ABSTRACT
Hepatic encephalopathy (HE) is a neuropsychiatric complication of acute liver failure or chronic liver injury. Liver dysfunction impairs ammonia detoxification, allowing it to cross the blood-brain barrier (BBB) and disrupt brain function. The hippocampus becomes a crucial target during elevated ammonia levels, causing spatial memory impairment and decreased learning ability. Leuprolide acetate (LA), a GnRH agonist, has been implicated in neuroprotection and neuroregeneration in several regions of the central nervous system (CNS) including hippocampus. In this study, we aim to evaluate the effects of LA treatment on hippocampus of rats with HE induced by portocaval anastomosis (PCA) trough cognitive tests, histology analysis and expression of neuronal recovery marker proteins, such as neurofilament (NF200) and neurabin II, and astrocyte marker glial fibrillary acidic protein (GFAP). Rats were divided into three groups: SHAM, portocaval anastomosis with saline solution (PCA + SS) and portocaval anastomosis treated with LA (PCA + LA). To evaluate learning and spatial memory elevated T-maze (ETM) and Y-maze test (YMT) were respectively used. Results indicated that LA-treated rats performed significantly better in ETM and YMT than untreated rats. Histological analysis of hippocampus showed increased neuron density, nuclear area, and layer thickness in dentate gyrus of PCA + LA group compared to PCA + SS. Additionally, neurabin II and NF200 expression were higher in LA-treated rats, while GFAP expression was elevated in the PCA + SS group compared to control and PCA + LA groups. In conclusion, LA enhances hippocampal neuron recovery and reduces astrogliosis, suggesting its potential as a therapeutic intervention for attenuating hippocampal damage during HE.
ABSTRACT
BACKGROUND: Mild hypoxic-ischemic encephalopathy (HIE) is a condition that predisposes to negative outcomes such as neuroanatomical injury, mood disorders, and motor or cognitive disabilities. The neuroinflammation plays an important role in the neurological damage; therefore, reducing it could provide neuroprotection. The leuprolide acetate (LA) has shown to have neuroregenerative and immunomodulator properties in other nervous system injuries. OBJECTIVE: The aim of this study was to evaluate the immunomodulatory effect of LA in the acute phase of mild HIE and its effects in motor activity and behavior in a subacute phase. METHOD: Forty-five Wistar rats on postnatal day 7 were divided into Sham, HIE treated with saline solution (HIE-SS), and HIE-LA. The HIE was performed cutting of the right carotid artery followed by 60 min of hypoxia. The expression of the inflammatory cytokines interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and the chemokine CXCL-1 were evaluated 72 h after HIE by RT-qPCR and the motor activity and behavior were evaluated by open field test at postnatal day 33. RESULTS: HIE-SS animals showed increased expression of IL-1ß, TNF-α, IFN-γ, and CXCL-1 genes in injured tissue. However, the HIE-LA group exhibited similar expression levels of IL-1ß and TNF-α to the Sham group, while IFN-γ and CXCL-1 mRNA expression were attenuated with LA treatment. LA treatment also prevented anxiety-like behavior in the open field test. CONCLUSION: Treatment with LA partially reverses HIE-induced neuroinflammation and prevents anxiety-like behavior in neonatal rats.
Subject(s)
Hypoxia-Ischemia, Brain , Animals , Rats , Hypoxia-Ischemia, Brain/drug therapy , Hypoxia-Ischemia, Brain/metabolism , Hypoxia-Ischemia, Brain/pathology , Animals, Newborn , Leuprolide/pharmacology , Leuprolide/therapeutic use , Tumor Necrosis Factor-alpha , Neuroinflammatory Diseases , Rats, Wistar , Immunologic Factors , Anxiety/drug therapy , Anxiety/etiologyABSTRACT
BACKGROUND: The hippocampus is highly vulnerable to damage in the brain ischemia-reperfusion injury model. Leuprolide acetate has been shown to promote neurological recovery after injury in various regions of the central nervous system. OBJECTIVE: The objective of this study was to assess the histology of the hippocampus and the expression of neuronal recovery markers, specifically the 200 kDa neurofilaments and the myelin basic protein, in rats with brain ischemia-reperfusion injury treated with leuprolide acetate. METHODS: The rats were divided into three groups: Sham, ischemia-reperfusion with saline solution, and ischemia-reperfusion treated with leuprolide acetate. Coronal brain slices were obtained and stained with hematoxylin-eosin. The histological analysis involved quantifying the number of neurons in the hippocampal regions CA1, CA3 and DG. The myelin basic protein and neurofilaments were quantified using western blot. RESULTS: The number of neurons in CA1 and DG was significantly higher in the leuprolide acetate group compared to the untreated group. Additionally, the expression of neurofilament and myelin basic protein markers was significantly increased in rats treated with leuprolide acetate compared to the untreated rats. CONCLUSIONS: Leuprolide acetate promotes the recovery of hippocampal neurons in an acute brain ischemia-reperfusion injury model. These findings suggest that leuprolide acetate could be a potential therapeutic intervention for reversing damage in hippocampal ischemic lesions.
Subject(s)
Brain Injuries , Brain Ischemia , Reperfusion Injury , Rats , Animals , Leuprolide/pharmacology , Leuprolide/therapeutic use , Leuprolide/metabolism , Myelin Basic Protein/metabolism , Hippocampus/pathology , Reperfusion Injury/drug therapy , Reperfusion Injury/metabolism , Ischemia/metabolism , Brain Ischemia/pathology , ReperfusionABSTRACT
Es bien sabido que el cáncer mamario es considerado un problema de salud a nivel mundial, la enorme tasa de mortalidad se debe a la recaída de la enfermedad, principalmente por la generación de resistencia a los diversos tratamientos. Hasta hace unos años, esta resistencia era atribuida a las mutaciones genéticas heredadas, sin embargo, evidencias recientes sugieren que el microambiente tumoral desempeña un papel clave en el desarrollo y la progresión del cáncer. La relación simbiótica entre las células tumorales y los fibroblastos asociados a cáncer (FAC), condicionan un ambiente propicio para el soporte estructural necesario, lleno de nutrientes que favorecen su crecimiento y progresión. Aquí se describe el papel que juega el microambiente tumoral y los FAC, desde su origen celular y activación, hasta los mecanismos de quimiorresistencia tumoral, además de los cambios epigenéticos y las proteínas involucradas, como las HDAC, que prometen ser blancos terapéuticos de nuevos fármacos dirigidos a su inhibición, al mitigar diversas vías que participan en la activación de los FAC o revertir su potencial promotor de tumores, lo que a su vez, mejoraría la calidad de vida de las pacientes. (AU)
It is well known that breast cancer is considered a worldwide health problem, the enormous mortality rate is due to the relapse of patients mostly due to the generation of resistance to various treatments. Until a few years ago, this resistance was attributed to inherited genetic mutations, however, recent evidence suggests that tumor microenvironment plays a key role in the development and progression of cancer. The symbiotic relationship between tumor cells and cancer-associated fibroblasts (CAF) provides an environment conducive to the necessary structural support, full of nutrients that favor their growth and progression. Here we describe the role played by the tumor microenvironment and CAF, from their cellular origin and activation to the mechanisms of tumor chemoresistance, in addition to the epigenetic changes and proteins involved, such as HDAC, which promise to be therapeutic targets for new drugs aimed at their inhibition, by mitigating various pathways involved in the activation of CAF or reversing their tumor-promoting potential, which in turn, would improve the quality of life of patients. (AU)
Subject(s)
Humans , Female , Breast Neoplasms , Tumor Microenvironment , Cancer-Associated Fibroblasts , Drug Resistance, Neoplasm , Histone DeacetylasesABSTRACT
Arginine vasopressin (AVP) is a naturally occurring hormone synthesized in the hypothalamus. AVP demonstrates pro-fibrotic effects as it stimulates hepatic stellate cells to secrete transforming growth factor-ß (TGF-ß) and collagen. Previous work in liver cirrhotic (CCL4 -induced) hamsters demonstrated that AVP deficiency induced by neurointermediate pituitary lobectomy (NIL) can restore liver function. Therefore, we hypothesized that liver fibrosis would decrease in portocaval anastomosis (PCA) rats, which model chronic liver diseases, when they are treated with the V1a-V2 AVP receptor antagonist conivaptan (CV). In this study, changes in liver histology and gene expression were analysed in five experimental groups: control, PCA, NIL, PCA + NIL and PCA + CV, with NIL surgery or CV treatment administered 8 weeks after PCA surgery. Body weight gain was assessed on a weekly basis, and serum liver function, liver weight and liver glycogen content were assessed following euthanasia. Most PCA-induced phenotypes were reverted to normal levels following AVP-modelled deficiency, though hypoglycemia and ammonium levels remained elevated in the PCA + CV group. Liver histopathological findings showed a significant reversal in collagen content, less fibrosis in the triad and liver septa and increased regenerative nodules. Molecular analyses showed that the expression of fibrogenic genes (TGF-ß and collagen type I) decreased in the PCA + CV group. Our findings strongly suggest that chronic NIL or CV treatment can induce a favourable microenvironment to decrease liver fibrosis and support CV as an alternative treatment for liver fibrosis.
Subject(s)
Diabetes Insipidus, Neurogenic , Receptors, Vasopressin , Cricetinae , Rats , Animals , Receptors, Vasopressin/genetics , Antidiuretic Hormone Receptor Antagonists/pharmacology , Arginine Vasopressin/pharmacology , Liver Cirrhosis/drug therapy , Anastomosis, Surgical , ArginineABSTRACT
Multiple sclerosis (MS) is a chronic demyelinating and neurodegenerative disease that affects the central nervous system. MS is a heterogeneous disorder of multiple factors that are mainly associated with the immune system including the breakdown of the blood-brain and spinal cord barriers induced by T cells, B cells, antigen presenting cells, and immune components such as chemokines and pro-inflammatory cytokines. The incidence of MS has been increasing worldwide recently, and most therapies related to its treatment are associated with the development of several secondary effects, such as headaches, hepatotoxicity, leukopenia, and some types of cancer; therefore, the search for an effective treatment is ongoing. The use of animal models of MS continues to be an important option for extrapolating new treatments. Experimental autoimmune encephalomyelitis (EAE) replicates the several pathophysiological features of MS development and clinical signs, to obtain a potential treatment for MS in humans and improve the disease prognosis. Currently, the exploration of neuro-immune-endocrine interactions represents a highlight of interest in the treatment of immune disorders. The arginine vasopressin hormone (AVP) is involved in the increase in blood-brain barrier permeability, inducing the development and aggressiveness of the disease in the EAE model, whereas its deficiency improves the clinical signs of the disease. Therefore, this present review discussed on the use of conivaptan a blocker of AVP receptors type 1a and type 2 (V1a and V2 AVP) in the modulation of immune response without completely depleting its activity, minimizing the adverse effects associated with the conventional therapies becoming a potential therapeutic target in the treatment of patients with multiple sclerosis.
ABSTRACT
Secretions of beneficial intestinal bacteria can inhibit the growth and biofilm formation of a wide range of microorganisms. Curcumin has shown broad spectrum antioxidant, anti-inflammatory, and antimicrobial potential. It is important to evaluate the influence of these secretions with bioactive peptides, in combination with curcumin, to limit growth and inhibit biofilm formation of pathogenic bacteria of importance in aquaculture. In the present study, the supernatants of Lactoccocus lactis NZ9000, Lactobacillus rhamnosus GG and Pediococcus pentosaceus NCDO 990, and curcumin (0,1,10,25 and 50 µM) were used to evaluate their efficacy in growth, inhibition biofilm and membrane permeability of Aeromonas hydrophila CAIM 347 (A. hydrophila). The supernatants of probiotics and curcumin 1,10 and 25 µM exerted similar effects in reducing the growth of A. hydrophila at 12 h of interaction. The supernatants of the probiotics and curcumin 25 and 50 µM exerted similar effects in reducing the biofilm of A. hydrophila. There is a significant increase in the membrane permeability of A. hydrophila in interaction with 50 µM curcumin at two hours of incubation and with the supernatants separately in the same period. Different modes of action of curcumin and bacteriocins separately were demonstrated as effective substitutes for antibiotics in containing A. hydrophila and avoiding the application of antibiotics. The techniques implemented in this study provide evidence that there is no synergy between treatments at the selected concentrations and times.
Subject(s)
Curcumin , Lacticaseibacillus rhamnosus , Lactococcus lactis , Aeromonas hydrophila , Animals , Anti-Bacterial Agents/pharmacology , Curcumin/pharmacology , Pediococcus pentosaceusABSTRACT
Liver diseases, including cirrhosis, viral hepatitis, and hepatocellular carcinoma, account for approximately two million annual deaths worldwide. They place a huge burden on the global healthcare systems, compelling researchers to find effective treatment for liver fibrosis-cirrhosis. Portacaval anastomosis (PCA) is a model of liver damage and fibrosis. Arginine vasopressin (AVP) has been implicated as a proinflammatory-profibrotic hormone. In rats, neurointermediate pituitary lobectomy (NIL) induces a permanent drop (80%) in AVP serum levels. We hypothesized that AVP deficiency (NIL-induced) may decrease liver damage and fibrosis in a rat PCA model. Male Wistar rats were divided into intact control (IC), NIL, PCA, and PCA+NIL groups. Liver function tests, liver gene relative expressions (IL-1, IL-10, TGF-ß, COLL-I, MMP-9, and MMP-13), and histopathological assessments were performed. In comparison with those in the IC and PCA groups, bilirubin, protein serum, and liver glycogen levels were restored in the PCA+NIL group. NIL in the PCA animals also decreased the gene expression levels of IL-1 and COLL-I, while increasing those of IL-10, TGF-ß, and MMP-13. Histopathology of this group also showed significantly decreased signs of liver damage with lower extent of collagen deposition and fibrosis. Low AVP serum levels were not enough to fully activate the AVP receptors resulting in the decreased activation of cell signaling pathways associated with proinflammatory-profibrotic responses, while activating cell molecular signaling pathways associated with an anti-inflammatory-fibrotic state. Thus, partial reversion of liver damage and fibrosis was observed. The study supports the crucial role of AVP in the inflammatory-fibrotic processes and maintenance of immune competence. The success of the AVP deficiency strategy suggests that blocking AVP receptors may be therapeutically useful to treat inflammatory-fibrotic liver diseases.
Subject(s)
Arginine Vasopressin/deficiency , Liver Cirrhosis/pathology , Liver Failure/immunology , Pituitary Gland/metabolism , Receptors, Vasopressin/metabolism , Animals , Arginine Vasopressin/blood , Disease Models, Animal , Humans , Hypophysectomy , Liver Cirrhosis/blood , Liver Cirrhosis/immunology , Liver Failure/blood , Liver Failure/pathology , Male , Pituitary Gland/surgery , Portacaval Shunt, Surgical , Rats , Rats, Wistar , Signal Transduction/immunologyABSTRACT
BACKGROUND: Ovarian cancer is usually diagnosed at an advanced stage due to its early asymptomatic course and late-stage non-specific symptoms. This highlights the importance of researching the molecular mechanisms involved in ovarian carcinogenesis as well as the discovery of novel prognostic markers that could help improve the survival outcome of patients. The aim of this study was to evaluate the expression of the steroid sulfatase (STS) in 154 samples of primary ovarian tumors. This protein is crucial in the intracellular conversion of sulfated steroid hormones to active steroid hormones. The presence of STS, 3ß-HSD, and 17ß-HSD1 result in the production of testosterone which act through the androgen receptor (AR) in the tumor cell. The presence of STS and AR in epithelial ovarian tumors and their association to the overall survival of patients was evaluated using Kaplan-Meier and Cox regression analyses. RESULTS: Immunoreactivity for STS was detected in 65% of the tumors and no association was observed with histological subtypes and clinical stages of the tumor. The STS expression in the tumors exhibiting immunoreactive AR resulted in a reduced survival (log-rank test, p = 0.032) and a risk factor in univariate and multivariate analysis, HR = 3.46, CI95% 1.00-11.92, p = 0.049 and HR = 5.92, CI95% 1.34-26.09, p = 0.019, respectively. CONCLUSIONS: These findings suggest that the intracellular synthesis of testosterone acting through its receptor can promote tumor growth and progression. Moreover, the simultaneous expression of STS and AR constitutes an independent predictor of poor prognosis in epithelial ovarian tumors.
Subject(s)
Carcinoma, Ovarian Epithelial/genetics , Receptors, Androgen/metabolism , Steryl-Sulfatase/metabolism , Adult , Carcinoma, Ovarian Epithelial/mortality , Female , Humans , Middle Aged , Survival AnalysisABSTRACT
The episodes of cerebral dysfunction, known as encephalopathy, are usually coincident with liver failure. The primary metabolic marker of liver diseases is the increase in blood ammonium, which promotes neuronal damage. In the present project, we used an experimental model of hepatic encephalopathy in male rats by portacaval anastomosis (PCA) surgery. Sham rats had a false operation. After 13 weeks of surgery, the most distinctive finding was vacuolar/spongiform neurodegeneration exclusively in the molecular layer of the cerebellum. This cerebellar damage was further characterized by metabolic, histopathological, and behavioral approaches. The results were as follows: (a) Cellular alterations, namely loss of Purkinje cells, morphological changes, such as swelling of astrocytes and Bergmann glia, and activation of microglia; (b) Cytotoxic edema, shown by an increase in aquaporin-4 and N-acetylaspartate and a reduction in taurine and choline-derivate osmolytes; (c) Metabolic adjustments, noted by the elevation of circulating ammonium, enhanced presence of glutamine synthetase, and increase in glutamine and creatine/phosphocreatine; (d) Inflammasome activation, detected by the elevation of the marker NLRP3 and microglial activation; (e) Locomotor deficits in PCA rats as assessed by the Rotarod and open field tests. These results lead us to suggest that metabolic disturbances associated with PCA can generate the cerebellar damage that is similar to morphophysiological modifications observed in amyloidogenic disorders. In conclusion, we have characterized a distinctive cerebellar multi-disruption accompanied by high levels of ammonium and associated with spongiform neurodegeneration in a model of hepatic hypofunctioning.
Subject(s)
Cerebellum/metabolism , Cerebellum/pathology , Hepatic Encephalopathy/metabolism , Hepatic Encephalopathy/pathology , Locomotion/physiology , Portacaval Shunt, Surgical/trends , Animals , Astrocytes/metabolism , Astrocytes/pathology , Cerebellum/surgery , Hepatic Encephalopathy/surgery , Male , Microglia/metabolism , Microglia/pathology , Neurons/metabolism , Neurons/pathology , Purkinje Cells/metabolism , Purkinje Cells/pathology , Rats , Rats, WistarABSTRACT
Uncontrolled diabetes results in several metabolic alterations including hyperglycemia. Indeed, several preclinical and clinical studies have suggested that this condition may induce susceptibility and the development of more aggressive infectious diseases, especially those caused by some bacteria (including Chlamydophila pneumoniae, Haemophilus influenzae, and Streptococcus pneumoniae, among others) and viruses [such as coronavirus 2 (CoV2), Influenza A virus, Hepatitis B, etc.]. Although the precise mechanisms that link glycemia to the exacerbated infections remain elusive, hyperglycemia is known to induce a wide array of changes in the immune system activity, including alterations in: (i) the microenvironment of immune cells (e.g., pH, blood viscosity and other biochemical parameters); (ii) the supply of energy to infectious bacteria; (iii) the inflammatory response; and (iv) oxidative stress as a result of bacterial proliferative metabolism. Consistent with this evidence, some bacterial infections are typical (and/or have a worse prognosis) in patients with hypercaloric diets and a stressful lifestyle (conditions that promote hyperglycemic episodes). On this basis, the present review is particularly focused on: (i) the role of diabetes in the development of some bacterial and viral infections by analyzing preclinical and clinical findings; (ii) discussing the possible mechanisms by which hyperglycemia may increase the susceptibility for developing infections; and (iii) further understanding the impact of hyperglycemia on the immune system.
Subject(s)
Bacterial Infections/etiology , COVID-19/etiology , Diabetes Complications/immunology , Diabetes Complications/physiopathology , Disease Susceptibility , Hyperglycemia/complications , Virus Diseases/etiology , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle AgedABSTRACT
Lead exposure is known to affect the pituitary-thyroid axis. Likewise, ascorbic acid (AA) has a protective action against lead poisoning. We examine the protective role of AA in lead-induced damage to the thyroid gland. The Wistar rats were divided into three groups: control that received 0.2% AA in drinking water throughout the experiment (15 days), intoxicated with lead acetate (20 mg/kg) intraperitoneally every 48 h for 15 days, and the experimental group treated with lead acetate and 0.2% AA in drinking water throughout the experiment. Plasma thyroid-stimulating hormone, triiodothyronine, thyroxine, and lead were determined. The thyroid gland was weighed, then epithelial cell height and nuclear volume were measured on histological slides. The results show that AA reduced the thyroid atrophy caused by lead acetate, as well as the loss of weight of the gland. In addition, it prevented the decrease of the hormone triiodothyronine, although the thyroxine hormone remained lower than the control values ââand the thyroid-stimulating hormone remains high. Our results indicated that AA could play a protective role in lead poisoning in the thyroid gland.
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Glycomacropeptide (GMP) is a bioactive peptide derived from milk κ-casein with immune-modulatory and anti-inflammatory properties. Food allergy (FA) is an adverse immune reaction with a broad spectrum of manifestations. Allergen intake induces persistent intestinal inflammation and tissue damage. In this study, the anti-allergic activity of GMP was evaluated using a rat ovalbumin (OVA)-induced FA model with gastrointestinal manifestation. Rats were orally GMP treated from 3 days prior and during FA development. The severity of food anaphylaxis and diarrheal episodes, antibody production and histamine level were measured. Histopathological changes, inflammation and predominant cytokine profile at intestine were analyzed. Oral GMP intake decreased clinical signs and diarrhea severity induced by allergen, with a significant reduction in intestinal edema and expression level of IL-1ß and TNF-α. Prophylaxis with GMP also diminished serum anti-OVA IgE and IgG1, and histamine levels. GMP treatment markedly decreased eosinophil infiltration, mast cell and goblet cell hyperplasia, total IgE expression in intestine, and prevented histological changes in villi, crypts and internal muscularis layer. The treatment effectively suppressed IL-5, IL-13 and GATA3 expression and skewed the intestinal cytokine profile toward type 1 and regulatory. These results suggest that GMP may protect against FA through down-regulating the type 2 inflammatory response.
Subject(s)
Anti-Allergic Agents/therapeutic use , Caseins/pharmacology , Down-Regulation/drug effects , Food Hypersensitivity/drug therapy , Peptide Fragments/pharmacology , Allergens/immunology , Anaphylaxis/drug therapy , Anaphylaxis/prevention & control , Animals , Cytokines/metabolism , Disease Models, Animal , Food Hypersensitivity/immunology , Food Hypersensitivity/physiopathology , GATA3 Transcription Factor , Interleukin-13 , Interleukin-1beta/metabolism , Interleukin-5 , Intestines , Male , Mast Cells/drug effects , Ovalbumin/immunology , Peptide Fragments/metabolism , Rats , Rats, WistarABSTRACT
INTRODUCTION: Growth hormone and prolactin secretion is affected by thyroid hormones. To see if this influence is subsidiary to the hyptothalamus, we investigated the effects of thyroxin (T4) on hormone secretion and histology of sellar pituitaries and pituitary grafts detached from the hypothalamus (autografted or allografted under the kidney capsule). MATERIALS AND METHODS: Male Wistar rats were divided into eight groups: control, thyroidectomised, pituitary autografted, pituitary allografted, and four additional groups that were injected with T4 for two weeks, starting four weeks after surgery. At sacrifice, adenohypophysial hormone blood levels were assessed, and tissue from sellar and grafted pituitaries were investigated by histology and electron microscopy. RESULTS: Growth hormone and prolactin blood levels, as well as the number of growth hormone immunopositive cells increased in T4-treated groups. Both pituitary auto- and allo-grafts showed lactotroph hyperplasia and displayed spongiform areas containing cells with vesicles in their cytoplasm resembling thyroidectomy cells. This phenomenon was minimized in their respective T4-treated group. Thyroidectomy cells were identified in pituitary grafts, indicating that hypothalamic control was not essential to induce them. DISCUSSION AND CONCLUSION: It is intriguing that the pituitary allografted group, even maintaining normal T4 blood levels, developed thyroidectomy cells in their grafts, suggesting that a long- term deficit of vascularization (>4 weeks) prevented T4 from reaching the graft. After 6 weeks, post T4 treatment of two weeks seemed to be the determining factor to minimize thyroidectomy cells in both pituitary autografted + T4 and pituitary allografted + T4 grafts compared to the untreated groups, although more time and/or higher T4 doses may be required to fully restore the euthyroid morphology.
Subject(s)
Pituitary Gland/surgery , Pituitary Gland/transplantation , Thyroxine/pharmacology , Transplants/drug effects , Analysis of Variance , Animals , Body Weight , Densitometry , Female , Male , Microscopy, Electron, Transmission , Pituitary Gland/metabolism , Rats , Rats, Wistar , Thyroxine/metabolism , Transplants/metabolismABSTRACT
The blood-brain barrier (BBB) plays a significant pathophysiological role in multiple sclerosis (MS). Vasopressin (AVP) is released after brain injury and contributes to the inflammatory response. We propose that AVP may be modulating BBB permeability and hence affecting EAE clinical signs. Female Lewis rats were immunized s.c. with guinea-pig brain extract suspended in complete Freund's adjuvant. Prior to that, animals were subjected to Neurointermediate pituitary lobectomy (NIL) or treated with AVP receptor antagonist (conivaptan). BBB permeability assays were performed. Western blot for claudin-5 and histological analysis were performed in conivaptan treated EAE rats. EAE increase in BBB permeability to Evans blue was reverted by the NIL surgery. AVP receptor blockade reverted the EAE BBB hyperpermeability to Evans blue and 10-kDa FITC-dextran in almost all brain regions. Both, AVP low levels and AVP receptor blockade attenuated EAE clinical signs. Conivaptan reduced perivascular cuffs in EAE rats. A decrease in claudin-5 expression was observed in EAE rats and conivaptan treatment partially restored normal levels. Our data indicate that V1a and V2 AVP receptors can modulate BBB permeability and consequently are involved in the CNS inflammatory process during EAE. Future research is required to characterize the utility of vasopressin antagonist in MS treatment.
Subject(s)
Arginine Vasopressin/metabolism , Blood-Brain Barrier/metabolism , Cell Membrane Permeability , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental/physiopathology , Receptors, Vasopressin/chemistry , Animals , Biological Transport , Blood-Brain Barrier/pathology , Female , Rats , Rats, Inbred Lew , Receptors, Vasopressin/metabolismABSTRACT
Tuberculosis (TB) is a highly complex infectious disease caused by the intracellular pathogen Mycobacterium tuberculosis (Mtb). It is characterized by chronic granulomatous inflammation of the lung and systemic immune-neuroendocrine responses that have been associated with pathophysiology and disease outcome. Vasopressin (VP), a neurohypophysial hormone with immunomodulatory effects, is abnormally high in plasma of some patients with pulmonary TB, and is apparently produced ectopically. In this study, a BALB/c mouse model of progressive pulmonary TB was used to determine whether VP may play a role in TB pathophysiology. Our results show that VP gene is expressed in the lung since early infection, increasing as the infection progressed, and localized mainly in macrophages, which are key cells in mycobacterial elimination. Pharmacologic manipulation using agonist and antagonist compounds showed that high and sustained stimulation of VPR resulted in increased bacillary burdens and fibrosis at lungs, while blockade of VP receptors reduced bacterial loads. Accordingly, treatment of infected alveolar macrophages with VP in cell cultures resulted in high numbers of intracellular Mtb and impaired cytokine production. Thus, we show that VP is ectopically produced in the tuberculous lungs, with macrophages being its most possible target cell. Further, it seems that chronic vasopressinergic stimulation during active late disease causes anti-inflammatory and tissue reparative effects, which could be deleterious while its pharmacologic suppression reactivates protective immunity and contributes to shorten conventional chemotherapy, which could be a new possible form of immune-endocrine therapy.
ABSTRACT
A surgical connection between portal and inferior cava veins was performed to generate an experimental model of high circulating ammonium and hepatic hypofunctioning. After 13 weeks of portacaval anastomosis (PCA), hyperammonemia and shrinkage in the liver were observed. Low glycemic levels accompanied by elevated levels of serum alanine aminotransferase were recorded. However, the activity of serum aspartate aminotransferase was reduced, without change in circulating urea. Histological and ultrastructural observations revealed ongoing vascularization and alterations in the hepatocyte nucleus (reduced diameter with indentations), fewer mitochondria, and numerous ribosomes in the endoplasmic reticulum. High activity of hepatic caspase-3 suggested apoptosis. PCA promoted a marked reduction in lipid peroxidation determined by TBARs in liver homogenate but specially in the mitochondrial and microsomal fractions. The reduced lipoperoxidative activity was also detected in assays supplemented with Fe2+. Only discreet changes were observed in conjugated dienes. Fluorescent probes showed significant attenuation in mitochondrial membrane potential, reactive oxygen species (ROS), and calcium content. Rats with PCA also showed reduced food intake and decreased energy expenditure through indirect calorimetry by measuring oxygen consumption with an open-flow respirometric system. We conclude that experimental PCA promotes an angiogenic state in the liver to confront the altered blood flow by reducing the prooxidant reactions associated with lower metabolic rate, along with significant reduction of mitochondrial content, but without a clear hepatic dysfunction.
Subject(s)
Lipid Peroxidation , Liver/metabolism , Liver/surgery , Portacaval Shunt, Surgical , Anastomosis, Surgical , Animals , Cell Membrane/metabolism , Energy Metabolism , Feeding Behavior , Fluorescent Dyes/metabolism , Hepatocytes/metabolism , Hepatocytes/ultrastructure , Liver/pathology , Liver/ultrastructure , Male , Mitochondria/metabolism , Oxidants/metabolism , Rats, Wistar , Subcellular Fractions/metabolismABSTRACT
AIM: To evaluate the effects of a treatment with leuprolide acetate (LA) on bladder overactivity as well as the expression of gonadotropin releasing hormone receptor (GnRH-R), and neurofilaments NF68 and NF200 in female rats with overactive bladder induced by castration. METHODS: Changes in the urodynamic parameters were determined in SHAM, ovariectomized (OVX) and ovariectomized rats treated with LA (OVX-LA). A semi-quantitative analysis for the expression pattern of GnRH-R and neurofilaments NF68 and NF200 were determined. RESULTS: Forty-three days after ovariectomy, rats from the OVX group have significant lower values for intercontractile interval (ICI) and compliance (C); as well as higher values for basal bladder pressure (BP) and frequency of non-voiding contractions (NVC). The systemic application of LA increased voiding volume (Vv) and pressure threshold (ThP) in the OVX-LA animals. The application of LA reduced the high frequency of NVC in the OVX rats. No significant differences were found for Vv and NVCs between the OVX-LA vs SHAM groups. At the mid part of the bladder, the presence of GnRH-R was evidenced in the urothelium of the SHAM group. The OVX animals showed different pattern of immunolabeling for GnRH-R as well as for neurofilaments NF200 and NF68, whereas in the OVX-LA group the immunofluorescence pattern was similar to the one seen in SHAM bladders (P < 0.05 for OVX vs OVX + LA). CONCLUSIONS: the results suggest that systemic application of LA can improve bladder dysfunction in castrated rats, and perhaps considered as a treatment for overactive bladder conditions secondary to menopause.
Subject(s)
Leuprolide/pharmacology , Ovariectomy , Receptors, LHRH/agonists , Urodynamics/drug effects , Animals , Compliance/drug effects , Female , Muscle Contraction/drug effects , Neurofilament Proteins/biosynthesis , Neurofilament Proteins/genetics , Rats , Rats, Wistar , Receptors, LHRH/biosynthesis , Urinary Bladder/drug effects , Urinary Bladder/metabolism , Urothelium/drug effects , Urothelium/metabolismABSTRACT
Toxocariasis is a zoonotic disease produced by ingestion of larval Toxocara spp. eggs. Prolactin (PRL) has been considered to have an important role in Toxocara canis infection. Recent evidence has found that PRL directly can increase parasite growth and differentiation of T. canis The present study, evaluated the effect of high PRL levels on the immune system's response and parasites clearance in chronic infection. Our results showed that hyperprolactinemia did not affect the number of larvae recovered from several tissues in rats. Parasite-specific antibody production, showed no difference between the groups. Lung tissue presented eosinophilic granulomas typical of a chronic infection in all the experimental groups. Flow cytometry analysis was made in order to determine changes in the percentage of innate and adaptive immune cell subpopulations in the spleen, peripheric (PLN) and mesenteric (MLN) lymphatic nodes. The results showed a differential effect of PRL and infection on different immune compartments in the percent of total T cells, T helper cells, T cytotoxic cells, B cells, NK cells, and Tγδ cells. To our knowledge, for the first time it is demonstrated that PRL can have an immunomodulatory role during T. canis chronic infection in the murine host.
Subject(s)
Prolactin/immunology , Toxocara canis/immunology , Toxocariasis/immunology , Adaptive Immunity , Animals , Host-Parasite Interactions , Immunity, Innate , Larva/immunology , Lung/immunology , Lung/parasitology , Lung/pathology , Male , Prolactin/analysis , Rats, Wistar , T-Lymphocytes/immunology , T-Lymphocytes/parasitology , T-Lymphocytes/pathology , Toxocara canis/physiology , Toxocariasis/blood , Toxocariasis/pathology , Zoonoses/blood , Zoonoses/immunology , Zoonoses/pathologyABSTRACT
Toxocara canis is the helminth causing Toxocariasis, a parasitic disease with medical and veterinary implications. Their final host are members of the family Canidae and as paratenic hosts, most of the mammals are sensitive (man, rat, mouse, among others). It has been reported that a pituitary hormone, prolactin, it is responsible for reactivation and migration of larvae to the uterus and mammary gland during the last third of gestation in bitches. In addition, this hormone has been shown to play an important role in the regulation of the immune response. Thus, the aim of this study, was to evaluate the effect of hypophysectomy in the rat model of Toxocariasis, on the immune response against this parasite during a chronic infection, for which parasite loads were analyzed in different organs (lung and brain). Furthermore, serum specific antibody titers, and percentages of different cells of the immune system were also determined. The results showed a decrease in the number of larvae recovered from lung and brain in the hypophysectomized animals. In this same group of animals, there was no production of specific antibodies against the parasite. As for the percentages of the cells of the immune system, there are differences in some subpopulations due to surgery and others due to infection. Our results demonstrated that the lack of pituitary hormones alters parasite loads and the immune response to the helminth parasite Toxocara canis.