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Protein tyrosine phosphatase 1B (PTP1B) is a molecular brake on the leptin signaling pathway. Deletion of PTP1B increases leptin sensitivity and triggers hypertension in mice on a ...Balb/C background but not on a C57Bl/6 background. While leptin increases sympathetic tone (ST), whether PTP1B deletion differently increases ST in Balb/C and C57Bl/6 mice remains to be determined. To test the hypothesis that PTP1B deletion increases sympathetic tone in mice on the Balb/C background only, male and female wild‐type (WT) and knockout (KO) mice from both backgrounds were instrumented with jugular and carotid catheters to measure mean arterial pressure response to ganglionic blockade (mecamylamine) and adrenergic stimulation (phenylephrine). On the Balb/C background, PTP1B deletion increases sympathetic tone and reduces vascular adrenergic tone in both male (WT: −39±3% vs KO: −43±4%) and female mice (WT: −34±5% vs KO: − 35±4%). PTP1B deletion similarly increased ST in KO mice on the C57Bl/6 background (WT: 76±8% vs KO: 129±41%) but did not affect their adrenergic tone. Furthermore, in WT animals, sympathetic tone was higher in C57Bl/6 compared to Balb/c mice. Together these data suggest that the hypertension observed in PTP1B KO mice on the Balb/c background cannot be explained by an enhanced sympathetic tone.
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Protein Tyrosine Phosphatase 1B (PTP1B) modulates endoplasmic reticulum stress (ERS). However, whether PTP1B regulates ERS‐nduced endothelial dysfunction is unknown. To test the ...hypothesis that PTP1B deletion protects against ERS‐mediated endothelial dysfunction, ERS was induced with either tunicamycin (TUNICA) in aortic rings from PTP1B null (KO) and control mice (WT) or by treating WT and KO mice with STZ for 4 weeks. Assessment of the vascular function demonstrated that TUNICA reduced endothelial function by 30% in WT mice while endothelial function remained intact in KO mice. ACh relaxation was completely abolished by LNAME but neither tempol nor indomethacin improved ERS‐mediated endothelial dysfunction, suggesting that neither ROS nor COX derivatives are involved in the dysfunction. TUNICA blunted Ca2+‐mediated relaxation in WT mice only, suggesting that PTP1B deletion preserves eNOS sensitivity to Ca2+. Four weeks of STZ treatment significantly reduced endothelial function in WT mice. Acute treatment of aortic rings with the ERS inhibitor TUDCA restored endothelial function and confirmed that type I diabetes induces endothelial dysfunction via ERS. Despite a higher glycemia compared to WT mice, PTP1B KO mice did not develop an endothetlial dysfunction in response to STZ and TUDCA did not affect vascular relaxation. Consequently, PTP1B appears to be a key target to prevent endothelial function.
Recent studies support the concept that obesity is associated with different forms of cancers. PTP1B is a major negative regulator of the Insulin receptor and JAK2 kinase acting downstream of leptin ...and growth hormone signaling, and thus an important mediator towards the pathogenesis of diabetes and obesity. More recently, it was also found to act as an oncogene in breast cancer. Human studies have also reported that PTP1B levels are increased with diabetes, obesity and cancer making this enzyme an exceptional drug target.
Obesity is characterized by excessive fat deposition and increased free fatty acids (FFA) into the circulation. FFA may also contribute to the development of some cancers, on the basis that FFA concentrations are elevated in several cancer patients. Despite a growing interest in the oncogenic contribution of FFA, the metabolic basis for this correlation remains unclear. In this context dysregulated de novo FFA biosynthesis pathway is due in large part, to increased expression and activity of fatty acid synthase (FAS), a key lipogenic enzyme. Increased expression of hormone sensitive lipase (HSL) has been also shown to be a major cause in enhanced lipolysis in cancer cachexia. We present data suggesting that PTP1B may play a crucial role in developing obesity and insulin resistance through the control of expression and activity of specific lipases involved in the pathway hydrolyzing triacylglycerols into FFA and glycerol. We believe that PTP1B act in the control of FFA levels in cancer cells, through the regulation of lipases and in promoting the production of FFA‐derived signaling molecules that contribute to tumor growth.
Numerous factors are known to affect the plasma metabolism of HDL, including lipoprotein receptors, lipid transfer protein, lipolytic enzymes and HDL apolipoproteins. In order to better define the ...role of HDL apolipoproteins in determining plasma HDL concentrations, the aims of the present study were: a) to compare the in vivo rate of plasma turnover of HDL apolipoproteins i.e., apolipoprotein A-I (apoA-I), apoC-I, apoC-III, and apoE, and b) to investigate to what extent these metabolic parameters are related to plasma HDL levels. We thus studied 16 individuals with HDL cholesterol levels ranging from 0.56–1.66 mmol/l and HDL apoA-I levels ranging from 89–149 mg/dl. Plasma kinetics of HDL apolipoproteins were investigated using a primed constant (12 h) infusion of deuterated leucine. Plasma HDL apolipoprotein levels were 41.8 ± 1.5, 9.7 ± 0.5, 4.9 ± 0.5, and 0.7 ± 0.1 μmol/l for apoA-I, apoC-I, apoC-III and apoE. Plasma transport rates (TRs) were 388.6 ± 24.7, 131.5 ± 12.5, 66.5 ± 9.1, and 31.4 ± 3.3 nmol·kg−1·day−1; and residence times (RTs) were 5.1 ± 0.4, 3.7 ± 0.3, 3.6 ± 0.3, and 1.1 ± 0.1 days, respectively. HDL cholesterol and apoA-I levels were significantly correlated with HDL apoA-I RT (r = 0.69 and r = 0.56), and were not significantly correlated with HDL apoA-I TR. In contrast, HDL apoC-I, apoC-III, and apoB levels were all positively related to their TRs and not their RTs. HDL apoC-III TR was postively correlated with levels of HDL apoC-III (r = 0.73, P < 0.01), and with those of HDL cholesterol and apoA-I (r = 0.54 and r = 0.53, P < 0.05, respectively). HDL apoC-III TR was in turn related to HDL apoA-I RT (r = 0.51, P < 0.05).Together, these results provide in vivo evidence for a link between the metabolism of HDL apoC-III and apoA-I, and suggest a role for apoC-III in the regulation of plasma HDL levels.
AbstractThis paper presents the results obtained from the estimation of free-flow speed on two-lane rural highways. The data used for the analysis were collected in Northwest Italy using video ...cameras and a laser speed gun. The model structure adopted separates the estimate of the central tendency of speeds from the typical deviations of individual speeds. Hence, in the model, the same set of variables can be used to determine both the mean value and the standard deviation of the speed distribution; the desired speed percentile is then calculated by considering the associated standard normal random variable (Z). Random effects (RE) were included in the model to account for the variability in time and space of the data that contain multiple measurements for the same road/section/direction and to remove any dependency between estimation errors from individual observations.
This research examines the role played by an employee's supervisor and organization in the relationship between structural and content plateauing, affective commitment to the organization, and ...psychological distress. Our analyses, based on data taken from a sample of 575 hospital employees, reveal that there is a significant relationship between the two forms of plateauing and perceived supervisor support, whereas only hierarchical plateauing is related to perceived organizational support. Our results also highlight the mediating effect of perceived organizational support in the relationship between hierarchical plateauing, perceived supervisor support, and the consequences examined.
Cette étude vise à examiner dans quelle mesure l'effet de la justice procédurale et de la fierté organisationnelle sur l'engagement affectif d'un individu envers son organisation varie selon ...l'internalité ou l'externalité de son locus de contrôle. Les résultats indiquent que le locus de contrôle exerce un effet modérateur dans la relation entre l'engagement affectif et ses deux antécédents proposés, de sorte que les perceptions de justice procédurale et la fierté organisationnelle conduisent davantage à lengagement affectif chez les individus qui croient détenir le contrôle sur leur environnement. En plus d'enrichir notre compréhension du mécanisme de développement de l'engagement, les résultats mettent de l'avant l'importance d'investiguer l'interaction de facteurs individuels et organisationnels dans la prédiction des attitudes et comportements au travail. Ces résultats permettent aux professionnels en relations industrielles (RI) et en relations du travail (RT) de mieux comprendre les réactions des salariés en regard des perceptions de justice organisationnelle.//Numerous studies have identified the factors that promote the affective commitment of employees to their organization. However, further research is still needed in order to understand the mechanisms by which these factors affect affective organizational commitment (AOC), and to identify in what context and under which conditions their effects prove to be the most powerful. This research is in line with recent studies that seek to overcome this limitation by investigating the interaction between organizational factors and individual characteristics in predicting AOC, arguing that individual factors affect perceptions of work experience, thereby influencing attitudes and behaviours at work. Based on social exchange theory and on the group engagement model, the purpose of this study is to examine the effect of the interaction between the locus of control (internal/external) and perceptions of procedural justice, as well as the organizational pride of employees on their level of emotional commitment. The results show that the locus of control has a significant moderating effect between the AOC and the two aspects mentioned above.
Summary
Drug resistance is a major public health challenge in leishmaniasis chemotherapy, particularly in the case of emerging
L
eishmania
/
HIV
‐1 co‐infections. We have delineated the mechanism of ...cell death induced by the
HIV
‐1 protease inhibitor,
N
elfinavir, in the
L
eishmania
parasite. In order to further study
N
elfinavir–
L
eishmania
interactions, we selected
N
elfinavir‐resistant axenic amastigotes
in vitro
and characterized them.
RNA
expression profiling analyses and comparative genomic hybridizations of closely related
L
eishmania
species were used as a screening tool to compare
N
elfinavir‐resistant and ‐sensitive parasites in order to identify candidate genes involved in drug resistance. Microarray analyses of
N
elfinavir‐resistant and ‐sensitive
L
eishmania
amastigotes suggest that parasites regulate
mRNA
levels either by modulating gene copy numbers through chromosome aneuploidy, or gene deletion/duplication by homologous recombination. Interestingly, supernumerary chromosomes 6 and 11 in the resistant parasites lead to upregulation of the
ABC
class of transporters. Transporter assays using radiolabelled
N
elfinavir suggest a greater drug accumulation in the resistant parasites and in a time‐dependent manner. Furthermore, high‐resolution electron microscopy and measurements of intracellular polyphosphate levels showed an increased number of cytoplasmic vesicular compartments known as acidocalcisomes in
N
elfinavir‐resistant parasites. Together these results suggest that
N
elfinavir is rapidly and dramatically sequestered in drug‐induced intracellular vesicles.
HIV-1 pathogenesis is intimately linked with microbial infections and innate immunity during all stages of the disease. While the impact of microbial-derived products in transmission of R5-using ...virus to CD4.sup.+ T cells by dendritic cells (DCs) has been addressed before, very limited data are available on the effect of such compounds on DC-mediated dissemination of X4-tropic variant. Here, we provide evidence that treatment of DCs with dectin-1/TLR2 and NOD2 ligands increases cis-infection of autologous CD4.sup.+ T cells by X4-using virus. This phenomenon is most likely associated with an enhanced permissiveness of DCs to productive infection with X4 virus, which is linked to increased surface expression of CXCR4 and the acquisition of a maturation profile by DCs. The ensuing DC maturation enhances susceptibility of CD4.sup.+ T cells to productive infection with HIV-1. This study highlights the crucial role of DCs at different stages of HIV-1 infection and particularly in spreading of viral strains displaying a X4 phenotype.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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