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1.
Pharmaceuticals (Basel) ; 15(1)2022 Jan 11.
Artículo en Inglés | MEDLINE | ID: mdl-35056141

RESUMEN

The fruit of Garcinia mangostana (mangosteen) is known in ancient traditional Asian medicine for its antioxidant, anti-inflammatory, immunomodulatory and anticancer activities. These effects are mainly due to the action of polyphenols known as xanthones, which are contained in the pericarp of the fruit. In recent years, there has been a growing interest from pharmaceutical companies in formulating new topicals based on mangosteen full extracts to prevent skin aging. However, the molecules responsible for these effects and the mechanisms involved have not been investigated so far. Here, the arils and shells of Garcinia mangostana were extracted with chloroform and methanol, and the extracts were further purified to yield 12 xanthone derivatives. Their effects were evaluated using in vitro cultures of human epidermal keratinocytes. After confirming the absence of cytotoxicity, we evaluated the antioxidant potential of these compounds, identifying mangostanin as capable of both protecting and restoring oxidative damage induced by H2O2. We showed how mangostanin, by reducing the generation of intracellular reactive oxygen species (ROS), prevents the activation of AKT (protein kinase B), ERK (extracellular signal-regulated kinase), p53, and other cellular pathways underlying cell damage and apoptosis activation. In conclusion, our study is the first to demonstrate that mangostanin is effective in protecting the skin from the action of free radicals, thus preventing skin aging, confirming a potential toward its development in the nutraceutical and cosmeceutical fields.

2.
Antioxidants (Basel) ; 10(3)2021 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-33809389

RESUMEN

BACKGROUND: Arterial hypertension is the most important risk factor for cardiovascular diseases, myocardial infarction, heart failure, renal failure and peripheral vascular disease. In the last decade, milk-derived bioactive peptides have attracted attention for their beneficial cardiovascular properties. METHODS: Here, we combined in vitro chemical assay such as LC-MS/MS analysis of buffalo ice cream, ex vivo vascular studies evaluating endothelial and smooth muscle responses using pressure myograph, and translational assay testing in vivo the vascular actions of PG1 administration in murine models. RESULTS: We demonstrate that a novel buffalo ice-cream-derived pentapeptide "QKEPM", namely PG1, is a stable peptide that can be obtained at higher concentration after gastro-intestinal digestions (GID) of buffalo ice-cream (BIC). It owns potent vascular effect in counteract the effects of angiotensin II-evoked vasoconstriction and high blood pressure levels. Its effects are mediated by the inhibitory effect on AT1 receptor leading to a downregulation of p-ERK½/Rac1-GTP and consequent reduction of oxidative stress. CONCLUSIONS: These results strongly candidate PG1, as a novel bioactive peptide for the prevention and management of hypertension, thus expanding the armamentarium of preventive strategies aimed at reducing the incidence and progression of hypertension and its related cardiovascular complications.

3.
Int J Mol Sci ; 22(5)2021 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-33670966

RESUMEN

3-hydroxytyrosol (HT) is the main phenolic compound found in olive oil with known antioxidant, anti-inflammatory, and antimicrobial properties in several dermatological conditions, both when taken in the form of olive oil or pure in cosmeceutical formulations. To date, its direct effect on the wound healing process and the molecular mechanisms involved have not yet been elucidated. Thus, in the present study, we aimed to explore its effects in vitro in epidermal keratinocyte cultures focusing on the molecular mechanism implied. HT was able to induce keratinocyte proliferation in the low micromolar range, increasing the expression of cyclin dependent kinases fundamental for cell cycle progression such as CDK2 and CDK6. Furthermore, it increased cell migration through the activation of tissue remodeling factors such as matrix metalloproteinase-9 (MMP-9) protein. Then, we evaluated whether HT also showed antioxidant activity at this concentration range, protecting from H2O2-induced cytotoxicity. The HT prevented the activation of ATM serine/threonine kinase (ATM), Checkpoint kinase 1 (Chk1), Checkpoint kinase 2 (Chk2), and p53, reducing the number of apoptotic cells. Our study highlighted novel pharmacological properties of HT, providing the first evidence of its capability to induce keratinocyte migration and proliferation required for healing processes and re-epithelialization.


Asunto(s)
Movimiento Celular , Proliferación Celular , Epidermis/fisiología , Depuradores de Radicales Libres/farmacología , Radicales Libres/efectos adversos , Queratinocitos/fisiología , Alcohol Feniletílico/análogos & derivados , Antioxidantes/farmacología , Células Cultivadas , Epidermis/efectos de los fármacos , Humanos , Peróxido de Hidrógeno/efectos adversos , Queratinocitos/citología , Queratinocitos/efectos de los fármacos , Oxidantes/efectos adversos , Alcohol Feniletílico/farmacología , Transducción de Señal , Cicatrización de Heridas
4.
Artículo en Inglés | MEDLINE | ID: mdl-33525735

RESUMEN

Mevalonate kinase deficiency (MKD) is a rare autoinflammatory genetic disorder characterized by recurrent fever attacks and systemic inflammation with potentially severe complications. Although it is recognized that the lack of protein prenylation consequent to mevalonate pathway blockade drives IL1ß hypersecretion, and hence autoinflammation, MKD pathogenesis and the molecular mechanisms underlaying most of its clinical manifestations are still largely unknown. In this study, we performed a comprehensive bioinformatic analysis of a microarray dataset of MKD patients, using gene ontology and Ingenuity Pathway Analysis (IPA) tools, in order to identify the most significant differentially expressed genes and infer their predicted relationships into biological processes, pathways, and networks. We found that hematopoiesis linked biological functions and pathways are predominant in the gene ontology of differentially expressed genes in MKD, in line with the observed clinical feature of anemia. We also provided novel information about the molecular mechanisms at the basis of the hematological abnormalities observed, that are linked to the chronic inflammation and to defective prenylation. Considering the broad and unspecific spectrum of MKD clinical manifestations and the difficulty in its diagnosis, a better understanding of MKD molecular bases could be translated to the clinical level to facilitate diagnosis, and improve management and therapy.


Asunto(s)
Deficiencia de Mevalonato Quinasa , Niño , Expresión Génica , Hematopoyesis/genética , Humanos , Inflamación , Deficiencia de Mevalonato Quinasa/genética , Prenilación de Proteína
5.
Pharmaceuticals (Basel) ; 13(9)2020 Aug 29.
Artículo en Inglés | MEDLINE | ID: mdl-32872510

RESUMEN

Ganoderma lucidum or Reishi is recognized as the most potent adaptogen present in nature, and its anti-inflammatory, antioxidant, immunomodulatory and anticancer activities are well known. Moreover, lately, there has been an increasing interest from pharmaceutical companies in antiaging G. lucidum-extract-based formulations. Nevertheless, the pharmacological mechanisms of such adaptogenic and regenerative actions remain unclear. The present investigation aimed to explore its molecular and cellular effects in vitro in epidermal keratinocyte cultures by applying liquid chromatography coupled to ion trap time-of-flight mass spectrometry (LCMS-IT-TOF) for analysis of ethanol extracts using ganoderic acid-A as a reference compound. The G. lucidum extract showed a keratinocyte proliferation induction accompanied by an increase of cyclic kinase protein expressions, such as CDK2 and CDK6. Furthermore, a noteworthy migration rate increase and activation of tissue remodelling factors, such as matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9), were observed. Finally, the extract showed an antioxidant effect, protecting from H2O2-induced cytotoxicity; preventing activation of AKT (protein kinase B), ERK (extracellular signal-regulated kinase), p53 and p21; and reducing the number of apoptotic cells. Our study paves the path for elucidating pharmacological properties of G. lucidum and its potential development as cosmeceutical skin products, providing the first evidence of its capability to accelerate the healing processes enhancing re-epithelialization and to protect cells from free-radical action.

6.
J Transl Med ; 18(1): 352, 2020 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-32933522

RESUMEN

BACKGROUND: Understanding how HLA polymorphisms may affect both susceptibility, course and severity of Covid-19 infection could help both at the clinical level to identify individuals at higher risk from the disease and at the epidemiological one to explain the differences in the epidemic trend among countries or even within a specific country. Covid-19 disease in Italy showed a peculiar geographical distribution from the northern most affected regions to the southern ones only slightly touched. METHODS: In this study we analysed the regional frequencies for the most common Italian haplotypes from the Italian Bone Marrow Donor Registry (HLA-A, -B, -C and -DRB1 at four-digit level). Then we performed Pearson correlation analyses among regional haplotypes estimated frequency in the population and Covid-19 incidence and mortality. RESULTS: In this study we found that the two most frequent HLA haplotypes in the Italian population, HLA-A*:01:01g-B*08:01 g-C*07:01g-DRB1*03:01g and HLA-A*02.01g-B*18.01g-C*07.01g-DRB1*11.04g, had a regional distribution overlapping that of Covid-19 and showed respectively a positive (suggestive of susceptibility) and negative (suggestive of protection) significant correlation with both Covid-19 incidence and mortality. CONCLUSIONS: Based on these results, in order to define such HLA haplotypes as a factor effectively associated to the disease susceptibility, the creation of national networks that can collect patients' samples from all regions for HLA typing should be highly encouraged.


Asunto(s)
Betacoronavirus , Infecciones por Coronavirus/genética , Infecciones por Coronavirus/inmunología , Antígenos HLA/genética , Neumonía Viral/genética , Neumonía Viral/inmunología , COVID-19 , Infecciones por Coronavirus/epidemiología , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genética de Población , Geografía , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Antígenos HLA-C/genética , Cadenas HLA-DRB1/genética , Haplotipos , Humanos , Incidencia , Italia/epidemiología , Pandemias , Neumonía Viral/epidemiología , SARS-CoV-2 , Investigación Biomédica Traslacional
7.
Int J Mol Sci ; 21(10)2020 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-32455901

RESUMEN

Cardiovascular diseases, followed by strokes, represent the leading cause of mortality worldwide. Despite its success in preventing cardiovascular diseases, the therapeutic potential of 3-Hydroxytyrosol (HT) for treating ischemic diseases is yet to be investigated in detail, especially with regard to ischemic heart disease, which is a major challenge for humans. We assessed that low concentrations (1-5 µM) of HT, generally achieved after the ingestion of olive oil, stimulate endothelial cells migration and angiogenesis in an in vitro model. At early time points (1-6 h), HT induces the expression of different proteins such as proto-oncogene tyrosine-protein kinase Src (Src), rho-associated protein kinase (ROCK) and matrix metalloproteinase-2 (MMP-2) protein influencing cell adhesion, cytoskeletal dynamics and cell migration. We observed that at the same time, HT induces prominent vascular formation in the tube formation assay, accompanied by an increase in the expression of the vascular endothelial growth factor receptor (VEGF-R2) and PI3K-Akt-eNOS protein pathways, which are recognized for their central role in angiogenesis. Therefore, in addition to the proven capability of HT to regulate reactive oxygen species (ROS) levels, through both direct scavenging properties and indirect antioxidant efficacy, our results revealed that HT promotes angiogenesis, arguing in favor of great pharma-nutritional potential in ischemic injuries.


Asunto(s)
Movimiento Celular/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Neovascularización Fisiológica/efectos de los fármacos , Alcohol Feniletílico/análogos & derivados , Transducción de Señal/efectos de los fármacos , Receptor 1 de Factores de Crecimiento Endotelial Vascular/metabolismo , Movimiento Celular/genética , Supervivencia Celular/efectos de los fármacos , Células Endoteliales/metabolismo , Células Endoteliales de la Vena Umbilical Humana , Humanos , Metaloproteinasa 2 de la Matriz/metabolismo , Neovascularización Fisiológica/genética , Alcohol Feniletílico/farmacología , Fosforilación , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/genética , Cicatrización de Heridas/efectos de los fármacos , Quinasas Asociadas a rho/metabolismo , Familia-src Quinasas/metabolismo
8.
Bioorg Chem ; 98: 103449, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32057422

RESUMEN

Farnesyl pyrophosphate synthase (FPPS) is a crucial enzyme for the synthesis of isoprenoids and the key target of nitrogen-containing bisphosphonates (N-BPs). N-BPs are potent and selective FPPS inhibitors that are used in the treatment of bone-related diseases, but have poor pharmacokinetic properties. Given the key role played by FPPS in many cancer-related pathways and the pharmacokinetic limits of N-BPs, hundreds of molecules have been screened to identify new FPPS inhibitors characterized by improved drug-like properties that are useful for broader therapeutic applications in solid, non-skeletal tumours. We have previously shown that N6-isopentenyladenosine (i6A) and its related compound N6-benzyladenosine (2) exert anti-glioma activity by interfering with the mevalonate pathway and inhibiting FPPS. Here, we report the design and synthesis of a panel of N6-benzyladenosine derivatives (compounds 2a-m) incorporating different chemical moieties on the benzyl ring. Compounds 2a-m show in vitro antiproliferative activity in U87MG glioma cells and, analogous to the bisphosphonate FPPS inhibitors, exhibit immunogenic properties in ex vivo γδ T cells from stimulated peripheral blood mononuclear cells (PBMCs). Using saturation transfer difference (STD) and quantitative 1H nuclear magnetic resonance (NMR) experiments, we found that 2f, the N6-benzyladenosine analogue that includes a tertbutyl moiety in the para position of the benzyl ring, is endowed with increased FPPS binding and inhibition compared to the parent compounds i6A and 2. N6-benzyladenosine derivatives, characterized by structural features that are significantly different from those of N-BPs, have been confirmed to be promising chemical scaffolds for the development of non N-BP FPPS inhibitors, exerting combined cytotoxic and immunostimulatory activities.


Asunto(s)
Antineoplásicos/farmacología , Inhibidores Enzimáticos/farmacología , Geraniltranstransferasa/antagonistas & inhibidores , Resonancia Magnética Nuclear Biomolecular , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Geraniltranstransferasa/genética , Geraniltranstransferasa/metabolismo , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-Actividad
10.
Eur J Med Chem ; 154: 155-171, 2018 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-29793210

RESUMEN

The endocannabinoid system (ECS) represents one of the major neuromodulatory systems involved in different physiological and pathological processes. Multi-target compounds exert their activities by acting via multiple mechanisms of action and represent a promising pharmacological modulation of the ECS. In this work we report 4-substituted and 4,5-disubstituted 1,2-dihydro-2-oxo-pyridine-3-carboxamide derivatives with a broad spectrum of affinity and functional activity towards both cannabinoid receptors and additional effects on the main components of the ECS. In particular compound B3 showed high affinity for CB1R (Ki = 23.1 nM, partial agonist) and CB2R (Ki = 6.9 nM, inverse agonist) and also significant inhibitory activity (IC50 = 70 nM) on FAAH with moderate inhibition of ABHD12 (IC50 = 2.5 µΜ). Compounds B4, B5 and B6 that act as full agonists at CB1R and as partial agonists (B5 and B6) or antagonist (B4) at CB2R, exhibited an additional multi-target property by inhibiting anandamide uptake with sub-micromolar IC50 values (0.28-0.62 µΜ). The best derivatives showed cytotoxic activity on U937 lymphoblastoid cells. Finally, molecular docking analysis carried out on the three-dimensional structures of CB1R and CB2R and of FAAH allowed to rationalize the structure-activity relationships of this series of compounds.


Asunto(s)
Endocannabinoides/farmacología , Piridinas/farmacología , Receptores de Cannabinoides/metabolismo , Relación Dosis-Respuesta a Droga , Endocannabinoides/síntesis química , Endocannabinoides/química , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Piridinas/síntesis química , Piridinas/química , Relación Estructura-Actividad , Células Tumorales Cultivadas , Células U937
11.
Int J Cancer ; 142(1): 176-190, 2018 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-28884474

RESUMEN

Cancer cell stress induced by cytotoxic agents promotes antitumor immune response. Here, we observed that N6-isopentenyladenosine (iPA), an isoprenoid modified adenosine with a well established anticancer activity, was able to induce a significant upregulation of cell surface expression of natural killer (NK) cell activating receptor NK Group 2 member D (NKG2D) ligands on glioma cells in vitro and xenografted in vivo. Specifically suboptimal doses of iPA (0.1 and 1 µM) control the selective upregulation of UL16-binding protein 2 on p53wt-expressing U343MG and that of MICA/B on p53mut-expressing U251MG cells. This event made the glioblastoma cells a potent target for NK cell-mediated recognition through a NKG2D restricted mechanism. p53 siRNA-mediated knock-down and pharmacological inhibition (pifithrin-α), profoundly prevented the iPA action in restoring the immunogenicity of U343MG cells through a mechanism that is dependent upon p53 status of malignancy. Furthermore, accordingly to the preferential recognition of senescent cells by NK cells, we found that iPA treatment was critical for glioma cells entry in premature senescence through the induction of S and G2/M phase arrest. Collectively, our results indicate that behind the well established cytotoxic and antiangiogenic effects, iPA can also display an immune-mediated antitumor activity. The indirect engagement of the innate immune system and its additional activity in primary derived patient's glioma cell model (GBM17 and GBM37), fully increase its translational relevance and led to the exploitation of the isoprenoid pathway for a valid therapeutic intervention in antiglioma research.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias Encefálicas/patología , Glioma/patología , Isopenteniladenosina/farmacología , Células Asesinas Naturales/patología , Animales , Antineoplásicos/inmunología , Neoplasias Encefálicas/inmunología , Línea Celular Tumoral , Glioma/inmunología , Humanos , Isopenteniladenosina/inmunología , Células Asesinas Naturales/inmunología , Ratones , Ensayos Antitumor por Modelo de Xenoinjerto
12.
Sci Rep ; 7(1): 14123, 2017 10 26.
Artículo en Inglés | MEDLINE | ID: mdl-29075041

RESUMEN

Glioblastoma (GBM), the most aggressive brain cancer, is highly dependent on the mevalonate (MVA) pathway for the synthesis of lipid moieties critical for cell proliferation but the function and regulation of key intermediate enzymes like farnesyl-diphosphate synthase (FDPS), up to now, remained unknown. A deregulated expression and activity of FDPS was the central research idea of the present study. FDPS mRNA, protein and enzyme activity were analyzed in a cohort of stage III-IV glioma patients (N = 49) and primary derived cells. FDPS silencing helped to clarify its function in the maintenance of malignant phenotype. Interestingly, compared to tumor-free peripheral (TFB) brain and normal human astrocytes (NHA), FDPS protein expression and enzyme activity were detected at high degree in tumor mass where a correlation with canonical oncogenic signaling pathways such as STAT3, ERK and AKT was also documented. Further, FDPS knockdown in U87 and GBM primary cells but not in NHA, enhanced apoptosis. With the effort to develop a more refined map of the connectivity between signal transduction pathways and metabolic networks in cancer FDPS as a new candidate metabolic oncogene in glioblastoma, might suggest to further target MVA pathway as valid therapeutic tool.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Geraniltranstransferasa/genética , Geraniltranstransferasa/metabolismo , Glioblastoma/patología , Apoptosis , Ciclo Celular , Línea Celular Tumoral , Humanos , Transducción de Señal
13.
Int J Mol Sci ; 18(8)2017 Jul 28.
Artículo en Inglés | MEDLINE | ID: mdl-28788056

RESUMEN

We assessed the immunomodulatory and anti-inflammatory effects of 9,11-dihydrogracilin A (DHG), a molecule derived from the Antarctic marine sponge Dendrilla membranosa. We used in vitro and in vivo approaches to establish DHG properties. Human peripheral blood mononuclear cells (PBMC) and human keratinocytes cell line (HaCaT cells) were used as in vitro system, whereas a model of murine cutaneous irritation was adopted for in vivo studies. We observed that DHG reduces dose dependently the proliferative response and viability of mitogen stimulated PBMC. In addition, DHG induces apoptosis as revealed by AnnexinV staining and downregulates the phosphorylation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), signal transducer and activator of transcription (STAT) and extracellular signal-regulated kinase (ERK) at late time points. These effects were accompanied by down-regulation of interleukin 6 (IL-6) production, slight decrease of IL-10 and no inhibition of tumor necrosis factor-alpha (TNF-α) secretion. To assess potential properties of DHG in epidermal inflammation we used HaCaT cells; this compound reduces cell growth, viability and migration. Finally, we adopted for the in vivo study the croton oil-induced ear dermatitis murine model of inflammation. Of note, topical use of DHG significantly decreased mouse ear edema. These results suggest that DHG exerts anti-inflammatory effects and its anti-edema activity in vivo strongly supports its potential therapeutic application in inflammatory cutaneous diseases.


Asunto(s)
Antiinflamatorios/farmacología , Organismos Acuáticos/química , Factores Inmunológicos/farmacología , Poríferos/química , Terpenos/farmacología , Animales , Antiinflamatorios/química , Productos Biológicos/química , Productos Biológicos/farmacología , Movimiento Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/inmunología , Citocinas/biosíntesis , Humanos , Factores Inmunológicos/química , Inmunomodulación/efectos de los fármacos , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Transducción de Señal/efectos de los fármacos , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/metabolismo , Terpenos/química
14.
Br J Pharmacol ; 174(14): 2287-2301, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28419419

RESUMEN

BACKGROUND AND PURPOSE: N6 -Isopentenyladenosine (i6A) is a modified nucleoside exerting in vitro and in vivo antiproliferative effects. We previously demonstrated that the actions of i6A correlate with the expression and activity of farnesyl pyrophosphate synthase (FPPS), a key enzyme involved in the mevalonate (MVA) pathway, which is aberrant in brain cancer. To develop new anti-glioma strategies, we tested related compounds exhibiting greater activity than i6A. EXPERIMENTAL APPROACH: We designed and synthesized i6A derivatives characterized by the introduction of diverse chemical moieties in the N6 position of adenosine and tested for their efficacy in U87 cells and in primary glioma cultures, derived from patients. NMR-based structural analysis, molecular docking calculations and siRNA mediated knockdown were used to clarify the molecular basis of their action, targeting FPPS protein. KEY RESULTS: CM223, the i6A derivative including a benzyl moiety in N6 position of adenine, showed marked activity in selectively targeting glioma cells, but not normal human astrocytes. This was due to induction of intrinsic pathways of apoptosis and inhibition of proliferation, along with blockade of FPPS-dependent protein prenylation, which counteracted oncogenic signalling mediated by EGF receptors. CONCLUSION AND IMPLICATIONS: The biological effects together with structural data on interaction of CM223 with FPPS, provided additional evidence for the correlation of the i6A/CM223 antitumor activity with FPPS modulation. Because the MVA pathway is an important promising target, CM223 and its derivatives should be considered interesting active molecules in antiglioma research.


Asunto(s)
Adenosina/farmacología , Antineoplásicos/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Glioma/tratamiento farmacológico , Ácido Mevalónico/metabolismo , Terpenos/farmacología , Adenosina/análogos & derivados , Adenosina/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Glioma/metabolismo , Glioma/patología , Humanos , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Terpenos/síntesis química , Terpenos/química
15.
Pharmacol Ther ; 175: 133-150, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28232276

RESUMEN

Over the past years, several lines of evidence support a therapeutic potential of Cannabis derivatives and in particular phytocannabinoids. Δ9-THC and cannabidiol (CBD) are the most abundant phytocannabinoids in Cannabis plants and therapeutic application for both compounds have been suggested. However, CBD is recently emerging as a therapeutic agent in numerous pathological conditions since devoid of the psychoactive side effects exhibited instead by Δ9-THC. In this review, we highlight the pharmacological activities of CBD, its cannabinoid receptor-dependent and -independent action, its biological effects focusing on immunomodulation, angiogenetic properties, and modulation of neuronal and cardiovascular function. Furthermore, the therapeutic potential of cannabidiol is also highlighted, in particular in nuerological diseases and cancer.


Asunto(s)
Cannabidiol/uso terapéutico , Animales , Cannabidiol/farmacología , Humanos , Enfermedades del Sistema Nervioso/tratamiento farmacológico
16.
Int J Cancer ; 140(4): 959-972, 2017 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-27813087

RESUMEN

Malignant gliomas are highly dependent on the isoprenoid pathway for the synthesis of lipid moieties critical for cell proliferation. The isoprenoid derivative N6-isopentenyladenosine (iPA) displays pleiotropic biological effects, including a direct anti-tumor activity in several tumor models. The antiglioma effects of iPA was then explored in U87MG cells both in vitro and grafted in mice and the related molecular mechanism confirmed in primary derived patients' glioma cells. iPA powerfully inhibited tumor cell growth and induced caspase-dependent apoptosis through a mechanism involving a marked accumulation of the pro-apoptotic BIM protein and inhibition of EGFR. Indeed, activating AMPK following conversion into its iPAMP active form, iPA stimulated EGFR phosphorylation and ubiquitination along a proteasome-mediated pathway which was responsible for receptor degradation and its downstream signaling pathways inhibition, including the STAT3, ERK and AKT cascade. The inhibition of AMPK by compound C prevented iPA-mediated phosphorylation of EGFR, known to precede receptor loss. As expected the block of EGFR degradation, by exposure to the proteasome inhibitor MG132, significantly reduced iPA-induced cell death. Given the importance of receptor degradation in iPA-mediated cytotoxicity, we also documented that the EGFR expression levels in a panel of primary glioma cells confers them a high sensitivity to iPA treatment. In conclusion our study provides the first evidence of iPA antiglioma effect. Indeed, as glioma is driven by aberrant signaling of growth factor receptors, particularly the EGFR, iPA, alone or in association with EGFR targeted therapies, might be a promising therapeutic tool to achieve a potent anti-tumoral effect.


Asunto(s)
Neoplasias Encefálicas/patología , Receptores ErbB/biosíntesis , Glioma/patología , Isopenteniladenosina/farmacología , Proteínas de Neoplasias/biosíntesis , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas Activadas por AMP/fisiología , Animales , Apoptosis/efectos de los fármacos , Astrocitos/efectos de los fármacos , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Regulación hacia Abajo/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Receptores ErbB/genética , Femenino , Glioma/metabolismo , Humanos , Ratones , Ratones Desnudos , Proteínas de Neoplasias/genética , Fosforilación/efectos de los fármacos , Complejo de la Endopetidasa Proteasomal/metabolismo , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Ubiquitinación/efectos de los fármacos
17.
Rev. argent. cir ; 50(5): 220-6, mayo 1986. tab
Artículo en Español | LILACS | ID: lil-46826

RESUMEN

Se presenta el análisis de 138 pacientes de alto riesgo, intervenidos quirúrgicamente por patología abdominal entre octubre de 1974 y noviembre de 1984, internados en la Unidad de Terapia Intensiva. Se analizó la mortalidad en relación con la edad, sepsis, oportunidad quirúrgica, síndrome de insuficiencias múltiples y el número de órganos o sistemas que presentaron fallas. Se comprobó que este síndrome incrementa la mortalidad y es más grave en la sepsis y en la cirugía de urgencia, y que dicha mortalidad se halla en relación directa al número de órganos o sistemas que presentan fallas. La cirugía que originó mayor mortalidad e incidencia de dicho síndrome fue la del tracto yeyuno-íleo-colónico y la de las complicaciones sépticas parietales y peritoneales. Se hacen consideraciones sobre la etiología y fisiopatología del síndrome de Baue (insuficiencias múltiples de órganos y sistemas


Asunto(s)
Adulto , Persona de Mediana Edad , Humanos , Masculino , Femenino , Insuficiencia Multiorgánica/mortalidad , Complicaciones Posoperatorias/mortalidad , Sepsis/complicaciones , Abdomen/cirugía , Insuficiencia Multiorgánica/complicaciones , Estudios Retrospectivos
18.
Rev. argent. cir ; 50(5): 220-6, mayo 1986. Tab
Artículo en Español | BINACIS | ID: bin-31101

RESUMEN

Se presenta el análisis de 138 pacientes de alto riesgo, intervenidos quirúrgicamente por patología abdominal entre octubre de 1974 y noviembre de 1984, internados en la Unidad de Terapia Intensiva. Se analizó la mortalidad en relación con la edad, sepsis, oportunidad quirúrgica, síndrome de insuficiencias múltiples y el número de órganos o sistemas que presentaron fallas. Se comprobó que este síndrome incrementa la mortalidad y es más grave en la sepsis y en la cirugía de urgencia, y que dicha mortalidad se halla en relación directa al número de órganos o sistemas que presentan fallas. La cirugía que originó mayor mortalidad e incidencia de dicho síndrome fue la del tracto yeyuno-íleo-colónico y la de las complicaciones sépticas parietales y peritoneales. Se hacen consideraciones sobre la etiología y fisiopatología del síndrome de Baue (insuficiencias múltiples de órganos y sistemas (AU)


Asunto(s)
Adulto , Persona de Mediana Edad , Anciano , Humanos , Masculino , Femenino , Complicaciones Posoperatorias/mortalidad , Insuficiencia Multiorgánica/mortalidad , Sepsis/complicaciones , Estudios Retrospectivos , Insuficiencia Multiorgánica/complicaciones , Abdomen/cirugía
19.
Rev. argent. cir ; 49(6): 310-2, dic. 1985.
Artículo en Español | LILACS | ID: lil-26762

RESUMEN

Se exponen los resultados de la utilización intensiva de la canalización subclavia infraclavicular. Los datos prospectivos fueron recabados de 1.620 punciones efectuadas en 1.240 pacientes, utilizándose la técnica clásica en 1.411 ocasiones y la variante SDP en el resto (12,9%). La efectividad fue del 90%, no hubo diferencias significativas con referencia al lado utilizado, pero sí con las técnicas (la clásica fue más eficaz (P < 0.001). El total de complicaciones fue de 64 (3,9%). De las mayores ocurrieron 16 (0,9%), todas asociadas a la técnica clásica y el 75% de ellas al acceso izquierdo (p NS), 14 fueron neumotórax, 1 hemoneumotórax y 1 hidreneumotórax; la mortalidad fue nula. De las menores se presentaron 48 (2,9%). La más frecuente fue la infección local y su relación estadística significativa (p .005) entre su aparición y tiempo de permanencia de la vía, ellas al igual que los hematomas y las punciones arteriales no tuvieron otra importancia que la estadística. Por su efectividad, baja incidencia de complicaciones mayores (ninguna con la técnica SDP) y la ventaja de preservar el vaso para futuras canalizaciones, la punción subclavia puede ser considerada como de elección


Asunto(s)
Niño , Adolescente , Adulto , Persona de Mediana Edad , Humanos , Punciones/métodos , Vena Subclavia/cirugía
20.
Rev. argent. cir ; 49(6): 310-2, dic. 1985.
Artículo en Español | BINACIS | ID: bin-33232

RESUMEN

Se exponen los resultados de la utilización intensiva de la canalización subclavia infraclavicular. Los datos prospectivos fueron recabados de 1.620 punciones efectuadas en 1.240 pacientes, utilizándose la técnica clásica en 1.411 ocasiones y la variante SDP en el resto (12,9%). La efectividad fue del 90%, no hubo diferencias significativas con referencia al lado utilizado, pero sí con las técnicas (la clásica fue más eficaz (P < 0.001). El total de complicaciones fue de 64 (3,9%). De las mayores ocurrieron 16 (0,9%), todas asociadas a la técnica clásica y el 75% de ellas al acceso izquierdo (p NS), 14 fueron neumotórax, 1 hemoneumotórax y 1 hidreneumotórax; la mortalidad fue nula. De las menores se presentaron 48 (2,9%). La más frecuente fue la infección local y su relación estadística significativa (p .005) entre su aparición y tiempo de permanencia de la vía, ellas al igual que los hematomas y las punciones arteriales no tuvieron otra importancia que la estadística. Por su efectividad, baja incidencia de complicaciones mayores (ninguna con la técnica SDP) y la ventaja de preservar el vaso para futuras canalizaciones, la punción subclavia puede ser considerada como de elección (AU)


Asunto(s)
Niño , Adolescente , Adulto , Persona de Mediana Edad , Anciano , Humanos , Punciones/métodos , Vena Subclavia/cirugía
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