ABSTRACT
Diets rich in grains and meat and low in fruits and vegetables (acid-producing diets) associate with incident hypertension, whereas vegetarian diets associate with lower blood pressure (BP). However, the pathways that sense and mediate the effects of acid-producing diets on BP are unknown. Here, we examined the impact of the deletion of an acid sensor GPR4 on BP. GPR4 is a proton-sensing G protein-coupled receptor and an acid sensor in brain, kidney, and blood vessels. We found that GPR4 mRNA was higher in subfornical organ (SFO) than other brain regions. GPR4 protein was abundant in SFO and present in capillaries throughout the brain. Since SFO partakes in BP regulation through the renin-angiotensin system (RAS), we measured BP in GPR4-/- and GPR4+/+ mice and found that GPR4 deletion associated with lower systolic BP: 87 ± 1 mmHg in GPR4-/- (n = 35) vs. 99 ± 2 mmHg (n = 29) in GPR4+/+; P < 0.0001, irrespective of age and sex. Angiotensin II receptors detected by 125I-Sarthran binding were lower in GPR4-/- than GPR4+/+ mice in SFO and in paraventricular nucleus of hypothalamus. Circulating angiotensin peptides were comparable in GPR4-/- and GPR4+/+ mice, as were water intake and excretion, serum and urine osmolality, and fractional excretion of sodium, potassium, or chloride. A mild metabolic acidosis present in GPR4-/- mice did not associate with elevated BP, implying that deficiency of GPR4 may preclude the effect of chronic acidosis on BP. Collectively, these results posit the acid sensor GPR4 as a novel component of central BP control through interactions with the RAS.
Subject(s)
Blood Pressure/genetics , Receptor, Angiotensin, Type 2/metabolism , Receptors, G-Protein-Coupled/genetics , Renin-Angiotensin System/physiology , Subfornical Organ/metabolism , Animals , Female , Male , Mice , Mice, Knockout , Receptor, Angiotensin, Type 2/genetics , Receptors, G-Protein-Coupled/metabolismABSTRACT
BACKGROUND: Chlamydia trachomatis (C. trachomatis) is a clinically significant human pathogen and one of the leading causative agents of sexually transmitted diseases. As obligate intracellular bacteria, C. trachomatis has evolved strategies to redirect the host's signaling and resources for its own survival and propagation. Despite the clinical notoriety of Chlamydia infections, the molecular interactions between C. trachomatis and its host cell proteins remain elusive. RESULTS: In this study, we focused on the involvement of the host cell epidermal growth factor receptor (EGFR) in C. trachomatis attachment and development. A combination of molecular approaches, pharmacological agents and cell lines were used to demonstrate distinct functional requirements of EGFR in C. trachomatis infection. We show that C. trachomatis increases the phosphorylation of EGFR and of its downstream effectors PLCγ1, Akt and STAT5. While both EGFR and platelet-derived growth factor receptor-ß (PDGFRß) are partially involved in bacterial attachment to the host cell surface, it is only the knockdown of EGFR and not PDGFRß that affects the formation of C. trachomatis inclusions in the host cells. Inhibition of EGFR results in small immature inclusions, and prevents C. trachomatis-induced intracellular calcium mobilization and the assembly of the characteristic F-actin ring at the inclusion periphery. By using complementary approaches, we demonstrate that the coordinated regulation of both calcium mobilization and F-actin assembly by EGFR are necessary for maturation of chlamydial inclusion within the host cells. A particularly important finding of this study is the co-localization of EGFR with the F-actin at the periphery of C. trachomatis inclusion where it may function to nucleate the assembly of signaling protein complexes for cytoskeletal remodeling required for C. trachomatis development. CONCLUSION: Cumulatively, the data reported here connect the function of EGFR to C. trachomatis attachment and development in the host cells, and this could lead to new venues for targeting C. trachomatis infections and associated diseases.
Subject(s)
Bacterial Adhesion , Chlamydia trachomatis/growth & development , ErbB Receptors/metabolism , Host-Pathogen Interactions , Transcriptional Activation , Animals , Chlamydia trachomatis/physiology , HeLa Cells , Humans , Mice , NIH 3T3 Cells , Phosphorylation , Protein Processing, Post-TranslationalABSTRACT
In rats, as in humans, normal aging is characterized by a decline in hippocampal-dependent learning and memory, as well as in glutamatergic function. Both growth hormone (GH) and insulin-like growth factor-I (IGF-I) levels have been reported to decrease with age, and treatment with either GH or IGF-I can ameliorate age-related cognitive decline. Interestingly, acute GH and IGF-I treatments enhance glutamatergic synaptic transmission in the rat hippocampus of juvenile animals. However, whether this enhancement also occurs in old rats, when cognitive impairment is ameliorated by GH and IGF-I (des-IGF-I), remains to be determined. To address this issue, we used an in vitro CA1 hippocampal slice preparation and extracellular recording techniques to study the effects of acute application of GH and IGF-I on compound field excitatory postsynaptic potentials (fEPSPs), as well as AMPA- and NMDA-dependent fEPSPs, in young adult (10 months) and old (28 months) rats. The results indicated that both GH and IGF-I increased compound-, AMPA-, and NMDA-dependent fEPSPs to a similar extent in slices from both age groups and that this augmentation was likely mediated via a postsynaptic mechanism. Initial characterization of the signaling cascades underlying these effects revealed that the GH-induced enhancement was not mediated by the JAK2 signaling element in either young adult or old rats but that the IGF-I-induced enhancement involved a PI3K-mediated mechanism in old, but not young adults. The present findings are consistent with a role for a GH- or IGF-I-induced enhancement of glutamatergic transmission in mitigating age-related cognitive impairment in old rats.
Subject(s)
Aging/metabolism , Growth Hormone/pharmacology , Hippocampus/metabolism , Insulin-Like Growth Factor I/pharmacology , Aging/drug effects , Animals , Cognition Disorders/drug therapy , Cognition Disorders/metabolism , Cognition Disorders/physiopathology , Disease Models, Animal , Hippocampus/drug effects , Male , Rats , Rats, Inbred BN , Rats, Inbred F344 , Synaptic Transmission/drug effectsABSTRACT
Alterations in the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor (AMPA-R) and N-methyl-D-aspartate receptor (NMDA-R) have been documented in aged animals and may contribute to changes in hippocampal-dependent memory. Growth hormone (GH) regulates AMPA-R and NMDA-R-dependent excitatory transmission and decreases with age. Chronic GH treatment mitigates age-related cognitive decline. An in vitro CA1 hippocampal slice preparation was used to compare hippocampal excitatory transmission and plasticity in old animals treated for 6-8 months with either saline or GH. Our findings indicate that GH treatment restores NMDA-R-dependent basal synaptic transmission in old rats to young adult levels and enhances both AMPA-R-dependent basal synaptic transmission and long-term potentiation. These alterations in synaptic function occurred in the absence of changes in presynaptic function, as measured by paired-pulse ratios, the total protein levels of AMPA-R and NMDA-R subunits or in plasma or hippocampal levels of insulin-like growth factor-I. These data suggest a direct role for GH in altering age-related changes in excitatory transmission and provide a possible cellular mechanism through which GH changes the course of cognitive decline.
Subject(s)
Aging , Excitatory Postsynaptic Potentials/drug effects , Hippocampus/drug effects , Intercellular Signaling Peptides and Proteins/pharmacology , Long-Term Potentiation/drug effects , Synaptic Transmission/drug effects , Analysis of Variance , Animals , Bicuculline/analogs & derivatives , Bicuculline/pharmacology , Biophysics , Electric Stimulation , Enzyme-Linked Immunosorbent Assay , Excitatory Amino Acid Agonists/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , GABA-A Receptor Antagonists/pharmacology , Glycine/pharmacology , Hippocampus/metabolism , In Vitro Techniques , Insulin-Like Growth Factor I/metabolism , Long-Term Potentiation/physiology , Male , Patch-Clamp Techniques , Rats , Rats, Inbred F344 , Receptors, AMPA/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/pharmacologyABSTRACT
Radiation therapy is used widely to treat primary and metastatic brain tumors, but also can lead to delayed neurological complications. Since maintenance of myelin integrity is important for cognitive function, the present study used a rat model that demonstrates spatial learning and memory impairment 12 months following fractionated whole-brain irradiation (WBI) at middle age to investigate WBI-induced myelin changes. In this model, 12-month Fischer 344 x Brown Norway rats received 9 fractions of 5 Gy delivered over 4.5 weeks (WBI rats); Sham-IR rats received anesthesia only. Twelve months later, the brains were collected and measures of white matter integrity were quantified. Qualitative observation did not reveal white matter necrosis one year post-WBI. In addition, the size of major forebrain commissures, the number of oligodendrocytes, the size and number of myelinated axons, and the thickness of myelin sheaths did not differ between the two groups. In summary, both the gross morphology and the structural integrity of myelin were preserved one year following fractionated WBI in a rodent model of radiation-induced cognitive impairment. Imaging studies with advanced techniques including diffusion tensor imaging may be required to elucidate the neurobiological changes associated with the cognitive impairment in this model.
Subject(s)
Brain/pathology , Brain/radiation effects , Cognition Disorders/pathology , Nerve Fibers, Myelinated/pathology , Nerve Fibers, Myelinated/radiation effects , Radiation Injuries, Experimental/pathology , Animals , Brain/ultrastructure , Cell Count , Cell Size , Cognition Disorders/etiology , Disease Models, Animal , Learning Disabilities/etiology , Learning Disabilities/pathology , Male , Memory Disorders/etiology , Memory Disorders/pathology , Myelin Sheath/pathology , Myelin Sheath/radiation effects , Myelin Sheath/ultrastructure , Necrosis/pathology , Nerve Fibers, Myelinated/ultrastructure , Oligodendroglia/pathology , Oligodendroglia/radiation effects , Oligodendroglia/ultrastructure , Organ Size , Random Allocation , Rats , Rats, Inbred F344 , Space Perception/radiation effects , Time FactorsABSTRACT
PURPOSE: To determine whether hippocampal neurons are lost 12 months after middle-aged rats received a fractionated course of whole-brain irradiation (WBI) that is expected to be biologically equivalent to the regimens used clinically in the treatment of brain tumors. METHODS AND MATERIALS: Twelve-month-old Fischer 344 X Brown Norway male rats were divided into WBI and control (CON) groups (n = 6 per group). Anesthetized WBI rats received 45 Gy of (137)Cs gamma rays delivered as 9 5-Gy fractions twice per week for 4.5 weeks. Control rats were anesthetized but not irradiated. Twelve months after WBI completion, all rats were anesthetized and perfused with paraformaldehyde, and hippocampal sections were immunostained with the neuron-specific antibody NeuN. Using unbiased stereology, total neuron number and the volume of the neuronal and neuropil layers were determined in the dentate gyrus, CA3, and CA1 subregions of hippocampus. RESULTS: No differences in tissue integrity or neuron distribution were observed between the WBI and CON groups. Moreover, quantitative analysis demonstrated that neither total neuron number nor the volume of neuronal or neuropil layers differed between the two groups for any subregion. CONCLUSIONS: Impairment on a hippocampal-dependent learning and memory test occurs 1 year after fractionated WBI at middle age. The same WBI regimen, however, does not lead to a loss of neurons or a reduction in the volume of hippocampus.
Subject(s)
Cranial Irradiation/methods , Hippocampus/radiation effects , Neurons/radiation effects , Age Factors , Animals , Cell Count , Cesium Isotopes , Dentate Gyrus/cytology , Dentate Gyrus/radiation effects , Dose Fractionation, Radiation , Hippocampus/cytology , Male , Neurons/cytology , Random Allocation , Rats , Rats, Inbred F344 , Time FactorsABSTRACT
This is a clinical study that attempts to determine the incidence and patterns of cutaneous lesions in 109 pediatric patients with leukemia. Non-specific lesions, namely, adverse reactions to chemotherapy, complications of immunosuppression, and hemorrhagic diathesis were seen in 88.7 per cent of those patients with acute lymphocytic leukemia and in 88.9 per cent of patients with acute non-lymphocytic leukemia. Leukemia cutis was seen in three patients with acute non-lymphocytic leukemia, and in one patient with congenital leukemia. It seems that although skin complications are a frequent event in the course of childhood leukemia, leukemic infiltration of the skin a is rare event
Subject(s)
Adolescent , Child , Child, Preschool , Humans , Infant , Infant, Newborn , Leukemia/complications , Skin Diseases/epidemiology , Antineoplastic Agents/adverse effects , Incidence , Leukemia/drug therapy , Skin Diseases/etiologyABSTRACT
Pseudomonas aeruginosa es un bacilo gram negativo, oportunista que causa serias infecciones nosocomiales. Sin embargo, este puede causar infecciones con presentaciones poco usuales adquiridas fuera del ambiente hospitalariao. En este trabajo se discutirá la patogénesis, presentaciones clínicas, y el tratamiento de éstas infecciones poco comunes, como por ejemplo: 1) Foliculitis: infección bacteriana superficial o profunda que se asocia a el uso de saunas y piscinas contaminadas. 2) Otitis externa invasiva: infección que puede progresar hasta la base del cerebro y está asociada mayormente con pacientes diabéticos de avanzada edad. Usualmente esta condición es secundaria a irrigación aural con agua contaminada. 3) Osteomielitis: infección que usualmente se asocia con heridas punzantes con clavos en especial si se tienen puesto zapatos deportivos. 4) Infección entre los dedos de los pies: infección mayormente asociada a individuos utilizando agentes antimicrobianos tópicos. 5) "Green nail syndrome": lesión en la paranoquia no dolorosa que aparece mas comunnente en personas cuyas manos estan en constante exposición al agua, jabones, detergentes o a traumas mecánicos. 6) Keratitis-úlcera en al cornea: mayormente asociada a usuarios de lentes de contacto suave, gotas para los ojos, mascara o piscinas contaminadas. Esta condición podría terminar en una panoftalmitis. 7) Endocarditis: condición mayormente asociada a adictos a drogas intravenosas
