RESUMO
INTRODUCTION: Sleep apnea (SA) is an important comorbidity in end-stage renal disease (ESRD) patients. The association between SA and cardiac and neurological disease is known. This study investigates the relationship between SA and cardiovascular and cerebrovascular outcomes in the ESRD population. METHODS: In a retrospective cohort study, the United States Renal Data System was queried to identify ESRD patients aged 18-100 years in whom hemodialysis had been initiated between 2005 and 2013. Diagnoses of SA and clinical comorbidities were determined from International Classification of Disease-9 codes. Demographic variables were obtained from Centers for Medicare and Medicaid Services Form-2728. Logistic regression was used to examine the association of SA with myocardial infarction (MI) or with stroke, controlling for demographic and clinical variables. RESULTS: Of 858,131 subjects meeting the inclusion criteria, 587 had central SA, and 22,724 had obstructive SA. The SA cohort was younger, more likely to be male and Caucasian compared to the non-SA cohort. Patients with SA also had more tobacco and alcohol use, hypertension, heart failure, and diabetes. Central SA (aRR = 1.69, 95% CI = 1.28-2.23) and obstructive SA (aRR = 1.15, 95% CI = 1.09-1.21) were associated with an increased risk of stroke but not MI. CONCLUSION: In the ESRD population, a diagnosis of central SA or obstructive SA increased the risk of stroke, but not MI. Early identification and treatment of SA in the ESRD population may help reduce the risk of stroke in these patients.
Assuntos
Falência Renal Crônica , Infarto do Miocárdio , Síndromes da Apneia do Sono , Apneia Obstrutiva do Sono , Acidente Vascular Cerebral , Humanos , Masculino , Idoso , Estados Unidos/epidemiologia , Feminino , Estudos Retrospectivos , Fatores de Risco , Medicare , Falência Renal Crônica/complicações , Falência Renal Crônica/epidemiologia , Síndromes da Apneia do Sono/complicações , Síndromes da Apneia do Sono/epidemiologia , Síndromes da Apneia do Sono/diagnóstico , Apneia Obstrutiva do Sono/diagnóstico , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/epidemiologiaRESUMO
PURPOSE: Hashimoto's thyroiditis (HT) is a common autoimmune thyroid disorder that can disrupt thyroid function and homeostasis. As HT results from a dysregulated immune system, we hypothesized that these patients might be more susceptible to transplant failure; however, literature on this association is limited. The purpose of this study is to examine the association of HT with the risk of renal transplant failure. METHODS: We utilized the United States Renal Database System dataset collected from 2005 to 2014 and compared the time from first renal transplant to transplant failure in end-stage renal disease (ESRD) patients with a HT diagnosis to ESRD patients without a HT diagnosis that underwent renal transplant. RESULTS: A total of 144 ESRD patients had International Classification of Disease-9 claim codes for HT prior to renal transplant, amongst a total cohort of 90,301 renal transplant patients aged 18-100 and meeting criteria. Patients with HT were significantly more likely to be female, white, and to have a diagnosis of cytomegalovirus compared to patients without. ESRD patients with a HT diagnosis that underwent renal transplant had a significantly increased risk of renal transplant failure compared to those ESRD renal transplant patients without an HT diagnosis. There was a significantly increased adjusted hazard ratio for graft failure in patients with a HT diagnosis compared to those without. CONCLUSION: Thyroid health and HT may play a significant role in the development of the increased risk of renal transplant failure observed in this study. Additional studies are needed to investigate the underlying mechanisms for this association.
Assuntos
Doença de Hashimoto , Nefropatias , Falência Renal Crônica , Transplante de Rim , Humanos , Feminino , Masculino , Transplante de Rim/efeitos adversos , Doença de Hashimoto/complicações , Falência Renal Crônica/etiologia , Falência Renal Crônica/cirurgiaRESUMO
A commercial resin-based pine oil (PO) derived from Pinus palustris and Pinus elliottii was the major focus of this investigation. Extracts of pine resins, needles, and bark are folk medicines commonly used to treat skin ailments, including burns. The American Burn Association estimates that 500,000 people with burn injuries receive medical treatment each year; one-half of US burn victims are children, most with scald burns. This systematic study was initiated as follow-up to personal anecdotal evidence acquired over more than 10 years by MH Bhattacharyya regarding PO's efficacy for treating burns. The results demonstrate that PO counteracted dermal inflammation in both a mouse ear model of contact irritant-induced dermal inflammation and a second degree scald burn to the mouse paw. Furthermore, PO significantly counteracted the tactile allodynia and soft tissue injury caused by the scald burn. In mouse dorsal root ganglion neuronal cultures, PO added to the medium blocked adenosine triphosphate-activated, but not capsaicin-activated, pain pathways, demonstrating specificity. These results together support the hypothesis that a pine-oil-based treatment can be developed to provide effective in-home care for second degree burns.
Assuntos
Queimaduras/tratamento farmacológico , Gânglios Espinais/efeitos dos fármacos , Pinus/química , Óleos de Plantas/farmacologia , Trifosfato de Adenosina , Animais , Capsaicina , Células Cultivadas , Dermatite/tratamento farmacológico , Modelos Animais de Doenças , Hiperalgesia/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Dor/tratamento farmacológico , Resinas Vegetais/farmacologia , Pele/patologiaRESUMO
Retinoic acid (RA) is essential for regulation of epithelial cell differentiation. The intracellular effects of RA are mediated by RA-binding nuclear receptors, including the RA receptors (RARs) alpha, beta, and gamma. The ligand-activated receptors induce the transcription of target genes by binding to RA-responsive elements in the promoter regions. One target gene is the RAR beta gene, which encodes a potential tumor suppressor. Loss of RA inducibility of RAR beta gene expression is assumed to play a role in the development of several types of human carcinomas, including carcinomas of the uterine cervix. We have analyzed RAR beta gene expression in normal cervical cells and in cervical carcinoma cell lines. The results show that the RAR beta mRNA levels are high and RA inducible in the primary keratinocytes, whereas they are low and not inducible or only slightly inducible by RA in all of the cervical carcinoma cell lines analyzed. The basal and the RA-induced RAR beta mRNA levels tend to increase with senescence of the normal cells. Fusion of primary ectocervical keratinocytes with HeLa cervical carcinoma cells revealed that the characteristics of RAR beta gene expression of the normal cells are dominant over that of the tumor cells. Using synthetic retinoids with receptor-preferential agonist activities and a RAR alpha-specific antagonist, we show that RAR alpha is the major endogenous RAR subtype for induction of RA-dependent RAR beta gene expression. Taken together, our results indicate that abnormal downregulation of RAR beta gene expression may be an important step in the multifactorial process of cervical carcinogenesis.
Assuntos
Colo do Útero/metabolismo , Regulação Neoplásica da Expressão Gênica , Receptores do Ácido Retinoico/genética , Receptores do Ácido Retinoico/fisiologia , Neoplasias do Colo do Útero/genética , Northern Blotting , Regulação para Baixo , Epitélio/metabolismo , Feminino , Células HeLa , Humanos , Células Híbridas/metabolismo , Queratinócitos/metabolismo , RNA Mensageiro/metabolismo , Neoplasias do Colo do Útero/metabolismoRESUMO
Retinoids, cytokines as well as 1,25-dihydroxyvitamin D3 and its analogs are all classes of compounds with pleiotropic actions. They inhibit proliferation in human transformed epithelial cell lines and induce differentiation in human transformed hemopoietic cell lines. In a murine model of tumor cell-induced angiogenesis all three classes of compounds inhibit the formation of new blood vessels, necessary for supplying the growing tumor with oxygen and nutrients. Combinations of compounds from the three different classes lead to higher efficacy than the compounds administered as single agents. The effects of combinations vary depending on the individual representatives of the three classes and on the particular test models used. Additive, synergistic and potentiating effects have been observed. The results obtained in experimental systems raise hope that combination therapy might be useful in the treatment of certain human neoplastic diseases.
Assuntos
Retinoides/uso terapêutico , Animais , Calcitriol/farmacologia , Calcitriol/uso terapêutico , Diferenciação Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Citocinas/farmacologia , Citocinas/uso terapêutico , Sinergismo Farmacológico , Quimioterapia Combinada , Humanos , Leucemia Promielocítica Aguda/patologia , Camundongos , Neoplasias Experimentais/irrigação sanguínea , Neovascularização Patológica/prevenção & controle , Retinoides/farmacologia , Células Tumorais Cultivadas/efeitos dos fármacos , Células Tumorais Cultivadas/patologiaRESUMO
Retinoids, cytokines as well as 1,25-dihydroxyvitamin D3 and its analogs are all classes of compounds with pleiotropic actions. They inhibit proliferation in human transformed epithelial cell lines and induce differentiation in human transformed hemopoietic cell lines. In a murine model of tumor cell-induced angiogenesis all three classes of compounds inhibit the formation of new blood vessels, necessary for supplying the growing tumor with oxygen and nutrients. Combinations of compounds from the three different classes lead to higher efficacy than the compounds administered as single agents. The effects of combinations vary depending on the individual representatives of the three classes and on the particular test models used. Additive, synergistic and potentiating effects have been observed. The results obtained in experimental systems raise hope that combination therapy might be useful in the treatment of certain human neoplastic diseases.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Retinoides/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Calcitriol/uso terapêutico , Diferenciação Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Citocinas/uso terapêutico , Sinergismo Farmacológico , Humanos , Neovascularização Patológica/prevenção & controle , Retinoides/uso terapêuticoRESUMO
Preclinical data indicate that the combination of retinoids and interferons have synergistic antiproliferative and differentiating effects in some hematologic and solid tumor models. These observations have led to clinical trials in which 13-cis-retinoic acid (13cRA) 1 mg/kg/day was combined with interferon alpha-2a (IFN alpha) 3 or 6 x 10(6) U/day. The first two such trials produced exciting results: 50% response rate in patients with previously untreated stages IB-IVA cervix cancer and 68% in patients with advanced squamous cell skin cancer. These data led to a number of additional trials of the combination, but the high response rates seen in the initial cervix and skin trials have not been duplicated in the other squamous tumors tested (head and neck, lung, pretreated cervix). In addition, trials in two nonsquamous histologies were negative (lung and melanoma). However, the regimen was not always studied in an optimal population of previously untreated patients and the negative results in pretreated cervix patients point to the relevance of this consideration. Nevertheless, the observation that the combination of 13cRA and IFN alpha (both of which bind to specific receptors and change gene expression) is able to induce regression in advanced tumors, must be regarded as highly important. Key questions to be addressed include an understanding of the biologic mechanism of specific tumor sensitivity (why some squamous tumors and not others?), and mechanisms of resistance in sensitive tumor types (e.g. cervix). Such data may lead to trials targeted to tumor types with defined biologic features having a high liklihood of clinical benefit. In the meantime, studies integrating this combination with other active treatment modalities such as radiation is warranted in cervix and skin carcinomas.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Ensaios Clínicos como Assunto , Feminino , Humanos , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Proteínas Recombinantes , Tretinoína/administração & dosagemRESUMO
Preclinical data indicate that the combination of retinoids and interferons have synergistic antiproliferative and differentiating effects in some hematologic and solid tumor models. These observations have led to clinical trials in which 13-cis-retinoic acid (13cRA) 1 mg/kg/day was combined with interferon alpha-2a (IFN alpha) 3 or 6 x 10(6) U/day. The first two such trials produced exciting results: 50% response rate in patients with previously untreated stages IB-IVA cervix cancer and 68% in patients with advanced squamous cell skin cancer. These data led to a number of additional trials of the combination, but the high response rates seen in the initial cervix and skin trials have not been duplicated in the other squamous tumors tested (head and neck, lung, pretreated cervix). In addition, trials in two non-squamous histologies were negative (lung and melanoma). However, the regimen was not always studied in an optimal population of previously untreated patients and the negative results in pretreated cervix patients point to the relevance of this consideration. Nevertheless, the observation that the combination of 13cRA and IFN alpha (both of which bind to specific receptors and change gene expression) is able to induce regression in advanced tumors, must be regarded as highly important. Key questions to be addressed include an understanding of the biologic mechanism of specific tumor sensitivity (why some squamous tumors and not others?), and mechanisms of resistance in sensitive tumor types (e.g. cervix). Such data may lead to trials targeted to tumor types with defined biologic features having a high likelihood of clinical benefit. In the meantime, studies integrating this combination with other active treatment modalities such as radiation is warranted in cervix and skin carcinomas.
Assuntos
Interferon-alfa/uso terapêutico , Isotretinoína/uso terapêutico , Neoplasias/terapia , Carcinoma de Células Escamosas/terapia , Ensaios Clínicos Fase II como Assunto , Terapia Combinada , Feminino , Humanos , Interferon alfa-2 , Masculino , Neoplasias/tratamento farmacológico , Proteínas Recombinantes , Neoplasias Cutâneas/terapia , Neoplasias do Colo do Útero/terapiaRESUMO
We have investigated the effects of Ro 31-7549, a selective protein kinase C (PKC) inhibitor, on DNA synthesis and proliferation in two primary mouse epidermal keratinocyte culture systems. In differentiating keratinocytes incubated in medium containing 10% serum and high calcium (approximately 0.5 mM), Ro 31-7549 blocked the inhibitory effect of the phorbol ester 12-0-tetradecanoyl-13-acetate (TPA) (a PKC activator) on keratinocyte DNA synthesis at 24 h [50% maximal response concentration (EC50) = 1 microM], consistent with inhibition of PKC-mediated differentiation. Continuous treatment of the differentiative culture system with the PKC inhibitor resulted in a marked (fourfold) stimulation of [3H]thymidine incorporation at day 7 of exposure, with an EC50 of 0.25 microM. The potencies of these effects of Ro 31-7549 are comparable to that reported for inhibition of TPA-induced platelet 47-kD protein phosphorylation [50% inhibitory concentration (IC50) = 4.4 microM]. The time course of [3H]thymidine incorporation indicated that Ro 31-7549 did not directly stimulate DNA synthesis but instead prevented the loss of proliferative capacity associated with continued culture in this medium. Maximal stimulation (2.6 times) of DNA synthesis was observed on day 4, whereas DNA synthesis at day 1 was unaffected. In a highly proliferative culture system using serum-free medium containing 25 microM calcium, TPA dose-dependently inhibited proliferation with an IC50 of approximately 0.3 mM. This antiproliferative effect of TPA was largely reversed by 0.1 microM Ro 31-7549. In the proliferative culture system, 0.75 microM Ro 31-7549 also essentially reversed the inhibition of proliferation caused by switching to high (1.0 mM) calcium. These results suggest that the loss of proliferative capacity in differentiating epidermal keratinocyte cultures may be mediated, at least in part, by PKC.
Assuntos
Indóis/farmacologia , Queratinócitos/citologia , Queratinócitos/efeitos dos fármacos , Maleimidas/farmacologia , Proteína Quinase C/antagonistas & inibidores , Animais , Divisão Celular/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos , Proteína Quinase C/fisiologia , Fatores de TempoRESUMO
Tumor cell-induced angiogenesis, i.e., new blood vessel formation within tumor tissue, is an essential requirement for the growth of solid neoplasms. Interleukin-12 (IL-12) inhibits growth of a variety of experimental tumors in vivo. We tested whether antitumor activity of IL-12 is related to the inhibition of angiogenesis induced by tumor cell lines. Angiogenesis was induced in x-ray immunosuppressed Balb/c mice by intradermal injection of the following human tumor cells: T47D, originating from mammary carcinoma; A431, derived from vulval carcinoma; and Skv, established from bowenoid papulosis, Systemic treatment of the mice with murine IL-12 significantly decreased angiogenesis induced by human tumor cells in a time-and dose-dependent manner. Preincubation of human cells in vitro with IL-12 did not inhibit tumor cell-induced angiogenesis, suggesting that the antiangiogenic capacity of IL-12 is restricted to in vivo conditions. Treatment of the mice with rat antibody against murine interferon-gamma (IFN-gamma) resulted in counteracting the antiangiogenic effect of murine IL-12. Furthermore, human IFN-gamma inhibited the angiogenic activity of human tumor cell lines. This indicates that IFN-gamma is a mediator of the antiangiogenic effect of IL-12. The results show that the mechanism of antitumor action of IL-12 may depend not only on the immunostimulatory activity of this cytokine but also on its effect on tumor cell-induced angiogenesis. IL-12 should be considered as a potential candidate for the treatment of angiogenesis-dependent malignancies.
Assuntos
Interleucina-12/farmacologia , Neoplasias/irrigação sanguínea , Neovascularização Patológica/prevenção & controle , Animais , Relação Dose-Resposta a Droga , Feminino , Humanos , Interferon gama/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Ratos , Células Tumorais CultivadasRESUMO
In some cell systems, the antiproliferative effects of 8-Cl-cAMP, a site-selective cAMP analog specific for the type I cAMP-dependent protein kinase, are mediated by its metabolite, 8-Cl-adenosine. These effects were once thought to be specific to transformed cells. We investigated the ability of 8-Cl-adenosine to regulate growth and differentiation in primary cultures of mouse epidermal keratinocytes. A 24 h exposure of keratinocytes to 8-Cl-adenosine inhibited [3H]thymidine incorporation in a dose-dependent manner with an apparent IC(50) of 7.5 microM, and these effects were completely reversible. To determine the ability of 8-Cl-adenosine to induce differentiation of primary keratinocytes, we measured keratin-1 expression and transglutaminase activity, markers of early and later stages of keratinocyte differentiation, respectively. Interestingly, exposure of keratinocytes to 25 microM 8-Cl-adenosine for 24 h had no effect on keratin-1 expression or transglutaminase activity. The 8-Cl-adenosine-induced growth arrest of keratinocytes required uptake of the compound and was accompanied by an increase in protein expression of the cyclin-dependent protein kinase inhibitor p21(WAF1/Cip1). These results demonstrate that 8-Cl-adenosine inhibits growth in a non-transformed/non-immortalized cell system, possibly through an elevation in p21(WAF1/Cip1) protein levels, without inducing differentiation.
Assuntos
8-Bromo Monofosfato de Adenosina Cíclica/análogos & derivados , 8-Bromo Monofosfato de Adenosina Cíclica/farmacologia , Antineoplásicos/farmacologia , Queratinócitos/citologia , Animais , Biomarcadores , Diferenciação Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células Epidérmicas , Fase G1/efeitos dos fármacos , Queratinócitos/efeitos dos fármacos , Queratinócitos/enzimologia , Queratinas/biossíntese , Camundongos , Camundongos Endogâmicos ICR , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Transglutaminases/metabolismoRESUMO
We have previously determined that sustained phospholipase D (PLD) activation is associated with differentiation induction in primary mouse epidermal keratinocytes. We therefore investigated the effect of two bacterial PLD on keratinocyte proliferation and differentiation. We found that Streptomyces sp. PLD was much less potent at inhibiting proliferation than S. chromofuscus PLD, with a half-maximal inhibitory concentration of 0.05 versus less than 0.001 IU per ml for S. chromofuscus PLD. Similarly, S. chromofuscus PLD stimulated transglutaminase activity more effectively and potently than S. sp. PLD. When we examined the formation of products by the two PLD, we found that the S. sp. PLD showed higher activity at all concentrations. Whereas the PLD from S. sp. is relatively inactive on sphingomyelin, S. chromofuscus PLD is known to hydrolyze both glycerophospholipids and sphingomyelin. Based on recent data indicating a role for ceramide in regulating cell growth and differentiation, we hypothesized that the ability of S. chromofuscus PLD to hydrolyze sphingomyelin might underlie its greater potency. Therefore, we examined the effect of exogenous sphingomyelinase and synthetic ceramides on DNA synthesis. We found that sphingomyelinase exhibited a potent concentration-dependent effect on [3H]thymidine incorporation, much like S. chromofuscus PLD. Synthetic cell-permeable ceramides (C6- and C2-ceramide) also concentration dependently inhibited DNA synthesis, with a half-maximal inhibitory concentration of approximately 12 microM. Finally, we obtained evidence suggesting that ceramide is generated in response to a physiologically relevant agent, because tumor necrosis factor-alpha, a known effector of sphingomyelin turnover in other systems and a cytokine that is produced and released by keratinocytes, increased ceramide levels in primary epidermal keratinocytes.
Assuntos
Ceramidas/fisiologia , Células Epidérmicas , Queratinócitos/citologia , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Divisão Celular/efeitos dos fármacos , Divisão Celular/fisiologia , Permeabilidade da Membrana Celular/fisiologia , Células Cultivadas , Ceramidas/farmacocinética , Ceramidas/farmacologia , Hidrólise , Camundongos , Camundongos Endogâmicos ICR , Ácidos Fosfatídicos/metabolismo , Fosfolipase D/análise , Fosfolipase D/farmacologia , Esfingomielina Fosfodiesterase/farmacologia , Esfingomielinas/metabolismo , Streptomyces/química , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
Angiotensin-II (Ang II) not only increases aldosterone secretion from bovine adrenal glomerulosa (AG) cells, but also primes these cells to respond to a subsequent challenge with the calcium channel agonist Bay K 8644. In cultured AG cells we investigated the hypothesis that this priming effect was the result of a persistent elevation in diacylglycerol (DAG) content. Ang II elicited an increase in DAG content, which was maintained for up to 75 min after the removal of Ang II, an effect which could underlie the ability of Ang II to prime the cells to respond to Bay K 8644. We then investigated the possibility that the DAG found in bovine AG cells consists of multiple species and the potential relationship of the species to the persistent elevation. We found that [3H]arachidonate and [14C]myristate were differentially incorporated into phospholipids, with approximately 80-85% of the latter radiolabel contained in phosphatidylcholine. Ang II elicited increases in the levels of both arachidonate- and myristate-containing DAG. The subsequent addition of an Ang II antagonist resulted in a rapid decrease in [3H]arachidonate-labeled DAG levels, but a much slower decline in myristate-containing DAG. These results suggest that the species of DAG generated in response to hormonal stimulation may be important in determining the speed with which this signal is terminated. Ang II also stimulated the release of water-soluble [3H]choline metabolites, in particular choline and phosphorylcholine, from prelabeled cells. These results indicate that 1) various DAG species exhibit different turnover rates; and 2) perhaps as a result of this disparity, the increase in DAG induced by an agonist may persist for a considerable period of time after the removal of the agonist or the inhibition of its action.
Assuntos
Aldosterona/metabolismo , Angiotensina II/metabolismo , Diglicerídeos/metabolismo , Lipídeos de Membrana/metabolismo , Zona Glomerulosa/metabolismo , Éster Metílico do Ácido 3-Piridinacarboxílico, 1,4-Di-Hidro-2,6-Dimetil-5-Nitro-4-(2-(Trifluormetil)fenil)/farmacologia , Aldosterona/biossíntese , Animais , Ácido Araquidônico , Ácidos Araquidônicos/metabolismo , Bovinos , Membrana Celular/metabolismo , Células Cultivadas , Colina/metabolismo , Ácido Mirístico , Ácidos Mirísticos/metabolismo , Fosfolipídeos/metabolismo , Saralasina/farmacologia , Zona Glomerulosa/efeitos dos fármacosRESUMO
The mechanism by which angiotensin-II (Ang II) stimulates aldosterone secretion from adrenal glomerulosa cells involves a phospholipase-C-mediated increase in phosphoinositide turnover and diacylglycerol (DAG) production. Because agonist-induced activation of phospholipase-D (PLD) also contributes to elevations in DAG in other cell types, the ability of Ang II to stimulate PLD activity in cultured bovine adrenal glomerulosa cells was examined. Ang II elicited significant increases in the levels of phosphatidic acid and, in the presence of ethanol, of phosphatidylethanol, a more specific marker for PLD activation. The potential role of this increased PLD activity in the regulation of aldosterone secretion was examined by investigating the ability of exogenous PLD to alter secretory rates. PLD alone dose-dependently increased aldosterone secretion from 5.9 +/- 0.5 to 135 +/- 48 pg/min.mg protein. In the presence of the calcium channel agonist Bay K 8644, which by itself had only a modest effect on aldosterone production, the stimulatory action of PLD was enhanced, yielding a secretory rate (442 +/- 119 pg/min.mg protein) that was approximately 60% of that elicited by 10 nM Ang II (763 +/- 182 pg/min.mg protein). Exogenous PLD also induced a significant increase in DAG levels (from 0.76 +/- 0.03 to 1.10 +/- 0.1 nmol/mg protein), which was not altered by the addition of Bay K 8644. However, PLD did not stimulate inositol phosphate production. These data indicate that 1) Ang II activates PLD; 2) exogenous PLD can elevate aldosterone secretory rates and DAG levels without eliciting phosphoinositide hydrolysis; and 3) the stimulatory action of exogenous PLD on aldosterone secretion is enhanced in the presence of Bay K 8644. Thus, PLD-induced DAG production may play an important role in the Ang II-mediated stimulation of aldosterone secretion from the adrenal zona glomerulosa.
Assuntos
Aldosterona/metabolismo , Angiotensina II/farmacologia , Fosfolipase D/fisiologia , Fosfolipases/fisiologia , Zona Glomerulosa/metabolismo , Éster Metílico do Ácido 3-Piridinacarboxílico, 1,4-Di-Hidro-2,6-Dimetil-5-Nitro-4-(2-(Trifluormetil)fenil)/farmacologia , Animais , Bovinos , Células Cultivadas , Diglicerídeos/metabolismo , Ativação Enzimática/efeitos dos fármacos , Etanol/farmacologia , Cinética , Ácidos Fosfatídicos/metabolismo , Fosfatidiletanolaminas/metabolismo , Fosfolipase D/farmacologia , Zona Glomerulosa/efeitos dos fármacosRESUMO
The effect of PTH on aldosterone secretion from isolated bovine adrenal glomerulosa cells was examined. PTH binding was autoradiographically localized to the adrenal cortex, suggesting a specific effect. This binding of PTH was displaceable by cold PTH, but not by ACTH. No binding was observed in the adrenal medulla. In addition, PTH was shown to stimulate aldosterone secretion in a dose-dependent manner and to potentiate aldosterone secretion in response to angiotensin-II, such that PTH (10(-9)M) elevated the secretory rate from 58.6 +/- 6.8 to 110.9 +/- 19 pg/min.million cells in the presence of 10 nM angiotensin-II. The magnitude of the synergism between the two hormones depended on the concentrations of PTH and angiotensin-II as well as the time during which aldosterone secretion was measured. Within the first 15 min of stimulation, PTH increased the sensitivity to angiotensin-II, shifting the Ka for activation from 1.0 to 0.3 nM. In contrast, between 30-45 min of angiotensin-II stimulation, PTH elevated the maximal secretory response to angiotensin-II from 109 +/- 3.4 to 219 +/- 13.3 pg/min.million cells. By itself PTH elicited only a small increase in the intracellular Ca2+ concentration, as measured by aequorin luminescence in glomerulosa cells. In cells pretreated with angiotensin-II or 15 mM potassium, the intracellular calcium response to PTH was markedly potentiated. PTH was also found to cause a small increase in the cellular cAMP content. Thus, PTH stimulates aldosterone secretion from adrenal glomerulosa cells, both alone and in combination with angiotensin-II.
Assuntos
Aldosterona/metabolismo , Angiotensina II/farmacologia , Hormônio Paratireóideo/farmacologia , Zona Glomerulosa/metabolismo , Córtex Suprarrenal/metabolismo , Medula Suprarrenal/metabolismo , Hormônio Adrenocorticotrópico/antagonistas & inibidores , Hormônio Adrenocorticotrópico/farmacologia , Animais , Autorradiografia , Cálcio/metabolismo , Bovinos , AMP Cíclico/metabolismo , Sinergismo Farmacológico , Hormônio Paratireóideo/metabolismo , Fragmentos de Peptídeos/farmacologia , Zona Glomerulosa/efeitos dos fármacosRESUMO
Retinoids varied in their capacity to induce differentiation in HL-60 cells in this order: Ro 13-6307, tretinoin, isotretinoin, acitretin and Ro 13-7410 (high to low). In contrast, retinoids lacking a polar carboxylic acid, such as temarotene and Ro 14-6113, were inactive. Various cytokines had no differentiation-inducing effect by themselves. However, the addition of cytokines to retinoids increased differentiation. Combined with tretinoin, cytokines increased differentiation in this order: interferon (IFN) gamma, granulocyte colony-stimulating factor, interleukin-1 alpha (IL-1 alpha), IL-4, tumour necrosis factor alpha and IFN-alpha. Combination of cytokines with isotretinoin, acitretin, Ro 13-7410, and Ro 13-6307 showed a similar pattern of potentiation to that of tretinoin. Temarotene or Ro 14-6113 did not induce differentiation, alone or with cytokines. Combinations of cytokines were not synergistic in the presence of retinoids; antagonism was even observed. In U937 cells, lower levels of differentiation-induction were observed. Potentiation of the differentiation-inducing effect of retinoids by cytokines might indicate a clinical differentiation therapy of tumours.
Assuntos
Citocinas/farmacologia , Leucemia Promielocítica Aguda/patologia , Linfoma Difuso de Grandes Células B/patologia , Retinoides/farmacologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Sinergismo Farmacológico , Humanos , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
The syntheses of the ring and four side-chain dihydroretinoic acids and/or their esters, 3-7, are described. The syntheses of several other retinoids containing a substituted aromatic ring are also included. The biological activity of the compounds was evaluated in vivo in a chemically induced mouse skin papilloma test and in vitro in two vitamin A deficient assays. The activity observed for 1a, 1c, and 2a in the former test was partially retained in the dihydro derivatives 4b, 4c, and 6b. Similar results were found in the in vitro assays.
Assuntos
Tretinoína/análogos & derivados , Vitamina A/análogos & derivados , Animais , Células Cultivadas , Cricetinae , Feminino , Camundongos , Neoplasias Experimentais/tratamento farmacológico , Técnicas de Cultura de Órgãos , Papiloma/tratamento farmacológico , RNA/metabolismo , Pele/citologia , Pele/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Tretinoína/síntese química , Tretinoína/farmacologia , Tretinoína/uso terapêutico , Deficiência de Vitamina A/tratamento farmacológicoRESUMO
Tretinoin, isotretinoin and acitretin were examined for their capacity to modulate the proliferation of the cell lines: HL-60 (acute promyelocytic leukemia), MCF7 (mammary carcinoma), SCC4, SCC15 and A431 (squamous cell carcinomas). Retinoids inhibited proliferation to a varying extent in all 5 cell lines. The cytokine IFN alpha had a significant antiproliferative effect only on HL-60, SCC4 and SCC15. The combination of retinoids with IFN alpha led in all 5 cell lines to a more profound reduction in proliferation than either retinoids or IFN alpha alone.
Assuntos
Divisão Celular/efeitos dos fármacos , Inibidores do Crescimento , Interferon Tipo I/administração & dosagem , Retinoides/administração & dosagem , Acitretina , Sinergismo Farmacológico , Humanos , Técnicas In Vitro , Isotretinoína/farmacologia , Tretinoína/análogos & derivados , Tretinoína/farmacologia , Células Tumorais CultivadasRESUMO
Various combinations of retinoids and cytokines were examined for their synergistic effect on inhibition in proliferation of four human transformed epithelial cell lines, MCF7 (mammary carcinoma), SCC4, SCC15 and A431 (squamous cell carcinomas). Synergism depended on the cell line tested, to some degree on the specific retinoid but particularly on the type of cytokine used. IFN alpha had the widest spectrum of activity. IFN gamma, TNF-alpha, IL-1, EGF and TGF-beta also exerted a synergistic effect on proliferation inhibition in certain cell lines, whereas G-CSF was inactive. Association of retinoids and cytokines represents a new approach to antitumor chemotherapy.
Assuntos
Citocinas/farmacologia , Retinoides/farmacologia , Neoplasias da Mama/patologia , Carcinoma de Células Escamosas/patologia , Divisão Celular/efeitos dos fármacos , Linhagem Celular Transformada , Combinação de Medicamentos , Sinergismo Farmacológico , Feminino , Humanos , Neoplasias da Língua/patologia , Neoplasias Vulvares/patologiaRESUMO
Retinoids combined with interferon alpha-2a (IFN alpha) or 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] have shown marked synergistic inhibitory effects on angiogenesis induced by tumor cell lines harboring DNA of oncogenic human papillomaviruses (HPV) type 16 or 18. This report demonstrates comparable effects of these compounds on angiogenesis induced by non-HPV-bearing transformed cell lines, including breast carcinoma (T47D) and vulval carcinoma (A431) cell lines. Systemic treatment of mice with all-trans retinoic acid, 13-cis retinoic acid, 9-cis retinoic acid, IFN alpha or 1,25(OH)2D3 significantly decreased tumor cell-induced angiogenesis (TIA). In vitro pretreatment of T47D and A431 cells with these compounds also led to inhibition of their angiogenic capability when tested in the TIA assay. The inhibitory effects of retinoids could be counteracted by a selective antagonist of the nuclear retinoic acid receptor RAR alpha, suggesting a RAR alpha mediated mechanism of angiogenesis inhibition. The antiangiogenic effect of retinoids could be significantly enhanced by combination with IFN alpha or 1,25(OH)2D3. The results provide a further basis for the use of combinations of retinoids with IFN alpha or 1,25(OH)2D3 in the treatment of angiogenesis-dependent malignancies.