The effects of aerobic exercise on the intestinal tumors and flora of the ApcMin/+ mouse

IntroductionIntestinal tumor is one of the most common tumors that seriously threaten the health of residents all over the world. Studies suggest that the imbalance of intestinal flora is associated with tumorgenesis; meanwhile, long-term regular aerobic exercise can improve the occurrence and development of tumors. However, moderate aerobic exercise affecting the development of intestinal tumors and their related flora has not been explored. Thus, the purpose of our study is to explore the effects of aerobic exercise on intestinal tumor growth and flora changes in ApcMin/+ mice, and try to answer whether there is a correlation between them after exercise intervention.MethodsIn this study, 18 required ApcMin/+ mice were randomly divided into Model group (n = 6), Exercise group (n = 6), and Aspirin group (positive control, n = 6), while C57BL/6 J wild-type mice were used as the blank control group. Each group is given corresponding intervention. Weight monitoring, tumor counts, hematoxylin–eosin staining, TdT-mediated dUTP nick-end labeling (TUNEL) fluorescence assay, immunohistochemistry (IHC), fecal sampling and grouping, and bacterial 16S rDNA gene analysis were completed after 12 weeks’ intervention for each group of mice.ResultsAs a result, we were able to show significant improvements in mice’ body weight changing rates (Exercise group 8.6% higher than Model control group), tumor numbers (Exercise group 4.33 ± 0.94 vs. Model control group 7.33 ± 2.49.

Bovine mammary gland X chromosome inactivation.

X chromosome inactivation (XCI) is a process by which 1 of the 2 copies of the X chromosomes present in female mammals is inactivated. The transcriptional silencing of one X chromosome achieves dosage compensation between XX females and XY males and ensures equal expression of X-linked genes in both sexes. Although all mammals use this form of dosage compensation, the complex mechanisms that regulate XCI vary between species, tissues, and development. These mechanisms include not only varying levels of inactivation, but also the nature of inactivation, which can range from being random in nature to driven by parent of origin. To date, no data describing XCI in calves or adult cattle have been reported and we are reliant on data from mice to infer potential mechanisms and timings for this process. In the context of dairy cattle breeding and genomic prediction, the implications of X chromosome inheritance and XCI in the mammary gland are particularly important where a relatively small number of bulls pass their single X chromosome on to all of their daughters. We describe here the use of RNA-seq, whole genome sequencing and Illumina BovineHD BeadChip (Illumina, San Diego, CA) genotypes to assess XCI in lactating mammary glands of dairy cattle. At a population level, maternally and paternally inherited copies of the X chromosome are expressed equally in the lactating mammary gland consistent with random inactivation of the X chromosome. However, average expression of the paternal chromosome ranged from 10 to 90% depending on the individual animal. These results suggest that either the mammary gland arises from 1 or 2 stem cells, or a nongenetic mechanism that skews XCI exists. Although a considerable amount of future work is required to fully understand XCI in cattle, the data reported here represent an initial step in ensuring that X chromosome variation is captured and used in an appropriate manner for future genomic selection.

Yes-Associated Protein in Hepatocellular Carcinoma is Associated with Tumor Differentiation and Patient Age at Diagnosis, but not Markers of HBV Infection.

BACKGROUND: It was necessary to assess the relationship between Yes-associated protein (YAP) and some clinical features of hepatocellular carcinoma (HCC), especially hepatitis B virus (HBV) correlation factors as they relate to tumorigenesis. METHODS: A tissue microarray including 84 HCC samples was retrospectively analyzed by immunohistochemistry. RESULTS: This study showed that YAP expression was associated with HCC differentiation and the patient age at diagnosis of HCC. The mean age at diagnosis of YAP(+) HCC patients was 46.19 ± 9.45 years old, which is youn- ger than 51.40 ± 12.51 years old found for YAP(-) HCC patients (< 0.048). There was no significant correlation between YAP expression and HBV correlation factors (HBsAg, HBV DNA, and the duration of hepatitis B infec- tion). CONCLUSIONS: YAP(+) HCC patients had a younger mean age at diagnosis and more poor-differentiation charac- teristics of HCC. However, there were no independent HBV correlation factors.

[Reactive oxygen species are triggers and mediators of an increase in cardiac tolerance to impact of ischemia-reperfusion].

Reactive oxygen species (ROS) are triggers of ischemic preconditioning (IP). On the role of intracellular messengers of such cardioprotective effect of preconditioning claim: O2*, H2O2, OH*. However, we cannot exclude the possibility that other reactive oxygen metabolites also involved in the IP. Presented data suggest that IP enhances the production of ROS. The source of ROS may be mitochondrial respiratory chain and NADPH oxidase. Exogenous reactive oxygen species (O2*, H2O2) mimic the cardioprotective effect of preconditioning. Preconditioning prevents free radical damage of the heart during ischemia-reperfusion. The protective effect of IP is the consequence of reducing the production of ROS or the result of increased formation of endogenous antioxidants. Antioxidant enzymes are not involved in the protective effect of IP. Cardioprotective effect of many compounds (bradykinin, opioids, acetylcholine, phenylephrine, tumor necrosis factor-α, volatile anesthetics, protonophores, diazoxide, angiotensin II) depends on the increased production of ROS.

[Receptor and signalling mechanisms of antiarrhythmic effects of ischemic pre-conditioning].

It has been established that ischemic preconditioning (IP) exerts significant antiarrhythmic effects, as revealed in experiments both in vivo and in vitro. Consequently, processes arising within the myocardium play a key role in adaptive tolerance to ischemia/reperfusion. Preconditioning enhances cardiac electrical stability both in animals and humans. The antiarrhythmic effect of preconditioning is transient, with enhanced tolerance to ischemia-reperfusion triggered arrhythmogenesis dissipating 2-3 after the IP stimulus. The basis of the antiarrhythmic and cardioprotective effects of IP may differ. Preconditioning improves conduction of the cardiac electrical impulse, thereby preventing occurrence of re-entrant arrhythmias. NO-synthase and peroxynitrite play an important role in evolution of the antiarrhythmic effects of IP. Furthermore, intracellular Ca2+ may be a trigger of improved cardiac electrical stability after IP. It has been established that G(i/o)-protein coupled receptors are not involved in antiarrhythmic effects of IP, whereas bradykinin B2 and alpha1 adrenergic receptor activities are involved in IP-dependent improvements in cardiac electrical stability. Adenosine receptors contribute only partially to these effects. In terms of signalling mechanisms, protein kinase C appears essential to the antiarrhythmic effects of IP, whereas PI3-kinase and cyclooxygenase do not appear to be significantly involved. It has also been established that cardiac mast cells are involved in IP effects. Some data indicate that increased cardiac electrical stability with preconditioning depends upon mitoK(ATP) channel opening. Other data provide evidence that antiarrhythmic effects of preconditioning depends upon sarcK(ATP) channel opening. Some data indicate that an increase in electrical stability of heart after preconditioning depends upon mitoK(ATP) channel opening. Other data are evidence that antiarrhythmic effect of preconditioning depends upon sarCK(ATP) channel opening. Further work is needed to fully delineate the mechanistic basis of antiarrhythmic effects of IP.

[Problem of end-effector of ischemic postconditioning of the heart].

Analysis of literature source indicates that main pretenders to the role of end-effectors of ischemic postconditioning of the heart are: 1) Ca(2+)-dependent K+ channel of BK-type (big conductance K+ channel), 2) mitoK(ATP) channel (mitochondrial ATP-sensitive K(+)-channel), 3) MPT pore (mitochondrial permeability transition pore). At the same time, some investigators consider that mitoK(ATP) channel is only an intermediate link in the series of signaling events ensured an increase in cardiac tolerance to impact of ischemia-reperfusion. The most likely end-effector of the three structures is MPT pore. Alternatively, it is possible, that unique molecular complex appearing a single end-effector of postconditioning does not exist. Perhaps, that there are several effectors ensured cardioprotective effect of adaptive phenomenon of postconditioning.

[Intracellular mechanisms of cardioprotection during adaptation to hypoxia. Triggers and kinase cascades].

Adaptation to chronic hypoxia increases myocardial ischemic tolerance to injury caused by acute ischemia-reperfusion. In this article, we provide a brief overview of current literary data dealing with signalling mechanisms that can play a certain role in chronic hypoxia-induced cardioprotection. It has been shown that reactive oxygen species are major contributors to induction of the protective cardiac phenotype. In this context, we discuss the role of cytochromes, NADPH oxidase, heme oxygenase-1, mitochondrial monoamme oxidase, and prolyl 4-hydroxylase in triggering adaptive responses resulting in myocardial salvage. Moreover, we point to other cytoprotective proteins that can be involved in the protection from chronic hypoxia, such as protein kinase C, mitogen-activated protein kinases, 5'AMP-activated protein kinase, NO-synthases, mitochondrial ATP-sensitive K+ channels, Ca(2+)-activated large-conductance K+ channels, and MPT pore. Understanding the molecular mechanism of this long-lasting form of cardioprotection may help in providing basis for development of future therapeutic strategies to protect ischemic heart.

[Role of heat shock proteins in the mechanism of cardioprotective effect of transient hyperthermia and delayed preconditioning].

This review article focuses on discussing the role of the heat shock proteins (HSP) in myocardial protection against ischemia-reperfusion injury. In the present time, it has also been recognized that HSP may responsible for the increase in cardiac tolerance to ischemia-reperfusion after heat shock or after delayed ischemic preconditioning. The enhancement of the HSP expression in transgenic mice promotes an elevation of cardiac resistance to ischemia-reperfusion. The same effect is induced by transfection of the HSP genes. It has been established that deletion of the HSP70.1 and HSP70.3 genes abolishes a cardioprotective effect of delayed preconditioning. The mechanism by which HSP protect the heart against ischemia-reperfusion remains obscure. It has been proposed that HSP protect the heart via refolding proteins, an increase in 5'-nucleotidase activity, an improvement of Ca(2+)-pump function in sarcoplasmic reticulum during ischemia-reperfusion.

The effect of polymorphisms of MTHER gene and vitamin B on hyperhomocysteinemia.

The relationship between hyperhomocysteinemia and coronary artery disease (CAD) was investigated and the influence of environmental factors (Folate, VitB12) and genetic factors [N5, N10-methylenetetrahydrofolate reductase gene (MTHFR) or MTHFR gene mutation] on plasma homocysteine (Hcy) levels and the risk of CAD observed. Fifty-one CAD patients and 30 CAD-free subjects were recruited in the study. The polymorphisms of MTHFR gene were analyzed by PCR-RFLP and plasma total Hcy levels were measured by high performance liquid chromatography with fluorescence detection. Plasma folate and vitamin B12 concentrations were measured by an automated chemiluminescence method. It was found that mean total plasma Hcy concentrations were significantly higher in CAD patients than in CAD-free subjects (P < 0.01). The differences were also apparent among the three genotypes of MTHFR gene in CAD group (P < 0.05). There was no significant difference in the genotype distributions and allele frequencies between the two groups. A strong inverse correlation was found between folate or vitamin B12 and plasma Hcy levels according to MTHFR genotype (P < 0.01). It was concluded that hyperhomocysteinemia is a new independent risk factor for CAD. However, MTHFR gene mutation alone does not relate significantly to the morbidity of CAD since hyperhomocysteinemia and its influence on the risk of CAD are decided by both environmental and genetic factors. Supplementary treatment with vitamins B can effectively lower the plasma levels of Hcy, thus maybe reducing the risk of CAD.

Hydrogels with enhanced mass transfer for transdermal drug delivery.

The sonophoretic transport rates of monomeric insulin and vasopressin across human skin in vitro in the presence of a 20 kHz ultrasound field are shown to differ substantially depending on whether molecules enter the skin from a saline solution or from a viscous ultrasonic coupling medium (specifically, a methyl cellulose hydrogel or viscous sol). Theoretically, the reduction in sonophoretic transport caused by the hydrogels can be explained by boundary layers that form within the hydrogel owing to the relatively rapid rate of molecular transport across the (ultrasonically) permeated stratum corneum as well as poor diffusive mass transfer between the skin and gel. The results of in vitro experiments performed with an ac current accompanying the ultrasound show that the mass-transfer barrier posed by the hydrogel can be eliminated for both vasopressin and insulin by suppressing the diffusive boundary layers, indicating that relatively high rates of sonophoretic molecular transport across human skin are achievable when hydrogels are used as the ultrasound coupling medium as long as method is used to induce molecular mixing within the gel.

Spontaneous vesicle formation at lipid bilayer membranes.

Unilamellar vesicles are observed to form spontaneously at planar lipid bilayers agitated by exothermic chemical reactions. The membrane-binding reaction between biotin and streptavidin, two strong transmembrane neutralization reactions, and a weak neutralization reaction involving an "antacid" buffer, all lead to spontaneous vesicle formation. This formation is most dramatic when a viscosity differential exists between the two phases bounding the membrane, in which case vesicles appear exclusively in the more viscous phase. A hydrodynamic analysis explains the phenomenon in terms of a membrane flow driven by liberated reaction energy, leading to vesicle formation. These results suggest that energy liberated by intra- and extracellular chemical reactions near or at cell and internal organelle membranes can play an important role in vesicle formation, membrane agitation, or enhanced transmembrane mass transfer.

The prognostic significance of histomorphometry and immunohistochemistry in giant cell tumors of bone.

Eighty-two cases of giant cell tumor (GCT) were reviewed. Hematoxylin-eosin-and hematoxylin, phloxine, saffron, and alcian green-stained sections (82 cases) were examined for mitotic rate, the number of giant cells, and the pleomorphism of the stromal cells. In 29 cases, the tumor was stained for CD68, alpha 1-antichymotrypsin (AIACT), S100 protein, Muramidase, and von Willebrand factor (factor VIII). The staining properties of mononuclear and multinucleated giant cells were compared. Morphometric analysis was performed on 14 cases with a LECO 2001 computer-assisted image analyzer (LECO Instruments Ltd, Mississauga, Ontario, Canada) and included absolute cell count, nuclear area, perimeter, roughness, roundness, and aspect and nuclear versus cytoplasmic ratios, measured both in the stromal cells and giant cells. The cases were divided into four groups: (1) cases with metastasis, (2) cases with recurrence, (3) cases with both metastasis and recurrence, and (4) cases with neither metastasis nor recurrence. Immunohistochemistry revealed a stronger AIACT than muramidase positivity in general. The staining was stronger in stromal cells than in giant cells. Giant cells in all tumors were positive for CD68. Stromal cells showed weaker positivity for the same stain. The number of asymmetrical mitotic figures was significantly greater in group 3 than in group 4 (P < .05). Morphometric assessment has identified a statistically significant difference in the aspect ratio and the roundness of the nuclei between these two groups. The other parameters did not differ significantly. In this article, the significance of these findings in prognostication and the histogenesis of the giant cell tumor are discussed. Their clinical applicability is yet to be determined.

T cell vaccination in multiple sclerosis.

T cell responses to myelin basic protein (MBP) are implicated to play an important role in the pathogenesis of multiple sclerosis (MS). These MBP autoreactive T cells are found to undergo in vivo activation and clonal expansion in patients with MS. They accumulate in the brain compartment and may reside in the brain lesions of patients with MS. As MBP-reactive T cells potentially hold a central position in initiation and perpetuation of the brain inflammation, specific immune therapies designed to deplete them may improve the clinical course of the disease. In this paper, the therapeutic potential of T cell vaccination in the treatment of MS is discussed in context of its immunological and clinical effect. The results of our phase one clinical trial indicate that T cell vaccination with inactivated MBP autoreactive T cells induces specific regulatory T cell network of the host immune system to deplete circulating MBP-reactive T cells in a clonotype-specific fashion. The immunity induced by T cell vaccination is clonotype-specific and long-lasting. Our longitudinal clinical evaluation further suggests a moderate reduction of rate of clinical exacerbation, disability score and the brain lesions (measured by magnetic resonance imaging) in vaccinated patients, as compared to matched controls. Our study should encourage further investigation on the treatment efficacy of T cell vaccination and further improvement for its clinical application.

The nucleation of receptor-mediated endocytosis.

A theory of the mechanical origins of receptor-mediated endocytosis shows that a spontaneous membrane complex formation can provide the stimulus for a local membrane motion toward the cytosol. This motion is identified with a nucleation stage of receptor-mediated endocytosis. When membrane complexes cluster, membrane deformation is predicted to be most rapid. The rate of growth of membrane depressions depends upon the relative rates of approach of aqueous cytosolic and extracellular fluids toward the cell membrane. With cytosolic and extracellular media characterized by apparent viscosities, the rate of growth of membrane depressions is predicted to increase as the extracellular viscosity nears the apparent viscosity of the cytosol and then to decrease when the extracellular viscosity exceeds that of the cytosol. To determine whether these trends would be apparent in the overall endocytosis rate constant, an experimental study of transferrin-mediated endocytosis in two different cell lines was conducted. The experimental results reveal the same dependence of internalization rate on extracellular viscosity as predicted by the theory. These and other comparisons with experimental data suggest that the nucleation stage of receptor-mediated endocytosis is important in the overall endocytosis process.