Hybrid lineages of CD4+ T cells: a handbook update.

CD4+ T lymphocytes have been classified into several lineages, according to their gene expression profiles and their effector responses. Interestingly, recent evidence is showing that many lineages could yield hybrid phenotypes with unique properties and functions. It has been reported that such hybrid lineages might underlie pathologies or may function as effector cells with protection capacities against molecular threats. In this work, we reviewed the characteristics of the hybrid lineages reported in the literature, in order to identify the expression profiles that characterize them and the markers that could be used to identify them. We also review the differentiation cues that elicit their hybrid origin and what is known about their physiological roles.

Leptin in the Commissural Nucleus Tractus Solitarii Increases the Glucose Responses to Carotid Chemoreceptors Activation by Cyanide.

Leptin is a protein hormone that plays a key role in the regulation of energy balance and glucose homeostasis. Leptin and all leptin receptor isoforms are present in the carotid bodies, but its precise function in glucose regulation and metabolism is not yet known. The aim of this study was to determine whether exogenous leptin, microinjected into the commissural nucleus tractus solitarii (cNTS), preceding sodium cyanide (NaCN) injection into the circulatory isolated carotid sinus (ICS), in vivo, modifies hyperglycemic reflex (HR) and brain glucose retention (BGR). In anesthetized Wistar rats (sodium pentobarbital, i.p. 3.3 mg/100 g/saline, Pfizer, Mex), arterial and venous blood samples were collected from silastic catheters implanted in the abdominal aorta and jugular sinus. Exogenous leptin (50 ng/20 nL of aCSF) or leptin vehicle (20 nL of aCSF) microinjected (stereotaxically) into the cNTS 4 min before NaCN (5 µg/100 g/50 µL saline into ICS) (experimental 1 [E1] and control 1[C1] groups, respectively) significantly increased HR and BGR compared with their basal values, but the increase was bigger in the E1 group. When leptin or aCSF were injected into the cNTS before saline (E2 and C2 groups, respectively) glucose responses did not vary when compared with their basal levels. Leptin and its receptors in the cNTS cells probably contribute to their sensitization during hypoxia.

Effects of moderate- and high-intensity chronic exercise on brain-derived neurotrophic factor expression in fast and slow muscles.

INTRODUCTION: Brain-derived neurotrophic factor (BDNF) protein expression is sensitive to cellular activity. In the sedentary state, BDNF expression is affected by the muscle phenotype. METHODS: Eighteen Wistar rats were divided into the following 3 groups: sedentary (S); moderate-intensity training (MIT); and high-intensity training (HIT). The training protocol lasted 8 weeks. Forty-eight hours after training, total RNA and protein levels in the soleus and plantaris muscles were obtained. RESULTS: In the plantaris, the BDNF protein level was lower in the HIT than in the S group (P < 0.05). A similar effect was found in the soleus (without significant difference). In the soleus, higher Bdnf mRNA levels were found in the HIT group (P < 0.001 vs. S and MIT groups). In the plantaris muscle, similar Bdnf mRNA levels were found in all groups. CONCLUSIONS: These results indicate that high-intensity chronic exercise reduces BDNF protein level in fast muscles and increases Bdnf mRNA levels in slow muscles.

Chronic exercise increases plasma brain-derived neurotrophic factor levels, pancreatic islet size, and insulin tolerance in a TrkB-dependent manner.

BACKGROUND: Physical exercise improves glucose metabolism and insulin sensitivity. Brain-derived neurotrophic factor (BDNF) enhances insulin activity in diabetic rodents. Because physical exercise modifies BDNF production, this study aimed to investigate the effects of chronic exercise on plasma BDNF levels and the possible effects on insulin tolerance modification in healthy rats. METHODS: Wistar rats were divided into five groups: control (sedentary, C); moderate- intensity training (MIT); MIT plus K252A TrkB blocker (MITK); high-intensity training (HIT); and HIT plus K252a (HITK). Training comprised 8 weeks of treadmill running. Plasma BDNF levels (ELISA assay), glucose tolerance, insulin tolerance, and immunohistochemistry for insulin and the pancreatic islet area were evaluated in all groups. In addition, Bdnf mRNA expression in the skeletal muscle was measured. PRINCIPAL FINDINGS: Chronic treadmill exercise significantly increased plasma BDNF levels and insulin tolerance, and both effects were attenuated by TrkB blocking. In the MIT and HIT groups, a significant TrkB-dependent pancreatic islet enlargement was observed. MIT rats exhibited increased liver glycogen levels following insulin administration in a TrkB-independent manner. CONCLUSIONS/SIGNIFICANCE: Chronic physical exercise exerted remarkable effects on insulin regulation by inducing significant increases in the pancreatic islet size and insulin sensitivity in a TrkB-dependent manner. A threshold for the induction of BNDF in response to physical exercise exists in certain muscle groups. To the best of our knowledge, these are the first results to reveal a role for TrkB in the chronic exercise-mediated insulin regulation in healthy rats.

Brain-derived neurotrophic factor in the nucleus tractus solitarii modulates glucose homeostasis after carotid chemoreceptor stimulation in rats.

Neuronal systems, which regulate energy intake, energy expenditure and endogenous glucose production, sense and respond to input from hormonal related signals that convey information from body energy availability. Carotid chemoreceptors (CChr) function as sensors for circulating glucose levels and contribute to glycemic counterregulatory responses. Brain-derived neurotrophic factor (BDNF) that plays an important role in the endocrine system to regulate glucose metabolism could play a role in hyperglycemic glucose reflex with brain glucose retention (BGR) evoked by anoxic CChr stimulation. Infusing BDNF into the nucleus tractus solitarii (NTS) before CChr stimulation, showed that this neurotrophin increased arterial glucose and BGR. In contrast, BDNF receptor (TrkB) antagonist (K252a) infusions in NTS resulted in a decrease in both glucose variables.

Reflexiones sobre las relaciones ciencia, tecnología, sociedad en el curso del proceso de investigación del óxido nítrico / Reflections on the relationships between science, technology, and society throughout the research process of nitric oxide

Se abordan la interrelación dialéctica entre la ciencia, la tecnología y la sociedad, y los estudios sobre el óxido nítrico en la fase preclínica. Los estudios de la ciencia, la tecnología y la sociedad permiten comprender la responsabilidad ética y social del científico, quien la asume desde el comienzo del proceso con la elaboración de la idea primaria que luego da lugar al proyecto, hasta su culminación con la difusión e implementación de los resultados. Se analizan algunas de las condicionantes sociales de la investigación en el contexto de América Latina. Se señala la necesidad del uso del óxido nítrico como neuromodulador en la respuesta hiperglucemiante en la fase de investigación aplicada.

We approach the dialectical interrelation between science, technology, and society and the pre-clinical trials of nitric oxide. The studies on science, technology, and society help understanding the scientist’s ethical and social responsibility assumed since the beginning when the primary idea is elaborated to later become a project, until its termination with the diffusion and implementation of results. Within the Latin American context, we analyzed some of the social determining factors of this research. We support the necessary use of nitric oxide as a neuromodulator on the hyperglycemic response in the applied research phase.

GabaB receptors activation in the NTS blocks the glycemic responses induced by carotid body receptor stimulation.

The carotid body receptors participate in glucose regulation sensing glucose levels in blood entering the cephalic circulation. The carotid body receptors information, is initially processed within the nucleus tractus solitarius (NTS) and elicits changes in circulating glucose and brain glucose uptake. Previous work has shown that gamma-aminobutyric acid (GABA) in NTS modulates respiratory reflexes, but the role of GABA within NTS in glucose regulation remains unknown. Here we show that GABA(B) receptor agonist (baclofen) or antagonists (phaclofen and CGP55845A) locally injected into NTS modified arterial glucose levels and brain glucose retention. Control injections outside NTS did not elicit these responses. In contrast, GABA(A) agonist and antagonist (muscimol or bicuculline) produced no significant changes in blood glucose levels. When these GABAergic drugs were applied before carotid body receptors stimulation, again, only GABA(B) agonist or antagonist significantly affected glycemic responses; baclofen microinjection significantly reduced the hyperglycemic response and brain glucose retention observed after carotid body receptors stimulation, while phaclofen produced the opposite effect, increasing significantly hyperglycemia and brain glucose retention. These results indicate that activation of GABA(B), but not GABA(A), receptors in the NTS modulates the glycemic responses after anoxic stimulation of the carotid body receptors, and suggest the presence of a tonic inhibitory mechanism in the NTS to avoid hyperglycemia.

Papel del óxido nítrico en la retención de glucosa cerebral post-estimulación de los receptores carotídeos con cianuro de sodio en ratas / The role of the nitric oxide to retain the cerebral glucose post-stimulation of the carotid receptors with sodium cyanide in rats

Se realizó un estudio experimental, con el objetivo de medir la acción del óxido nítrico (NO) en la captación de glucosa cerebral, después de la estimulación con cianuro de sodio (NaCN-5µg/100g) de los receptores del cuerpo carotídeo (RCC). Los experimentos se realizaron en ratas (280-310g) anestesiadas, mantenidas con respiración artificial a una temperatura de 25°C. Los protocolos fueron el control I, la perfusión en cisterna magna (CM) de líquido cefalorraquídeo artificial-LCRa (5 µL/30 s), el control II, la ERC en forma simultánea con la perfusión de LCRa, la perfusión de un donador de NO (nitroglicerina) (NG-3µg/5µL de LCRa) en CM, la ERC en forma simultánea con NG en CM, la perfusión de un inhibidor de NO (L-NAME) (250µg/5µL de LCRa), la ERC en forma simultánea con L-NAME en CM. Los resultados obtenidos indican que la combinación de NG con ERC no altera la retención de glucosa cerebral, mientras que en los controles, la NG sola aumentó la retención cerebral de glucosa. Por el contrario, el L-NAME en combinación con ERC aumentó la captación de glucosa cerebral e indicó que el óxido nítrico desempeña un papel modulador en la respuesta hiperglucemiante en los estados de hipoxia

Papel del óxido nítrico en la retención de glucosa cerebral post-estimulación de los receptores carotídeos con cianuro de sodio en ratas / The role of the nitric oxide to retain the cerebral glucose post-stimulation of the carotid receptors with sodium cyanide in rats

Se realizó un estudio experimental, con el objetivo de medir la acción del óxido nítrico (NO) en la captación de glucosa cerebral, después de la estimulación con cianuro de sodio (NaCN-5µg/100g) de los receptores del cuerpo carotídeo (RCC). Los experimentos se realizaron en ratas (280-310g) anestesiadas, mantenidas con respiración artificial a una temperatura de 25°C. Los protocolos fueron el control I, la perfusión en cisterna magna (CM) de líquido cefalorraquídeo artificial-LCRa (5 µL/30 s), el control II, la ERC en forma simultánea con la perfusión de LCRa, la perfusión de un donador de NO (nitroglicerina) (NG-3µg/5µL de LCRa) en CM, la ERC en forma simultánea con NG en CM, la perfusión de un inhibidor de NO (L-NAME) (250µg/5µL de LCRa), la ERC en forma simultánea con L-NAME en CM. Los resultados obtenidos indican que la combinación de NG con ERC no altera la retención de glucosa cerebral, mientras que en los controles, la NG sola aumentó la retención cerebral de glucosa. Por el contrario, el L-NAME en combinación con ERC aumentó la captación de glucosa cerebral e indicó que el óxido nítrico desempeña un papel modulador en la respuesta hiperglucemiante en los estados de hipoxia(AU)

Carotid chemoreceptor reflex modulation by arginine-vasopressin microinjected into the nucleus tractus solitarius in rats.

BACKGROUND: In addition to their role of sensing O2, pH, CO2, osmolarity and temperature, carotid body receptors (CBR) were proposed by us and others to have a glucose-sensing role in the blood entering the brain, integrating information about blood glucose and O2 levels essential for central nervous system (CNS) metabolism. The nucleus tractus solitarius (NTS) is an important relay station in central metabolic control and receives signals from peripheral glucose-sensitive hepatoportal afferences, from central glucose-responsive neurons in the brainstem and from CBR and arginine-vasopressin (AVP)-containing axons from hypothalamic nuclei. METHODS: In normal Wistar rats anesthetized with pentobarbital, permanent cannulas were placed stereotaxically in the NTS. Glucose changes were induced in vivo after CBR stimulation with sodium cyanide (NaCN-5 microg/100 g), preceded by an infusion of AVP [(10 or 40 pmol/100 nL of artificial cerebrospinal fluid) aCSF] or an antagonist for V1a receptors (anti-glycogenolytic vasopressin analogue-VP1-A) (100 pmol/100 nL of aCSF) into the NTS. RESULTS: CBR stimulation after an AVP infusion (larger dose) into the NTS resulted in a significantly higher arterial glucose and lower brain arterial-venous glucose difference. In the same way, VP1-A administration in the NTS significantly decreased the effects observed after AVP priming before CBR stimulation or preceding the CBR stimulation, alone. CONCLUSIONS: We propose that AVP in the NTS could participate in glucose homeostasis, modulating the information arising in CBR after histotoxic-anoxia stimulation.

Induction of brain glucose uptake by a factor secreted into cerebrospinal fluid.

It is well established that the carotid body receptors (CBR), at the bifurcation of the carotid artery, inform the brain of changes in the concentration of CO(2) and O(2) in arterial blood. More recent work suggests that these receptors are also extremely sensitive to blood glucose levels suggesting that they may play an important role as sensors of blood components important for brain energy metabolism. Much less is known about changes in brain glucose metabolism in response to CBR activation. Here we show that 2-8 min after local injection of sodium cyanide (NaCN) into the CBR or after electrical stimulation of the carotid sinus nerve in dogs and rats, brain glucose uptake increased fourfold. Cerebrospinal fluids (CSF) transferred from dogs, 2-8 min after CBR stimulation, into the cisterna magna of non-stimulated dogs or rats induced a similar increase in brain glucose uptake. CSF from stimulated dogs was also active when injected intravenously in anesthetized or awake rats. The activity was destroyed when the stimulated CSF was heated to 100 degrees C or treated with trypsin. We conclude that a peptide important for brain glucose regulation appears in the CSF shortly after CBR stimulation.