Zaburzenia unerwienia autonomicznego układu sercowo-naczyniowego a występowanie omdleń u osób z chorobą Parkinsona

Background and purpose The aim of the study was to investigate the relationship between syncope or presyncope occurrence and dysfunction of the cardiovascular autonomic system in patients with Parkinson disease (PD). Material and methods Twenty-four PD patients were studied, including 10 subjects with syncope/presyncope and 14 controls without those symptoms. Ambulatory blood pressure monitoring (ABPM), Holter electrocardiographic monitoring, carotid sinus massage, tilt test, and cardiac scintigraphy with 123I metaiodobenzylguanidine (MIBG) were performed. Results Differences between the two groups were found in myocardial scintigraphy and ABPM. The stepwise regression analyses suggest that the values of late phase reduced uptake of MIBG (95% CI: 0.0–0.77; p < 0.05) and daytime minimum systolic blood pressure (95% CI: 0.78–0.98; p = 0.007) may be related to the occurrence of syncope/presyncope. Conclusions The findings suggest an association between syncope/presyncope occurrence and dysfunction of the cardiovascular autonomic system in PD patients. Both 123I MIBG myocardial scintigraphy and ABPM may help identify a group of patients with an elevated risk for syncopic episodes which, in turn, may affect the choice of treatment.Wstęp i cel pracy Celem pracy była analiza wpływu uszkodzenia unerwienia układu sercowo-naczyniowego na występowanie omdleń i stanów przedomdleniowych w grupie osób z chorobą Parkinsona (ChP). Materiał i metody Do badania włączono 24 chorych, u których rozpoznano prawdopodobną ChP. Grupę badaną stanowiło 10 osób, które zgłaszały występowanie omdleń i stanów przedomdleniowych, a grupę kontrolną 14 pacjentów bez takich incydentów w wywiadzie. Protokół badawczy obejmował następujące czynności: masaż zatoki szyjnej, monitorowanie EKG i ciśnienia tętniczego metodą Holtera (ABPM), test pochyleniowy oraz badanie scyntygraficzne serca z zastosowaniem 123I metajodobenzylguanidyny (MIBG). Wyniki W analizie regresji logistycznej wykazano istnienie związku między występowaniem omdleń/stanów przedomdleniowych a wynikami ABPM – minimalnym ciśnieniem skurczowym w interwale dziennym (95% CI: 0,78–0,98; p = 0,007), a także wynikami fazy późnej badania scyntygraficznego serca z użyciem MIBG (95% CI: 0,0–0,77; p < 0,05). Wnioski Wyniki badań sugerują związek pomiędzy występowaniem omdleń i stanów przedomdleniowych a zaburzeniami unerwienia autonomicznego układu sercowo-naczyniowego u chorych na ChP. Scyntygrafia serca z użyciem 123I MIBG oraz ABPM mogą być użyteczne przy ocenie narażenia na występowanie omdleń i stanów przedomdleniowych w tej grupie pacjentów, co powinno mieć wpływ na postępowanie terapeutyczne. Scyntygrafia serca z użyciem 123I MIBG jest badaniem bezpiecznym. W przypadku metod jakościowych, takich jak test pochyleniowy czy masaż zatoki szyjnej, stwierdza się większy odsetek powikłań

The Signal Transducer and Activator of Transcription 1 (STAT1) Inhibits Mitochondrial Biogenesis in Liver and Fatty Acid Oxidation in Adipocytes

The transcription factor STAT1 plays a central role in orchestrating responses to various pathogens by activating the transcription of nuclear-encoded genes that mediate the antiviral, the antigrowth, and immune surveillance effects of interferons and other cytokines. In addition to regulating gene expression, we report that STAT1-/- mice display increased energy expenditure and paradoxically decreased release of triglycerides from white adipose tissue (WAT). Liver mitochondria from STAT1-/- mice show both defects in coupling of the electron transport chain (ETC) and increased numbers of mitochondria. Consistent with elevated numbers of mitochondria, STAT1-/- mice expressed increased amounts of PGC1α, a master regulator of mitochondrial biogenesis. STAT1 binds to the PGC1α promoter in fed mice but not in fasted animals, suggesting that STAT1 inhibited transcription of PGC1α. Since STAT1-/-mice utilized more lipids we examined white adipose tissue (WAT) stores. Contrary to expectations, fasted STAT1-/- mice did not lose lipid from WAT. β-adrenergic stimulation of glycerol release from isolated STAT1-/- WAT was decreased, while activation of hormone sensitive lipase was not changed. These findings suggest that STAT1-/- adipose tissue does not release glycerol and that free fatty acids (FFA) re-esterify back to triglycerides, thus maintaining fat mass in fasted STAT1-/- mice

Być czy nie być otyłym : nowa rola ścieżki przekazu sygnału Jak/Stat w rozwoju brunatnej tkanki tłuszczowej i zapobieganiu otyłości

Obesity is defined as abnormal or excessive fat accumulation that presents a significant risk to health and is a major risk factor for a number of chronic diseases such as diabetes, cardiovascular disorders and cancer. Janus kinases (Jaks) and signal transducers and activators of transcription (Stats) have emerged as critical regulators of numerous fundamental biological processes and are important in the etiology of various disease conditions. The Jak/Stat pathway is a primary mediator of leptin signaling, which has been implicated in obesity. We found that mice lacking Tyk2, one of the Jak’s, become spontaneously obese. We discovered that expression of a variety of mRNAs that regulate fatty acid and glucose homeostasis are altered in liver, skeletal muscle and adipose tissue of Tyk2- null mice, which is consistent with metabolic syndrome. Proper energy balance prevents the development of obesity and is dependent on energy expenditure. Brown adipose tissue (BAT) dissipates chemical energy in the form of heat in response to excess of calories and constitutes a natural defense mechanism against hypothermia and obesity. Our data suggest that differentiation and function of BAT is defective in mice that do not express Tyk2, which might explain the obese phenotype in these animals. Using an in vitro differentiation model of brown preadipocytes isolated from mice with a Tyk2 deletion, we were able to restore the differentiation by expression of either wild type or kinase inactive Tyk2 (Tyk2KD), as well as constitutively active form of Stat3 (Stat3CA). Recent data provided evidence that PRDM16 is the master regulator controlling the brown fat/skeletal muscle switch from a common progenitors. Consistent with severe decrease in PRDM16 expression, we observed up-regulation of muscle-specific mRNAs in Tyk2- null cells. Remarkably, differentiation of Tyk2 -/- preadipocytes cannot be rescued by PRDM16. These data suggest that Tyk2 is key player in brown preadipocytes differentiation acting upstream of PRDM16 or in parallel with it. Interestingly, we also found that the absence of Tyk2 results in epigenetic changes in the promoters of BAT- specific genes such as UCP1 (uncoupling protein 1) and Cidea (cell death-inducing DFFA-like effector a), abrogating their expression. Consistent with our in vitro data, BAT- specific expression of the Stat3CA transgene restores BAT differentiation in mice. Animals expressing Stat3CA in BAT exhibit significantly reduced body weight and improved insulin sensitivity in comparison to control mice, which demonstrate that the obese phenotype of Tyk2 -/- mice is most likely a result of defects in BAT differentiation occurring in these animals. The above observations present a novel role of Jak/Stat pathway in development of BAT and the control of obesity. The fact that kinase inactive Tyk2 also restores brown adipocytes differentiation reinforces the innovative concept that the actions of this kinase are not mediated by its well described activation in cytokine activation of the Jak/Stat cascade

EBF1 primes B-lymphoid enhancers and limits the myeloid bias in murine multipotent progenitors.

Funder: Max-Planck-GesellschaftHematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) generate all cells of the blood system. Despite their multipotency, MPPs display poorly understood lineage bias. Here, we examine whether lineage-specifying transcription factors, such as the B-lineage determinant EBF1, regulate lineage preference in early progenitors. We detect low-level EBF1 expression in myeloid-biased MPP3 and lymphoid-biased MPP4 cells, coinciding with expression of the myeloid determinant C/EBPα. Hematopoietic deletion of Ebf1 results in enhanced myelopoiesis and reduced HSC repopulation capacity. Ebf1-deficient MPP3 and MPP4 cells exhibit an augmented myeloid differentiation potential and a transcriptome with an enriched C/EBPα signature. Correspondingly, EBF1 binds the Cebpa enhancer, and the deficiency and overexpression of Ebf1 in MPP3 and MPP4 cells lead to an up- and downregulation of Cebpa expression, respectively. In addition, EBF1 primes the chromatin of B-lymphoid enhancers specifically in MPP3 cells. Thus, our study implicates EBF1 in regulating myeloid/lymphoid fate bias in MPPs by constraining C/EBPα-driven myelopoiesis and priming the B-lymphoid fate

Mitochondrial-targeted Signal transducer and activator of transcription 3 (STAT3) protects against ischemia-induced changes in the electron transport chain and the generation of reactive oxygen species

Expression of the STAT3 transcription factor in the heart is cardioprotective and decreases the levels of reactive oxygen species. Recent studies indicate that a pool of STAT3 resides in the mitochondria where it is necessary for the maximal activity of complexes I and II of the electron transport chain. However, it has not been explored whether mitochondrial STAT3 modulates cardiac function under conditions of stress. Transgenic mice with cardiomyocyte-specific overexpression of mitochondria-targeted STAT3 with a mutation in the DNA-binding domain (MLS-STAT3E) were generated. We evaluated the role of mitochondrial STAT3 in the preservation of mitochondrial function during ischemia. Under conditions of ischemia heart mitochondria expressing MLS-STAT3E exhibited modest decreases in basal activities of complexes I and II of the electron transport chain. In contrast to WT hearts, complex I-dependent respiratory rates were protected against ischemic damage in MLS-STAT3E hearts. MLS-STAT3E prevented the release of cytochrome c into the cytosol during ischemia. In contrast to WT mitochondria, ischemia did not augment reactive oxygen species production in MLS-STAT3E mitochondria likely due to an MLS-STAT3E-mediated partial blockade of electron transport through complex I. Given the caveat of STAT3 overexpression, these results suggest a novel protective mechanism mediated by mitochondrial STAT3 that is independent of its canonical activity as a nuclear transcription factor

The role of Tyk2 in regulation of breast cancer growth

The antigrowth and immunomodulatory actions of interferons (IFNs) have enabled these cytokines to be used therapeutically for the treatment of a variety of hematologic and solid malignancies. IFNs exert their effects by activation of the Jak/Stat signaling pathway. IFNγ stimulates the tyrosine kinases Jak1 and Jak2, resulting in activation of the Stat1 transcription factor, whereas type 1 IFNs (IFNα/β) activate Jak1 and Tyk2, which mediate their effects through Stat1 and Stat2. Disruption in the expression of IFNγ, IFNα receptors, or Stat1 inhibits antitumor responses and blunt cancer immunosurveillance in mice. Mutations in Jak2 or constitutive activation of Jak1 or Jak2 also promote the development of a variety of malignancies. Although there are data indicating that Tyk2 plays a role in the pathogenesis of lymphomas, the effects of Tyk2 expression on tumorigenesis are unknown. We report here that Tyk2(−/−) mice inoculated with 4T1 breast cancer cells show enhanced tumor growth and metastasis compared to Tyk2(+/+) animals. Accelerated growth of 4T1 cells in Tyk2(−/−) animals does not appear to be due to decreased function of CD4(+), CD8(+) T cells, or NK cells. Rather, the tumor suppresive effects of Tyk2 are mediated at least in part by myeloid-derived suppressor cells, which appear to be more effective in inhibiting T cell responses in Tyk2(−/−) mice. Our results provide the first evidence for a role of Tyk2 in suppressing the growth and metastasis of breast cancer

<i>STAT1</i>^<i>-/-</i> mice display increased mitochondrial biogenesis in liver.

<p>a. Amounts of PGC1α mRNA were measured by qRT-PCR and quantitated relative to tubulin in livers of fed or fasted <i>STAT1</i>^<i>+/+</i> and <i>STAT1</i>^<i>-/-</i> mice. Values were normalized to <i>STAT1</i>^<i>+/+</i> fed. * Significantly different p< 0.05(<i>STAT1</i>^<i>+/+</i> fed vs. <i>STAT1</i>^<i>+/+</i> fasted and <i>STAT1</i>^<i>+/+</i> fed vs. <i>STAT1</i>^<i>-/-</i> fed) as determined by two-way ANOVA + Holm-Sidak’s post-test, n = 5, 8–10 week old male mice per group. b. Mitochondrial DNA (ND4, ND6, Cytb, Cox1 and ATPase6) in livers of <i>STAT1</i>^<i>+/+</i> and <i>STAT1</i>^<i>-/-</i> mice was quantitated relative to actin DNA and normalized to <i>STAT1</i>^<i>+/+</i>. * Significantly different p< 0.05, Student’s T-test, correction for multiple testing c. Amount of mitochondrial protein in <i>STAT1</i>^<i>+/+</i> and <i>STAT1</i>^<i>-/-</i> livers, which was normalized to the weight of the liver. d. Number of mitochondria in <i>STAT1</i>^<i>+/+</i> and <i>STAT1</i>^<i>-/-</i> livers. n = 3 mice. * Significantly different p < 0.05, Student’s T-test. e. Mitochondrial DNA from <i>STAT1</i>^<i>+/+</i> and <i>STAT1</i>^<i>-/-</i> hearts. f. Amounts of mitochondrial RNAs in hearts in <i>STAT1</i>^<i>+/+</i> and <i>STAT1</i>^<i>-/-</i> mice. n = 6 mice per group.</p

<i>STAT1</i>^<i>-/-</i> mice have lower oxygen consumption.

<p>Oxygen consumption was measured from isolated liver mitochondria of male mice either fed or fasted using substrates that donate to specific sites in the ETC a. Glutamate-malate for Complex I, b. Succinate (+rotenone) for complex II, and c. TMPD-ascorbate (+rotenone) for Complex IV. Significance of p < 0.05 was determined with two-way ANOVA + Holm Sidak’s post test, n = 6, 8–10 week old male mice d. Amounts of UCP2 mRNA levels were measured in male mice either fed or fasted using qRT-PCR and quantitated relative to tubulin in livers. Values were normalized to <i>STAT1</i>^<i>+/+</i> fed. Significance of p < 0.05 were determined by two-way ANOVA + Holm Sidak’s post test, n = 4, 8–10 week old male mice.</p

STAT1 binding to the PGC1α promoter is increased in fed mice, and levels of STAT1 protein are decreased in fasted mice.

<p>a. STAT1 binding to the PGC1α promoter was performed by ChIP assays from fed or fasted <i>STAT1</i>^<i>+/+</i> mice. * Significantly different p < 0.05, Student’s T-test b. Whole cell liver extracts (WCE) from fasted or fed <i>STAT1</i>^<i>+/+</i> mice were immunoblotted for STAT1, STAT2 and tubulin as a loading marker. STAT1 or STAT2 protein levels as determined by densitometry were quantitated relative to tubulin and then normalized to control. * Significantly different p < 0.05, Student’s T-test. c. STAT1-Tyrosine 701 phosphorylation in livers of fed and fasted <i>STAT1</i>^<i>+/+</i> mice. Liver WCE from <i>STAT1</i>^<i>+/+</i> and <i>STAT1</i>^<i>-/-</i> mice under fed or fasted conditions were analyzed for total STAT1 (middle panel), STAT1 701 tyrosine phosphorylation (upper panel), or tubulin as a loading control (bottom panel). n = 3 mice per group.</p