Dental pulp mesenchymal stem/stromal cells labeled with iron sucrose release exosomes and cells applied intra-nasally migrate to intracerebral glioblastoma.

We report on a simple iron oxide (Venofer) labeling procedure of dental pulp mesenchymal stem cells (DP-MSCs) and DP-MSCs transduced with yeast cytosinedeaminase::uracilphosphoribosyltransferase (yCD::UPRT-DP-MSCs). Venofer is a drug approved for intravenous application to treat iron deficiency anemia in patients. Venofer labeling did not affect DP-MSCs or yCD::UPRT-DP-MSCs viability and growth kinetics. Electron microscopy of labeled cells showed internalized Venofer nanoparticles in endosomes. MRI relativity measurement of Venofer labeled DP-MSCs in a phantom arrangement revealed that 100 cells per 0.1 ml were still detectable. DP-MSCs or yCD::UPRT-DP-MSCs and the corresponding Venofer labeled cells release exosomes into conditional medium (CM). CM from yCD::UPRT-DP-MSCs in the presence of a prodrug 5-fluorocytosine caused tumor cell death in a dose dependent manner. Iron labeled DP-MSCs or yCD::UPRT-DP-MSCs sustained their tumor tropism in vivo; intra-nasally applied cells migrated and specifically engrafted orthotopic glioblastoma xenografts in rats.

Deafferentation of the hypothalamic paraventricular nucleus (PVN) exaggerates the sympathoadrenal system activity in stressed rats.

OBJECTIVE: The hypothalamic paraventricular nucleus is a key structure in the regulation of the autonomic and neuroendocrine systems response to acute and chronic stress challenges. In this study, we examined the effect of a mechanical posterolateral deafferentation of the PVN on the activity of sympathoadrenal system (SAS) and hypothalamo-pituitary-adrenal (HPA) axis by measuring plasma concentrations of epinephrine (EPI), norepinephrine (NE), and corticosterone (CORT) in rats exposed to acute immobilization (IMO) stress. METHODS: The surgical posterolateral deafferentation of the PVN (PVN-deaf) was performed by Halasz knife, in brain of the adult male Sprague Dawley rats, according to coordinates of a stereotaxic atlas. Sham-operated (SHAM) animals underwent a craniotomy only. The animals were allowed to recover 14 days. Thereafter, the tail artery was cannulated and the animals exposed to acute IMO for 2 h. The blood samples were collected via cannula at the time points of 0, 5, 30, 60, and 120 min of the IMO. Concentrations of plasma EPI, NE, and CORT were determined by radioimmunoassay. RESULTS: The IMO-induced elevation of plasma EPI concentrations in the PVN-deaf rats reached statistical significance at 60 min of the IMO, when compared to SHAM rats. Similarly, the stress-induced elevation of the NE plasma levels in the PVN-deaf rats was significantly exaggerated at all time intervals of IMO in comparison with SHAM rats, whereas plasma CORT levels were significantly reduced. CONCLUSIONS: In contrast to the traditional view of excitatory role of the PVN in response to stress, our data indicate that some projections from the PVN to caudally localized hypothalamic structures, the brainstem or the spinal cord, exert inhibitory effect on the SAS system activity during acute IMO stress. The data indicate that stress-induced activation of the HPA axis is partially dependent on inputs from the brainstem to the PVN.

Medial prefrontal cortex transection enhanced stress-induced activation of sympathoadrenal system in rats.

OBJECTIVE: The medial prefrontal cortex (mPFC) projects to the sympathetic premotor and preganglionic neurons. Besides the well described modulatory effect on the hypothalamo-pituitary-adrenal (HPA) axis activity, the mPFC also exerts modulatory effect on the activity of the sympathoadrenal system (SAS). The aim of the present study was to find out whether interruption of the anatomical interconnections between the mPFC neurons and hypothalamic, brainstem and spinal cord structures may affect the SAS and HPA axis activities determined by the plasma catecholamines (epinephrine, EPI and norepinephrine, NE) and corticosterone (CS) levels in the rats exposed to a single immobilization (IMO) stress. METHODS: The posterior transection of the mPFC was performed bilaterally by inserting a V-shaped blade into the brain of adult male Sprague Dawley rats. Sham-operated animals (controls) underwent a craniotomy only. The animals were allowed to recover for 14 days. Thereafter, the tail artery was cannulated and the animals exposed to acute IMO for 2 h. The blood samples were collected at 5, 30, 60, 120 min of the IMO. Concentrations of the plasma EPI, NE, and CS were determined by radioimmunoassay. RESULTS: The IMO-induced elevation of the plasma EPI levels in the mPFC-transected rats reached statistical significance at 120 min of the IMO, when compared to controls. Similarly, plasma NE levels were significantly increased at 60 and 120 min of the IMO in the mPFC-transected animals in comparison with controls. The transection had no significant effect on the plasma CS levels. CONCLUSION: The data indicate that the mPFC transection may enhance the IMO-induced SAS activity without affecting the activity of the HPA axis. We found that the mPFC may exert an inhibitory effect on the SAS activity in the stressed animals.

Multilevel interactions between the sympathetic and parasympathetic nervous systems: a minireview.

In order to allow precise regulation of bodily functions, the activity of the autonomic nervous system must be precisely regulated. The traditional model concerning the regulation of norepinephrine and acetylcholine release in target tissues suggests that the activities of the efferent arms of the autonomic nervous system are more or less independent of each other. However, plenty of experimental and clinical studies have demonstrated the presence of multiple interactions between the sympathetic and parasympathetic nervous system that are mediated through several pathways and mechanisms at both central and peripheral levels of the neuraxis. Interactions within the central nervous system are mediated predominantly by neurons within the nucleus of the solitary tract and paraventricular hypothalamic nucleus. Peripheral interactions are based on the morphological-functional organization of the sympathetic and parasympathetic pathways at the levels of the sympathetic prevertebral ganglia or neuroeffector connections. Furthermore, evidence suggests that neuroeffector connections may be realized at the axo-axonal, presynaptic, postsynaptic, and post-receptor levels. Alterations in interactions between the sympathetic and parasympathetic nervous system can lead to unbalanced autonomic activities, which may influence the development of various disorders, including cardiovascular, inflammatory, metabolic, neurological, and psychiatric diseases. The aim of this article is to illustrate the complexity of interaction between the sympathetic and parasympathetic nervous systems and to describe the role of these interactions in the heart, adrenal medulla, and vagal trunk.

Do monoamine-synthesizing cells constitute a complex network of oxygen sensors?

Oxygen represents an essential molecule for organisms. Because of this, sophisticated systems of sensors have evolved to monitor oxygenation of tissues. We propose that monoamine-synthesizing cells represent an important part of this system. It is well known that the carotid body, which contains chromaffin cells, serves as a chemical sensor of blood oxygenation. Similarly, the activity of adrenal medullary chromaffin cells is increased during hypoxia. Moreover, neurons located in the central nervous system containing catecholamines, serotonin, and histamine are also sensitive to hypoxia. On the basis of this common sensitivity of monoamine-synthesizing cells to changes in oxygenation we propose the hypothesis that these cells constitute a widely distributed network of sensors that monitor oxygen levels. The role of monoamine-synthesizing cells in monitoring tissue oxygen supply during both physiological and pathological conditions is also discussed.

Enriched environment influences hormonal status and hippocampal brain derived neurotrophic factor in a sex dependent manner.

The present study is aimed at testing the hypothesis that an enriched environment (EE) induces sex-dependent changes in stress hormone release and in markers of increased brain plasticity. The focus was on hypothalamic-pituitary-adrenocortical (HPA) axis activity, plasma levels of stress hormones, gene expression of glutamate receptor subunits and concentrations of brain-derived neurotrophic factor (BDNF) in selected brain regions. Rats exposed to EE were housed in groups of 12 in large cages with various objects, which were frequently changed, for 6 weeks. Control animals were housed four per cage under standard conditions. In females the EE-induced rise in hippocampal BDNF, a neurotrophic factor associated with increased neural plasticity, was more pronounced than in males. Similar sex-specific changes were observed in BDNF concentrations in the hypothalamus. EE also significantly attenuated oxytocin and aldosterone levels only in female but not male rats. Plasma testosterone positively correlated with hippocampal BDNF in female but not male rats housed in EE. In male rats housing in EE led to enhanced levels of testosterone and adrenocorticotropic hormone (ACTH), this was not seen in females. Hippocampal glucocorticoid but not mineralocorticoid receptor levels decreased in rats housed in EE irrespective of sex. Housing conditions failed to modify mRNA levels of glutamate receptor type 1 (Glur1) and metabotropic glutamate receptor subtype 5 (mGlur5) subunits of glutamate receptors in the forebrain. Moreover, a negative association between corticosterone and BDNF was observed in both sexes. The results demonstrate that the association between hormones and changes in brain plasticity is sex related. In particular, testosterone seems to be involved in the regulatory processes related to neuroplasticity in females.