Exendin-4 protects beta-cells from interleukin-1 beta-induced apoptosis by interfering with the c-Jun NH2-terminal kinase pathway.

OBJECTIVE: The pro-inflammatory cytokine interleukin-1 beta (IL-1 beta) generates pancreatic beta-cells apoptosis mainly through activation of the c-Jun NH(2)-terminal kinase (JNK) pathway. This study was designed to investigate whether the long-acting agonist of the hormone glucagon-like peptide 1 (GLP-1) receptor exendin-4 (ex-4), which mediates protective effects against cytokine-induced beta-cell apoptosis, could interfere with the JNK pathway. RESEARCH DESIGN AND METHODS: Isolated human, rat, and mouse islets and the rat insulin-secreting INS-1E cells were incubated with ex-4 in the presence or absence of IL-1 beta. JNK activity was assessed by solid-phase JNK kinase assay and quantification of c-Jun expression. Cell apoptosis was determined by scoring cells displaying pycnotic nuclei. RESULTS: Ex-4 inhibited induction of the JNK pathway elicited by IL-1 beta. This effect was mimicked with the use of cAMP-raising agents isobutylmethylxanthine and forskolin and required activation of the protein kinase A. Inhibition of the JNK pathway by ex-4 or IBMX and forskolin was concomitant with a rise in the levels of islet-brain 1 (IB1), a potent blocker of the stress-induced JNK pathway. In fact, ex-4 as well as IBMX and forskolin induced expression of IB1 at the promoter level through cAMP response element binding transcription factor 1. Suppression of IB1 levels with the use of RNA interference strategy impaired the protective effects of ex-4 against apoptosis induced by IL-1 beta. CONCLUSIONS: The data establish the requirement of IB1 in the protective action of ex-4 against apoptosis elicited by IL-1 beta and highlight the GLP-1 mimetics as new potent inhibitors of the JNK signaling induced by cytokines.

Dissecting gastrointestinal dysfunction and inflammation in a “pre-motor” rodent model of Parkinson’s disease

Research on Parkinson’s disease (PD) has mainly focused on the degeneration of the dopaminergic neurons of nigro-striatal (NS) pathway; also, post-mortem studies have demonstrated that the noradrenergic and the serotonergic transmitter systems are also affected (Jellinger, 1999). Degeneration of these neuronal cell bodies is generally thought to start prior to the loss of dopaminergic neurons in the NS pathway and precedes the appearance of the motor symptoms that are the “hallmark” of PD. Gastrointestinal (GI) motility is often disturbed in PD, manifesting chiefly as impaired gastric emptying and constipation. These GI dysfunction symptoms may be the result of a loss in noradrenergic and serotonergic innervation. GI deficits were evaluated using an organ bath technique. Groups treated with different combinations of neurotoxins (6-OHDA alone, 6-OHDA + pCA or 6-OHDA + DSP-4) presented significant differences in gut contractility compared to control groups. Since a substantial body of literature suggests the presence of an inflammatory process in parkinsonian state (Whitton, 2007), changes in pro-inflammatory cytokines in the gut were assessed using a cytokine microarray. It has been found in this work that groups with a combined dopaminergic and noradrenergic lesion have a significant increase in both expressions of IL-13 and VEGF. IL-6 also shows a decrease in treatment groups; however this decrease did not reach statistical significance. The therapeutic value of Exendin-4 (EX-4) was evaluated. It has been previously demonstrated that EX-4, a glucagon-like peptide-1 receptor (GLP-1R) agonist, is neuroprotective in rodent models of PD (Harkavyi et al., 2008). In this thesis it has been found that EX-4 was able to reverse a decrease in gut contractility obtained through intracerebral bilateral 6-OHDA injection. Although more studies are required, EX-4 could be used as a possible therapy for the GI symptoms prominent in the early stages of PD.

Role and regulation of islet-Brain 1 in pancreatic β-cells

Résumé : L'insuline est produite et sécrétée par la cellule ß-pancréatique. Son rôle est de régler le taux de sucre dans le sang. Si ces cellules meurent ou échouent à produire suffisamment de l'insuline, les sujets développent le diabète de type 2 (DT2), une des maladies les plus communes dans les pays développés. L'excès chronique des lipoprotéines LDL oxydés (oxLDL) et/ou des cytokines pro-inflammatoires comme l'interleukine-1ß (IL-1ß) participent au dérèglement et à la mort des cellules ß. Nous avons montré qu'une chute des niveaux d'expression de la protéine nommée «mitogen activated protein kinase 8 interacting protein 1» ou «islet brain 1 (IB 1)» est en partie responsable des effets provoqués par les oxLDL ou IL-1ß. IB1 régule l'expression de l'insuline et la survie cellulaire en inhibant la voie de signalisation « c-jun N-terminal Kinase (JNK)». La réduction des niveaux d'expression d'IB1 provoque l'activation de la voie JNK en réponse aux facteurs environnementaux, et ainsi initie la réduction de l'expression de l'insuline et l'induction du programme de mort cellulaire. Les mimétiques de l'hormone "Glucagon-like peptide 1", tel que l'exendin-4 (ex-4), sont une nouvelle classe d'agents hypoglycémiants utilisés dans le traitement du DT2. Les effets bénéfiques de l'ex-4 sont en partie accomplis en préservant l'expression de l'insuline et la survie des cellules ß contre les stress associés au DT2. La restauration des niveaux d'expression d'IB1 est un des mécanismes par lequel l'ex-4 prodigue son effet sur la cellule. En effet, cette molécule stimule l'activité du promoteur du gène et ainsi compense la réduction du contenu en IB1 causée par le stress. Outre ce rôle anti-apoptotique, dans ce travail de thèse nous avons mis en évidence une autre fonction d'IB1 dans la cellule ß. La réduction de l'activité ou des niveaux d'expression d'IB1 induisent une réduction importante de la sécrétion de l'insuline en réponse au glucose. Le mécanisme par lequel IB1 régule la sécrétion de l'insuline implique à la fois le métabolisme du glucose et éventuellement le transport vésiculaire en contrôlant l'expression de la protéine annexin A2. En résumé, IB 1 est une molécule clé à travers laquelle l'environnement du diabétique pourrait exercer un effet délétère sur la cellule ß. L'amélioration de l'activité d'IB1 et/ou de son expression devrait être considérée dans les approches thérapeutiques futures visant à limiter la perte des cellules ß dans le diabète. Abstract : ß-cells of the pancreatic islets of Langerhans produce and secrete insulin when blood glucose rises. In turn, insulin ensures that plasma glucose concentrations return within a relatively narrow physiological range. If ß-cells die or fail to produce enough insulin, individuals develop one of the most common diseases in Western countries, namely type 2 diabetes (T2D). Chronic excess of oxidized low density lipoproteins (oxLDL) and/or pro-inflammatory cytokines such as interleukin 1-ß (IL-1ß) contribute to decline of ß-cells and thereby are thought to accelerate progression of the disease overtime. We showed that profound reduction in the levels of the mitogen activated protein kinase 8 interacting protein 1 also called islet brain 1 (IB1) causes ß-cell failure accomplished by oxLDL or IL-1 ß. IB1 regulates insulin expression and cell survivals by inhibiting the c-Jun N-terminal Kinase pathway. Diminution in IB 1 levels leads to an increase in activation of the JNK pathway induced by environmental stressors, and thus initiates loss of insulin expression and programmed cell death. The mimetic agents of the glucoincretin glucagon-like peptide 1 such as exendin-4 (ex-4) are new class of hypoglycaemic medicines for treatment of T2D. The beneficial property is in part achieved by preserving insulin expression and ß-cell survival against stressors related to diabetes. Restored levels in IB 1 account for the cytoprotective effect of the ex-4. In fact, the latter molecule .stimulates the promoter activity of the gene and thus compensates loss of IB1 content triggered by stress. Beside of the anti-apoptotic role, an additional leading function for IB 1 in ß-cells was highlighted in this thesis. Impairment in IB1 activity or silencing of the gene in ß-cells revealed a major reduction in insulin secretion elicited by glucose. The mechanisms whereby IB 1 couples glucose to insulin release involve glucose metabolism and potentially, vesicles trafficking by maintaining the levels of annexin A2. IB 1 is therefore a key molecule through which environmental factors related to diabetes may exert harmful effects on ß-cells. Improvement in IB 1 activity and/or expression should be considered as a target for therapeutic purpose.

A single resistance exercise session improves myocardial contractility in spontaneously hypertensive rats

Resistance training evokes myocardial adaptation; however, the effects of a single resistance exercise session on cardiac performance are poorly understood or investigated. This study aimed to investigate the effects of a single resistance exercise session on the myocardial contractility of spontaneously hypertensive rats (SHRs). Male 3-month-old SHRs were divided into two groups: control (Ct) and exercise (Ex). Control animals were submitted to sham exercise. Blood pressure was measured in conscious rats before the exercise session to confirm the presence of arterial hypertension. Ten minutes after the exercise session, the animals were anesthetized and killed, and the hearts were removed. Cardiac contractility was evaluated in the whole heart by the Langendorff technique and by isometric contractions of isolated left ventricular papillary muscles. SERCA2a, phospholamban (PLB), and phosphorylated PLB expression were investigated by Western blot. Exercise increased force development of isolated papillary muscles (Ex=1.0±0.1 g/mg vs Ct=0.63±0.2 g/mg, P<0.05). Post-rest contraction was greater in the exercised animals (Ex=4.1±0.4% vs Ct=1.7±0.2%, P<0.05). Papillary muscles of exercised animals developed greater force under increasing isoproterenol concentrations (P<0.05). In the isolated heart, exercise increased left ventricular isovolumetric systolic pressure (LVISP; Δ +39 mmHg; P<0.05) from baseline conditions. Hearts from the exercised rats presented a greater response to increasing diastolic pressure. Positive inotropic intervention to calcium and isoproterenol resulted in greater LVISP in exercised animals (P<0.05). The results demonstrated that a single resistance exercise session improved myocardial contractility in SHRs.

Excitación vibracional de moléculas adsorbidas por fotoelectrones de muy baja energía

En esta Tesis Doctoral se demuestra, en primer lugar, la existencia de efectos catalíticos inducidos por láser en procesos de captura electrónica disociativa para las moléculas SF6, acrilonitrilo o 2-propenenitrilo (ACN) y CH3I adsorbidas en Ba y ACN adsorbida en Cu policristalino, detectándose como productos SF−5 y SF−6 para SF6/Ba, CN− para ACN/Ba y ACN/Cu y I− para CH3I/Ba. Para el sistema ACN/Cu, la medida del cociente CN−/e− en función de la longitud de onda del láser, demostró la selectividad vibracional del proceso al replicar el espectro de IR del ACN en fase gaseosa desplazado 20,17 cm−1 hacia el rojo. Estos experimentos se realizaron en un sistema experimental expresamente orientado a la espectroscopía en el infrarrojo. En un segundo sistema experimental especialmente diseñado para la detección y el análisis de electrones de baja energía generados en metal mediante luz láser visible, se estudiaron por primera vez las transiciones intrabanda entre estados sp de cobre generadas mediante 2PPE en Cu(100). Como resultado se consiguió identificar y medir la posición en energía del estado de volumen X′4 con alta precisión EX′4 =2,08±0,04 eV. En este sentido se desarrolló un modelo teórico para estudiar las transiciones intrabanda cerca del estado de alta simetría X. Los ajustes del modelo ofrecieron un valor de energía por fonón de ≈5 meV...

Effect of 4% titanium tetrafluoride solution on dental erosion by a soft drink: An in situ/ex vivo study

Objective: This in situ/ex vivo study assessed the effect of titanium tetrafluoride (TiF4) on permanent human enamel subjected to erosion. Design: Ten volunteers took part in this study performed in two phases. In the first phase (ERO), they wore acrylic palatal appliances containing two enamel blocks, divided into two rows: TiF4 (F) and no-TiF4 (no-F). During the 1st day, the formation of a salivary pellicle was allowed. In the 2nd day, the TiF4 solution was applied on one row (ERO + F), whereas on the other row no treatment was performed (ERO + no-F). From 3rd until 7th day, the blocks were subjected to erosion, 4x per day. In the 2nd phase (no-ERO), the volunteers wore acrylic palatal appliances containing one enamel block, during 2 days, to assess the effect of TiF4 only (no-ERO + F). Enamel alterations were determined using profilometry (wear), microhardness (%SMHC) tests, scanning electron microscope and microprobe analysis. The %SMHC and wear were tested using ANOVA and Tukey`s post hoc tests (p < 0.05). Results: The mean of %SMHC and wear ( mu m) values ( +/- S.D.) were, respectively: ERO + F -73.32 +/- 5.16(A)/2.40 +/- 0.60(a); ERO + no-F -83.49 +/- 4.59B/1.17 +/- 0.48(b) and no-ERO + F -67.92 +/- 6.16(A)/0.21:E 0.09(c). In microscope analysis, the no-F group showed enamel with honeycomb appearance. For F groups, it was observed a surface coating with microcracks. The microprobe analysis revealed the presence of the following elements (%) in groups ERO + F, ERO + no-F and no-ERO + F, respectively: Ca (69.9, 72.5, 66.25); P (25.9, 26.5, 26.06); Ti (3.0, 0, 5.93). Conclusions: The TiF4 was unable to reduce dental erosion. (c) 2007 Elsevier Ltd. All rights reserved.

1.° Alexandri de Sancto Elpidio, ordinis Eremitarum sancti Augustini, tractatus de ecclesiastica potestate : inserta est donatio Constantini Magni facta Ecclesiae Romanae. — 2.° Ejusdem expositio in principium evangelii secundum Joannem. — 3.° Ejusdem epitome librorum sancti Augustini de civitate Dei. — 4.° Sancti Isidori, synonymorum, sive soliloquiorum liber. — 5.° Fratris Dionysii de Colle, ordinis Eremitarum sancti Augustini, tractatus de fato et praescientia divina. — 6.° Testimonia duodecim Patriarcharum de Christo. — 7.° Tractatus de Antichristo. — 8.° Excerptum ex tractatu Origenis de novem festivitatibus in Veteri Testamento. — 9.° Bernardi Oliverii, ordinis Eremitarum sancti Augustini, tractatus contra Judaeos. — 10.° Fratris Ricoldi, Florentini, ordinis Praedicatorum, disputatio contra Saracenos et Alcoranum. — 11.° Tractatus qui mensa pauperum inscribitur : authore A. ordinis Eremitarum sancti Augustini

Colbertinus

1.° Jacobi Alexandri le Taneur disputatio physico-mathematica de aequabili motus acceleratione, et de motu telluris : in qua Galilaei decreta de motu gravium perpendiculariter cadentium confirmantur ; et ostenditur vulgarem seu Ptolemaïcam de motu solis opinionem non minùs esse contrariam sacris litteris, quam Copernicanam de motu terrae : ac proinde nihil certi ex iis, quoad illam quaestionem, posse deduci : ad Petrum Cazraeum, societatis Jesu. — 2.° Ejusdem epistolae duae ad eundem, de descensu gravium. — 3.° Petri Cazraei, societatis Jesu, ad Alexandrum le Taneur epistola, qua sententiam Galilaei de descensu gravium impugnat. — 4.° Lettre de monsieur le Taneur au Pere Mersenne, Minime, sur la chûte des corps. — 5.° Ejusdem ad eundem epistola contra Fabrianam de incremento motus accelerati opinionem.

Melchisedechi Thevenotii

1.° Codicis Theodosiani libri sexdecim ; hîc solae occurrunt interpretationes : author hujus breviarii Monachus, qui in prologo testatur se illud opus fuisse aggressum sui Abbatis jussu. — 2.° Theodosii Junioris, Valentiniani III. Martiani, Majoriani et Severi novellae constitutiones. — 3.° Gaii institutionum epitome. — 4.° Julii Pauli sententiarum libri quinque, cum interpretationibus. — 5.° Excerpta ex Codicibus Gregoriano, Hermogeniano et Papianeo : subjicitur ad calcem epitaphium Richardi, Burgundiae Ducis

Colbertinus

1.° Codicis Theodosiani libri sexdecim ; hîc solae occurrunt interpretationes : praemittitur opusculum quod inscribitur ; Judicia Dei. — 2.° Theodosii Junioris, Valentiniani III. Marciani et Majoriani novellae constitutiones. — 3.° Gaii Institutionum epitome. — 4.° Julii Pauli sententiarum libri quinque, cum interpretationibus. — 5.° Excerpta e Codice Gregoriano, Hermogeniano et Papianeo. — 6.° Leges divi Anthemii. — 7.° Alia excerpta ex Codice Gregoriano

Colbertinus, antea Jacobi Augusti Thuani

1.° Hilperici tractatus de arte calculatoria : praemittitur calendarium ad usum Cisterciensium. — 2.° Ratio Gaii Caesaris de ordine anni per duodecim menses. — 3.° Bedae opusculum de loquela digitorum. — 4.° Expositio tabulae de luna quotidiè per rationem epactarum invenienda. — 5.° Excerptum ex etymologiis Isidori, de coelo ejusque luminaribus. — 6.° Carmen de temporibus anni. — 7.° Ratio epactarum. — 8.° Anonymi expositio super tabulam Dionysii Exigui, Abbatis. — 9.° Fragmentum Macrobii de mensura terrae. — 10.° Anonymi figurata expositio duodecim signorum zodiaci. — 11.° Scholium de temporibus et aetatibus mundi. — 12.° Alcuini opusculum de vita Antichristi. — 13.° Hieronymus de quindecim signis praecedentibus diem judicii. — 14.° Beda de die judicii. — 15.° Anonymi chronicon in epitomen contractum, et à mundi creatione ad Leonis III. imperium productum. — 16.° Provincialis Romanae Ecclesiae fragmentum.

Colbertinus