RESUMO
Chronic prurigo is itself a common condition, but it can also occur secondary to a large number of diseases. Management is challenging as historically chronic prurigo has been poorly defined and very few treatments are available. Clinically, it presents as excoriated, hyperkeratotic lesions. When chronic prurigo is suspected, a comprehensive differential diagnosis is essential. New diagnostic criteria have appeared in recent years and new drugs have been developed. Although no truly effective treatment is yet available, patients will benefit from a greater understanding of this condition.
Assuntos
Prurigo , Diagnóstico Diferencial , Humanos , Prurigo/diagnóstico , Prurigo/tratamento farmacológico , Prurigo/etiologia , Prurido/diagnóstico , Resultado do TratamentoAssuntos
Linfangioma , Melanoma , Diagnóstico Diferencial , Humanos , Linfangioma/diagnóstico , Melanoma/diagnósticoAssuntos
COVID-19/complicações , Pérnio/complicações , Dedos/patologia , Dermatopatias/complicações , Adolescente , Adulto , Idoso , COVID-19/epidemiologia , COVID-19/virologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Pandemias , Estudos Prospectivos , SARS-CoV-2/isolamento & purificação , Adulto JovemRESUMO
Chronic urticaria is a relatively common condition in dermatology and is usually diagnosed on clinical grounds. Skin biopsy, however, may be indicated in certain cases to confirm diagnosis and rule out other conditions that can cause hive-like rashes. We review histopathologic findings seen in both chronic urticaria and other entities in the differential diagnosis. We then propose an algorithm of indications for skin biopsy in patients with hive-like rashes and suggest possible diagnoses based on the histopathologic findings.
Assuntos
Urticária Crônica , Urticária , Biópsia , Doença Crônica , Humanos , Pele , Urticária/diagnósticoRESUMO
Recent years have seen important advances in our understanding of calciphylaxis, especially regarding newly identified risk factors and histologic findings that may aid diagnosis. This retrospective study of cases of calciphylaxis treated in our hospital in the last 13 years focuses on newly revealed aspects of this disease. We describe 16 patients (62.5% women; mean age, 67.9 years). In addition to advanced kidney disease (in 75% of our patients), other factors associated with the presence of calciphylaxis were a history of treatments related to phosphorus and calcium metabolism (75%) and anticoagulation (62.5%), usually with vitamin-K antagonists. Histology showed alterations in elastic fibers in only 25% of the biopsy specimens. Eleven of the patients died: sepsis was most often the cause.
RESUMO
We report here that glyceraldehyde-3-phosphate dehydrogenase (GAPDH) interacts in vitro and in vivo with the protein SET. This interaction is performed through the acidic domain of SET located at the carboxy terminal region. On analysing the functional relevance of SET-GAPDH interaction, we observed that GAPDH reverses in a dose-dependent manner, the inhibition of cyclin B-cdk1 activity produced by SET. Similarly to SET, GAPDH associates with cyclin B, suggesting that the regulation of cyclin B-cdk1 activity might be mediated not only by the interaction of GAPDH with SET but also with cyclin B. To analyse the putative role of GAPDH on cell cycle progression, HCT116 cells were transfected with a GAPDH expression vector. Results indicate that overexpression of GAPDH does not affect the timing of DNA replication but induces an increase in the number of mitosis, an advancement of the peak of cyclin B-cdk1 activity and an acceleration of cell cycle progression. All these results suggest that GAPDH might be involved in cell cycle regulation by modulating cyclin B-cdk1 activity.
Assuntos
Proteína Quinase CDC2/metabolismo , Ciclo Celular , Proteínas Cromossômicas não Histona/metabolismo , Ciclina B/metabolismo , Gliceraldeído-3-Fosfato Desidrogenases/metabolismo , Proteínas de Neoplasias/metabolismo , Fatores de Transcrição/metabolismo , Ciclo Celular/genética , Linhagem Celular Tumoral , Replicação do DNA/genética , DNA de Neoplasias/biossíntese , Proteínas de Ligação a DNA , Ativação Enzimática , Vetores Genéticos , Gliceraldeído-3-Fosfato Desidrogenases/genética , Chaperonas de Histonas , Humanos , Ligação Proteica , Estrutura Terciária de Proteína/genética , TransfecçãoRESUMO
The tumor suppressor p21 regulates cell cycle progression and peaks at mid/late G1. However, the mechanisms regulating its expression during cell cycle are poorly understood. We found that embryonic fibroblasts from p27 null mice at early passages progress slowly through the cell cycle. These cells present an elevated basal expression of p21 suggesting that p27 participates to its repression. Mechanistically, we found that p27 represses the expression of Pitx2 (an activator of p21 expression) by associating with the ASE-regulatory region of this gene together with an E2F4 repressive complex. Furthermore, we found that Pitx2 binds to the p21 promoter and induces its transcription. Finally, silencing Pitx2 or p21 in proliferating cells accelerates DNA replication and cell cycle progression. Collectively, these results demonstrate an unprecedented connection between p27, Pitx2 and p21 relevant for the regulation of cell cycle progression and cancer and for understanding human pathologies associated with p27 germline mutations.
Assuntos
Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p27/genética , Replicação do DNA , DNA/genética , Fibroblastos/citologia , Proteínas de Homeodomínio/genética , Fatores de Transcrição/genética , Animais , Ciclo Celular , Células Cultivadas , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Fibroblastos/metabolismo , Perfilação da Expressão Gênica , Técnicas de Inativação de Genes , Células HEK293 , Proteínas de Homeodomínio/metabolismo , Humanos , Camundongos , Regiões Promotoras Genéticas , Fatores de Transcrição/metabolismo , Proteína Homeobox PITX2RESUMO
When rats were infused with a solution containing triiodothyronine, amino acids, glucagon and heparin (solution A) the hepatocytes increased DNA synthesis and decreased plasma membrane sialic acid. In order to study whether the reduced levels of sialic acid in the plasma membrane were associated with hepatocyte proliferation, different mixtures of three components of solution A were infused into rats and the DNA synthetic activity as well as the sialic acid content measured. Results reported here show a correlation between DNA synthetic activity and sialic acid reduction suggesting that the decrease in the plasma membrane sialic acid can be a pre-replicative step associated to cell proliferation.
Assuntos
Regeneração Hepática , Fígado/metabolismo , Ácidos Siálicos/metabolismo , Aminoácidos/farmacologia , Animais , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Replicação do DNA/efeitos dos fármacos , Glucagon/farmacologia , Heparina/farmacologia , Fígado/efeitos dos fármacos , Ratos , Tri-Iodotironina/farmacologiaRESUMO
The data reported here summarize a series of results which reveal new functions for nuclear calmodulin (CaM). The addition of CaM inhibitors to cultures of proliferating NRK cells blocked the activity of the cyclin-dependent protein kinases 4 (cdk4) and 2 (cdk2), which are enzymes implicated in the progression of G1 and in the onset of DNA replication, respectively. CaM modulates the activity of cdk4 by regulating the nuclear location of both cdk4 and cyclin D, its associated regulatory subunit. By using CaM-affinity chromatography, we have recently identified two new nuclear CaM-binding proteins: (i) the protein La/SSB, which is an autoantigen implicated in several autoimmune diseases such as lupus erythematosus and Sjögren's syndrome (since La/SSB participates in the process of transcription mediated by RNA polymerase III, CaM could be involved in the regulation of this process); and (ii) the protein SAP145, a member of the spliceosome-associated proteins (SAPs) which is a subunit of the splicing factor SF3(b). This finding suggests the involvement of CaM in pre-mRNA splicing. Finally, a screening for new CaM-binding proteins in the fission yeast performed by using the phage display analysis, revealed that several nucleolar-ribosomal proteins associate to CaM, suggesting that CaM modulates ribosomal assembly and/or function.
Assuntos
Calmodulina/fisiologia , Núcleo Celular/metabolismo , Animais , Bacteriófagos , Proteínas de Ligação a Calmodulina/classificação , Proteínas de Ligação a Calmodulina/fisiologia , Quinases Ciclina-Dependentes/metabolismo , Humanos , RNA Polimerase III/metabolismo , Precursores de RNA/metabolismo , Splicing de RNA , Schizosaccharomyces , Transcrição GênicaRESUMO
In the present study, a relationship between convulsant activity and two cellular events, changes in calmodulin (CaM) concentration and proto-oncogene c-fos expression has been considered. c-fos has been found activated after the administration of the organochlorine insecticide lindane, the Ca2+ channel agonist Bay K, and N-methyl-D-aspartate (NMDA). The administration of the voltage-dependent Ca2+ channel antagonist nifedipine was able to block the expression elicited by lindane. The effect of lindane on c-fos expression could not be blocked by prior administration of MK-801, a non-competitive antagonist of the NMDA receptor. These results suggest a possible role for the voltage-dependent Ca2+ channels in the mechanism of action of lindane. By means of in situ hybridization, the different patterns of c-fos expression after the administration of the mentioned compounds have been described. A possible modification of the levels of CaM has also been investigated. Among all the subcellular fractions considered, only levels of nuclear CaM appeared to be affected after the different treatments. The changes observed seemed to follow a similar pattern to that described for c-fos induction. Calcium entry through these voltage-dependent calcium channels would be the link between membrane depolarizing events and expression of c-fos and/or increase in nuclear CaM.
Assuntos
Calmodulina/metabolismo , Convulsivantes/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Genes fos/genética , Hexaclorocicloexano/farmacologia , Proteínas do Tecido Nervoso/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio/efeitos dos fármacos , Canais de Cálcio/fisiologia , Núcleo Celular/ultraestrutura , Masculino , Neurônios/efeitos dos fármacos , Neurônios/ultraestrutura , Ratos , Ratos Endogâmicos , Estereoisomerismo , Sinaptossomos/ultraestruturaRESUMO
The cyclin-cdk (cyclin-dependent kinase) inhibitor p27Kip1 (p27) has a crucial negative role on cell cycle progression. In addition to its classical role as a cyclin-cdk inhibitor, it also performs cyclin-cdk-independent functions as the regulation of cytoskeleton rearrangements and cell motility. p27 deficiency has been associated with tumor aggressiveness and poor clinical outcome, although the mechanisms underlying this participation still remain elusive. We report here a new cellular function of p27 as a transcriptional regulator in association with p130/E2F4 complexes that could be relevant for tumorigenesis. We observed that p27 associates with specific promoters of genes involved in important cellular functions as processing and splicing of RNA, mitochondrial organization and respiration, translation and cell cycle. On these promoters p27 co-localizes with p130, E2F4 and co-repressors as histone deacetylases (HDACs) and mSIN3A. p27 co-immunoprecipitates with these proteins and by affinity chromatography, we demonstrated a direct interaction of p27 with p130 and E2F4 through its carboxyl-half. We have also shown that p130 recruits p27 on the promoters, and there p27 is needed for the subsequent recruitment of HDACs and mSIN3A. Expression microarrays and luciferase assays revealed that p27 behaves as transcriptional repressor of these p27-target genes (p27-TGs). Finally, in human tumors, we established a correlation with overexpression of p27-TGs and poor survival. Thus, this new function of p27 as a transcriptional repressor could have a role in the major aggressiveness of tumors with low levels of p27.
Assuntos
Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Fator de Transcrição E2F4/metabolismo , Regulação Neoplásica da Expressão Gênica , Regiões Promotoras Genéticas , Proteína p130 Retinoblastoma-Like/metabolismo , Transcrição Gênica , Animais , Proteínas Correpressoras/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/genética , Expressão Gênica , Humanos , Camundongos , Modelos Biológicos , Células NIH 3T3 , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/mortalidade , Prognóstico , Ligação ProteicaRESUMO
The administration of the alpha 1-adrenergic antagonist prazosin to hepatectomized rats inhibited DNA synthesis induced in the remaining hepatocytes. This inhibitory effect could be reversed by the simultaneous injection of the agonist phenylephrine. In order to establish how the alpha 1-adrenergic receptors can regulate DNA replication, the effect of prazosin administration on DNA polymerase alpha was examined. At 24 h after partial hepatectomy, the activity of DNA polymerase alpha increased 5, 7 and 9 fold in the homogenates, nuclei and nuclear matrix, respectively. This increase was inhibited by 70%-80% when prazosin was injected at 1, 8 or 11 h after surgery. Kinetic studies revealed that the Km for DNA was 2 fold lower in hepatectomized than in control animals. The administration of prazosin to hepatectomized rats increased the Km to the control values. These results indicate that the alpha 1-adrenergic receptors are involved in the regulation of DNA synthesis through the activation of DNA polymerase alpha and that this activation could be produced by increasing its affinity for DNA.
Assuntos
DNA Polimerase II/metabolismo , Regeneração Hepática , Fígado/fisiologia , Prazosina/farmacologia , Receptores Adrenérgicos alfa/fisiologia , Animais , Divisão Celular , Replicação do DNA/efeitos dos fármacos , Hepatectomia , Homeostase , Cinética , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Ratos , Ratos Endogâmicos , Receptores Adrenérgicos alfa/efeitos dos fármacos , Frações Subcelulares/enzimologia , Fatores de TempoRESUMO
The infusion of a solution containing triiodothyronine, amino acids, glucagon, and heparin (TAGH solution) triggered rat liver cell proliferation. It also induced a transient prereplicative surge of cytosolic calmodulin (between 6 and 20 hr postinfusion) similar to that observed in liver cells proliferatively activated by partial hepatectomy. The injection of the beta-adrenergic blocker dl-propanolol (20 mg/kg of body weight) at the time of the infusion prevented this transient rise of cytosolic calmodulin and also inhibited the early prereplicative surge of total liver cyclic AMP, which usually occurred between 1 and 4 hr after infusion. Propanolol also inhibited the early prereplicative surge of cyclic AMP and the increase of calmodulin in liver cells proliferatively activated by partial hepatectomy. The infusion of a solution containing cyclic AMP (5 mumoles) and theophylline (10 mg) into normal rats produced an increase of cytosolic calmodulin similar to that observed after infusion of TAGH solution or after partial hepatectomy. Thus it seems that the prereplicative rise of cytosolic calmodulin observed in proliferatively activated liver cells may be regulated by the early prereplicative surge of cyclic AMP.
Assuntos
Calmodulina/metabolismo , AMP Cíclico/fisiologia , Replicação do DNA , Fígado/citologia , Animais , Divisão Celular/efeitos dos fármacos , AMP Cíclico/farmacologia , Citosol/metabolismo , Replicação do DNA/efeitos dos fármacos , Cinética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Regeneração Hepática , Masculino , Propranolol/farmacologia , Ratos , Ratos Endogâmicos , Valores de Referência , Teofilina/farmacologiaRESUMO
Carcinogenesis is a multi-step process in which genetic--phenotypic instability and sequential selection of preneoplastic cells for increased growth capacity and other neoplastic characteristics are essential phenomena. During chemical carcinogenesis in rat liver, the development of enzyme-deficient foci, their clonal origin and their relationship to tumour formation are known. We report the results of four carcinogenesis protocols consisting of one or two cycles of diethylnitrosamine and phenobarbital. Histochemistry of three enzymes on serial sections has revealed seven different kinds of homogeneous liver foci, resulting from simple and combined enzyme deficiencies, and also heterogeneous foci showing smaller foci inside. We consider such secondary foci as subclones originating from cells already modified that have developed an additional phenotypic change. Some of such foci develop after the first cycle if the promotion phase is as long as 57 weeks. Comparing the number of foci per surface area of liver section with the number of secondary foci per surface area of focus section, it seems clear that cells already modified are less stable than other hepatocytes, showing a higher tendency to develop secondary changes.
Assuntos
Neoplasias Hepáticas Experimentais/patologia , Fígado/patologia , Lesões Pré-Cancerosas/patologia , 5'-Nucleotidase , Adenosina Trifosfatases/metabolismo , Animais , Dietilnitrosamina , Glucose-6-Fosfatase/metabolismo , Fígado/enzimologia , Neoplasias Hepáticas Experimentais/enzimologia , Masculino , Nucleotidases/metabolismo , Fenobarbital , Fenótipo , Lesões Pré-Cancerosas/enzimologia , Ratos , Ratos EndogâmicosRESUMO
Calmodulin increases about three-fold in rat liver nuclei after partial hepatectomy. The increase is maximal after 24 hours, when DNA synthesis is also maximal. During the same time re-distribution of calmodulin within the nuclear structure takes place, leading to its association with the nuclear matrix. Incubation of normal rat liver nuclei with Ca2+ induces association of calmodulin with the matrix, indicating that the re-distribution of calmodulin during the replicative period is related to the increase in nuclear Ca2+. The nuclear matrix contains several calmodulin binding proteins of which one, having Mr of 130 kDa, has been identified as myosin light chain kinase (MLCK). Three acceptor proteins, having Mr of 120, 65, and 60 kDa decrease 24 hours after partial hepatectomy, MLCK and a protein of Mr 150 kDa instead increase.
Assuntos
Calmodulina/metabolismo , Núcleo Celular/metabolismo , Hepatectomia , Fígado/metabolismo , Animais , Cálcio/farmacologia , Proteínas de Ligação a Calmodulina/metabolismo , Divisão Celular , DNA/biossíntese , Cinética , Fígado/efeitos dos fármacos , Fígado/ultraestrutura , Masculino , Peso Molecular , Quinase de Cadeia Leve de Miosina/metabolismo , Ratos , Ratos EndogâmicosRESUMO
Proliferative advantage of putative preneoplastic hepatocytes measured as the ratio of tritiated thymidine incorporation into cells of hyperplastic nodules with respect to the incorporation in hepatocytes of extranodular liver has been found to be about 2 in rats treated according to 4 carcinogenesis protocols consisting in one or two cycles of diethylnitrosamine and phenobarbital administration. The proliferative response of hepatocytes in hyperplastic nodules to the intravenous infusion of triiodothyronine, amino-acids, glucagon, and heparine (TAGH) has been found higher or similar--except in one case--than the response of surrounding liver but the proliferative advantage of preneoplastic hepatocytes is lower after TAGH stimulation than in basal conditions in all cases.
Assuntos
Aminoácidos/farmacologia , Glucagon/farmacologia , Heparina/farmacologia , Neoplasias Hepáticas/patologia , Lesões Pré-Cancerosas/patologia , Tri-Iodotironina/farmacologia , Animais , Divisão Celular/efeitos dos fármacos , Dietilnitrosamina , Hiperplasia , Neoplasias Hepáticas/induzido quimicamente , Masculino , Fenobarbital , Lesões Pré-Cancerosas/induzido quimicamente , Ratos , Ratos EndogâmicosRESUMO
Enzyme biochemical and histochemical assays during chemical carcinogenesis in rat liver have revealed that several adult enzyme activities are lost and some fetal enzyme activities are re-expressed in the hyperplastic foci as well as in the developed hepatomas. How these enzyme alterations are acquired and to what extent these changes are specifically related to the growth alterations leading to neoplastic development are decisive questions. Using a carcinogenesis protocol that combines a single dose of diethylnitrosamine and phenobarbital given continuously as the promoting agent and by assaying serial liver sections for glucose-6-phosphatase, adenosine-5'-triphosphatase and 5'-nucleotidase, we have identified the three-enzyme pattern of 1,746 islands and measured their section areas. We found a clear trend that clones with more deviated enzyme pattern grow faster than less deviated ones.
Assuntos
Dietilnitrosamina , Neoplasias Hepáticas Experimentais/enzimologia , Nitrosaminas , Lesões Pré-Cancerosas/enzimologia , 5'-Nucleotidase , Adenosina Trifosfatases/análise , Animais , Células Clonais , Glucose-6-Fosfatase/análise , Hepatectomia , Histocitoquímica , Injeções Intraperitoneais , Neoplasias Hepáticas Experimentais/induzido quimicamente , Neoplasias Hepáticas Experimentais/patologia , Masculino , Nucleotidases/análise , Lesões Pré-Cancerosas/induzido quimicamente , Lesões Pré-Cancerosas/patologia , RatosRESUMO
Diethylnitrosamine was injected to Sprague-Dawley rats after a partial hepatectomy, and enzyme histochemistry analysis was made after 35 weeks in the preneoplastic liver. The areas and volumes of the induced enzyme-deficient islands were calculated for glucose-6-triphosphatase, adenosine triphosphatase, and 5'-nucleotidase. The preneoplastic enzyme-deficient zones showed also an increased incorporation of tritiated thymidine.