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1.
Hum Mol Genet ; 26(22): 4416-4428, 2017 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-28973411

RESUMO

Although it has been speculated that proteasome dysfunction may contribute to the pathogenesis of Huntington's disease (HD), a devastating neurodegenerative disorder, how proteasome activity is regulated in HD affected stem cells and somatic cells remains largely unclear. To better understand the pathogenesis of HD, we analyzed proteasome activity and the expression of FOXO transcription factors in three wild-type (WT) and three HD induced-pluripotent stem cell (iPSC) lines. HD iPSCs exhibited elevated proteasome activity and higher levels of FOXO1 and FOXO4 proteins. Knockdown of FOXO4 but not FOXO1 expression decreased proteasome activity. Following neural differentiation, the HD-iPSC-derived neural progenitor cells (NPCs) demonstrated lower levels of proteasome activity and FOXO expressions than their WT counterparts. More importantly, overexpression of FOXO4 but not FOXO1 in HD NPCs dramatically enhanced proteasome activity. When HD NPCs were further differentiated into DARPP32-positive neurons, these HD neurons were more susceptible to death than WT neurons and formed Htt aggregates under the condition of oxidative stress. Similar to HD NPCs, HD-iPSC-derived neurons showed reduced proteasome activity and diminished FOXO4 expression compared to WT-iPSC-derived neurons. Furthermore, HD iPSCs had lower AKT activities than WT iPSCs, whereas the neurons derived from HD iPSC had higher AKT activities than their WT counterparts. Inhibiting AKT activity increased both FOXO4 level and proteasome activity, indicating a potential role of AKT in regulating FOXO levels. These data suggest that FOXOs modulate proteasome activity, and thus represents a potentially valuable therapeutic target for HD.


Assuntos
Proteína Forkhead Box O1/metabolismo , Doença de Huntington/patologia , Células-Tronco Pluripotentes Induzidas/enzimologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Fatores de Transcrição/metabolismo , Proteínas de Ciclo Celular , Diferenciação Celular/fisiologia , Linhagem Celular , Proteína Forkhead Box O1/genética , Fatores de Transcrição Forkhead , Humanos , Proteína Huntingtina/metabolismo , Doença de Huntington/enzimologia , Doença de Huntington/genética , Doença de Huntington/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Neurais/enzimologia , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia , Neurônios/enzimologia , Neurônios/metabolismo , Neurônios/patologia , Complexo de Endopeptidases do Proteassoma/genética , Fatores de Transcrição/genética
2.
Mol Med ; 20: 302-12, 2014 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-24960246

RESUMO

Thyroid dysfunction is common in individuals with diabetes mellitus (DM) and may contribute to the associated cardiac dysfunction. However, little is known about the extent and pathophysiological consequences of low thyroid conditions on the heart in DM. DM was induced in adult female Sprague Dawley (SD) rats by injection of nicotinamide (N; 200 mg/kg) followed by streptozotocin (STZ; 65 mg/kg). One month after STZ/N, rats were randomized to the following groups (N = 10/group): STZ/N or STZ/N + 0.03 µg/mL T3; age-matched vehicle-treated rats served as nondiabetic controls (C). After 2 months of T3 treatment (3 months post-DM induction), left ventricular (LV) function was assessed by echocardiography and LV pressure measurements. Despite normal serum thyroid hormone (TH) levels, STZ/N treatment resulted in reductions in myocardial tissue content of THs (T3 and T4: 39% and 17% reduction versus C, respectively). Tissue hypothyroidism in the DM hearts was associated with increased DIO3 deiodinase (which converts THs to inactive metabolites) altered TH transporter expression, reexpression of the fetal gene phenotype, reduced arteriolar resistance vessel density, and diminished cardiac function. Low-dose T3 replacement largely restored cardiac tissue TH levels (T3 and T4: 43% and 10% increase versus STZ/N, respectively), improved cardiac function, reversed fetal gene expression and preserved the arteriolar resistance vessel network without causing overt symptoms of hyperthyroidism. We conclude that cardiac dysfunction in chronic DM may be associated with tissue hypothyroidism despite normal serum TH levels. Low-dose T3 replacement appears to be a safe and effective adjunct therapy to attenuate and/or reverse cardiac remodeling and dysfunction induced by experimental DM.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Terapia de Reposição Hormonal , Miocárdio/metabolismo , Hormônios Tireóideos/uso terapêutico , Animais , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Feminino , Hemodinâmica , Miocárdio/patologia , Ratos Sprague-Dawley , Hormônios Tireóideos/sangue , Hormônios Tireóideos/farmacologia , Remodelação Ventricular/efeitos dos fármacos
3.
S D Med ; 66(11): 449, 451, 453-5, 457, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24383261

RESUMO

BACKGROUND: Avoidance of influenza among college students requires understanding the risks for falling ill, outcomes of this disease, and utilizing methods to prevent developing influenza. We hypothesized that the behavior and knowledge of college students in the midst of a pandemic situation would be different than that during a regular influenza season. METHODS: We evaluated influenza knowledge of 311 university students in 2008 prior to and 318 students during the 2009-2010 H1N1 pandemic using voluntary online surveys that contained 25 questions regarding vaccination behaviors and influenza knowledge. Data were analyzed according to year and vaccination uptake. RESULTS: Very similar overall knowledge levels were found in the two cohorts independent of vaccination status. Both cohorts overestimated the prevalence of influenza and the number of people hospitalized due to influenza, but underestimated the number of deaths. Vaccination rates for seasonal influenza were in the two cohorts about 36 percent. By contrast, 4.8 percent participants had received the H1N1 vaccine, 40.1 percent intended to and 54.8 percent had no intentions of being vaccinated. CONCLUSIONS: The overall knowledge levels and vaccination behaviors of college students were not affected by the presence of an influenza pandemic. However, students' responses displayed a shift in belief toward greater rates of hospitalization and deaths in the 2009 sample, suggesting a change in perception due to the ongoing pandemic.


Assuntos
Conhecimentos, Atitudes e Prática em Saúde , Influenza Humana/epidemiologia , Estudantes/estatística & dados numéricos , Universidades/estatística & dados numéricos , Vacinação/métodos , Feminino , Seguimentos , Humanos , Vírus da Influenza A Subtipo H1N1/imunologia , Vacinas contra Influenza/uso terapêutico , Influenza Humana/prevenção & controle , Masculino , Pandemias , Estudos Retrospectivos , Estações do Ano , Inquéritos e Questionários , Estados Unidos/epidemiologia , Adulto Jovem
4.
S D Med ; 65(7): 265-7, 269-71, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22866347

RESUMO

BACKGROUND: An estimated 25.8 million people in the United States have type 2 diabetes, including seven million people who have the disease but are undiagnosed. These numbers indicate that education about diabetes is needed. METHODS: To evaluate university students' knowledge about diabetes (risk factors, signs and symptoms and complications) we utilized a survey. Specifically, we determined: (1) knowledge of type 2 diabetes; (2) if participants' academic field of study affected their knowledge of type 2 diabetes; (3) if participants who had a family member with type 2 diabetes had a greater knowledge of the disease; and (4) if age affected students' knowledge of the disease. RESULTS: A questionnaire was completed by 469 students from The University of South Dakota. Students' knowledge of type 2 diabetes was poor: 30.1 percent of the students scored higher than 70 percent (with only 6.8 percent of the students scoring higher than 80 percent). No significant differences in knowledge scores were found between students who pursued health-related fields of study versus students who did not. Participants who had a family member with type 2 diabetes had a greater knowledge of the disease and felt that they had a higher risk for getting the disease. Significant differences in knowledge were only found between the youngest and oldest age groups. CONCLUSIONS: USD students' knowledge of type 2 diabetes is limited. Solutions need to communicate the risk factors and severity of the disease. Possible ways for improving diabetes education is to include health fairs as well as to integrate diabetes modules into K-12 education courses.


Assuntos
Diabetes Mellitus Tipo 2 , Conhecimentos, Atitudes e Prática em Saúde , Estudantes , Adolescente , Diabetes Mellitus Tipo 2/diagnóstico , Feminino , Educação em Saúde , Humanos , Masculino , South Dakota , Universidades , Adulto Jovem
5.
Brain Res ; 1187: 146-53, 2008 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-18036574

RESUMO

During exposure of animals to hypoxia, brain and blood dopamine levels increase stimulating dopaminergic receptors which influence the integrated ventilatory response to low oxygen. The purpose of the present study is to test the hypothesis that in conscious hamsters, systemic antagonism of D(1) receptors would depress their breathing in air and in response to hypoxic and hypercapnic challenges. Nine male hamsters were treated with saline or 0.25 mg/kg SCH-23390 (SCH), a D(1) receptor antagonist that crosses the blood-brain barrier. Ventilation was determined using the barometric method, and oxygen consumption and CO(2) production were evaluated utilizing the flow-through method. During exposure to air, SCH decreased frequency of breathing. During exposure to hypoxia (10% oxygen in nitrogen), relative to saline, SCH-treated hamsters decreased minute ventilation by decreasing tidal volume and oxygen consumption but not CO(2) production. During exposure to hypercapnia (5% CO(2) in 95% O(2)), frequency of breathing was decreased with SCH, but there was no significant effect on minute ventilation. Relative to saline treatment body temperature was lower in SCH-treated hamsters by 0.6 degrees C. These results demonstrate that in hamsters D(1) receptors can modulate control of ventilation in air and during hypoxia and hypercapnic exposures. Whether D(1) receptors located centrally or on carotid bodies modulate these effects is not clear from this study.


Assuntos
Células Quimiorreceptoras/metabolismo , Dopamina/metabolismo , Hipóxia/fisiopatologia , Receptores de Dopamina D1/antagonistas & inibidores , Insuficiência Respiratória/fisiopatologia , Fenômenos Fisiológicos Respiratórios/efeitos dos fármacos , Animais , Benzazepinas/farmacologia , Temperatura Corporal/efeitos dos fármacos , Temperatura Corporal/fisiologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Corpo Carotídeo/efeitos dos fármacos , Corpo Carotídeo/metabolismo , Corpo Carotídeo/fisiopatologia , Células Quimiorreceptoras/efeitos dos fármacos , Cricetinae , Antagonistas de Dopamina/farmacologia , Hipercapnia/metabolismo , Hipercapnia/fisiopatologia , Hipóxia/metabolismo , Masculino , Mesocricetus , Receptores de Dopamina D1/metabolismo , Insuficiência Respiratória/induzido quimicamente
6.
Viral Immunol ; 31(6): 457-469, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29870311

RESUMO

Influenza virus infections can be complicated by bacterial superinfections, which are medically relevant because of a complex interaction between the host, the virus, and the bacteria. Studies to date have implicated several influenza virus genes, varied host immune responses, and bacterial virulence factors, however, the host-pathogen interactions that predict survival versus lethal outcomes remain undefined. Previous work by our group showed that certain influenza viruses could yield a survival phenotype (A/swine/Texas/4199-2/98-H3N2, TX98), whereas others were associated with a lethal phenotype (A/Puerto Rico/8/34-H1N1, PR8). Based on this observation, we developed the hypothesis that individual influenza virus genes could contribute to a superinfection, and that the host response after influenza virus infection could influence superinfection severity. The present study analyzes individual influenza virus gene contributions to superinfection severity using reassortant viruses created using TX98 and PR8 viral genes. Host and pathogen interactions, relevant to survival and lethal phenotypes, were studied with a focus on pathogen clearance, host cellular infiltrates, and cytokine levels after infection. Specifically, we found that the hemagglutinin gene expressed by an influenza virus can contribute to the severity of a secondary bacterial infection, likely through modulation of host proinflammatory responses. Altogether, these results advance our understanding of molecular mechanisms underlying influenza virus-bacteria superinfections and identify viral and corresponding host factors that may contribute to morbidity and mortality.


Assuntos
Alphainfluenzavirus/imunologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Influenza Humana/imunologia , Vírus Reordenados/imunologia , Infecções Estreptocócicas/imunologia , Streptococcus pyogenes/imunologia , Superinfecção/imunologia , Animais , Modelos Animais de Doenças , Feminino , Interações Hospedeiro-Patógeno/imunologia , Humanos , Influenza Humana/diagnóstico , Influenza Humana/mortalidade , Influenza Humana/virologia , Alphainfluenzavirus/metabolismo , Camundongos Endogâmicos BALB C , Vírus Reordenados/metabolismo , Índice de Gravidade de Doença , Infecções Estreptocócicas/microbiologia , Infecções Estreptocócicas/mortalidade , Superinfecção/microbiologia , Superinfecção/mortalidade , Fatores de Virulência/imunologia
7.
Respir Physiol Neurobiol ; 155(3): 203-12, 2007 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-16861057

RESUMO

We investigated effects of dextromethophan (DXM), an NMDA receptor antagonist, on ventilation and metabolism in unanesthetized male and female weanling rats, and densities of neurons positive for the NR1 subunit in four medullary nuclei. Relative to saline, DXM treatment decreased oxygen consumption 12% in males and increased it 9% in females (interaction, P<0.05). DXM compared to saline decreased frequency of breathing significantly more in females than males when exposed to hypercapnia. During hypoxia, DXM relative to saline significantly decreased frequency and minute ventilation in males and increased these variables in females. NR1 positive neuron densities were significantly greater in females than males in the nucleus tractus solitarius (NTS), commissural nucleus of the NTS and hypoglossal nucleus due to higher counts. Few sex differences were noted in the dorsal vagal motor nucleus. Thus, in weanling rats NMDA receptor modulation of breathing is sex specific, as are the densities of NR1 positive neurons in medullary nuclei associated with control of breathing.


Assuntos
Agonistas de Aminoácidos Excitatórios/farmacologia , Bulbo/metabolismo , N-Metilaspartato/farmacologia , Receptores de N-Metil-D-Aspartato/biossíntese , Mecânica Respiratória/efeitos dos fármacos , Animais , Dióxido de Carbono/metabolismo , Contagem de Células , Dextrometorfano/farmacologia , Feminino , Nervo Hipoglosso/citologia , Nervo Hipoglosso/efeitos dos fármacos , Nervo Hipoglosso/fisiologia , Imuno-Histoquímica , Masculino , Bulbo/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Músculos Respiratórios/fisiologia , Caracteres Sexuais , Núcleo Solitário/fisiologia , Língua/inervação , Língua/fisiologia , Desmame
8.
Respir Physiol Neurobiol ; 245: 37-44, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-27756648

RESUMO

The arcuate nucleus of the hypothalamus (ANH) interacts with other hypothalamic nuclei, forebrain regions, and downstream brain sites to affect autonomic nervous system outflow, energy balance, temperature regulation, sleep, arousal, neuroendocrine function, reproduction, and cardiopulmonary regulation. Compared to studies of other ANH functions, how the ANH regulates cardiopulmonary function is less understood. Importantly, the ANH exhibits structural and functional sexually dimorphic characteristics and contains numerous neuroactive substances and receptors including leptin, neuropeptide Y, glutamate, acetylcholine, endorphins, orexin, kisspeptin, insulin, Agouti-related protein, cocaine and amphetamine-regulated transcript, dopamine, somatostatin, components of renin-angiotensin system and gamma amino butyric acid that modulate physiological functions. Moreover, several clinically relevant disorders are associated with ANH ventilatory control dysfunction. This review highlights how ANH neurotransmitter systems and receptors modulate breathing differently in male and female rodents. Results highlight the significance of the ANH in cardiopulmonary regulation. The paucity of studies in this area that will hopefully spark investigations of sexually dimorphic ANH-modulation of breathing.


Assuntos
Núcleo Arqueado do Hipotálamo/fisiologia , Coração/fisiologia , Respiração , Caracteres Sexuais , Animais , Núcleo Arqueado do Hipotálamo/anatomia & histologia , Núcleo Arqueado do Hipotálamo/fisiopatologia , Coração/fisiopatologia , Humanos
9.
Physiol Rep ; 5(8)2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28420763

RESUMO

Ubiquilin-1 (Ubqln1), a ubiquitin-like protein, is implicated in a variety of pathophysiological processes, but its role in mediating body weight gain or metabolism has not been determined. Here, we demonstrate that global overexpression of Ubqln1 in a transgenic (Tg) mouse reduces the animal's body weight gain. The decreased body weight gain in Tg mice is associated with lower visceral fat content and higher metabolic rate. The Ubqln1 Tg mice exhibited reduced leptin and insulin levels as well as increased insulin sensitivity manifested by homeostatic model assessment of insulin resistance. Additionally, the reduced body weight in Tg mice was associated with the upregulation of two energy-sensing proteins, sirtuin1 (SIRT1) in the hypothalamus and AMP-activated protein kinase (AMPK) in the skeletal muscle. Consistent with the in vivo results, overexpression of Ubqln1 significantly increased SIRT1 and AMPK levels in the mouse embryonic fibroblast cell culture. Thus, our results not only establish the link between Ubqln1 and body weight regulation but also indicate that the metabolic function of Ubqln1 on body weight may be through regulating energy-sensing proteins.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/genética , Proteínas Quinases/metabolismo , Sirtuína 1/metabolismo , Magreza/genética , Quinases Proteína-Quinases Ativadas por AMP , Proteínas Adaptadoras de Transdução de Sinal , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Animais , Proteínas Relacionadas à Autofagia , Células Cultivadas , Feminino , Fibroblastos/metabolismo , Hipotálamo/metabolismo , Insulina/sangue , Resistência à Insulina , Gordura Intra-Abdominal/crescimento & desenvolvimento , Gordura Intra-Abdominal/metabolismo , Leptina/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Proteínas Quinases/genética , Sirtuína 1/genética , Magreza/metabolismo
10.
Brain Res ; 1123(1): 89-100, 2006 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-17045976

RESUMO

In rats ventilatory responses to N-methyl-d-aspartate (NMDA) receptor modulation are sexually dimorphic and may be altered by manipulating brain levels of estrogen receptors. Here we used image analysis and immunohistochemistry in weanling male and female rats to quantitate areas and densities of ER alpha and ER beta-positive neurons within medullary regions associated with cardiopulmonary regulation including the hypoglossal nucleus, subnuclei of the nucleus of the solitary tract (NTS), and the dorsal motor nucleus of the vagus. Weanling rats were selected because ventilation, metabolic rate, and body and brain weights are comparable at this age and there are no large fluctuations in plasma hormone levels. Females, relative to males, had smaller areas in the A2 region and parts of the NTS. Counts and densities for ER alpha were greater in females than males in almost all regions studied. In contrast sex differences in ER beta were found in fewer nuclei, but in those higher counts and densities were noted in females. In general, ER beta-positive neurons in the brainstem regions examined were less prevalent than ER alpha neurons. Thus, in weanling rats sex affected ER alpha and ER beta neuronal densities in brainstem regions associated with cardiopulmonary regulation that may be responsible for sex differences in control of breathing.


Assuntos
Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Bulbo/metabolismo , Neurônios/metabolismo , Respiração , Análise de Variância , Animais , Feminino , Imuno-Histoquímica , Masculino , Bulbo/citologia , Ratos , Ratos Sprague-Dawley , Fatores Sexuais , Núcleo Solitário/citologia , Núcleo Solitário/metabolismo , Distribuição Tecidual
11.
Respir Physiol Neurobiol ; 227: 34-40, 2016 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-26934718

RESUMO

Effects of microinjection of 2 doses of γ-aminobutyric acid (GABA)A receptor agonist, muscimol (M), into the hypothalamic arcuate nucleus on oxygen consumption and control of ventilation over time and body temperature (BT) at the end of the experiment were compared in adult male and female rats. Relative to cerebrospinal fluid (CSF, 0 nmol), BT was decreased only in male rats with both doses of M, while in female rats, the 5 nmol dose depressed oxygen consumption. Ventilation was depressed by 5 nmol M in male and 10 nmol M in female rats by decreasing tidal volume. M did not affect the ventilatory response of male or female rats to hypoxia, whereas in females 5 and 10 nmol M and in males 10 nmol M depressed the ventilatory response to hypercapnia. Thus, in rats GABAA receptors in the arcuate nucleus modulate BT, oxygen consumption, and ventilation in air and in response to hypercapnia in a sexually dimorphic manner.


Assuntos
Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Temperatura Corporal/efeitos dos fármacos , Agonistas de Receptores de GABA-A/administração & dosagem , Muscimol/administração & dosagem , Consumo de Oxigênio/efeitos dos fármacos , Respiração/efeitos dos fármacos , Animais , Núcleo Arqueado do Hipotálamo/fisiologia , Temperatura Corporal/fisiologia , Relação Dose-Resposta a Droga , Feminino , Hipóxia/tratamento farmacológico , Hipóxia/fisiopatologia , Masculino , Microinjeções , Consumo de Oxigênio/fisiologia , Ratos Sprague-Dawley , Caracteres Sexuais , Volume de Ventilação Pulmonar/efeitos dos fármacos , Volume de Ventilação Pulmonar/fisiologia
12.
Respir Physiol Neurobiol ; 218: 32-9, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26232642

RESUMO

Hypothyroidism affects cardiopulmonary regulation and function of dopaminergic receptors. Here we evaluated effects of 5 months of hypothyroidism on dopamine D1 receptor modulation of breathing in female hamsters using a D1 receptor antagonist SCH 23390. Euthyroid hamsters (EH) served as controls. Results indicated that hypothyroid female hamsters (HH) exhibited decreased body weights and minute ventilation (VE) following hypoxia due to decreased frequency of breathing (F). Moreover, SCH 23390 administration in HH increased VE by increasing tidal volume during exposure to air, hypoxia and following hypoxia. Relative to vehicle, SCH 23390 treatment decreased body temperature and hypoxic VE responsiveness in both groups. In EH, SCH 23390 decreased F in air, hypoxia and post hypoxia, and VE during hypoxia trended to decrease (P=0.053). Finally, expression of D1 receptor protein was not different between the two groups in any region evaluated. Thus, hypothyroidism in older female hamsters affected D1 receptor modulation of ventilation differently relative to euthyroid animals, but not expression of D1 receptors.


Assuntos
Hipotireoidismo/fisiopatologia , Receptores de Dopamina D1/metabolismo , Respiração , Animais , Benzazepinas/farmacologia , Western Blotting , Temperatura Corporal/efeitos dos fármacos , Temperatura Corporal/fisiologia , Peso Corporal/fisiologia , Dióxido de Carbono/metabolismo , Modelos Animais de Doenças , Antagonistas de Dopamina/farmacologia , Feminino , Mesocricetus , Consumo de Oxigênio/efeitos dos fármacos , Consumo de Oxigênio/fisiologia , Propiltiouracila , Receptores de Dopamina D1/antagonistas & inibidores , Respiração/efeitos dos fármacos , Volume de Ventilação Pulmonar/efeitos dos fármacos , Volume de Ventilação Pulmonar/fisiologia
13.
Respir Physiol Neurobiol ; 205: 92-8, 2015 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-25447679

RESUMO

Type II diabetes mellitus (T2DM) can affect ventilation, metabolism, and fasting blood glucose levels. Hypothyroidism may be a comorbidity of T2DM. In this study T2DM was induced in 20 female Sprague Dawley rats using Streptozotocin (STZ) and Nicotinamide (N). One of experimental STZ/N groups (N=10 per group) was treated with a low dose of triiodothyronine (T3). Blood glucose levels, metabolism and ventilation (in air and in response to hypoxia) were measured in the 3 groups. STZ/N-treated rats increased fasting blood glucose compared to control rats eight days and 2 months post-STZ/N injections indicating stable induction of T2DM state. Treatments had no effects on ventilation, metabolism or body weight. After one month of T3 supplementation, there were no physiological indications of hyperthyroidism, but T3 supplementation altered ventilatory timing and decreased blood glucose levels compared to STZ/N rats. These results suggest that low levels of T3 supplementation could offer modest effects on blood glucose and ventilatory timing in this T2M model.


Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Ventilação Pulmonar/efeitos dos fármacos , Tri-Iodotironina/farmacologia , Animais , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Ratos , Ratos Sprague-Dawley
14.
J Appl Physiol (1985) ; 92(6): 2457-66, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12015360

RESUMO

We hypothesized that administration of estradiol benzoate to males and testosterone propionate to female neonatal rat pups alters sex-specific ventilatory responses to aspartic acid with correspondent changes in N-methyl-D-aspartate receptor subunit 1 (NR1) expression determined by Western blot in specific brain regions. One-day-old rat pups received estradiol benzoate, testosterone propionate, or vehicle and were studied at weanling and adulthood. Different groups had distinct patterns of changes in tidal volume and frequency of breathing after aspartic acid administration. NR1 expression in hypothalamus was altered by age, sex, and treatment. Medullary and pontine NR1 expression correlated with baseline ventilation and magnitude of the ventilatory response to aspartic acid in some groups. Thus 1) tidal volume and breathing frequency patterns in response to aspartic acid are gender, age, and treatment dependent; 2) sex, age, and exogenous steroid hormones affect NR1 expression primarily in the hypothalamus; and 3) there is correlation between NR1 expression in pons and medulla with ventilatory parameters.


Assuntos
Animais Recém-Nascidos/fisiologia , Ácido Aspártico/farmacologia , Estradiol/farmacologia , Hormônios Esteroides Gonadais/farmacologia , Receptores de N-Metil-D-Aspartato/metabolismo , Respiração/efeitos dos fármacos , Testosterona/farmacologia , Animais , Animais Recém-Nascidos/crescimento & desenvolvimento , Western Blotting , Peso Corporal , Encéfalo/metabolismo , Soluções Tampão , Feminino , Masculino , Fosfatos/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Cloreto de Sódio/farmacologia , Distribuição Tecidual
15.
J Appl Physiol (1985) ; 97(4): 1387-94, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15194673

RESUMO

We hypothesized that, in male rats, 10% fructose in drinking water would depress ventilatory responsiveness to acute hypoxia (10% O2 in N2) and hypercapnia (5% CO2 in O2) that would be depressed further by exposure to intermittent hypoxia. Minute ventilation (Ve) in air and in response to acute hypoxia and hypercapnia was evaluated in 10 rats before fructose feeding (FF), during 6 wk of FF, and after FF was removed for 2 wk. During FF, five rats were exposed to intermittent air and five to intermittent hypoxia for 13 days. Six rats given tap water acted as control and were exposed to intermittent air and subsequently intermittent hypoxia. In FF rats, plasma insulin levels increased threefold in the rats exposed to intermittent hypoxia and during washout returned to levels observed in rats exposed to intermittent air. During FF, ventilatory responsiveness to acute hypoxia was depressed because of decreased tidal volume (Vt) responsiveness. During washout, Ve decreased as a result of decreased Vt and frequency of breathing, and the ventilatory responsiveness to hypoxia in intermittent hypoxia rats did not recover. In all rats, the ventilatory responses to hypercapnia were decreased during FF and recovered after washout because of an increased Vt responsiveness. In the control group, hypoxic responsiveness was not depressed after intermittent hypoxia and was augmented after washout. Thus FF attenuated the ventilatory responsiveness of conscious rats to hypoxia and hypercapnia. Intermittent hypoxia interacted with FF to increase insulin levels and depress ventilatory responses to acute hypoxia that remained depressed during washout.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Frutose/administração & dosagem , Frequência Cardíaca/efeitos dos fármacos , Hipercapnia/fisiopatologia , Hipóxia/fisiopatologia , Troca Gasosa Pulmonar/efeitos dos fármacos , Ventilação Pulmonar/efeitos dos fármacos , Adaptação Fisiológica/efeitos dos fármacos , Adaptação Fisiológica/fisiologia , Administração Oral , Animais , Hipercapnia/complicações , Hipóxia/classificação , Hipóxia/complicações , Masculino , Ratos , Ratos Sprague-Dawley , Índice de Gravidade de Doença
16.
Respir Physiol Neurobiol ; 138(2-3): 179-91, 2003 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-14609509

RESUMO

A decrease in the frequency of breathing following a hypoxic exposure that is below baseline values is called the post-hypoxic frequency decline (phfd) and is due to an elongation of expiratory time (TE). We hypothesized that lesioning the pontine A5 region would eliminate the phfd in conscious rats. Fourteen conscious male rats that demonstrated a phfd received lesions either within the A5 region (n=9) or outside this region (controls, n=5). Compared with pre-lesion values, body temperature decreased and frequency of breathing was lower during exposure to air, hypoxia, and hypercapnia in A5-lesioned, but not in the control-lesioned rats. No effect of A5 lesions was noted on tidal volume. Rats with A5 lesions no longer exhibited a phfd, and TE values following hypoxia were comparable to baseline TE values. These data suggest that the A5 region of the ventrolateral pons modulates the phfd in conscious rats and affects frequency of breathing in response to both hypoxia and hypercapnia.


Assuntos
Hipóxia/fisiopatologia , Ponte/patologia , Respiração , Animais , Temperatura Corporal , Denervação , Estimulação Elétrica , Expiração , Nervo Facial/fisiologia , Hipercapnia/fisiopatologia , Masculino , Consumo de Oxigênio , Ratos , Ratos Sprague-Dawley , Volume de Ventilação Pulmonar , Fatores de Tempo , Ventilação , Vigília/fisiologia
17.
Respir Physiol Neurobiol ; 193: 29-37, 2014 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-24434437

RESUMO

Bromocriptine depressed ventilation in air and D2 receptor expression in the nucleus tractus solitaries (NTS) in male hypothyroid hamsters. Here we postulated that in age-matched hypothyroid female hamsters, the pattern of D2 receptor modulation of breathing and D2 receptor expression would differ from those reported in hypothyroid males. In females hypothyroidism did not affect D2 receptor protein levels in the NTS, carotid bodies or striatum. Bromocriptine, but not carmoxirole (a peripheral D2 receptor agonist), increased oxygen consumption and body temperature in awake air-exposed hypothyroid female hamsters and stimulated their ventilation before and following exposure to hypoxia. Carmoxirole depressed frequency of breathing in euthyroid hamsters prior to, during and following hypoxia exposures and stimulated it in the hypothyroid hamsters following hypoxia. Although hypothyroidism did not affect expression of D2 receptors, it influenced central D2 modulation of breathing in a disparate manner relative to euthyroid hamsters.


Assuntos
Corpo Carotídeo/metabolismo , Corpo Estriado/metabolismo , Hipotireoidismo/metabolismo , Receptores de Dopamina D2/metabolismo , Respiração , Núcleo Solitário/metabolismo , Ar , Animais , Temperatura Corporal/efeitos dos fármacos , Temperatura Corporal/fisiologia , Bromocriptina/farmacologia , Corpo Carotídeo/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Cricetinae , Agonistas de Dopamina/farmacologia , Feminino , Hipotireoidismo/tratamento farmacológico , Hipóxia/tratamento farmacológico , Hipóxia/metabolismo , Indóis/farmacologia , Masculino , Consumo de Oxigênio/efeitos dos fármacos , Consumo de Oxigênio/fisiologia , Propiltiouracila , Piridinas/farmacologia , Receptores de Dopamina D2/agonistas , Respiração/efeitos dos fármacos , Fatores Sexuais , Núcleo Solitário/efeitos dos fármacos , Tiroxina/sangue , Vigília/efeitos dos fármacos , Vigília/fisiologia
18.
Endocrinology ; 154(7): 2542-52, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23594789

RESUMO

Thyroid hormones (THs) play a pivotal role in regulating cardiovascular homeostasis. To provide a better understanding of the coordinated processes that govern cardiac TH bioavailability, this study investigated the influence of serum and cardiac TH status on the expression of TH transporters and cytosolic binding proteins in the myocardium. In addition, we sought to determine whether the administration of T(3) (instead of T(4)) improves the relationship between THs in serum and cardiac tissue and cardiac function over a short-term treatment period. Adult female Sprague Dawley rats were made hypothyroid by 7 weeks treatment with the antithyroid drug 6-n-propyl-2-thiouracil (PTU). After establishing hypothyroidism, rats were assigned to 1 of 5 graded T(3) dosages plus PTU for a 2-week dose-response experiment. Untreated, age-matched rats served as euthyroid controls. PTU was associated with depressed serum and cardiac tissue T(3) and T(4) levels, arteriolar atrophy, altered TH transporter and cytosolic TH binding protein expression, fetal gene reexpression, and cardiac dysfunction. Short-term administration of T(3) led to a mismatch between serum and cardiac tissue TH levels. Normalization of serum T(3) levels was not associated with restoration of cardiac tissue T(3) levels or cardiac function. In fact, a 3-fold higher T(3) dosage was necessary to normalize cardiac tissue T(3) levels and cardiac function. Importantly, this study provides the first comprehensive data on the relationship between altered TH status (serum and cardiac tissue), cardiac function, and the coordinated in vivo changes in cardiac TH membrane transporters and cytosolic TH binding proteins in altered TH states.


Assuntos
Hipotireoidismo/tratamento farmacológico , Hormônios Tireóideos/uso terapêutico , Animais , Modelos Animais de Doenças , Feminino , Coração/efeitos dos fármacos , Miocárdio/metabolismo , Ratos , Ratos Sprague-Dawley , Hormônios Tireóideos/sangue , Tiroxina/sangue , Tiroxina/uso terapêutico , Tri-Iodotironina/sangue , Tri-Iodotironina/uso terapêutico
19.
Respir Physiol Neurobiol ; 181(2): 123-31, 2012 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-22394514

RESUMO

Hypothyroidism, subclinical hypothyroidism and euthyroid sick syndrome, are prevalent disorders that affect all body systems including the respiratory system and control of breathing. The purpose of this review article is to discuss the regulation of thyroid hormone production and their function at the cellular level; the many causes of hypothyroidism; the effects of hypothyroidism on the respiratory system and on control of ventilation in hypothyroid patients; the variety of ways animal models of hypothyroidism are induced; and how in animal models hypothyroidism affects the respiratory system and control of breathing including neurotransmitters that influence breathing. Finally, this review will present controversies that exist in the field and thus encourage new research directions. Because of the high prevalence of hypothyroidism and subclinical forms of hypothyroidism and their influence on ventilation and the respiratory system, understanding underlying molecular mechanisms is necessary to ascertain how and sometimes why not thyroid replacement may normalize function.


Assuntos
Hipotireoidismo/fisiopatologia , Respiração , Sistema Respiratório/fisiopatologia , Animais , Modelos Animais de Doenças , Feminino , Humanos , Hipotireoidismo/induzido quimicamente , Masculino , Camundongos , Coelhos , Ratos , Músculos Respiratórios/fisiologia , Hormônios Tireóideos/biossíntese , Hormônios Tireóideos/fisiologia
20.
Respir Physiol Neurobiol ; 180(1): 69-78, 2012 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-22051191

RESUMO

Hypothyroidism can depress breathing and alter dopamine D2 receptor expression and function. We hypothesized that relative to euthyroid hamsters (EH), hypothyroid hamsters (HH) contain increased D2 receptors in brain regions associated with breathing and carotid bodies (CB), and that stimulation of D2 receptors would decease ventilation more in the HH compared to the EH. Hamsters were treated with vehicle, carmoxirile (peripherally acting D2 receptor agonist), or bromocriptine (central and peripherally acting D2 receptor agonist) and breathing was evaluated during exposure to air, hypoxia, and then air. HH exhibited increased D2 receptor protein levels in the striatum and CB, but decreased levels in the paraventricular hypothalamic nucleus. Relative to vehicle, carmoxirole and bromocriptine stimulated ventilation in the HH during and following exposure to hypoxia. Only bromocriptine depressed ventilation in the EH during and after exposure to hypoxia. Thus, hypothyroidism impacts the expression of D2 receptors in the carotid body, PVN and striatum, and D2 stimulation affects ventilation remarkably differently than in EH.


Assuntos
Encéfalo/metabolismo , Corpo Carotídeo/metabolismo , Hipotireoidismo/metabolismo , Receptores de Dopamina D2/biossíntese , Respiração , Animais , Western Blotting , Encéfalo/fisiopatologia , Corpo Carotídeo/fisiopatologia , Cricetinae , Modelos Animais de Doenças , Hipotireoidismo/fisiopatologia , Hipóxia/metabolismo , Hipóxia/fisiopatologia , Masculino , Mesocricetus
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