RESUMO
COVID-19 is an infectious disease caused by the SARS-CoV-2 virus that can affect lung physiology encompassing a wide spectrum of severities, ranging from asymptomatic and mild symptoms to severe and fatal cases; the latter including massive neutrophil infiltration, stroke and multiple organ failure. Despite many recents findings, a clear mechanistic description underlying symptomatology is lacking. In this article, we thoroughly review the available data involving risk factors, age, gender, comorbidities, symptoms of disease, cellular and molecular mechanisms and the details behind host/pathogen interaction that hints at the existence of different pathophysiological mechanisms of disease. There is clear evidence that, by targeting the angiotensin-converting enzyme II (ACE2) -its natural receptor-, SARS-CoV-2 would mainly affect the renin-angiotensin-aldosterone system (RAAS), whose imbalance triggers diverse symptomatology-associated pathological processes. Downstream actors of the RAAS cascade are identified, and their interaction with risk factors and comorbidities are presented, rationalizing why a specific subgroup of individuals that present already lower ACE2 levels is particularly more susceptible to severe forms of disease. Finally, the notion of endotype discovery in the context of COVID-19 is introduced. We hypothesize that COVID-19, and its associated spectrum of severities, is an umbrella term covering different pathophysiological mechanisms (endotypes). This approach should dramatically accelerate our understanding and treatment of disease(s), enabling further discovery of pathophysiological mechanisms and leading to the identification of specific groups of patients that may benefit from personalized treatments.
RESUMO
Histamine (HA) is a pleiotropic biogenic amine synthesized exclusively by histidine decarboxylase (HDC) in most mammalian tissues. The literature on the role of HA within the male gonad has expanded over the last years, attracting attention to potential unexpected side-effects of anti-histamines on testicular function. In this regard, HA receptors (HRH1, HRH2 and HRH4) have been described in Leydig cells of different species, including human. Via these receptors, HA has been reported to trigger positive or negative interactions with the LH/hCG signaling pathway depending upon its concentration, thereby contributing to the local control of testicular androgen levels. It should then be considered that anti-histamines may affect testicular homeostasis by increasing or decreasing steroid production. Additionally, HRH1 and HRH2 receptors are present in peritubular and germ cells, and HRH2 antagonists have been found to negatively affect peritubular cells and reduce sperm viability. The potential negative impact of anti-histamines on male reproduction becomes even more dramatic if we consider that HA has also been associated with human sexual behavior and penile erection. What is more, although testicular mast cells are the major source of locally produced HA, recent studies have described HDC expression in macrophages, Leydig cells and germ cells, revealing the existence of multiple sources of HA within the testis. Undoubtedly, the more we learn about the testicular histaminergic system, the more opportunities there will be for rational design of drugs aimed at treating HA-related pathologies, with minimum or nule negative impact on fertility.
Assuntos
Antagonistas dos Receptores Histamínicos/farmacologia , Reprodução/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Testículo/efeitos dos fármacos , Animais , Fertilidade/efeitos dos fármacos , Fertilidade/fisiologia , Humanos , Células Intersticiais do Testículo/efeitos dos fármacos , Células Intersticiais do Testículo/metabolismo , Masculino , Reprodução/fisiologia , Testículo/metabolismo , Testosterona/metabolismoRESUMO
The development of tumor-selective drugs with low systemic toxicity has always been a major challenge in cancer treatment. Our group previously identified the 7,8-dihydroxy-4-methylcoumarin (DHMC) as a potential chemotherapeutic agent due to its potent, selective anti-proliferative and apoptosis-inducing effects on several cancer cell lines over peripheral blood mononuclear cells. However, there are still no published reports that can explain such selectivity of action. Herein, we addressed this question by using the U-937 promonocytic leukemia cell line, which can be forced to differentiate into a monocyte-like phenotype in vitro. U-937 cells differentiation is dependent on the nuclear expression of p21(Cip1/WAF1), a protein that is absent in immature U-937 cells but present in both the nucleus and the cytoplasm of normal DHMC-resistant monocytes. Considering that induction of differentiation rendered U-937 cells resistant to DHMC, we evaluated the possible causal role of cytoplasmic p21(Cip1/WAF1) in the onset of such resistance by employing U-937 cells stably transfected with a ZnCl2-inducible p21(Cip1/WAF1) variant lacking the nuclear localization signal (U-937/CB6-ΔNLS-p21 cells). Expression of cytoplasmic p21(Cip1/WAF1) did not induce differentiation of the cells but turned them resistant to DHMC through inhibition of JNK, a crucial mediator of DHMC-induced apoptosis in U-937 cells. Sub-acute toxicity evaluation of DHMC in Balb/c mice indicated that DHMC administered intraperitoneally at doses up to 100mg/kg induced no systemic damage. Collectively, our results explain for the first time the selective cytotoxicity of DHMC for tumor cells over normal monocytes, and encourage further in vivo studies on this compound as potential anti-leukemic agent.
Assuntos
Cumarínicos/farmacologia , Inibidor de Quinase Dependente de Ciclina p21/fisiologia , Monócitos/efeitos dos fármacos , Animais , Western Blotting , Quimiotaxia de Leucócito , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Células U937RESUMO
Previous studies indicated the need of at least one phenolic hydroxyl group in the coumarin core for induction of cytotoxicity in different cell lines. Herein, we present an exhaustive structure-activity relationship study including ortho-dihydroxycoumarins (o-DHC) derivatives, cinnamic acid derivatives (as open-chain coumarin analogues) and 1,2-pyrones (representative of the δ-lactone ring of the coumarin core), carried out to further identify the structural features of o-DHC required to induce leukemic cell differentiation and apoptosis in U-937 cells. Our results show for the first time that the δ-lactone ring positively influences the aforementioned biological effects, by conferring greater potency to compounds with an intact coumarin nucleus. Most tellingly, we reveal herein the crucial role of this molecular portion in determining the selective toxicity that o-DHC show for leukemic cells over normal blood cells. From a pharmacological perspective, our findings point out that o-DHC may be useful prototypes for the development of novel chemotherapeutic agents.
Assuntos
Apoptose/efeitos dos fármacos , Lactonas/química , Leucócitos Mononucleares/efeitos dos fármacos , 4-Hidroxicumarinas/síntese química , 4-Hidroxicumarinas/química , 4-Hidroxicumarinas/farmacologia , Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Cinamatos/síntese química , Cinamatos/química , Cinamatos/farmacologia , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Humanos , Células Jurkat , Leucócitos Mononucleares/citologia , Pironas/síntese química , Pironas/química , Pironas/farmacologia , Relação Estrutura-Atividade , Células U937RESUMO
Chemotherapeutics represent the main approach for the treatment of leukemia. However, the occurrence of adverse side effects and the complete lack of effectiveness in some cases make it necessary to develop new drugs. As part of our screening program to evaluate the potential chemotherapeutic effect of natural coumarins, we investigated the anti-leukemic activities of a series of six prenylated coumarins isolated from the stem bark of Toddalia asiatica (Rutaceae). Among these, 6-(3-methyl-2-butenyl)-5,7-dimethoxycoumarin (toddaculin) displayed the most potent cytotoxic and anti-proliferative effects in U-937 cells. To determine whether these effects resulted from induction of cell death or differentiation, we further evaluated the expression of several apoptosis and maturation markers. Interestingly, while toddaculin at 250 µM was able to induce apoptosis in U-937 cells, involving decreased phosphorylation levels of ERK and Akt, 50 µM toddaculin exerted differentiating effects, inducing both the capacity of U-937 cells to reduce NBT and the expression of differentiation markers CD88 and CD11b, but no change in p-Akt or p-ERK levels. Taken together, these findings indicate that toddaculin displays a dual effect as a cell differentiating agent and apoptosis inducer in U-937 cells, suggesting it may serve as a pharmacological prototype for the development of novel anti-leukemic agents.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Cumarínicos/farmacologia , Leucemia/patologia , Rutaceae/química , Antineoplásicos Fitogênicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cumarínicos/química , Regulação para Baixo/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Leucemia/tratamento farmacológico , Leucemia/metabolismo , MAP Quinase Quinase 4/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
In the search for alternative chemotherapeutic strategies against leukemia, various 1-indanone thiosemicarbazones, as well as eight novel platinum(II) and palladium(II) complexes, with the formula [MCl2(HL)] and [M(HL)(L)]Cl, derived from two 1-indanone thiosemicarbazones were synthesized and tested for antiproliferative activity against the human leukemia U937 cell line. The crystal structure of [Pt(HL1)(L1)]Cl·2MeOH, where L1=1-indanone thiosemicarbazone, was solved by X-ray diffraction. Free thiosemicarbazone ligands showed no antiproliferative effect, but the corresponding platinum(II) and palladium(II) complexes inhibited cell proliferation and induced apoptosis. Platinum(II) complexes also displayed selective apoptotic activity in U937 cells but not in peripheral blood monocytes or the human hepatocellular carcinoma HepG2 cell line used to screen for potential hepatotoxicity. Present findings show that, in U937 cells, 1-indanone thiosemicarbazones coordinated to palladium(II) were more cytotoxic than those complexed with platinum(II), although the latter were found to be more selective for leukemic cells suggesting that they are promising compounds with potential therapeutic application against hematological malignancies.
Assuntos
Antineoplásicos/síntese química , Complexos de Coordenação/síntese química , Indanos/química , Paládio/química , Platina/química , Tiossemicarbazonas/química , Antineoplásicos/uso terapêutico , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Complexos de Coordenação/uso terapêutico , Complexos de Coordenação/toxicidade , Cristalografia por Raios X , Humanos , Leucemia/tratamento farmacológico , Conformação Molecular , Células U937RESUMO
OBJECTIVE: Show the efficacy of a tumor prosthesis after the resection of a giant cell knee tumor in the proximal tibia and the recovery of knee function. MATERIAL AND METHODS: This is a report of a retrospective observational clinical case of a male, 36-year-old patient with history of left knee arthrodesis in 1996 following the resection of a giant cell tumor in the distal femur. The latter relapsed in 2004 and a solitary pulmonary tumor node was detected. Broad resection of the femur and the arthrodesed tibia was performed together with the placement of a tumor prosthesis. RESULTS: At the 20th postoperative month the patient had remission of the pulmonary node, knee function with passive flexion of 120 degrees and total extension, gait without limitations, no pain, a Musculoskeletal Tumor Society functional knee score of 28 and a Knee Society score of 95. CONCLUSIONS: The resection of the arthrodesis zone and the giant cell tumor achieved the double goal of erradicating the tumor and recovering the knee mobility after 10 years of arthrodesis, which led to a very satisfied patient capable of resuming his activities.
Assuntos
Neoplasias Ósseas/cirurgia , Tumor de Células Gigantes do Osso/cirurgia , Prótese do Joelho , Tíbia , Adulto , Humanos , Masculino , Estudos RetrospectivosRESUMO
The presumption that some coumarins might be lead compounds in the search for new differentiation agents against leukemia is based on the fact that natural coumarins, 5-(3-methyl-2-butenyloxy)-6,7-methylenedioxycoumarin (C-2) and 5-methoxy-6,7-methylenedioxycoumarin (C-1) inhibit proliferation and induce differentiation in U-937 cells [Riveiro, M. E.; Shayo, C.; Monczor, F.; Fernandez, N.; Baldi, A.; De Kimpe, N.; Rossi, J.; Debenedetti, S.; Davio, C. Cancer Lett.2004, 210, 179-188]. These promising findings prompted us to investigate the anti-leukemia activity of a broader range of related polyoxygenated coumarins. Twenty related natural or synthetically prepared coumarins, including a range of 5-substituted ayapin derivatives which have become easy accessible via newly developed synthesis methods, were evaluated, where treatments with 5-(2,3-dihydroxy-3-methylbutoxy)-6,7-methylenedioxycoumarin (D-3) and 5-(2-hydroxy-3-methoxy-3-methylbutoxy)-6,7-methylenedioxycoumarin (D-2) were able to inhibit the cell growth and induce the differentiation of U-937 cells after 48 h treatment. These results provide insight into the correlation between some structural properties of polyoxygenated coumarins and their in vitro leukemic differentiation activity.
Assuntos
Antineoplásicos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Cumarínicos/farmacologia , Leucemia/tratamento farmacológico , Oxigênio/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cumarínicos/síntese química , Cumarínicos/química , Humanos , Relação Estrutura-AtividadeRESUMO
In the present study, we sought to establish the effect of diverse structural-related hydroxycoumarins on the proliferation, cytotoxicity, and induction of apoptosis in promonocytic leukemic cells (U-937). The dihydroxylated coumarins, 7,8-dihydroxy-coumarin and esculetin, induced DNA fragmentation as well as characteristic morphological changes of programmed cell death in U-937 cells. With the aim to perform a structure-activity relationship study, the correlation between the physicochemical properties of the molecules and their pro-apoptotic activity was carried out. Results showed that the presence of two adjacent phenolic hydroxyl groups was the most important factor in terms of the SAR. The exposure of leukemic cells to 7,8-dihydroxy-coumarin evoked a phenoxyl radical generation that was detected by electron spin resonance spectroscopy. The present study suggests that reactive oxygen species generation plays a critical role in dihydroxycoumarin-induced apoptosis in U-937 cells. These findings further suggest that these compounds may have a potential therapeutic role in the treatment of hematological malignancies.
Assuntos
Apoptose/efeitos dos fármacos , Cumarínicos/síntese química , Cumarínicos/farmacologia , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Cumarínicos/química , Espectroscopia de Ressonância de Spin Eletrônica , Humanos , Hidroxilação , Cinética , Estrutura Molecular , Relação Estrutura-Atividade , Células U937RESUMO
The search for new drugs requires a deep understanding of the molecular basis of drug action, being necessary the elucidation of the mechanism of action with the understanding of the relationship between structure and activity. In the present study, we evaluated the pro-apoptotic activity of 7,8-dihydroxy-4-methylcoumarin (DHMC) and its underlying mechanisms in human leukemic cells. Here, we present evidence that DHMC induced selective and concentration-dependent apoptosis in human leukemic cells. The pro-apoptotic effect of DHMC was mediated by activation of the JNKs and inhibition of the ERK1/2 and PI3K/Akt pathways, with no participation of the p38 cascade after 24h of treatment. Indeed, down-regulation of the proto-oncogene c-myc as well as induction of the cell cycle inhibitor p21(WAF1/CIP1) through a p53 independent mechanism were observed in U-937 cells. These findings suggest that DHCM may have a potential therapeutic role in the future treatment of hematological malignancies.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Cumarínicos/farmacologia , Leucemia/tratamento farmacológico , Diferenciação Celular/efeitos dos fármacos , Genes myc , Células HL-60 , Humanos , Leucemia/patologia , Leucócitos Mononucleares/efeitos dos fármacos , Quinases de Proteína Quinase Ativadas por Mitógeno/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/fisiologia , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-akt/fisiologia , Células U937RESUMO
Nosotros consideramos que la fijación in situ percutánea con tornillo de Schanz es suficiente para dar estabilidad de deslizamientos leves o moderados de la cadera femoral y este estudio tiene como objetivo analizar la eficacia de este método. Se estudiaron 38 niños (50 caderas) entre noviembre de 1993 y marzo de 1995 tratados con la técnica descrita. La edad de los pacientes varió de los 7 a los 15 encontrándose 35 caderas con deslizamiento grado I, 10 con deslizamiento grado II y 4 con deslizamiento grado III, 40 eran crónicos, 9 crónico-agudizados y uno agudo además de un predeslizamiento. Se observó un 94 por ciento de buenos resultados en los deslizamientos leves, 80 por ciento de buenos resultados en los moderados y 0 por ciento en los severos. Se demuestra un 86 por ciento de resultados satisfactorios en la serie, los malos resultados estuvieron directamente relacionados con la severidad del deslizamiento. En 7 caderas se presentó penetración articular, sin embargo ninguno desarrolló condrólisis. Consideramos que la fijación in situ con tornillo de Schanz da excelentes resultados en los deslizamientos leves y buenos en los moderados por lo que esta técnica es recomendable en estos pacientes y no así para los casos severos
Assuntos
Humanos , Masculino , Feminino , Adolescente , Fraturas do Quadril/cirurgia , Fraturas do Quadril/classificação , Epifise Deslocada/cirurgia , Epifise Deslocada/classificação , Parafusos Ósseos/classificação , Parafusos Ósseos , Estudos RetrospectivosRESUMO
Se realizó un estudio de corte transversal con 2 grupos de madres de lactantes con el fin de identificar el grado de conocimiento sobre algunas cuestiones técnicas de la lactancia materna. El grupo de estudio se constituyó con 29 madres atendidas por 6 consultorios del médico de la familia del Polilclínico Comunitario Centro de Camaguey y el grupo testigo por igual número de madres de lactantes no pertenecientes a esta área de salud y cuyos hijos se encontraban ingresados en ese momento en el Hospital Pediátrico Provincial. A ambos grupos de les aplicó un modelo de encuesta con variables seleccionadas y se procesan los datos obtenidos de forma manual. Los resultados más importantes obtenidos fueron: un predominio de madres adolescentes en el grupo testigo con un mayor grado de conocimiento en el grupo de estudio acerca de los pechos, el horario de las tetadas, la realización de la expresión de las mamas y la utilización de otros alimentos, con evidentes fallos en los 2 grupos de la educación a impartir en la consulta de puericultura prenatal. Se concluyó que en ambos grupos hay que mejorar el grado de conocimiento sobre estas cuestiones técnicas, y también, la educación sanitaria que se debe impartir en dicha consulta