fish’s diet, which alters their functionality.Ovim istraživanjem utvrđene su promjene na stanicama škrga zebrice (Danio rerio, Hamilton, 1822) kao rezultat hranjena 2,3,7,8 tetraklorodibenzo p-dioksinom (TCDD). Pedeset jedinki zebrice podijeljeno je u pet grupa, jednu kontrolnu grupu i četiri eksperimentalne. Eksperimentalnim grupama davano je 10, 40, 100 i 270 ng/riba/dan TCDD. Provedena su strukturalna, ultrastrukturalna i morfološka istraživanja škrga ribe, ukazujući da su škrge riba pokazivale hiperemiju s progresivnom erozijom endotel kapilara koja je rezultirala edemima i mikrokrvarenjima. Kod grupa kojima je dana manja koncentracija, u škrgama koje ne služe za disanje može se primijetiti da kloridne stanice pokazuju hipertrofiju kao posljedicu dilatacije međustaničnog kanala i oticanje mikroresica kojima se smanjuje aktivnost tijekom razgradnje kemijskih tvari (prema mišljenjima nekih autora) u onim grupama koje su bile izložene većim koncentracijama. Mukozne stanice pokazuju hiperplaziju i hipertrofiju. Osjetni pupoljci nisu bili izravno pogođeni, ali, zbog prisutnosti intersticijskog edema, oticanja potpornih stanica bez uključivanja neurosenzornih stanica. Zaključak je da dioksini utječu na škrge u većoj ili manjoj mjeri ovisno o njihovoj koncentraciji u ishrani ribe, što mijenja njihovu funkcionalnost

Prilog istraživanju promjena na škrgama zebrice (Danio rerio) prilikom izloženosti dioksinu

This study determined cell changes in the gills of zebrafish (Danio rerio, Hamilton, 1822) as a result of a dietary supply of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). 50 zebrafish were divided into five groups, one control group and four experimental ones. The experimental groups were supplied 10, 40, 100 and 270 ng/day/fish TCDD, respectively. Structural, ultrastructural and morphometric studies of the fish gill were carried out, indicating that, in low concentrations, fish gills presented hyperemia with progressive erosion of the endothelium of the capillaries resulting in edema and microhaemorrhages. In the non-respiratory gill, in those groups with low concentrations, it could be observed that the chloride cells presented hypertrophy as a result of dilatation of the intracellular canal and swelling of the microvilli, losing their activity in the degradation of chemical substances (according to some authors) in those groups with a higher concentration. Mucous cells presented hyperplasia and hypertrophy. The sensory buds were not directly affected, but, due to the presence of interstitial edema, swelling of the supporting cells occurred without the involvement of the neurosensory cells. We concluded that dioxins affect the gills to a greater or lesser extent depending on their concentration in the fish’s diet, which alters their functionality.Ovim istraživanjem utvrđene su promjene na stanicama škrga zebrice (Danio rerio, Hamilton, 1822) kao rezultat hranjena 2,3,7,8 tetraklorodibenzo p-dioksinom (TCDD). Pedeset jedinki zebrice podijeljeno je u pet grupa, jednu kontrolnu grupu i četiri eksperimentalne. Eksperimentalnim grupama davano je 10, 40, 100 i 270 ng/riba/dan TCDD. Provedena su strukturalna, ultrastrukturalna i morfološka istraživanja škrga ribe, ukazujući da su škrge riba pokazivale hiperemiju s progresivnom erozijom endotel kapilara koja je rezultirala edemima i mikrokrvarenjima. Kod grupa kojima je dana manja koncentracija, u škrgama koje ne služe za disanje može se primijetiti da kloridne stanice pokazuju hipertrofiju kao posljedicu dilatacije međustaničnog kanala i oticanje mikroresica kojima se smanjuje aktivnost tijekom razgradnje kemijskih tvari (prema mišljenjima nekih autora) u onim grupama koje su bile izložene većim koncentracijama. Mukozne stanice pokazuju hiperplaziju i hipertrofiju. Osjetni pupoljci nisu bili izravno pogođeni, ali, zbog prisutnosti intersticijskog edema, oticanja potpornih stanica bez uključivanja neurosenzornih stanica. Zaključak je da dioksini utječu na škrge u većoj ili manjoj mjeri ovisno o njihovoj koncentraciji u ishrani ribe, što mijenja njihovu funkcionalnost

Alectinib after failure to crizotinib in patients with ALK-positive non-small cell lung cancer : results from the Spanish early access program

Altres ajuts: Roche Farma, S.A.This retrospective observational study analyzed the clinical characteristics, treatment patterns and outcomes of 120 patients with advanced ALK-positive nonsmall-cell lung cancer (ALK+ NSCLC) according to data collected between November 2019 and October 2020 in 38 Spanish hospitals. Patients had progressed after 1-5 prior treatment lines (which included crizotinib in any prior line) and received subsequent therapy with alectinib in a local expanded access program. Median age was 58.7 years, 50% of patients were female, 64.1% had ECOG PS of 0-1, 85% presented stage IV, 95% had adenocarcinoma histology and 20.8% had brain metastases. After a median 9.6 months of alectinib treatment, objective response rate (ORR) was 54.5%, disease control rate (DCR) was 80%, median progression-free survival (PFS) was 9.4 months and median overall survival (OS) was 24.1 months. Patients with brain metastases achieved an intracranial DCR of 71.4%. Adverse events (AEs) were reported in 35.8% of patients (14.2% of AEs were grade ≥3). Over 40% of patients received some treatment after alectinib, most frequently lorlatinib (65.2%) and brigatinib (32.6%). This study provides information on real-world treatment patterns and confirms the tolerability and prolonged PFS and OS observed with alectinib in clinical trials, in unselected pretreated patients with advanced ALK+ NSCLC

Analysis of molecular changes induced by mineral trioxide aggregate on sPLA2

The aim of this study was to analyze the effects of MTA on the structure and enzymatic activity of sPLA2 in order to provide subsidies for improvement in the formulation of the product. MTA powder was incubated for 60 min in the presence of sPLA2 and was analyzed by chromatography, electrospray mass (ESI-MS) and small-angle X-ray scattering (SAXS). It was find that the elution profile, retention time, and fragmentation of sPLA2 were altered after treatment with MTA. Calcium was the MTA component that most amplified the inflammatory signal. Significant interactions were found between MTA and sPLA2, which could aid in our understanding of the mechanisms of action of MTA during the inflammatory process and it may facilitate the structural modification of MTA, thereby improving its biological safety and consequently the rate of the treatment success305453458The authors wish to thank the National Laboratory of Synchrotron Light (LNLS - Brazil) for the use of their facility and equipment and to Brazilian division of the IADR (SBPqO), which partially supported this study through PRONAC award. The authors also thanks to Prof. Marcos Toyama for its support on the chromatography graph