Hydrogen sulfide ameliorates hypertension and vascular dysfunction induced by insulin resistance in rats by reducing oxidative stress and activating eNOS.

Hydrogen sulfide (H2S) is a gasotransmitter implied in metabolic diseases, insulin resistance, obesity, and type 2 Diabetes Mellitus. This study aimed to determine the effect of chronic administration of sodium hydrosulfide (NaHS; inorganic H2S donor), L-Cysteine (L-Cys; substrate of H2S producing enzymes) and DL-Propargylglycine (DL-PAG; cystathionine-gamma-lyase inhibitor) on the vascular dysfunction induced by insulin resistance in rat thoracic aorta. For this purpose, 72 animals were divided into two main sets that received: 1) tap water (control group; n = 12); and 2) fructose 15% w/v in drinking water [insulin resistance group (IR); n = 60] for 20 weeks. After 16 weeks, the group 2 was divided into five subgroups (n = 12 each), which received daily i. p. injections during 4 weeks of: 1) non-treatment (control); 2) vehicle (phosphate buffer saline; PBS, 1 ml/kg); 3) NaHS (5.6 mg/kg); 4) L-Cys (300 mg/kg); and (5) DL-PAG (10 mg/kg). Hemodynamic variables, metabolic variables, vascular function, ROS levels and the expression of p-eNOS and eNOS were determined. IR induced: 1) hyperinsulinemia; 2) increased HOMA-index; 3) decreased Matsuda index; 4) hypertension, vascular dysfunction, increased ROS levels; 5) increased iNOS, and 6) decreased CSE, p-eNOS and eNOS expression. Furthermore, IR did not affect contractile responses to norepinephrine. Interestingly, NaHS and L-Cys treatment, reversed IR-induced impairments and DL-PAG treatment decreased and increased the HOMA and Matsuda index, respectively. Taken together, these results suggest that NaHS and L-Cys decrease the metabolic and vascular alterations induced by insulin resistance by reducing oxidative stress and activating eNOS. Thus, hydrogen sulfide may have a therapeutic application.

The multidimensionality of social wellbeing: interactions from the individual to the collective level in large cities.

This paper responds to two questions-What dimensions and indicators are relevant to the construction of social wellbeing? How are the levels of wellbeing distributed in the municipalities of Mexico City? To answer these questions, we use data from the Wellbeing Survey (N = 2,871) that is representative of Mexico City and its municipalities. We employed two methods, DM-R distances, and Mamdani's Fuzzy Inference Method. The results show that all the proposed dimensions and indicators contributed to the building of multidimensional social wellbeing; in the case of some indicators (social security, built environment, and public insecurity) they contributed less. This suggests government interventions should be designed in order to improve the gaps in those areas. The evidence also indicates that community wellbeing is a relevant dimension when measuring social wellbeing in large cities, in addition to identifying areas of intervention for the development of more efficient and inclusive public policies.

Probenecid, an Old Drug with Potential New Uses for Central Nervous System Disorders and Neuroinflammation.

Probenecid is an old uricosuric agent used in clinics to treat gout and reduce the renal excretion of antibiotics. In recent years, probenecid has gained attention due to its ability to interact with membrane proteins such as TRPV2 channels, organic anion transporters, and pannexin 1 hemichannels, which suggests new potential therapeutic utilities in medicine. Some current functions of probenecid include their use as an adjuvant to increase the bioavailability of several drugs in the Central Nervous System (CNS). Numerous studies also suggest that this drug has important neuroprotective, antiepileptic, and anti-inflammatory properties, as evidenced by their effect against neurological and neurodegenerative diseases. In these studies, the use of probenecid as a Panx1 hemichannel blocker to reduce neuroinflammation is highlighted since neuroinflammation is a major trigger for diverse CNS alterations. Although the clinical use of probenecid has declined over the years, advances in its use in preclinical research indicate that it may be useful to improve conventional therapies in the psychiatric field where the drugs used have a low bioavailability, either because of a deficient passage through the blood-brain barrier or a high efflux from the CNS or also a high urinary clearance. This review summarizes the history, pharmacological properties, and recent research uses of probenecid and discusses its future projections as a potential pharmacological strategy to intervene in neurodegeneration as an outcome of neuroinflammation.

NaHS restores the vascular alterations in the renin-angiotensin system induced by hyperglycemia in rats.

Hyperglycemia (HG) impairs the renin-angiotensin system (RAS), which may contribute to vascular dysfunction. Besides, hydrogen sulfide (H2S) exerts beneficial cardiovascular effects in metabolic diseases. Therefore, our study aimed to determine the effects of chronic administration of sodium hydrosulfide (NaHS; inorganic H2S donor) and DL-Propargylglycine [DL-PAG; cystathionine-×¥-lyase (CSE) inhibitor] on the RAS-mediated vascular responses impairments observed in thoracic aortas from male diabetic Wistar rats. For that purpose, neonatal rats were divided into two groups that received: 1) citrate buffer (n = 12) or 2) streptozotocin (STZ, 70 mg/kg; n = 48) on the third postnatal day. After 12 weeks, diabetic animals were divided into 4 subgroups (n = 12 each) that received daily i.p. injections during 4 weeks of: 1) non-treatment; 2) vehicle (PBS, 1 mL/kg); 3) NaHS (5.6 mg/kg); and 4) DL-PAG (10 mg/kg). After treatments (16 weeks), blood glucose, angiotensin-(1-7) [Ang-(1-7)], and angiotensin II (Ang II) levels, vascular responses to Ang-(1-7) and Ang II, and the expression of angiotensin AT1, AT2, and Mas receptors, angiotensin converting enzyme (ACE) and ACE type 2 (ACE2) were determined. HG induced: 1) increased blood glucose levels and expression of angiotensin II AT1 receptor; 2) impaired Ang-(1-7) and Ang II mediated vascular responses; 3) decreased angiotensin levels and expression of angiotensin II AT2 and angiotensin-(1-7) Mas receptors, and ACE2; and 4) no changes in ACE expression. Interestingly, NaHS, but not DL-PAG, reversed HG-induced impairments, except for blood glucose level changes. These results suggest that NaHS restores vascular function in streptozotocin-induced HG through RAS modulation.

Mexican Colorectal Cancer Research Consortium (MEX-CCRC): Etiology, Diagnosis/Prognosis, and Innovative Therapies.

In 2013, recognizing that Colorectal Cancer (CRC) is the second leading cause of death by cancer worldwide and that it was a neglected disease increasing rapidly in Mexico, the community of researchers at the Biomedicine Research Unit of the Facultad de Estudios Superiores Iztacala from the Universidad Nacional Autónoma de México (UNAM) established an intramural consortium that involves a multidisciplinary group of researchers, technicians, and postgraduate students to contribute to the understanding of this pathology in Mexico. This article is about the work developed by the Mexican Colorectal Cancer Research Consortium (MEX-CCRC): how the Consortium was created, its members, and its short- and long-term goals. Moreover, it is a narrative of the accomplishments of this project. Finally, we reflect on possible strategies against CRC in Mexico and contrast all the data presented with another international strategy to prevent and treat CRC. We believe that the Consortium's characteristics must be maintained to initiate a national strategy, and the reported data could be useful to establish future collaborations with other countries in Latin America and the world.

Hydrogen sulfide prevents the vascular dysfunction induced by severe traumatic brain injury in rats by reducing reactive oxygen species and modulating eNOS and H2S-synthesizing enzyme expression.

AIM: To assess the effects of subchronic administration with NaHS, an exogenous H2S donor, on TBI-induced hypertension and vascular impairments. MAIN METHODS: Animals underweministration does not prevent the body weight loss but slightly imnt a lateral fluid percussion injury, and the hemodynamic variables were measured in vivo by plethysmograph method. The vascular function in vitro, the ROS levels by the DCFH-DA method and the expression of H2S-synthesizing enzymes and eNOS by Western blot were measured in isolated thoracic aortas at day 7 post-TBI. The effect of L-NAME on NaHS-induced effects in vascular function was evaluated. Brain water content was determined 7 days after trauma induction. Body weight was recorded throughout the experimental protocol, whereas the sensorimotor function was evaluated using the neuroscore test at days -1 (basal), 2, and 7 after the TBI induction. KEY FINDINGS: TBI animals showed: 1) an increase in hemodynamic variables and ROS levels in aortas; 2) vascular dysfunction; 3) sensorimotor dysfunction; and 4) a decrease in body weight, the expression of H2S-synthesizing enzymes, and eNOS phosphorylation. Interestingly, NaHS subchronic administration (3.1 mg/kg; i.p.; every 24 h for six days) prevented the development of hypertension, vascular dysfunction, and oxidative stress. L-NAME abolished NaHS-induced effects. Furthermore, NaHS treatment restored H2S-synthesizing enzymes and eNOS phosphorylation with no effect on body weight, sensorimotor impairments, or brain water content. SIGNIFICANCE: Taken together, these results demonstrate that H2S prevents TBI-induced hypertension by restoring vascular function and modulating ROS levels, H2S-synthesizing enzymes expression, and eNOS phosphorylation.

Pharmacological evidence that potassium channels mediate hydrogen sulfide-induced inhibition of the vasopressor sympathetic outflow in pithed rats.

Hydrogen sulfide (H2S) is a gasotransmitter that modulates neurotransmission. Indeed, it has been recently demonstrated that H2S inhibits the sympathetic outflow in male rats, although the mechanisms remain elusive. Thus, this study evaluated the role of potassium channels on NaHS-induced sympathoinhibition. For this purpose, male and female Wistar rats were anesthetized, pithed, and cannulated. After that, animals received selective electrical stimulation of the vasopressor sympathetic outflow (T7-T9). Prior to 310 µg/kg·min NaHS i.v. continuous infusion animals received: (1) bidistilled water (tetraethylammonium, TEA; 4-aminopyridine, 4-AP; and barium chloride, BaCl2; vehicle; 1 ml/kg); (2) TEA (non-selective K+ channels blocker; 16.5 mg/kg); (3) 4-AP (non-selective voltage-dependent K+ channels blocker; 5 mg/kg); (4) BaCl2 (inward rectifier K+ channels blocker; 65 µg/kg); (5) DMF 5%, glucose 10% and NaOH 0.1 N (glibenclamide vehicle; 1 ml/kg); (6) glibenclamide (ATP-dependent K+ channels blocker; 10 mg/kg); (7) DMSO 4% (paxilline vehicle; 1 ml/kg); and (8) paxilline (large-conductance voltage- and Ca2+-activated K+ channel blocker; 90 µg/kg). The NaHS-induced sympathoinhibition was: (1) equally observed in male and female rats; (2) unaffected by vehicles; (3) reversed by the potassium channel blockers. Taken together, our results suggest that NaHS-induced sympathoinhibition does not depend on sex and it is mediated by the activation of several potassium channels.

Exogenous hydrogen sulfide restores CSE and CBS but no 3-MST protein expression in the hypothalamus and brainstem after severe traumatic brain injury.

Hydrogen sulfide (H2S) is a gasotransmitter endogenously synthesized by cystathionine-γ-lyase (CSE), cystathionine-ß-synthase (CBS), and 3-mercaptopiruvate sulfurtransferase (3-MST) enzymes. H2S exogenous administration prevents the development of hemodynamic impairments after traumatic brain injury (TBI). Since the hypothalamus and the brainstem highly regulate the cardiovascular system, this study aimed to evaluate the effect of NaHS subchronic treatment on the changes of H2S-sythesizing enzymes in those brain areas after TBI and in physiological conditions. For that purpose, animals were submitted to a lateral fluid percussion injury, and the changes in CBS, CSE, and 3-MST protein expression were measured by western blot at days 1, 2, 3, 7, and 28 in the vehicle group, and 7 and 28 days after NaHS treatment. After severe TBI induction, we found a decrease in CBS and CSE protein expression in the hypothalamus and brainstem; meanwhile, 3-MST protein expression diminished only in the hypothalamus compared to the Sham group. Remarkably, i.p. daily injections of NaHS, an H2S donor, (3.1 mg/kg) during seven days: (1) restored CBS and CSE but no 3-MST protein expression in the hypothalamus at day 28 post-TBI; (2) reestablished only CSE in brainstem 7 and 28 days after TBI; and (3) did not modify H2S-sythesizing enzymes protein expression in uninjured animals. Mainly, our results show that the NaHS effect on CBS and CSE protein expression is observed in a time- and tissue-dependent manner with no effect on 3-MST expression, which may suggest a potential role of H2S synthesis in hypothalamus and brainstem impairments observed after TBI.

Hydrogen Sulfide Subchronic Treatment Improves Hypertension Induced by Traumatic Brain Injury in Rats through Vasopressor Sympathetic Outflow Inhibition.

Traumatic brain injury (TBI) represents a critical public health problem around the world. To date, there are no accurate therapeutic approaches for the management of cardiovascular impairments induce by TBI. In this regard, hydrogen sulfide (H2S), a novel gasotransmitter, has been proposed as a neuro- and cardioprotective molecule. This study was designed to determine the effect of subchronic management with sodium hydrosulfide (NaHS) on hemodynamic, vasopressor sympathetic outflow and sensorimotor alterations produced by TBI. Animals underwent a lateral fluid percussion injury, and changes in hemodynamic variables were measured by pletismographic methods. In addition, vasopressor sympathetic outflow was assessed by a pithed rat model. Last, sensorimotor impairments were evaluated by neuroscore test and beam-walking test. At seven, 14, 21, and 28 days after moderate-severe TBI, the animals showed: (1) a decrease on sensorimotor function in the neuroscore test and beam-walking test; (2) an increase in heart rate, systolic, diastolic, and mean blood pressure; (3) progressive sympathetic hyperactivity; and (4) a decrease in vasopressor responses induced by noradrenaline (α1/2-adrenoceptors agonist) and UK 14,304 (selective α2-adrenoceptor agonist). Interestingly, intraperitoneal daily injections of NaHS, an H2S donor (3.1 and 5.6 mg/kg), during seven days after TBI prevented the development of the impairments in hemodynamic variables, which were similar to those obtained in sham animals. Moreover, NaHS treatment prevented the sympathetic hyperactivity and decreased noradrenaline-induced vasopressor responses. No effects on sensorimotor dysfunction were observed, however. Taken together, our results suggest that H2S ameliorates the hemodynamic and sympathetic system impairments observed after TBI.

Metabolite Profiling of Rosemary Cell Lines with Antiproliferative Potential against Human HT-29 Colon Cancer Cells.

Rosemary (Rosmarinus officinalis) is a culinary and medicinal plant used in food and pharmaceutical industry. The wide range of biological activities is mainly related to phenolic and terpenic compounds; like carnosic acid (CA), carnosol (CS) and rosmarinic acid (RA), mainly reported in rosemary leaf extracts, and recently described in rosemary callus extracts. The aim of this work was to investigate the chemical profile of rosemary cell lines and evaluate their antiproliferative potential against human HT-29 colorectal cancer cell lines. For this purpose, rosemary leaf explants were dedifferentiated on MS medium and added with 2, 4-D (2, 4-dichlorophenoxyacetic acid; 2 mg/L) and BAP (6-benzylaminopurine; 2 mg/L). Cell aggregates were separated according to colour and three rosemary cell lines cultures were established: green (RoG), yellow (RoY) and white (RoW). The chemical profile of rosemary cell lines extracts was characterized by combining HPLC and GC platforms coupled to HR-MS/MS. The antiproliferative activity against HT-29 cell line was analyzed with MTT assay. A total of 71 compounds, including hydroxycinnamic acid and hydroxybenzoic acid derivatives, flavonoids, phenolic di- and triterpenes, as well as relevant unsaturated fatty acids and their esters, phytosterols, and carotenoids were tentatively identified in the extract of the target cell lines. The antiproliferative activity test against HT-29 cell using the MTT assay revealed that the viability of HT-29 colon cancer cells was affected after treatment with the RoW extract (IC50 of 49.63 µg/mL) at 48 h. These results showed that rosemary cell lines can also accumulate other bioactive phytochemicals with demonstrated antiproliferative potential.

Hipoglucemia hiperinsulinémica congénita persistente, reporte de un caso / Persistent congenital hyperinsulinemic hypoglucemia, case report

Resumen La placenta y el hígado son los encargados del metabolismo de los carbohidratos. La glucosa es fundamental para el metabolismo cerebral. La hipoglucemia se define con valores < 47 mg/dl. La hipoglicemia que persiste más de 7 días se atribuye a problemas metabólicos o endocrinológicos y requiere un flujo de glucosa > 12 mg/kg/min para alcanzar normo-glicemia. La hipoglicemia hiperinsulinémica congénita persistente (HHCP) es poco común (1:50,000 nacidos vivos), es la causa más común de hipoglicemia persistente secundaria a una secreción inadecuada de insulina, que puede afectar el neurodesarrollo. Hay una forma difusa y una focal, con manifestaciones clínicas idénticas, pero con mecanismos patológicos diferentes. El tratamiento médico es a base de diazóxido y ocreótide. En el 95% de los casos no hay respuesta al tratamiento médico, requiriendo pancreatectomía subtotal. Se utilizó ocreótide y nifedipino. La tomografía computada con emisión de positrones (PET/TC 18F-DOPA) encontró incremento en la capación pancreática de insulina, se realizó pancreactectomía. Se egresó sin complicaciones y en seguimiento pediátrico sin alteraciones neurológicas.

Abstract The placenta and liver are responsible for the metabolism of carbohydrates. The glucose is fundamental for brain metabolism. Hypoglycaemia is defined as values < 47 mg/dl. Hypoglycaemia that persists for more than 7 days is attributed to metabolic or endocrine problems and requires glucose flow > 12 GKM to reach normoglycemia. Persistent congenital hyperinsulinemic hypoglycemia (PCHH) is uncommon (1:50,000 live births) is the most common cause of persistent hypoglycemia secondary to inadequate insulin secretion, can significantly affect neurodevelopment. There is a diffuse and a focal form, with identical clinical manifestations, but with different pathological mechanisms. The medical treatment is diazoxide and ocreotide. In 95% of cases there is no response to medical treatment, requiring subtotal pancreatectomy. Ocreotide and nifedipine were used. Positron emission computed tomography (PET/CT 18F-DOPA) found an increase in pancreatic insulin capacity, a pancreactectomy was performed. He was discharged without complications and in pediatric follow-up without neurological alterations.

Fenofibrate Protects Cardiomyocytes from Hypoxia/Reperfusion- and High Glucose-Induced Detrimental Effects.

Lesions caused by high glucose (HG), hypoxia/reperfusion (H/R), and the coexistence of both conditions in cardiomyocytes are linked to an overproduction of reactive oxygen species (ROS), causing irreversible damage to macromolecules in the cardiomyocyte as well as its ultrastructure. Fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, promotes beneficial activities counteracting cardiac injury. Therefore, the objective of this work was to determine the potential protective effect of fenofibrate in cardiomyocytes exposed to HG, H/R, and HG+H/R. Cardiomyocyte cultures were divided into four main groups: (1) control (CT), (2) HG (25 mM), (3) H/R, and (4) HG+H/R. Our results indicate that cell viability decreases in cardiomyocytes undergoing HG, H/R, and both conditions, while fenofibrate improves cell viability in every case. Fenofibrate also decreases ROS production as well as nicotinamide adenine dinucleotide phosphate oxidase (NADPH) subunit expression. Regarding the antioxidant defense, superoxide dismutase (SOD Cu2+/Zn2+ and SOD Mn2+), catalase, and the antioxidant capacity were decreased in HG, H/R, and HG+H/R-exposed cardiomyocytes, while fenofibrate increased those parameters. The expression of nuclear factor erythroid 2-related factor 2 (Nrf2) increased significantly in treated cells, while pathologies increased the expression of its inhibitor Keap1. Oxidative stress-induced mitochondrial damage was lower in fenofibrate-exposed cardiomyocytes. Endothelial nitric oxide synthase was also favored in cardiomyocytes treated with fenofibrate. Our results suggest that fenofibrate preserves the antioxidant status and the ultrastructure in cardiomyocytes undergoing HG, H/R, and HG+H/R preventing damage to essential macromolecules involved in the proper functioning of the cardiomyocyte.

Chronic administration of NaHS and L-Cysteine restores cardiovascular changes induced by high-fat diet in rats.

Hydrogen sulfide plays an important role in the regulation of the cardiovascular system, insulin secretion, and glucose homeostasis. The aim of the present study was to examine the effects of chronic treatment with sodium hydrosulfide (NaHS), L-Cysteine (L-Cys) and DL-Propargylglycine (DL-PAG) on the changes induced by a high-fat diet (HFD) in zoometric and metabolic variables as well as cardiovascular changes such as hypertension and sympathetic hyperactivity. For this purpose, male Wistar rats were fed a normal fat diet (NFD) or HFD for 12 weeks. Next, the HFD rats were divided into 5 subgroups which received daily i.p. injections during 4 weeks of: (1) nothing (no injection, Control); (2) vehicle (PBS; 1ml/kg); (3) NaHS (5.6 mg/kg); (4) L-Cys (300mg/kg); or (5) DL-PAG (1mg/kg). Then, an oral glucose tolerance test, hormone serum levels and blood pressure were determined. The cardiovascular responses to stimulation of the vasopressor sympathetic tone or intravenous administration of the agonists noradrenaline (α1/2-adrenoceptors), methoxamine (α1-adrenoceptors) and UK 14,304 (α2-adrenoceptors) were determined in pithed rats. Lastly, the heart, liver and adipose tissue were weighted. HFD significantly increased: (1) zoometric variables, which were decreased by NaHS and L-Cys; (2) metabolic variables, ameliorated by DL-PAG; (3) haemodynamic variables, which were reversed by NaHS and L-Cys; and (4) the vasopressor responses induced by sympathetic stimulation, which were diminished by NaHS and L-Cys. In conclusion, chronic treatment with NaHS and L-Cys are effective in reducing adipose tissue and ameliorating the cardiovascular changes induced by obesity; meanwhile, DL-PAG ameliorates metabolic variables.

Therapeutic effect of treatment with metformin and/or 4-hydroxychalcone in male Wistar rats with nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. Despite the impact of this pathology in the population, nowadays there is no specific treatment for this disease, focusing its treatment on risks factors. However, it is imperative the existence of a specific treatment, due to this, the aim of this study was to determine the therapeutic effect of treatment with metformin, 4-hydroxychalcone or co-treatment on male Wistar rats with NAFLD. Wistar rats were divided into two groups with free access to either tap water or 50% sucrose (NAFLD) during 25 weeks. After 20 weeks of induction each were divided into four groups that received daily p.o. administration of: i) saline solution (1 ml); ii) metformin (200 mg/kg/day); iii) 4-hydroxychalcone (80 mg/kg/day) and i.v.) co-treatment (metformin plus 4-hydroxychalcone at the doses mentioned above), for 5 weeks. In healthy rats: metformin and co-treatment modified food and total caloric intake and induced diarrhea; but none of the treatments changed the other parameters evaluated. Meanwhile in rats with NAFLD: i) metformin inhibited hepatic total cholesterol and TGF-ß, increased diarrhea frequency, and slightly decreased liver steatosis, and fibrosis; ii) 4-hydroxychalcone decreased IL-6, TNF-α and TGF-ß, increased IL-10, and markedly decreased liver steatosis and fibrosis; and iii) co-treatment markedly decreased food intake, total caloric intake, and body weight, increased diarrhea; increased IL-10, showing and intermediate effect on decrease TNF-α, TGF-ß, liver steatosis and fibrosis. Our results showed that 4-hydroxychalcone treatment was the most effective among the treatments tested against NAFLD.

Potential vascular α1-adrenoceptor blocking properties of metformin in rat aorta and tail artery.

Metformin is a widely used drug for the treatment of type 2 Diabetes Mellitus. Several studies have also suggested that metformin decreases blood pressure; although an interaction with α-adrenoceptors has been proposed, this mechanism needs to be further investigated. Since α1-adrenoceptors play a significant role to regulate vascular tone, this study has analysed the potential ability of metformin to block α1-adrenoceptors in rat aorta and tail artery. For this purpose, the contractile responses induced by noradrenaline, methoxamine, and phenylephrine were determined in the absence or presence of metformin in rat aorta and tail artery rings. In both arteries, noradrenaline, methoxamine, and phenylephrine produced concentration-dependent contractile responses. Interestingly, the contractile responses to noradrenaline, methoxamine, and phenylephrine were significantly and differentially blocked by metformin (1, 3.1 and/or 10 mM) but not by vehicle. These results suggest that metformin is capable to block α1-adrenoceptors and may explain, at least in part, the anti-hypertensive effect observed in several clinical trials.

Histopathological and biochemical changes in the development of nonalcoholic fatty liver disease induced by high-sucrose diet at different times.

The high intake of sweetened drinks is associated with obesity and insulin resistance. These pathologies are directly related to the development of nonalcoholic fatty liver disease (NAFLD), considered a condition of metabolic syndrome (MS). Due to their increasing worldwide prevalence, experimental animal models have been developed to gain a better understanding of its physiopathology; notwithstanding, few studies have evaluated its progression in association with MS and ingestion of sweetened drinks. Therefore, the aim of this study was to understand the pathophysiologic characteristics of NAFLD related to sucrose concentration and time of ingestion in rats. Wistar rats were divided into 2 groups with free access to either tap water or 30% sucrose, and euthanized at 12, 16, or 20 weeks; and 2 additional groups were given free access to either 40% or 50% sucrose and were euthanized at 20 weeks. Biochemical parameters and levels of serum cytokines were measured, and histology was performed. Ingestion of 30% sucrose induced liver steatosis until 16 weeks (grade 2) and 20 weeks (grade 3). Meanwhile, during 20 weeks, 40% sucrose induced grade 5 of nonalcoholic steatohepatitis (NASH) and 50% sucrose induced grade 6 of NASH and fibrosis. This study demonstrated that increasing time of induction and concentration of sucrose ingestion resulted in a higher grade of NAFLD.

Pharmacological evidence that metformin blocks the vasopressor responses mediated by stimulation of α1- and α2-adrenoceptors in pithed rats.

It has been reported that metformin reduces blood pressure although the mechanisms have not been described. Indeed, several mechanisms could be implicated including the interaction with α-adrenoceptors or inhibition of sympathetic outflow. Therefore, this study was designed to determine the capability of metformin to block the vasopressor responses induced by α1/2-adrenoceptor agonists or selective electrical stimulation of sympathetic outflow. For this purpose, Wistar male rats were anesthetized, pithed and cannulated for selective preganglionic stimulation of the vasopressor sympathetic outflow or drugs administration. The effect of i.v. bolus injection of metformin (180 and 310mg/kg) or its vehicle (bidistilled water) was studied on the vasopressor responses induced by: (1) selective sympathetic stimulation (0.03-3Hz); (2) exogenous noradrenaline (0.03-3µg/kg); (3) methoxamine (1-100µg/kg); and (4) UK 14,304 (0.1-30µg/kg). The tachycardic responses to noradrenaline were also investigated in presence of metformin. The vasopressor responses induced by selective electrical stimulation of sympathetic outflow were diminished by metformin (180 and 310mg/kg) and remained unchanged in presence of vehicle. Moreover, the vasopressor responses induced by exogenous noradrenaline, methoxamine and UK 14,304 were dose-dependently inhibited by i.v. bolus injections of metformin (180 and 310mg/kg) and were not affected by vehicle. Metformin practically did not block the tachycardic responses to noradrenaline except at the dose of 3µg/kg. Taken together, these results demonstrate that metformin is capable to block vascular α1/2-adrenoceptors but not cardiac ß-adrenoceptors. Thus, this mechanism could contribute, at least in part, on the hypotensive responses induced by metformin.

Pharmacological evaluation of metformin and N-benzylbiguanide, a novel analogue of metformin, on the vasopressor responses to adrenergic system stimulation in pithed rats with fructose-induced insulin resistance.

Metformin has been associated with cardioprotection, vasorelaxation and normalization of endothelial function during type 2 Diabetes Mellitus. However, few studies have analysed its effects on vascular adrenergic system. Our study has evaluated the vasopressor responses induced by sympathetic stimulation or by i.v. bolus injections of the agonists noradrenaline (α1/2), methoxamine (α1) and UK 14,304 (α2) in rats with fructose-induced insulin resistance chronically pretreated with either metformin or EGL-6M (N-benzylbiguanide), a novel analogue of metformin. Rats were treated with fructose (15%) or tap water (control) during 16 weeks. Next, both groups were treated daily during 4 weeks with: (1) vehicle; (2) metformin (50mg/kg); or (3) EGL-6M (50mg/kg). Blood glucose and plasma insulin were determined before and after administration of glucose during oral glucose tolerance test. Animals treated with fructose showed hyperinsulinemia and insulin resistance, which were decreased by metformin and EGL-6M. In animals treated with fructose, the vasopressor responses induced by: (1) sympathetic stimulation were decreased; (2) noradrenaline were increased; and (3) methoxamine and UK 14,304 remained unaffected compared with control group. In control animals, metformin failed to modify the vasopressor responses analysed, while EGL-6M increased the vasopressor responses to sympathetic stimulation. In rats treated with fructose, metformin decreased vasopressor response to noradrenaline but did not modify the sympathetic stimulation responses. EGL-6M increased the vasopressor responses to sympathetic stimulation without modifying those to noradrenaline, methoxamine or UK 14,304. Collectively, these data suggest that EGL-6M is capable to increase insulin sensitivity and the vasopressor sympathetic outflow in rats.

[From excluded individuals to rights-endowed citizens: The new approaches to disability]. / Del sujeto excluido al ciudadano con derechos: las nuevas conceptualizaciones en la discapacidad.

The new models for understanding persons with disabilities and their needs come with an expansion of their rights. This article discusses the new approaches, the changes produced in recent years, and the upcoming challenges posed by the implementation of the Convention on the Rights of Persons with Disabilities (CRPD), which, in Argentina, is on equal par with the Constitution. Additionally, the article mentions the incorporation of the World Health Organization's new multi-dimensional classifcation of disability, which takes into account the impairments suffered by persons along with any limitations on their activities and constraints on participation. The article discusses quality of life models and supports as guidelines for professional action. Finally, the article mentions some consequences of these new approaches for the relevant disciplines in general and for mental health in particular.

Pharmacological analysis of the cardiac sympatho-inhibitory actions of moxonidine and agmatine in pithed spontaneously hypertensive rats.

This study shows that in spontaneously hypertensive rats (SHR) of 14-weeks-old, the sympathetically-induced, but not noradrenaline-induced tachycardic response are higher than age-matched Wistar normotensive rats. Furthermore, in SHR the sympathetically-induced tachycardic response was: (1) unaffected by moxonidine (3µg/kgmin); (2) partially inhibited by B-HT 933 (30µg/kgmin), both at the lowest doses; and (3) completely inhibited by the highest doses of B-HT 933 (100µg/kgmin), moxonidine (10µg/kgmin) or agmatine (1000 and 3000µg/kgmin) while the noradrenaline-induced tachycardic responses remained unaffected by the above compounds, except by 3000µg/kgmin agmatine. In SHR, 300µg/kg rauwolscine failed to block the sympatho-inhibition to 100µg/kgmin B-HT 933 or 10µg/kgmin moxonidine, but 1000µg/kg rauwolscine abolished, partially antagonized, and did not modify the sympatho-inhibition to the highest doses of B-HT 933, moxonidine, and agmatine, respectively, 3000µg/kg AGN 192403 or 300µg/kg BU224 given alone had no effect in the moxonidine- or agmatine-induced sympatho-inhibition, and the combination rauwolscine plus AGN 192403 but not plus BU224, abolished the sympatho-inhibition to the highest doses of moxonidine and agmatine. In conclusion, the sympathetically-induced tachycardic responses in SHR are inhibited by moxonidine and agmatine. The inhibition of moxonidine is mainly mediated by prejunctional α2-adrenoceptors and to a lesser extent by I1-imidazoline receptors, while the inhibition of agmatine is mediated by prejunctional α2-adrenoceptors and I1-imidazoline receptors at the same extent. Notwithstanding, the inhibitory function of α2-adrenoceptors seems to be altered in SHR compared with Wistar normotensive rats.