Cancer is a complex, multifactorial disease that modern medicine ultimately aims to overcome. Downstream of tyrosine kinase 2 (DOK2) is a well-known tumor suppressor gene, and a member of the downstream protein DOK family of tyrosine kinases. Through a search of original literature indexed in PubMed and other databases, the present review aims to extricate the mechanisms by which DOK2 acts on cancer, thereby identifying more reliable and effective therapeutic targets to promote enhanced methods of cancer prevention and treatment. The review focuses on the role of DOK2 in multiple tumor types in the lungs, intestines, liver, and breast. Additionally, we discuss the potential mechanisms of action of DOK2 and the downstream consequences via the Ras/MPAK/ERK or PI3K/AKT/mTOR signaling pathways., Pei Sun, Rumeng Li, Yingying Meng, Shijun Xi, Qinqi Wang, Xiulan Yang, Xiaochun Peng, Jun Cai., and Obsahuje bibliografii
Lipoprotein (a) [Lp(a)] is an LDL-like particle that contains an apolipoprotein B100 molecule covalently bound to a plasminogen-like glycoprotein, apolipoprotein (a) [apo(a)]. Epidemiological evidence supports a direct and causal association between Lp(a) levels and coronary risk. On the contrary, a few prospective findings demonstrate inverse association of Lp(a) levels with risk of type 2 diabetes (T2DM). The aim of our study was to evaluate the association of Lp(a) with indicators of insulin resistance (IR) and metabolic syndrome (MS), which precede development of T2DM. We enrolled 607 asymptomatic dyslipidemic subjects (295 men and 312 women, mea n age 45.6±14.0 years) into our cross-sectional study. Lp(a) concentrations correlated inversely with TG, AIP, insulin, HOMA, C-peptide, BMI, waist circumference, and number of MS components (p<0.01 for all). Subjects with MS had significantly lower Lp(a) concentrations in comparison with those without the presence of this phenotype (p<0.0001). Serum concentrations of Lp(a) in the lower (1th 3rd) quartiles of insulin and HOMA were significantly higher than in the 4 th quartile of these insulin resistance markers (p<0.001). Odds ratios of having increased markers of IR (TG, HOMA) and MS in top quartile of Lp(a) also indicate inverse association of Lp(a) with IR. The results of our study support an inverse association of Lp(a) levels with IR and MS that precedes overt T2DM diagnosis., H. Vaverková, D. Karásek, M. Halenka, L. Cibíčková, V. Kubíčková., and Obsahuje bibliografii
Distension is a regular mechanical stimulus in gastrointestinal (GI) tract. This study was designed to investigate the effect of hypotonic stress on pacemaking activity and determine whether actin microfilament is involved in its mechanism in cultured murine intestinal interstitial cells of Cajal (ICCs) by using whole-cell patch-clamp and calcium imaging techniques. Hypotonic stress induced sustained inward holding current from the baseline to -650±110 pA and significantly decreased amplitudes of pacemaker current. Hypotonic stress increased the intensity of basal fluorescence ratio (F/F0) from baseline to 1.09±0.03 and significantly increased Ca2+ oscillation amplitude. Cytochalasin-B (20 μM), a disruptor of actin microfilaments, significantly suppressed the amplitudes of pacemaker currents and calcium oscillations, respectively. Cytochalasin-B also blocked hypotonic stress-induced sustained inward holding current and hypotonic stress-induced increase of calcium oscillations. Phalloidin (20 μM), a stabilizer of actin microfilaments, significantly enhanced the amplitudes of pacemaker currents and calcium oscillations, respectively. Despite the presence of phalloidin, hypotonic stress was still able to induce an inward holding current and increased the basal fluorescence intensity. These results suggest that hypotonic stress induces sustained inward holding current via actin microfilaments and the process is mediated by alteration of intracellular basal calcium concentration and calcium oscillation in cultured intestinal ICCs., Z. Y. Wang, X. Huang, D. H. Liu, H. L. Lu, Y. C. Kim, W. X. Xu., and Obsahuje bibliografii
Spontaneously hypertensive rats (SHR) are characterized by enhanced sympathetic vasoconstriction, whereas their vasodilator mechanisms are relatively attenuated compared to their high BP. The objective of our in vivo study was to evaluate whether the impaired function of BKCa and/or KV channels is responsible for abnormal cAMP-induced vasodilatation in genetic hypertension. Using conscious SHR and normotensive WKY rats we have shown that under the basal conditions cAMP overproduction elicited by the infusion of β-adrenoceptor agonist (isoprenaline) caused a more pronounced decrease of baseline blood pressure (BP) in SHR compared to WKY rats. Isoprenaline infusion prevented BP rises induced by acute NO synthase blockade in both strains and it also completely abolished the fully developed BP response to NO synthase blockade. These cAMP-induced vasodilator effects were diminished by the inhibition of either BKCa or KV channels in SHR but simultaneous blockade of both K+ channel types was necessary in WKY rats. Under basal conditions, the vasodilator action of both K+ channels was enhanced in SHR compared to WKY rats. However, the overall contribution of K+ channels to cAMP-induced vasodilator mechanisms is insufficient in genetic hypertension since a concurrent activation of both K+ channels by cAMP overproduction is necessary for the prevention of BP rise elicited by acute NO/cGMP deficiency in SHR. This might be caused by less effective activation of these K+ channels by cAMP in SHR. In conclusion, K+ channels seem to have higher activity in SHR, but their vasodilator action cannot match sufficiently the augmented vasoconstriction in this hypertensive strain., M. Pintérová, M. Behuliak, J. Kuneš, J. Zicha., and Obsahuje bibliografii
The skeleton shows an unconventional role in the physiology and pathophysiology of the human organism, not only as the target tissue for a number of systemic hormones, but also as endocrine tissue modulating some skeletal and extraskeletal systems. From this point of view, the principal cells in the skeleton are osteocytes. These cells primarily work as mechano-sensors and modulate bone remodeling. Mechanically unloaded osteocytes synthetize sclerostin, the strong inhibitor of bone formation and RANKL, the strong activator of bone resorption. Osteocytes also express hormonally active vitamin D (1,25(OH)2D) and phosphatonins, such as FGF23. Both 1,25(OH)2D and FGF23 have been identified as powerful regulators of the phosphate metabolism, including in chronic kidney disease. Further endocrine cells of the skeleton involved in bone remodeling are osteoblasts. While FGF23 targets the kidney and parathyroid glands to control metabolism of vitamin D and phosphates, osteoblasts express osteocalcin, which through GPRC6A receptors modulates beta cells of the pancreatic islets, muscle, adipose tissue, brain and testes. This article reviews some knowledge concerning the interaction between the bone hormonal network and phosphate or energy homeostasis and/or male reproduction., I. Zofkova., and Obsahuje bibliografii
In the last decade a growing body of data revealed that the cerebellum is involved in the regulation of the affective reactions as well as in forming the associ ation between sensory stimuli and their emotional values. In humans, cerebellar areas around the vermis are activated during mental recall of emotional personal episodes and during learning of a CS-US association. Lesions of the cerebellar vermis may affect retention of a fear memory without altering baseline motor/autonomic responses to the frightening stimuli in both human and animal models. Reversible inactivation of the vermis during the consolidation period impairs retention of fear memory in rodents. Recent findings demonstrate that long-term potentiation (LTP) of synapses in the cerebellar cortex occurs in relati on to associative fear learning similar to previously reported data in the hippocampus and amygdala. Plastic changes affect both excitatory and inhibitory synapses. This concomitant potentiation allows the cerebellar cortical network to detect co incident inputs, presumably conveying sensorial stimuli, with better efficacy by keeping the time resolution of the system unchanged. Collectively, these data suggest that the vermis participates in forming new CS-US association and translate an emotional stat e elaborated elsewhere into autonomic and motor responses., P. Strata, B. Scelfo, B. Sacchetti., and Obsahuje bibliografii a bibliografické odkazy
Membrane fluidity is a widely recognized biophysical variable that provides information about structural organization of the subcellular membranes exhibiting physical characteristics of liquid crystals. The term “fluidity” reflects in this case the tightness in packing of acyl parts of the membrane phospholipid molecules, a feature that may influence considerably the molecular mobility and via that also the sensitivity and reactivity of membranebound transporters, receptors and enzyme systems. Data presented in this review are aimed to demonstrate the substantial role of changes in membrane fluidity occurring in the processes associated with endogenous protection observed in cardiac sarcolemma and mitochondria in diverse pathologies, particularly in diabetes and hypertension., A. Ziegelhöffer, ... [et al.]., and Obsahuje seznam literatury
In experimental and human diabetes mellitus, evidence for an impaired function of the vascular endothelium has been found and has been suggested to contribute to the development of vascular complications in this disease. The aim of the study was to evaluate possible regional hemodynamic in vivo differences between healthy and diabetic rats which would involve nitric oxide (NO). Central hemodynamics and regional blood flow (RBF) were studied using radioactive microspheres in early streptozotocin (STZ)-diabetic rats and compared to findings in healthy control animals. This method provides a possibility to study the total blood flow and vascular resistance (VR) in several different organs simultaneously. L-NAME iv induced widespread vasoconstriction to a similar extent in both groups. In the masseter muscle of both groups, acetylcholine 2 μg/kg per min, induced a RBF increase, which was abolished by pretreatment with L-NAME, suggesting NO as a mediator of vasodilation. In the heart muscle of both groups, acetylcholine alone was without effect while the combined infusion of acetylcholine and L-arginine induced an L-NAME-sensitive increase in RBF. The vasodilation induced by high-dose acetylcholine (10 μg/kg per min) in the kidney was more pronounced in the STZ-diabetic rats. The results indicate no reduction in basal vasodilating NO-tone in the circulation of early diabetic rats. The sensitivity to vasodilating effects of acetylcholine at the level of small resistance arterioles vary between tissues but was not impaired in the diabetic rats. In the heart muscle the availability of L-arginine was found to limit the vasodilatory effect of acetylcholine in both healthy and diabetic rats. In conclusion, the results indicate a normal action of NO in the investigated tissues of the early STZ-diabetic rat., E. Granstam, S.-O. Granstam., and Obsahuje bibliografii
The mechanism of action by which insulin increases phosphatidic acid (PA) and diacylglycerol (DAG) levels was investigated in cultured hepatoma cells (HEPG2). Insulin stimulated phosphatidylcholine (PC) and phosphatidyl-inositol (PI) degradation through the activation of specific phospholipases C (PLC). The DAG increase appears to be biphasic. The early DAG production seems to be due to PI breakdown, probably through phosphatidyl-inositol-3-kinase (PI3K) involvement, whereas the delayed DAG increase is derived directly from the PC-PLC activity. The absence of phospholipase D (PLD) involvement was confirmed by the lack of PC-derived phosphatidylethanol production. Experiments performed in the presence of R59022, an inhibitor of DAG-kinase, indicated that PA release is the result of the DAG-kinase activity on the DAG produced in the early phase of insulin action., R. Novotná, P. de Vito, L. Currado, P. Luly, P. M. Baldini., and Obsahuje bibliografii