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 HeridasRESUMEN
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 TraslacionalRESUMEN
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/metabolismoRESUMEN
Serum composition is linked to metabolic diseases not only to understand their pathogenesis but also for diagnostic purposes. Quality and quantity of nutritional intake can affect disease risk and serum composition. It is then possible that diet derived serum components directly affect pathogenetic mechanisms. To identify involved factors, we evaluated the effect on gene expression of direct addition of dyslipidemic human serum samples to cultured human hepatoma cells (HepG2). Sera were selected on the basis of cholesterol level, considering this parameter as mostly linked to dietary intake. Cells were treated with 32 sera from hypercholesterolemic and normocholesterolemic subjects to identify differentially regulated mRNAs using DNA microarray analysis. We identified several mRNAs with the highest modulations in cells treated with dyslipidemic sera versus cells treated with normal sera. Since the two serum groups had variable polyunsaturated fatty acids (PUFAs) contents, selected mRNAs were further assessed for their regulation by docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) and arachidonic acid (AA). Four genes resulted both affected by serum composition and PUFAs: 3-hydroxy-3-methylglutaryl-CoenzymeA synthase 2 (HMGCS2), glutathione S-transferase alpha 1 (GSTA1), liver expressed antimicrobial peptide 2 (LEAP2) and apolipoprotein M (ApoM). HMGCS2 expression appears the most relevant and was also found modulated via transcription factors peroxysome proliferator activated receptor α (PPARα) and forkhead box O1 (FoxO1). Our data indicate that expression levels of the selected mRNAs, primarily of HMGCS2, could represent a reference of nutritional intake, PUFAs effects and dyslipidemic diseases pathogenesis.
Asunto(s)
Carcinoma Hepatocelular/tratamiento farmacológico , Dislipidemias/sangre , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias Hepáticas/tratamiento farmacológico , Suero/metabolismo , Péptidos Catiónicos Antimicrobianos/biosíntesis , Apolipoproteínas/biosíntesis , Apolipoproteínas M , Ácido Araquidónico/administración & dosificación , Proteínas Sanguíneas/biosíntesis , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Ácidos Docosahexaenoicos/administración & dosificación , Dislipidemias/metabolismo , Ácido Eicosapentaenoico/administración & dosificación , Glutatión Transferasa/biosíntesis , Células Hep G2 , Humanos , Hidroximetilglutaril-CoA Sintasa/biosíntesis , Lipocalinas/biosíntesis , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , Suero/químicaRESUMEN
Stearoyl-CoA desaturase 1 (SCD1) is the rate limiting enzyme in unsaturated fatty acid biosynthesis. This enzyme has an important role in the regulation of hepatic lipogenesis and lipid oxidation, and alterations in these pathways may lead to several diseases. We examined, in HepG2 cell cultures, the mechanism of SCD1 regulation considering the involvement of two transcription factors: liver X receptor alpha (LXRα) and sterol regulatory element-binding protein-1 (SREBP-1), also investigating the effect of dietary polyunsaturated fatty acids (PUFAs) on this process. The analysis of SCD1 promoter allowed to identify a functional SREBP-1 binding site (SRE 1). LXRα activation increased SCD1 protein level through upregulation of SREBP-1 and its consequent binding to SRE 1 sequence. Polyunsaturated docosahexaenoic acid (DHA, C22:6), eicosapentaenoic acid (EPA, C20:5) and arachidonic acid (AA, C20:4) were able to reduce SREBP-1 binding to SCD1 promoter, while saturated stearic acid (SA, C18:0) did not give any effect. Surface plasmon resonance analysis showed a direct binding of DHA, EPA and AA to LXRα. These data indicate a direct inhibitory interaction of PUFAs with LXRα, a consequent reduction of SREBP-1 and of its binding to SCD1 promoter. This information provides a mechanism to explain the regulation of lipogenic pathways induced by PUFAs.
Asunto(s)
Ácidos Grasos Insaturados/metabolismo , Receptores Nucleares Huérfanos/metabolismo , Elementos de Respuesta , Estearoil-CoA Desaturasa/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Células Hep G2 , Humanos , Receptores X del Hígado , Unión Proteica , Estearoil-CoA Desaturasa/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genéticaRESUMEN
We evaluated the effects, on cultured human SaOS-2 cells, of exposures to the low frequency (LF) electric signal (60 kHz sinusoidal wave, 24.5 V peak-to-peak voltage, amplitude modulated by a 12.5 Hz square wave, 50% duty cycle) from an apparatus of current clinical use in bone diseases requiring regenerating processes. Cells in flasks were exposed to a capacitively coupled electric field giving electric current density in the sample of 4 µA/cm(2). The whole expressed cellular mRNAs were systematically analyzed by "DNA microchips" technology to identify all individual species quantitatively affected by field exposure. Comparisons were made between RNA samples from exposed and control sham-exposed cells. Results indicated that immediately and 4 h after exposure there were almost no differentially modulated mRNA species. However, samples obtained at 24 h after exposure showed a small number of limitedly differential signals (7 down-regulated and 3 up-regulated with a cut-off value of ±1.5; 38 and 11, respectively, with a cut-off value of ±1.3), which included mostly mRNA encoding transcription factors and DNA binding proteins. Nevertheless, in identical experimental conditions, we previously demonstrated enzymatic changes of alkaline phosphatase occurring immediately after exposure and declining in a few hours. Therefore, since enzymatic changes occur before those observed at gene regulation level, it is conceivable that only earlier effects are directly due the treatment and then these effects are later able to affect gene expression only indirectly.
Asunto(s)
Huesos/citología , Campos Electromagnéticos , Regulación de la Expresión Génica/efectos de la radiación , Huesos/efectos de la radiación , Línea Celular Tumoral , Proliferación Celular/efectos de la radiación , Supervivencia Celular/efectos de la radiación , Humanos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factores de TiempoRESUMEN
Serum constituents might directly affect metabolic diseases pathogenesis and are commonly used as diagnostic tool. The aim of this study was to investigate the human serum effect on in vitro gene expression, related to nutrients action and involved in lipid metabolism. In detail, 40 human sera were firstly analyzed in fatty acids profile by gas-chromatography. Then samples were tested through direct addition within culture medium on Hep G2 human hepatoma cells, comparing samples from hypercholesterolemic (average 273 mg/dl) versus normocholesterolemic male subjects (average 155 mg/dl), since this condition is a relevant disease risk factor and is typically consequent to nutritional style. Hypercholesterolemic sera produced a 0.4-fold reduction of sterol regulatory element binding protein 1c (SREBP-1c) mRNA (P < 0.05) and a 1.5-fold increase of UDP-glucuronosyltransferase 1A1 (UGT1A1) mRNA (P < 0.01). Samples with higher concentrations of n-6 fatty acids produced a higher expression of UGT1A1 mRNA. Total fatty acids [docosahexaenoic, eicosopentanoic, arachidonic, linolenic, and linoleic acid (DHA, EPA, AA, LNA, and LA, respectively)] in each serum resulted roughly inverse with trend of SREBP-1c mRNA expression. Serum AA, LA, and trans fatty acids were more abundant in hypercholesterolemic subjects (P < 0.01) while DHA as quota of detected fatty acids was significantly higher in normocholesterolemic subjects (P < 0.05). While it is not possible to indicate which component was responsible for the observed gene modulations, our data indicate that sera differing in lipid profiles, mainly associated with dietary behavior, differentially affect gene expression known to be involved in metabolic and nutritional related conditions.
Asunto(s)
Colesterol/sangre , Ácidos Grasos/sangre , Expresión Génica , Suero/química , Adulto , Línea Celular Tumoral , Glucuronosiltransferasa/genética , Glucuronosiltransferasa/metabolismo , Humanos , Hipercolesterolemia/sangre , Canales Iónicos/genética , Canales Iónicos/metabolismo , Masculino , Persona de Mediana Edad , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , ARN Mensajero/metabolismo , Estearoil-CoA Desaturasa/genética , Estearoil-CoA Desaturasa/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Proteína Desacopladora 2RESUMEN
We evaluated, in human cell line HepG2, the action of individual dietary polyunsaturated fatty acids (PUFAs) on the expression of several lipid metabolism genes. The effects of docosahexaenoic acid, 22:6, n-3 (DHA), eicosapentaenoic acid, 20:5, n-3 (EPA), and arachidonic acid, 20:4, n-6 (AA) were studied alone and with vitamin E (Vit.E). DHA, EPA, and AA down-regulated mRNAs and encoded proteins of stearoyl-CoA desaturase (SCD) and sterol regulatory element binding protein (SREBP-1c), two major factors involved in unsaturated fatty acids synthesis. DHA affected SREBP-1c mRNA less markedly than EPA and AA. Vit.E did not affect these products, both when individually added or together with fatty acids. The expression of UDP-glucuronosyl transferase 1A1 (UGT1A1) mRNA, an enzyme of phase II drug metabolism with relevant actions within lipid metabolism, resulted also differentially regulated. DHA did not essentially reduce UGT1A1 mRNA expression while EPA and AA produced a considerable decrease. Nevertheless, when these PUFAs were combined with Vit.E, which by itself did not produce any effect, the result was a reduction of UGT1A1 mRNA with DHA, an increase reverting to basal level with EPA and no variation with AA. Observed regulations did not result to be mediated by peroxisome proliferator-activated receptor (PPAR). Our data indicate that major dietary PUFAs and Vit.E are differentially and selectively able to affect the expression of genes involved in lipid metabolism. The different actions of these slightly different molecules could be associated with their physiological role as relevant nutrient molecules.
Asunto(s)
Ácido Araquidónico/farmacología , Ácidos Docosahexaenoicos/farmacología , Ácido Eicosapentaenoico/farmacología , Glucuronosiltransferasa/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Vitamina E/farmacología , Línea Celular Tumoral , Supervivencia Celular , Relación Dosis-Respuesta a Droga , Regulación de la Expresión Génica/efectos de los fármacos , Glucuronosiltransferasa/genética , Humanos , PPAR alfa/genética , PPAR alfa/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Estearoil-CoA Desaturasa/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genéticaRESUMEN
Low-frequency (LF) electric fields (EFs) are currently used in clinical therapies of several bone diseases to increase bone regenerative processes. To identify possible molecular mechanisms involved in these processes, we evaluated the effects on cell cultures of 1 h exposures to the signal generated by an apparatus of current clinical use (frequency 60 kHz, frequency of the modulating signal 12.5 Hz, 50% duty cycle, peak-to-peak voltage 24.5 V). Two different human cell lines, bone SaOS-2 and liver HepG2, were used. Exposures significantly increased alkaline phosphatase (ALP) enzymatic activity in both cell lines. The increase was about 35% in SaOS-2 cells and about 80% in HepG2 cells and occurred in the first 4 h after exposure and decreased to almost no change by 24 h. Since ALP represents a typical marker of bone regeneration, these results represent a first molecular evidence of biological effects from 60 kHz EF exposures. The finding of similar effects in cells derived from two different tissues more likely indicates the effective operation of the mechanism in living organisms.
Asunto(s)
Fosfatasa Alcalina/metabolismo , Terapia por Estimulación Eléctrica/instrumentación , Supervivencia Celular , Células Hep G2 , Humanos , Factores de TiempoRESUMEN
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 ProteínaRESUMEN
Abacavir is one of the most efficacious nucleoside analogues, with a well-characterized inhibitory activity on reverse transcriptase enzymes of retroviral origin, and has been clinically approved for the treatment of AIDS. Recently, Abacavir has been shown to inhibit also the human telomerase activity. Telomerase activity seems to be required in essentially all tumours for the immortalization of a subset of cells, including cancer stem cells. In fact, many cancer cells are dependent on telomerase for their continued replication and therefore telomerase is an attractive target for cancer therapy. Telomerase expression is upregulated in primary primitive neuroectodermal tumours and in the majority of medulloblastomas suggesting that its activation is associated with the development of these diseases. Therefore, we decided to test Abacavir activity on human medulloblastoma cell lines with high telomerase activity. We report that exposure to Abacavir induces a dose-dependent decrease in the proliferation rate of medulloblastoma cells. This is associated with a cell accumulation in the G(2)/M phase of the cell cycle in the Daoy cell line, and with increased cell death in the D283-MED cell line, and is likely to be dependent on the inhibition of telomerase activity. Interestingly, both cell lines showed features of senescence after Abacavir treatment. Moreover, after Abacavir exposure we detected, by immunofluorescence staining, increased protein expression of the glial marker glial fibrillary acidic protein and the neuronal marker synaptophysin in both medulloblastoma cell lines. In conclusion, our results suggest that Abacavir reduces proliferation and induces differentiation of human medulloblastoma cells through the downregulation of telomerase activity. Thus, using Abacavir, alone or in combination with current therapies, might be an effective therapeutic strategy for the treatment of medulloblastoma.
Asunto(s)
Fármacos Anti-VIH/farmacología , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Neoplasias Cerebelosas/patología , Didesoxinucleósidos/farmacología , Meduloblastoma/patología , Neoplasias Peritoneales/secundario , Ciclo Celular/efectos de los fármacos , Neoplasias Cerebelosas/tratamiento farmacológico , Niño , Preescolar , Técnica del Anticuerpo Fluorescente , Proteína Ácida Fibrilar de la Glía/metabolismo , Humanos , Masculino , Meduloblastoma/tratamiento farmacológico , Neoplasias Peritoneales/tratamiento farmacológico , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sinaptofisina/metabolismo , Telomerasa/genética , Telomerasa/metabolismo , Células Tumorales CultivadasRESUMEN
Docosahexaenoic acid (DHA) is a well known chemopreventive nutrient within diet formulations, but it may also exert toxic effects on cultured cells, while this is limited when also another relevant nutrient as vitamin E is present. This effect, beside the involvement of the two nutrients in oxidative processes, likely affects the expression of specific genes. To obtain information on combined activities of DHA and vitamin E on some gene products previously resulted to be in vivo regulated from dietary unsaturated fats, the effect of the two nutrients was evaluated in human cell line HepG2. Independently, DHA and vitamin E resulted to affect only slightly UDP-glucuronosyltransferase 1A1 (UGT1A1) mRNA expression. Nevertheless, their combination produced a considerable reduction of this mRNA. DHA also downregulated stearoyl-CoA desaturase (SCD) and sterol regulatory element binding protein (SREBP-1) expression, while vitamin E did not affect these products. However, their combination abolished the downregulation of SCD but did not affect that of SREBP-1. Therefore the effect of the two nutrients is related to specific gene regulation processes resulting in a cooperation which might be related to their physiological effects as dietary components.
Asunto(s)
Ácidos Docosahexaenoicos/farmacología , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Glucuronosiltransferasa/genética , Vitamina E/farmacología , Apoptosis/efectos de los fármacos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Citometría de Flujo , Fluorescencia , Glucuronosiltransferasa/metabolismo , Humanos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Estearoil-CoA Desaturasa/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismoRESUMEN
Depression is a disorder that can be classified in the categories of non-organic psychiatric disorders and mood disorders. Mood tone is an important psychic function involved in the adaptation to both our internal and external world. It is flexible, that is, it goes up when we are in positive and favorable conditions, but it goes down when we are in negative and unpleasant states. We can define depression as a condition when mood tone loses its flexibility, it goes down and it's no longer influenced by favorable external events. In fact, depression is characterized by changes in the way how the affected individual thinks, feels and acts. Even if this change occurs gradually, a depressed subject is not the same as before. For example, a brilliant student could be persuaded to be not able to finish his studies; an affectionate mother could start to neglect her sons; an enterprising worker could lose every interest for his activity. Moreover, a depressed person doesn't care of his aspect or of himself. The surviving instinct could leave place to the desire to stop his own life. The most evident characteristic of depression in the adulthood is a sad mood, a gloomy solitary and apathetic attitude. A depressed subject could cry also with no apparent reason, he could have difficulty falling asleep or he could wake up very early in the morning and no longer returns to sleep. Or, instead, he could sleep more than usually and he could feel tired persistently. He could lose appetite and weight, or, in some cases, he could eat much more than usually and he could gain weight. Typically, a depressed person feels himself in a extremely negative way, he could think to be hopeless and helpless and he often condemns himself for small guilty. A depressed subject is pessimistic about himself and his own future; he loses interest in all what happens around him and he gets no satisfaction from the activities that before were pleasant. Some persons can be depressed also if they don't show evident signs of depression, but they complain for physical symptoms or they abuse of alcohol or other substances. It has been estimated that in the industrialized Western world one to six persons has a depressive episode at least once during his life; at present, the incidence of depression in the general population is around 5% with clear cut prevalence in the female sex. This leads to high social costs: behind the short-term inability, we have to consider also the long term inability (it has been estimated that, in 2020, depression will represent the second most frequent cause of permanent inability) as well as the suicide risk, the proved major susceptibility of depressed subjects to various non-psychiatric pathologies and the increased rate of premature deaths of depressed individuals as compared to the general population. The present work not only evaluates the drugs used for the treatment of depression, but it focuses also on those studies that investigated the efficacy of a second generation drug: Duloxetine that has a higher selectivity of action and a better tolerability profile as compared to first generation medications. These characteristics make Duloxetine the most effective therapeutic choice to improve both psychological and somatic symptoms of depression in order to get higher rates of symptomatic remission on depressive episodes.
Asunto(s)
Antidepresivos/uso terapéutico , Depresión/tratamiento farmacológico , Tiofenos/uso terapéutico , Animales , Depresión/clasificación , Depresión/etiología , Depresión/fisiopatología , Clorhidrato de Duloxetina , Humanos , PsicoterapiaRESUMEN
Vinorelbine (VRN) is one of the most representative compounds of its class: the vinca alkaloids. VRN interferes with microtubule assembly. VRN shows a better therapeutic index than the parent compound vincristine and vinblastine probably because of its higher affinity for mitotic microtubules. VNR high affinity for mitotic microtubules causes a high clinical efficacy for the treatment of non-small cell lung cancer (NSCLC) and for breast cancer (BC), together with a good tolerability at therapeutically effective doses. The vinca alkaloids are structurally similar compounds comprised of 2 multiringed units, vindoline and catharanthine. Unlike other vinca alkaloids, the catharanthine unit is the site of structural modification for VRN. The antitumor activity of VNR is thought to be due primarily to inhibition of mitosis at metaphase through its interaction with tubulin. Like other vinca alkaloids, VNR may also interfere with: 1) amino acid, cyclic AMP, and glutathione metabolism, 2) calmodulin-dependent Ca²âº-transport ATPase activity, 3) cellular respiration, and 4) nucleic acid and lipid biosynthesis. The VNR is also characterized by improved hematologic tolerance and less neurotoxicity compared to parent compound. The aim of this review is 1) to explore the efficacy and tolerability of VNR in cancer therapy and 2) to examine the more recent approaches to improve the efficacy and tolerability of VNR in cancer therapy.
Asunto(s)
Antineoplásicos Fitogénicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Vinblastina/análogos & derivados , Animales , Antineoplásicos Fitogénicos/efectos adversos , Antineoplásicos Fitogénicos/farmacología , Humanos , Microtúbulos/metabolismo , Mitosis/efectos de los fármacos , Neoplasias/patología , Tubulina (Proteína)/efectos de los fármacos , Tubulina (Proteína)/metabolismo , Vinblastina/efectos adversos , Vinblastina/farmacología , Vinblastina/uso terapéutico , VinorelbinaRESUMEN
There have been a few studies that examined the oxidative stress effects of nicotine during pregnancy and lactation. The adverse effect of prenatal smoking exposure on human fetal development and growth has been a major public health issue. Active or passive smoking during pregnancy can result in a wide variety of adverse outcomes, including intrauterine growth retardation (IUGR), prematurity, stillbirth, and the sudden infant death syndrome. Smoking in pregnancy has also been associated with an increased risk of attention deficit and learning problems in childhood. Some studies argued that as a principal component of tobacco smoke, nicotine alone is responsible for the majority of negative reproductive outcomes. Nicotine and its major metabolite cotinine can cross the placental barrier. The level of nicotine in fetal tissues was found to be equal to or greater than the plasma nicotine level in the mothers. The oxidative stress induce by nicotine has been increasingly postulated as a major contributor to endothelial dysfunction. A large body of research has investigated the potential role of antioxidant nutrients in the prevention of endothelial dysfunction in women. Therefore, the present study was undertaken to assess the potential benefit of antioxidant supplementation on markers of placental oxidative stress in an in vitro model of endothelial dysfunction induced by nicotine, since it was previously found that nicotine is able to trigger the placental secretion of stress molecules. In this regard, we evaluated the effects of vitamin C, vitamin E and N-acetylcysteine (NAC), alone or in combination, in placental villi culture after exposure to nicotine. The effect of antioxidant nutrients on trophoblast cells proliferation and vitality was also evaluated. The results obtained suggest that in a patho-physiological condition, such as endothelial dysfunction induced by nicotine, the deleterious effect of reactive oxygen species may be counteracted by an antioxidant therapy, and there is the need to investigate the optimum dosing and timing of antioxidants administration, since an inappropriate antioxidant treatment in pregnant women may have deleterious consequences, reducing placental cells proliferation until to cell death.