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1.
Angiogenesis ; 26(1): 129-166, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36183032

RESUMEN

Cancer cells are embedded within the tissue and interact dynamically with its components during cancer progression. Understanding the contribution of cellular components within the tumor microenvironment is crucial for the success of therapeutic applications. Here, we reveal the presence of perivascular GFAP+/Plp1+ cells within the tumor microenvironment. Using in vivo inducible Cre/loxP mediated systems, we demonstrated that these cells derive from tissue-resident Schwann cells. Genetic ablation of endogenous Schwann cells slowed down tumor growth and angiogenesis. Schwann cell-specific depletion also induced a boost in the immune surveillance by increasing tumor-infiltrating anti-tumor lymphocytes, while reducing immune-suppressor cells. In humans, a retrospective in silico analysis of tumor biopsies revealed that increased expression of Schwann cell-related genes within melanoma was associated with improved survival. Collectively, our study suggests that Schwann cells regulate tumor progression, indicating that manipulation of Schwann cells may provide a valuable tool to improve cancer patients' outcomes.


Asunto(s)
Neoplasias , Neuroglía , Humanos , Estudios Retrospectivos , Neuroglía/metabolismo , Células de Schwann/metabolismo , Células de Schwann/patología , Pericitos , Microambiente Tumoral/fisiología , Neoplasias/patología
2.
Semin Cell Dev Biol ; 95: 98-110, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-30550812

RESUMEN

Stroke consists of an abrupt reduction of cerebral blood flow resulting in hypoxia that triggers an excitotoxicity, oxidative stress, and neuroinflammation. After the ischemic process, neural precursor cells present in the subventricular zone of the lateral ventricle and subgranular zone of the dentate gyrus proliferate and migrate towards the lesion, contributing to the brain repair. The neurogenesis is induced by signal transduction pathways, growth factors, attractive factors for neuroblasts, transcription factors, pro and anti-inflammatory mediators and specific neurotransmissions. However, this endogenous neurogenesis occurs slowly and does not allow a complete restoration of brain function. Despite that, understanding the mechanisms of neurogenesis could improve the therapeutic strategies for brain repair. This review presents the current knowledge about brain repair process after stroke and the perspectives regarding the development of promising therapies that aim to improve neurogenesis and its potential to form new neural networks.


Asunto(s)
Isquemia Encefálica/complicaciones , Isquemia Encefálica/fisiopatología , Regeneración Nerviosa , Neurogénesis , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/fisiopatología , Animales , Isquemia Encefálica/patología , Transdiferenciación Celular , Humanos , Trasplante de Células Madre , Accidente Cerebrovascular/patología , Accidente Cerebrovascular/terapia
3.
Histochem Cell Biol ; 156(2): 165-182, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-34003355

RESUMEN

Diagnosis and prognosis of breast cancer is based on disease staging identified through histopathological and molecular biology techniques. Animal models are used to gain mechanistic insights into the development of breast cancer. C(3)1-TAg is a genetically engineered mouse model that develops mammary cancer. However, carcinogenesis caused by this transgene was characterized in the Friend Virus B (FVB) background. As most genetic studies are done in mice with C57BL/6 J background, we aimed to define the histological alterations in C3(1)-TAg C57BL/6 J animals. Our results showed that C3(1)-TAg animals with C57BL/6 J background develop solid-basaloid adenoid cystic carcinomas with increased fibrosis, decreased area of adipocytes, and a high proliferative index, which are triple-negative for progesterone, estrogen, and human epidermal growth factor receptor 2 (HER2) receptors. Our results also revealed that tumor development is slower in the C57BL/6 J background when compared with the FVB strain, providing a better model to study the different stages in breast cancer progression.


Asunto(s)
Antígenos Virales de Tumores/genética , Neoplasias de la Mama/genética , Carcinoma Adenoide Quístico/genética , Modelos Genéticos , Animales , Antígenos Virales de Tumores/inmunología , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Carcinoma Adenoide Quístico/inmunología , Carcinoma Adenoide Quístico/patología , Femenino , Virus de la Leucemia Murina de Friend/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos
4.
Hepatology ; 59(1): 274-83, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23839970

RESUMEN

UNLABELLED: Insulin's metabolic effects in the liver are widely appreciated, but insulin's ability to act as a hepatic mitogen is less well understood. Because the insulin receptor (IR) can traffic to the nucleus, and Ca(2+) signals within the nucleus regulate cell proliferation, we investigated whether insulin's mitogenic effects result from activation of Ca(2+)-signaling pathways by IRs within the nucleus. Insulin-induced increases in Ca(2+) and cell proliferation depended upon clathrin- and caveolin-dependent translocation of the IR to the nucleus, as well as upon formation of inositol 1,4,5,-trisphosphate (InsP3) in the nucleus, whereas insulin's metabolic effects did not depend on either of these events. Moreover, liver regeneration after partial hepatectomy also depended upon the formation of InsP3 in the nucleus, but not the cytosol, whereas hepatic glucose metabolism was not affected by buffering InsP3 in the nucleus. CONCLUSION: These findings provide evidence that insulin's mitogenic effects are mediated by a subpopulation of IRs that traffic to the nucleus to locally activate InsP3 -dependent Ca(2+)-signaling pathways. The steps along this signaling pathway reveal a number of potential targets for therapeutic modulation of liver growth in health and disease.


Asunto(s)
Señalización del Calcio , Insulina/metabolismo , Regeneración Hepática , Receptor de Insulina/metabolismo , Animales , Núcleo Celular/metabolismo , Proliferación Celular , Inositol 1,4,5-Trifosfato/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley
5.
J Biochem Mol Toxicol ; 27(11): 479-85, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23868213

RESUMEN

Hypnophilin (HNP) is a sesquiterpene that is isolated from Lentinus cf. strigosus and has cytotoxic activities. Here, we studied the calcium signaling and cytotoxic effects of HNP in UACC-62 cells, a human skin melanoma cell line. HNP was able to increase the intracellular calcium concentration in UACC-62 cells, which was blocked in cells stimulated in Ca(2+) -free media. HNP treatment with BAPTA-AM, an intracellular Ca(2+) chelator, caused an increase in calcium signals. HNP showed cytotoxicity against UACC-62 cells in which it induced DNA fragmentation and morphological alterations, including changes in the nuclear chromatin profile and increased cytoplasmatic vacuolization, but it had no effect on the plasma membrane integrity. These data suggest that cytotoxicity in UACC-62 cells, after treatment with HNP, is associated with Ca(2+) influx. Together, these findings suggest that HNP is a relevant tool for the further investigation of new anticancer approaches.


Asunto(s)
Señalización del Calcio/genética , Calcio/metabolismo , Sesquiterpenos/farmacología , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Señalización del Calcio/efectos de los fármacos , Línea Celular , Fragmentación del ADN/efectos de los fármacos , Ácido Egtácico/análogos & derivados , Ácido Egtácico/farmacología , Humanos , Neoplasias/tratamiento farmacológico
6.
Stem Cell Rev Rep ; 19(4): 906-927, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36585572

RESUMEN

Hematopoietic stem cells are maintained in a specialized microenvironment, known as the 'niche', within the bone marrow. Understanding the contribution of cellular and molecular components within the bone marrow niche for the maintenance of hematopoietic stem cells is crucial for the success of therapeutic applications. So far, the roles of crucial mechanisms within the bone marrow niche have been explored in transgenic animals in which genetic modifications are ubiquitously introduced in the whole body. The lack of precise tools to explore genetic alterations exclusively within the bone marrow prevents our determination of whether the observed outcomes result from confounding effects from other organs. Here, we developed a new method - 'whole bone subcutaneous transplantation'- to study the bone marrow niche in transgenic animals precisely. Using immunolabeling of CD45.1 (donor) vs. CD45.2 (recipient) hematopoeitic stem cells, we demonstrated that hematopoeitic stem cells from the host animals colonize the subcutaneously transplanted femurs after transplantation, while the hematopoietic stem cells from the donor disappear. Strikinlgy, the bone marrow niche of these subcutaneously transplanted femurs remain from the donor mice, enabling us to study specifically cells of the bone marrow niche using this model. We also showed that genetic ablation of peri-arteriolar cells specifically in donor femurs reduced the numbers of hematopoietic stem cells in these bones. This supports the use of this strategy as a model, in combination with genetic tools, to evaluate how bone marrow niche specific modifications may impact non-modified hematopoietic stem cells. Thus, this approach can be utilized for genetic manipulation in vivo of specific cell types only within the bone marrow. The combination of whole bone subcutaneous transplantation with rodent transgenic models will facilitate a more precise, complex and comprehensive understanding of existing problems in the study of the hematopoietic stem cell bone marrow niche.


Asunto(s)
Médula Ósea , Trasplante de Células Madre Hematopoyéticas , Ratones , Animales , Células Madre Hematopoyéticas/metabolismo , Trasplante de Médula Ósea , Huesos
7.
Hepatology ; 54(1): 296-306, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21503946

RESUMEN

UNLABELLED: Subcellular Ca(2+) signals control a variety of responses in the liver. For example, mitochondrial Ca(2+) (Ca(mit)(2+)) regulates apoptosis, whereas Ca(2+) in the nucleus regulates cell proliferation. Because apoptosis and cell growth can be related, we investigated whether Ca(mit)(2+) also affects liver regeneration. The Ca(2+)-buffering protein parvalbumin, which was targeted to the mitochondrial matrix and fused to green fluorescent protein, was expressed in the SKHep1 liver cell line; the vector was called parvalbumin-mitochondrial targeting sequence-green fluorescent protein (PV-MITO-GFP). This construct properly localized to and effectively buffered Ca(2+) signals in the mitochondrial matrix. Additionally, the expression of PV-MITO-GFP reduced apoptosis induced by both intrinsic and extrinsic pathways. The reduction in cell death correlated with the increased expression of antiapoptotic genes [B cell lymphoma 2 (bcl-2), myeloid cell leukemia 1, and B cell lymphoma extra large] and with the decreased expression of proapoptotic genes [p53, B cell lymphoma 2-associated X protein (bax), apoptotic peptidase activating factor 1, and caspase-6]. PV-MITO-GFP was also expressed in hepatocytes in vivo with an adenoviral delivery system. Ca(mit)(2+) buffering in hepatocytes accelerated liver regeneration after partial hepatectomy, and this effect was associated with the increased expression of bcl-2 and the decreased expression of bax. CONCLUSION: Together, these results reveal an essential role for Ca(mit)(2+) in hepatocyte proliferation and liver regeneration, which may be mediated by the regulation of apoptosis.


Asunto(s)
Apoptosis/fisiología , Calcio/metabolismo , Regeneración Hepática/fisiología , Mitocondrias Hepáticas/metabolismo , Animales , Señalización del Calcio/fisiología , Proliferación Celular , Masculino , Modelos Animales , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratas , Ratas Sprague-Dawley , Proteína X Asociada a bcl-2/metabolismo
8.
Stem Cell Rev Rep ; 18(8): 2852-2871, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-35962176

RESUMEN

Neurogenesis is a biological process characterized by new neurons formation from stem cells. For decades, it was believed that neurons only multiplied during development and in the postnatal period but the discovery of neural stem cells (NSCs) in mature brain promoted a revolution in neuroscience field. In mammals, neurogenesis consists of migration, differentiation, maturation, as well as functional integration of newborn cells into the pre-existing neuronal circuit. Actually, NSC density drops significantly after the first stages of development, however in specific places in the brain, called neurogenic niches, some of these cells retain their ability to generate new neurons and glial cells in adulthood. The subgranular (SGZ), and the subventricular zones (SVZ) are examples of regions where the neurogenesis process occurs in the mature brain. There, the potential of NSCs to produce new neurons has been explored by new advanced methodologies and in neuroscience for the treatment of brain damage and/or degeneration. Based on that, this review highlights endogenous factors and drugs capable of stimulating neurogenesis, as well as the perspectives for the use of NSCs for neurological and neurodegenerative diseases.


Asunto(s)
Células-Madre Neurales , Neurogénesis , Animales , Humanos , Recién Nacido , Adulto , Neurogénesis/fisiología , Ventrículos Laterales , Neuronas , Neuroglía , Mamíferos
9.
Stem Cell Rev Rep ; 18(2): 732-751, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34780018

RESUMEN

Stem cell therapy is an interesting approach for neural repair, once it can improve and increase processes, like angiogenesis, neurogenesis, and synaptic plasticity. In this regard, adult neural stem cells (NSC) are studied for their mechanisms of proliferation, differentiation and functionality in neural repair. Here, we describe novel neural differentiation methods. NSC from adult mouse brains and human adipose-derived stem cells (hADSC) were isolated and characterized regarding their neural differentiation potential based on neural marker expression profiles. For both cell types, their capabilities of differentiating into neuron-, astrocyte- and oligodendrocytes-like cells (NLC, ALC and OLC, respectively) were analyzed. Our methodologies were capable of producing NLC, ALC and OLC from adult murine and human transdifferentiated NSC. NSC showed augmented gene expression of NES, TUJ1, GFAP and PDGFRA/Cnp. Following differentiation induction into NLC, OLC or ALC, specific neural phenotypes were obtained expressing MAP2, GalC/O4 or GFAP with compatible morphologies, respectively. Accordingly, immunostaining for nestin+ in NSC, GFAP+ in astrocytes and GalC/O4+ in oligodendrocytes was detected. Co-cultured NLC and OLC showed excitability in 81.3% of cells and 23.5% of neuron/oligodendrocyte marker expression overlap indicating occurrence of in vitro myelination. We show here that hADSC can be transdifferentiated into NSC and distinct neural phenotypes with the occurrence of neuron myelination in vitro, providing novel strategies for CNS regeneration therapy. Superior Part: Schematic organization of obtaining and generating hNSC from hADSC and differentiation processes and phenotypic expression of neuron, astrocyte and oligodendrocyte markers (MAP2, GFAP and O4, respectively) and stem cell marker (NES) of differentiating hNSC 14 days after induction. The nuclear staining in blue corresponds to DAPI. bar = 100 µm. Inferior part: Neural phenotype fates in diverse differentiation media. NES: nestin; GFAP: Glial fibrillary acidic protein. MAP2: Microtubule-associated protein 2. TUJ1: ß-III tubulin. PDGFRA: PDGF receptor alpha. Two-way ANOVA with Bonferroni post-test with n = 3. * p < 0.05 and ** p < 0.01: (NSCiM1 NSC induction medium 1) vs differentiation media.


Asunto(s)
Transdiferenciación Celular , Células-Madre Neurales , Animales , Diferenciación Celular , Células Cultivadas , Humanos , Ratones , Nestina , Neurogénesis , Neuronas , Oligodendroglía
10.
J Mol Med (Berl) ; 100(2): 151-165, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34735579

RESUMEN

Psychological stress predisposes our body to several disorders. Understanding the cellular and molecular mechanisms involved in the physiological responses to psychological stress is essential for the success of therapeutic applications. New studies show, by using in vivo inducible Cre/loxP-mediated approaches in combination with pharmacological blockage, that sympathetic nerves, activated by psychological stress, induce brown adipocytes to produce IL-6. Strikingly, this cytokine promotes gluconeogenesis in hepatocytes, that results in the decline of tolerance to inflammatory organ damage. The comprehension arising from this research will be crucial for the handling of many inflammatory diseases. Here, we review recent advances in our comprehension of the sympathetic nerve-adipocyte axis in the tissue microenvironment.


Asunto(s)
Adipocitos/metabolismo , Estrés Psicológico/metabolismo , Sistema Nervioso Simpático/metabolismo , Animales , Humanos , Interleucina-6/metabolismo , Microambiente Tumoral
11.
Biometals ; 24(4): 595-601, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21221718

RESUMEN

Complexes [Sb(QN)(2)Cl] (1), [Sb(QC)(2)Cl] (2) and [Sb(QI)(2)Cl] (3) were obtained with 8-hydroxyquinoline (HQN), 5-chloro-8-hydroxyquinoline (HQC) and 5-chloro-7-iodo-8-hydroxyquinoline (clioquinol, HQI). The quinoline derivatives and their antimony(III) complexes were evaluated for their anti-trypanosomal activity as well as for their cytotoxicity against HL-60 and Jurkat human leukemia cell lines. Upon coordination to antimony(III) the anti-trypanosomal activity of HQC and HQI increases, the highest improvement being observed for complex (3), which was the most active among all studied compounds against both epimastigote and trypomastigote forms of Trypanosoma cruzi. All quinoline derivatives proved to be cytotoxic against both leukemia cell lineages. Upon coordination to antimony(III) the cytotoxicity of HQN improved against Jurkat leukemia cells. While SbCl(3) proved to be cytotoxic against HL-60 cells, it was not active against Jurkat cells. However, its coordination to the quinoline derivatives resulted in complexes with significant cytotoxicity against Jurkat cells.


Asunto(s)
Antimonio/química , Antineoplásicos/farmacología , Antiprotozoarios/farmacología , Hidroxiquinolinas/química , Compuestos Organometálicos/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Células HL-60 , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/química , Pruebas de Sensibilidad Parasitaria , Bazo/citología , Bazo/efectos de los fármacos , Relación Estructura-Actividad , Trypanosoma cruzi/crecimiento & desarrollo
12.
Acta Neuropathol Commun ; 9(1): 183, 2021 11 16.
Artículo en Inglés | MEDLINE | ID: mdl-34784974

RESUMEN

Sensory neurons have recently emerged as components of the tumor microenvironment. Nevertheless, whether sensory neuronal activity is important for tumor progression remains unknown. Here we used Designer Receptors Exclusively Activated by a Designer Drug (DREADD) technology to inhibit or activate sensory neurons' firing within the melanoma tumor. Melanoma growth and angiogenesis were accelerated following inhibition of sensory neurons' activity and were reduced following overstimulation of these neurons. Sensory neuron-specific overactivation also induced a boost in the immune surveillance by increasing tumor-infiltrating anti-tumor lymphocytes, while reducing immune-suppressor cells. In humans, a retrospective in silico analysis of melanoma biopsies revealed that increased expression of sensory neurons-related genes within melanoma was associated with improved survival. These findings suggest that sensory innervations regulate melanoma progression, indicating that manipulation of sensory neurons' activity may provide a valuable tool to improve melanoma patients' outcomes.


Asunto(s)
Melanoma/genética , Melanoma/patología , Células Receptoras Sensoriales/patología , Animales , Conducta Animal/efectos de los fármacos , Biopsia , Línea Celular Tumoral , Simulación por Computador , Progresión de la Enfermedad , Humanos , Vigilancia Inmunológica , Linfocitos/patología , Melanoma Experimental/genética , Melanoma Experimental/patología , Ratones , Ratones Transgénicos , Canal de Sodio Activado por Voltaje NAV1.8/genética , Neovascularización Patológica/genética , Neovascularización Patológica/patología , Células Receptoras Sensoriales/metabolismo , Factores Supresores Inmunológicos , Microambiente Tumoral
13.
Stem Cell Rev Rep ; 17(5): 1874-1888, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34003465

RESUMEN

Multiple infectious diseases lead to impaired lung function. Revealing the cellular mechanisms involved in this impairment is crucial for the understanding of how the lungs shift from a physiologic to a pathologic state in each specific condition. In this context, we explored the pathogenesis of Paracoccidioidomycosis, which affects pulmonary functioning. The presence of cells expressing Nestin-GFP has been reported in different tissues, and their roles as tissue-specific progenitors have been stablished in particular organs. Here, we explored how Nestin-GFP+ cells are affected after lung infection by Paracoccidioides brasiliensis, a model of lung granulomatous inflammation with fibrotic outcome. We used Nestin-GFP transgenic mice, parabiosis surgery, confocal microscopy and flow cytometry to investigate the participation of Nestin-GFP+ cells in Paracoccidioides brasiliensis pathogenesis. We revealed that these cells increase in the lungs post-Paracoccidioides brasiliensis infection, accumulating around granulomas. This increase was due mainly to Nestin-GPF+ cells derived from the blood circulation, not associated to blood vessels, that co-express markers suggestive of hematopoietic cells (Sca-1, CD45 and CXCR4). Therefore, our findings suggest that circulating Nestin-GFP+ cells participate in the Paracoccidioides brasiliensis pathogenesis in the lungs.


Asunto(s)
Pulmón , Animales , Ratones , Nestina/genética , Paracoccidioides/genética
14.
Bioorg Med Chem ; 17(20): 7138-44, 2009 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-19773176

RESUMEN

The palladium(II) complexes [Pd(2Bz4oT)Cl], [Pd(2Bz4mT)Cl], and [Pd(2Bz4pT)Cl] were prepared with N(4)-ortho- (H2Bz4oT) N(4)-meta- (H2Bz4mT) and N(4)-para- (H2Bz4pT) tolyl-thiosemicarbazones derived from 2-benzoylpyridine. The free thiosemicarbazones proved to be highly cytotoxic against Jurkat, HL60 and the resistant HL60.Bcl-X(L) leukemia cell lines at nanomolar concentrations, but were much less cytotoxic to HepG2human hepatoma cells. Upon coordination to palladium(II) the cytotoxic activity against all studied cell lines decreases. However, the high cytotoxicity of the free thiosemicarbazones against leukemia, together with their hepatotoxic profile similar to that of cisplatin suggest that N(4)-tolyl thiosemicarbazones have potential as chemotherapeutic drug candidates.


Asunto(s)
Antineoplásicos/farmacología , Leucemia/patología , Paladio/química , Tiosemicarbazonas/farmacología , Antineoplásicos/química , Línea Celular Tumoral , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Tiosemicarbazonas/química
15.
Biomed Res Int ; 2019: 8480468, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30800679

RESUMEN

Ischemic stroke is a neurovascular disorder caused by reduced or blockage of blood flow to the brain, which may permanently affect motor and cognitive abilities. The diagnostic of stroke is performed using imaging technologies, clinical evaluation, and neuropsychological protocols, but no blood test is available yet. In this work, we analyzed amino acid concentrations in blood plasma from poststroke patients in order to identify differences that could characterize the stroke etiology. Plasma concentrations of sixteen amino acids from patients with chronic ischemic stroke (n = 73) and the control group (n = 16) were determined using gas chromatography coupled to mass spectrometry (GC-MS). The concentration data was processed by Partial Least Squares-Discriminant Analysis (PLS-DA) to classify patients with stroke and control. The amino acid analysis generated a first model able to discriminate ischemic stroke patients from control group. Proline was the most important amino acid for classification of the stroke samples in PLS-DA, followed by lysine, phenylalanine, leucine, and glycine, and while higher levels of methionine and alanine were mostly related to the control samples. The second model was able to discriminate the stroke subtypes like atherothrombotic etiology from cardioembolic and lacunar etiologies, with lysine, leucine, and cysteine plasmatic concentrations being the most important metabolites. Our results suggest an amino acid biosignature for patients with chronic stroke in plasma samples, which can be helpful in diagnosis, prognosis, and therapeutics of these patients.


Asunto(s)
Aminoácidos/sangre , Isquemia Encefálica/sangre , Plasma/metabolismo , Accidente Cerebrovascular/sangre , Anciano , Isquemia Encefálica/patología , Análisis Discriminante , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Accidente Cerebrovascular/patología
16.
Integr Biol (Camb) ; 8(2): 130-48, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26762767

RESUMEN

Biological processes, such as the induction of undifferentiated cells to enable neurogenesis, provide complex mechanisms for study. For further insight, subsets of these processes that are governed by metabolic pathways or key molecules called attractors need to be elucidated. In this review, we have focused on the role of calcium as a driving force of neuronal differentiation. The activity of calcium refers to peaks and waves, whose amplitudes and frequencies in stem and progenitor cells involve the activation of a great variety of signaling pathways that comprise neurotransmitters and their receptors, intracellular signaling factors and transcription factors, which form a complex network. The study of different subsets, from receptor-mediated calcium flux to the activation of transcription factors, can then be combined to understand the process of neuronal differentiation.


Asunto(s)
Señalización del Calcio , Diferenciación Celular , Animales , Calcio/metabolismo , Quimiotaxis , Homeostasis , Humanos , Modelos Teóricos , Neurogénesis , Neuronas/metabolismo , Oscilometría , Fenotipo , Transducción de Señal , Células Madre/citología
17.
Immunobiology ; 220(12): 1311-21, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26297425

RESUMEN

Beyond the classical actions of the renin-angiotensin system on the regulation of cardiovascular homeostasis, several studies have shown its involvement in acute and chronic inflammation. The G protein-coupled receptor Mas is a functional binding site for the angiotensin-(1-7); however, its role in the immune system has not been fully elucidated. In this study, we evaluated the effect of genetic deletion of Mas receptor in lipopolysaccharide (LPS)-induced systemic and cerebral inflammation in mice. Inflammatory response was triggered in Mas deficient (Mas(-/-)) and C57BL/6 wild-type (WT) mice (8-12 weeks-old) by intraperitoneal injection of LPS (5 mg/kg). Mas(-/-) mice presented more intense hypothermia compared to WT mice 24 h after LPS injection. Systemically, the bone marrow of Mas(-/-) mice contained a lower number of neutrophils and monocytes 3 h and 24 h after LPS injection, respectively. The plasma levels of inflammatory mediators KC, MCP-1 and IL-10 were higher in Mas(-/-) mice 24 h after LPS injection in comparison to WT. In the brain, Mas(-/-) animals had a significant increase in the number of adherent leukocytes to the brain microvasculature compared to WT mice, as well as, increased number of monocytes and neutrophils recruited to the pia-mater. The elevated number of adherent leukocytes on brain microvasculature in Mas(-/-) mice was associated with increased expression of CD11b - the alpha-subunit of the Mac-1 integrin - in bone marrow neutrophils 3h after LPS injection, and with increased brain levels of chemoattractants KC, MIP-2 and MCP-1, 24 h later. In conclusion, we demonstrated that Mas receptor deficiency results in exacerbated inflammation in LPS-challenged mice, which suggest a potential role for the Mas receptor as a regulator of systemic and brain inflammatory response induced by LPS.


Asunto(s)
Inflamación/genética , Inflamación/inmunología , Proteínas Proto-Oncogénicas/deficiencia , Proteínas Proto-Oncogénicas/genética , Receptores Acoplados a Proteínas G/deficiencia , Receptores Acoplados a Proteínas G/genética , Animales , Biomarcadores , Temperatura Corporal , Peso Corporal , Médula Ósea/patología , Encéfalo/irrigación sanguínea , Encéfalo/inmunología , Encéfalo/metabolismo , Encéfalo/patología , Antígeno CD11b/genética , Antígeno CD11b/metabolismo , Circulación Cerebrovascular , Quimiocinas/sangre , Quimiocinas/metabolismo , Quimiotaxis de Leucocito , Citocinas/sangre , Citocinas/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Inflamación/sangre , Inflamación/patología , Recuento de Leucocitos , Lipopolisacáridos/efectos adversos , Masculino , Ratones , Ratones Noqueados , Microcirculación , Monocitos/inmunología , Monocitos/metabolismo , Monocitos/patología , Neutrófilos/inmunología , Neutrófilos/metabolismo , Neutrófilos/patología , Proto-Oncogenes Mas
18.
Life Sci ; 89(21-22): 786-94, 2011 Nov 21.
Artículo en Inglés | MEDLINE | ID: mdl-21983296

RESUMEN

AIMS: We evaluated biological activity in leukemia cells lines of R and S enantiomers of tert-butyl 4-[(3-nitrophenoxy)-methyl]-2,2-dimethyloxazolidine-3-carboxylate (BNDC). MAIN METHODS: Cytotoxic activity was assessed by MTT assay. Flow cytometry assays were used to determined DNA fragmentation (Propidium Iodide-PI staining) and phosphatidylserine exposure (Annexin-V and PI staining). DNA condensation was evaluated by fluorescence microscopy using double-staining in leukemia cells (Hoechst and PI). Caspase activities were measured using Z-VAD-FMK, a non-selective caspase inhibitor, by flow cytometry and Z-DEVD-AMC, a selective caspase-3 substrate, by fluorescence spectrometry. KEY FINDINGS: Both enantiomers displayed cytotoxic activity against leukemia cell lines (HL60, HL60.Bcl-2, HL60.Bcl-XL and Jurkat) with low toxicity against human peripheral blood mononuclear cell--PBMC based on IC50 values. In HL60 cell lines, compounds induce exposure of phosphatidylserine and DNA fragmentation, which could be blocked by pretreatment of cells with Z-VAD-FMK. Confirming this observation, both enantiomers induced caspase-3 activation. Additional analysis revealed an increased percentage of apoptotic cells (defined as those with fragmented nuclei and condensed chromatin) after treatment with compounds. SIGNIFICANCE: Taken together, the results indicate that BNDC compounds exhibited cytotoxic and pro-apoptotic activities and have a potential for developing a new class of anticancer drugs.


Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Leucemia/tratamiento farmacológico , Oxazoles/síntesis química , Oxazoles/farmacología , Bencimidazoles , Caspasa 3/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Fragmentación del ADN , Descubrimiento de Drogas , Citometría de Flujo , Colorantes Fluorescentes , Células HL-60 , Humanos , Indicadores y Reactivos , Células Jurkat , Leucemia/patología , Microscopía Fluorescente , Fosfatidilserinas/farmacología , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Estereoisomerismo
19.
Eur J Med Chem ; 45(9): 3904-10, 2010 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-20576328

RESUMEN

The antimony(III) complexes [Sb(2Bz4DH)Cl(2)] (1), [Sb(H2Bz4M)Cl(3)] x 2 H(2)O (2) and [Sb(2Bz4Ph)Cl(2)] (3) were obtained with 2-benzoylpyridine thiosemicarbazone (H2Bz4DH) and its N(4)-methyl (H2Bz4M) and N(4)-phenyl (H2Bz4Ph) derivatives. H2Bz4DH, H2Bz4Ph and complexes (1-3) exhibited high cytotoxic activity against HL-60 and Jurkat human leukemia cell lines. When these compounds were tested against HL-60 cells with ectopic expression of BcrAbl, Bcl-2 or Bcl-X(L), which confer resistance to apoptosis against a variety of death-inducing agents, the cytotoxicity was much lower, indicating apoptosis to be part of their mechanism of action. The cytotoxic activity of complexes 2 and 3 against HL-60 and Jurkat cells was significantly higher than that of the corresponding thiosemicarbazones, suggesting coordination to be an interesting strategy of cytotoxic dose reduction.


Asunto(s)
Antimonio/química , Leucemia/patología , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacología , Tiosemicarbazonas/química , Línea Celular Tumoral , Descubrimiento de Drogas , Humanos , Concentración 50 Inhibidora , Compuestos Organometálicos/síntesis química , Análisis Espectral , Difracción de Rayos X
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