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Preeclampsia (PE) is a hypertensive pregnancy syndrome associated with target organ damage and increased cardiovascular risks, necessitating antihypertensive therapy. However, approximately 40% of patients are nonresponsive to treatment, which results in worse clinical outcomes. This study aimed to compare circulating proteomic profiles and identify differentially expressed proteins among 10 responsive (R-PE), 10 nonresponsive (NR-PE) patients, and 10 healthy pregnant controls (HP). We also explored correlations between these proteins and clinical data. Plasma protein relative quantification was performed using mass spectrometry, followed by bioinformatics analyses with the UniProt database, PatternLab for Proteomics 4.0, and MetaboAnalyst software (version 6.0). Considering a fold change of 1.5, four proteins were differentially expressed between NR-PE and R-PE: one upregulated (fibronectin) and three downregulated (pregnancy-specific beta-1-glycoprotein 1, complement C4B, and complement C4A). Between NR-PE and HP, six proteins were differentially expressed: two upregulated (clusterin and plasmin heavy chain A) and four downregulated (apolipoprotein L1, heparin cofactor II, complement C4B, and haptoglobin-related protein). Three proteins were differentially expressed between R-PE and HP: one downregulated (transthyretin) and two upregulated (apolipoprotein C1 and hemoglobin subunit beta). These findings suggest a complex interplay of these proteins involved in inflammatory, immune, and metabolic processes with antihypertensive therapy responsiveness and PE pathophysiology.

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Antihipertensivos , Preeclampsia , Proteómica , Humanos , Femenino , Embarazo , Preeclampsia/sangre , Preeclampsia/metabolismo , Preeclampsia/tratamiento farmacológico , Antihipertensivos/uso terapéutico , Antihipertensivos/farmacología , Adulto , Proteómica/métodos , Proteoma/metabolismo , Biomarcadores/sangre , Biología Computacional/métodos , Estudios de Casos y Controles

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BACKGROUND: Peyronie's disease is characterized by the formation of fibrotic plaques in the penile tunica albuginea. Effective treatments are limited, warranting the investigation of new promising therapies, such as the application of microRNAs that regulate fibrosis-related genes. OBJECTIVE: We aimed to investigate the therapeutic potential of mimicking microRNA-29b in a fibrin-induced rat model of Peyronie's disease. MATERIAL/METHODS: The study was designed in two phases. To establish an optimal Peyronie's disease model, rats received either human fibrin and thrombin or saline solutions into the tunica albuginea on days 0 and 5. The animal model validation was done through expression and histopathological analyses, the latest by an experienced uropathologist. After validation, we performed microRNA-29b treatment on days 14, 21, and 28 of the study. This phase had control (normal saline) and scramble (microRNA scramble) groups. The mid-penile shaft was removed on day 30 for histological examination and molecular analyses in both study stages. RESULTS: The control group displayed typical tunica albuginea histologic architecture in the animal model validation. In Peyronie's disease group, the Hematoxylin and eosin and Masson Trichrome staining methods demonstrated an interstitial inflammatory process with concomitant dense fibrotic plaques as well as disarrangement of collagen fibers. Additionally, we found out that reduced microRNA-29b (p = 0.05) was associated with significantly increased COL1A1 and transforming growth factor ß1 genes and proteins (p > 0.05) in the Peyronie's disease group. After treatment with mimic microRNA-29b stimulation, the Hematoxylin & eosin and Masson Trichrome staining revealed a discrete and less dense fibrotic plaque. This result was associated with significantly decreasing expression of COL1A1, COL3A1, and transforming growth factor ß1 genes and proteins (p < 0.05). DISCUSSION: The fibrin-induced animal model showed significant histopathological and molecular changes compared to the Control group, suggesting that our model was appropriate. Previous findings have shown that increased expression of microRNA-29b was associated with decreased pathological fibrosis. In the present study, treatment with microRNA-29b decreased the gene and protein expression of collagens and transforming growth factor ß1. This study reveals the therapeutic potential for Peyronie's disease involving molecular targets. CONCLUSION: MicroRNA-29b application on the rat's tunica albuginea attenuated fibrosis, arising as a novel potential strategy for Peyronie's disease management.

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Histoplasma capsulatum is a thermodymorphic fungus that causes histoplasmosis, a systemic mycosis that presents different clinical manifestations, ranging from self-limiting to acute lung infection, chronic lung infection and disseminated infection. Usually, it affects severely immunocompromised patients although immunocompetent patients can also be infected. Currently, there are no vaccines to prevent histoplasmosis and the available antifungal treatment presents moderate to high toxicity. Additionally, there are few options of antifungal drugs. Thus, the aim of this study was to predict possible protein targets for the construction of potential vaccine candidates and predict potential drug targets against H. capsulatum. Whole genome sequences from four previously published H. capsulatum strains were analyzed and submitted to different bioinformatic approaches such as reverse vaccinology and subtractive genomics. A total of four proteins were characterized as good protein candidates (vaccine antigens) for vaccine development, three of which are membrane-bound and one is secreted. In addition, it was possible to predict four cytoplasmic proteins which were classified as good protein candidates and, through molecular docking performed for each identified target, we found four natural compounds that showed favorable interactions with our target proteins. Our study can help in the development of potential vaccines and new drugs that can change the current scenario of the treatment and prevention of histoplasmosis.

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RESUMEN Fundamento: los fármacos modificadores, en la esclerosis múltiple, tienen la finalidad de reducir la frecuencia de recaídas, retardar la progresión de la discapacidad, así como la aparición de nuevas lesiones en el Sistema Nervioso Central. Objetivo determinar los indicadores precoces de respuesta al tratamiento con IFNb-1ª en pacientes con esclerosis múltiple remitente-recurrente. Métodos: estudio observacional, analítico de cohorte con prospectiva longitudinal en los pacientes con diagnóstico de esclerosis múltiple. Se conformaron dos cohortes de estudio, cada una con 39 pacientes. Resultados: la media y desviación estándar de la escala ampliada del estado de discapacidad a los 36 meses fue de 2.37 ± 1.86 en el grupo estudio y en el control de 3.15 ± 2.1. En los brotes de .13 ± .33 en el grupo estudio y en el grupo control de .41 ± .59. Las lesiones nuevas en T2 tras los 12 primeros meses de tratamiento fue de 0.90 ± 1.16 para el grupo estudio y para el control de 1 ± 1.10. La progresión por escala ampliada del estado de discapacidad, la tasa anualizada de brotes antes del tratamiento, la edad de inicio de la enfermedad, tiempo de evolución de la enfermedad y lesiones que realzan gadolinio se asociaron de forma significativa con la razón de ventaja de mayor probabilidad de no progresión para el grupo estudio con respecto al grupo control por la variable combinada progresión por escala ampliada del estado de discapacidad y brotes. Conclusiones: se identificaron indicadores precoces de respuesta al tratamiento con el interferón beta-1a, que ayudan a valorar la respuesta al tratamiento de forma precoz, lo que repercute de forma positiva en la evolución de la enfermedad.

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ABSTRACT Background: multiple sclerosis modifying drugs are intended to reduce the frequency of relapses, delay the progression of disability, as well as the appearance of new lesions in the Central Nervous System. Objective: to determine the early indicators of response to treatment with IFNb-1a. Methods: Observational, analytical longitudinal prospective cohort study in patients diagnosed with multiple sclerosis. Two study cohorts were formed, each with 39 patients. Results the mean and standard deviation of the expanded disability status scale at 36 months was 2.37 ± 1.86 in the study group and 3.15 ± 2.1 in the control group. In the outbreaks of .13 ± .33 in the study group and in the control group of .41 ± .59. New lesions in T2 after the first 12 months of treatment was 0.90 ± 1.16 for the study group and 1 ± 1.10 for the control. Extended-scale progression of disability status, pretreatment annualized relapse rate, age of disease onset, time since disease progression, and gadolinium-enhancing lesions were significantly associated with the odds ratio of older Probability of non-progression for the study group with respect to the control group for the combined variable progression by extended disability status scale and relapses. Conclusions: early indicators of response to treatment with interferon beta-1a were identified; that help assess the response to treatment early, which has a positive impact on the evolution of the disease.

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SUMMARY OBJECTIVE: The aim of this study was to investigate whether rosiglitazone-activated peroxisome proliferator-activated receptor gamma can inhibit the occurrence of benign biliary stricture and further elucidate the relevant molecular signaling mechanism. METHODS: The primary cultured rat biliary fibroblasts following experiments were performed using within the fifth generation cells, which were separated from the bile ducts of Sprague-Dawley rats. The primary cultured rat biliary fibroblasts were co-cultured with 10 ng/mL transforming growth factor-beta 1 for stimulating collagen formation. Competent cells were transfected with siRNA that specifically target Smad3 or connective tissue growth factor to inhibit the expression of the corresponding proteins. The cells were incubated with 10 μmol/L rosiglitazone to activate peroxisome proliferator-activated receptor gamma. The cells were incubated with 10 μmol/L GW9662 in the pretreatment session to inactivate peroxisome proliferator-activated receptor gamma. ELISA was used to determine the levels of connective tissue growth factor and type I collagen in the cell supernatant. Western blotting was used to detect the levels of intracellular p-Smad3/t-Smad3. RESULTS: Rosiglitazone-activated peroxisome proliferator-activated receptor gamma inhibited the secretion of type I collagen induced by transforming growth factor-beta 1. Peroxisome proliferator-activated receptor gamma inhibitor GW9662 could significantly reverse the rosiglitazone-triggered inhibition of transforming growth factor-beta 1-induced type I collagen secretion by suppressing peroxisome proliferator-activated receptor gamma activation (p<0.01). Furthermore, we also found that the activation of peroxisome proliferator-activated receptor gamma was accompanied by the inhibition of transforming growth factor-beta 1-induced Smad3 phosphorylation (p<0.01), increased connective tissue growth factor expression (p<0.01), and production of type I collagen (p<0.01), all of which effects elicited by rosiglitazone could be reversed by peroxisome proliferator-activated receptor gamma inhibitor GW9662. CONCLUSION: Peroxisome proliferator-activated receptor gamma activated by rosiglitazone inhibits the transforming growth factor-beta1 -induced phosphorylation of Smad3 and the increased connective tissue growth factor expression as well as inhibits the secretion of type I collagen in biliary fibroblasts.

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Advanced glycation end products (AGEs) may be associated with nonalcoholic fatty liver disease (NAFLD) from stimulation of oxidative stress, inflammation, and fibrosis. We hypothesized that patients with NAFLD would have a lower concentration of soluble AGEs receptor and higher quantity of serum and liver AGEs and an increase in hepatic smooth muscle actin alpha (α-SMA) and transforming growth factor beta 1 (TGF-ß1) compared with a control group. We compared the presence of hepatic and serum AGEs, AGE soluble receptor (sRAGE), and markers associated with hepatic damage between NAFLD patients and controls without disease. Histological characteristics, plasma biochemical parameters, serum AGEs, serum receptor sRAGE, and liver proteins (α-SMA, TGF-ß1, AGEs, immunohistochemistry) were assessed in participants aged 18 to 65 years, with NAFLD (simple steatosis [SS]: n = 7; steatohepatitis [NASH]: n = 15) and controls (n = 11). NASH patients presented higher glycated hemoglobin levels (%) (5.7; 5.4-6.3) compared with SS (5.4; 5.2-5.7) and controls (5.4; 5.3-5.5). The NAFLD activity score (NAS) for NASH patients was 4.9 ± 1.3; for SS patients, 2.0 ± 1.0. NASH patients showed higher hepatic AGEs, TGF-ß1, and α-SMA compared with SS and control groups. The NAS score indicates that patients with 5 to 8 had higher hepatic AGEs, TGF-ß1, and α-SMA compared with a NAS of 1 to 4 and 0. For α-SMA, a NAS of 1 to 4 was higher than NAS 0. No difference was found in serum AGEs and sRAGE between groups. Higher hepatic AGEs, TGF-ß1, and α-SMA were observed with increasing disease severity (according to NAS); therefore, endogenous liver AGEs may participate in hepatic damage progression.

Asunto(s)

Enfermedad del Hígado Graso no Alcohólico , Biomarcadores , Productos Finales de Glicación Avanzada , Humanos , Hígado/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo

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OBJECTIVE: The most used definition for fetal growth restriction (FGR) is a fetus whose estimated weight is below the 10th percentile for its gestational age. Pregnancy-specific beta-1-glycoprotein (PSG-1) is an immunomodulator found in maternal serum during pregnancy. This study aimed to determine the serum levels of PSG-1 and clarify the potential role of this molecule in the etiopathogenesis of FGR. METHODS: Eighty women carrying fetuses with FGR and 80 healthy pregnant women were included in the study. Demographic data, laboratory values, and Doppler Ultrasonography (USG) results of all cases were recorded. Venous blood samples were taken from all cases before birth. PSG-1 values were studied by the ELISA method. An Independent Samples T-test was used to evaluate the results. The correlations between parameters were evaluated based on Spearman's rank correlation coefficient. P-values <0.05 were considered statistically significant. RESULTS: When the groups were evaluated for serum PSG-1 levels, the median serum PSG-1 level was lower in pregnant women carrying fetuses with FGR than in controls (0.05 < p>0.10). Median serum PSG-1 was lower in patients with absent end diastolic flow (AEDF) in the umbilical artery in Doppler ultrasound scans than in patients without AEDF, but the difference was not statistically significant (p>0.05). In patients with serum PSG-1 values below 12.93 with 50% sensitivity and 76% specificity, the risk of FGR was higher. CONCLUSIONS: Serum PSG-1 levels may be lower in complicated pregnancies due to problems related to placental insufficiency and FGR.

Asunto(s)

Retardo del Crecimiento Fetal , Glicoproteínas beta 1 Específicas del Embarazo , Femenino , Retardo del Crecimiento Fetal/etiología , Glicoproteínas , Humanos , Placenta/irrigación sanguínea , Embarazo , Ultrasonografía Prenatal

RESUMEN

RESUMEN Introducción: El inicio de la terapia con interferón ha sido y es el primer paso en el tratamiento de muchos pacientes con esclerosis múltiple, con el propósito de retrasar la progresión de la enfermedad. Objetivo: Identificar los marcadores clínicos de respuesta al tratamiento con interferón beta-1a de pacientes con esclerosis múltiple remitente-recurrente. Métodos: Se realizó un estudio observacional, descriptivo, longitudinal, prospectivo, de una serie de casos de pacientes con diagnóstico de esclerosis múltiple remitente-recurrente, que recibían tratamiento con interferón beta-1a, en el periodo comprendido entre enero del 2014 a diciembre del 2020. Se incluyeron los 39 pacientes. Resultados: La media de edad fue de 34,54 años. La media del nivel de discapacidad en la línea base, 12, 24 y a los 36 meses fue de 1,76; 1,91; 2,1 y 2,37 respectivamente. La media de los brotes en la línea base, 12, 24 y a los 36 meses fue de 1,13; 0,26; 0,38 y 0,13 respectivamente. Se muestra la cifra de progresiones inferior en un 51 % a los 36 meses. La razón de ventajas (odds ratio) para la no presencia de brotes se muestra entre 2 y 4 veces en estos pacientes. Conclusiones: Se identifican marcadores clínicos de respuesta al tratamiento con interferón beta-1a que ayudan a valorar la respuesta al tratamiento, lo cual repercute de forma positiva en la evolución de la enfermedad.

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ABSTRACT Introduction: The initiation of interferon therapy has been and is the first step in the treatment of many patients with multiple sclerosis, with the aim of delaying the progression of the disease. Objective: To identify the clinical markers of response to treatment with Interferon beta-1a in patients with relapsing-remitting multiple sclerosis. Methods: An observational, descriptive, longitudinal, prospective study was carried out of a series of cases of patients diagnosed with relapsing-remitting multiple sclerosis, who received treatment with interferon beta-1a, in the period between January 2014 and December 2020. All 39 patients were included. Results: The mean age was 34.54 years. The mean disability level at baseline, 12, 24, and 36 months was 1.76; 1.91; 2.1 and 2.37 respectively. The mean number of flares at baseline, 12, 24, and 36 months was 1.13; 0.26; 0.38 and 0.13 respectively. The number of progressions lower by 51% at 36 months is shown. The odds ratio for the absence of relapses is between 2 and 4 times in these patients. Conclusions: Clinical markers of response to treatment with Interferon beta-1a are identified that help assess the response to treatment, which has a positive impact on the evolution of the disease.

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The purpose of this investigation was to study Descemet's membrane and corneal endothelial regeneration, myofibroblast generation and disappearance, and TGF beta-1 localization after Descemet's membrane-endothelial excision (Descemetorhexis) in rabbits. Thirty-six rabbits had 8 mm Descemetorhexis and standardized slit lamp photos at 1, 2 and 4 days, 1, 2 and 4 weeks, and 2, 4 and 6 months, as well as multiplex IHC for stromal cell markers keratocan, vimentin, and alpha-smooth muscle actin (SMA); basement membrane (BM) components perlecan, nidogen-1, laminin alpha-5, and collagen type IV; and corneal endothelial marker Na,K-ATPase ß1, and TGF beta-1, with ImageJ quantitation. Stromal transparency increased from the periphery beginning at two months after injury and progressed into the central cornea by six months. At six months, central transparency was primarily limited by persistent mid-stromal neovascularization. Stromal myofibroblast zone thickness in the posterior stroma peaked at one month after injury, and then progressively decreased until to six months when few myofibroblasts remained. The regeneration of a laminin alpha-5 and nidogen-1 Descemet's membrane "railroad track" structure was accompanied by corneal endothelial closure and stromal cell production of BM components in corneas from four to six months after injury. TGF beta-1 deposition at the posterior corneal surface from the aqueous humor peaked at one day after Descemetorhexis and diminished even before regeneration of the endothelium and Descemet's membrane. This decrease was associated with collagen type IV protein production by corneal fibroblasts, and possibly myofibroblasts, in the posterior stroma. Descemet's membrane and the corneal endothelium regenerated in the rabbit cornea by six months after eight mm Descemetorhexis. Real-time quantitative RT-PCR experiments in vitro with marker-verified rabbit corneal cells found that 5 ng/ml or 10 ng/ml TGF beta-1 upregulated col4a1 or col4a2 mRNA expression after 6 h or 12 h of exposure in corneal fibroblasts, but not in myofibroblasts. Stromal cells produced large amounts of collagen type IV that likely decreased TGF beta-1 penetration into the stroma and facilitated the resolution of myofibroblast-generated fibrosis.

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Córnea/patología , Lámina Limitante Posterior/lesiones , Endotelio Corneal/fisiología , Regeneración/fisiología , Cicatrización de Heridas/fisiología , Animales , Biomarcadores/metabolismo , Córnea/metabolismo , Queratocitos de la Córnea/metabolismo , Sustancia Propia/metabolismo , Proteínas del Ojo/metabolismo , Femenino , Fibrosis , Inmunohistoquímica , Conejos , Microscopía con Lámpara de Hendidura , Factor de Crecimiento Transformador beta1/metabolismo

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The aim of this study was to evaluate the association of the +869 T > C (rs1800470) and -509 C > T (rs1800469) TGFB1 variants, individually or in haplotypes structure, with susceptibility, autoantibodies, disease activity, and TGF-ß1 plasma levels in patients with systemic lupus erythematosus (SLE). The study included 203 patients with SLE and 165 healthy controls. TGFB1 variants were determined by real-time polymerase chain reaction (qPCR). Plasma levels of TGF-ß1 were determined using immunofluorimetric assay. The TGFB1 + 869 CC genotype was associated with SLE susceptibility (OR: 1.710, 95%CI: 1.020-2.866, p = 0.042) and with reduction of C4 (p = 0.040) and TGF-ß1 levels (p = 0.044). In addition, patients with TGFB1 + 869 TC and CC genotypes and positive anti-dsDNA had lower TGF-ß1 levels than those with TT (p = 0.004). TGFB1 -509 TT genotype was associated with reduced levels of C4 (p = 0.032). There was no association between haplotypes and clinical and laboratory parameters. Our data demonstrated that the TGFB1 + 869 T > C variant could be used as a genetic marker for SLE susceptibility and both variants as predictors of laboratory activity. This is the first study to demonstrate that TGF-ß1 levels could be modulated by the interaction between TGFB1 + 869 C allele, in homozygosity, or heterozygosity, and the presence of anti-dsDNA.

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Lupus Eritematoso Sistémico , Factor de Crecimiento Transformador beta1 , Alelos , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/genética , Polimorfismo de Nucleótido Simple , Factor de Crecimiento Transformador beta1/genética

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Neurodegenerative diseases are characterized by increased permeability of the blood-brain barrier (BBB) due to alterations in cellular and structural components of the neurovascular unit, particularly in association with neuroinflammation. A previous screening study of peptide ligands to identify molecular alterations of the BBB in neuroinflammation by phage-display, revealed that phage clone 88 presented specific binding affinity to endothelial cells under inflammatory conditions in vivo and in vitro. Here, we aimed to identify the possible target receptor of the peptide ligand 88 expressed under inflammatory conditions. A cross-link test between phage-peptide-88 with IL-1ß-stimulated human hCMEC cells, followed by mass spectrometry analysis, was used to identify the target of peptide-88. We modeled the epitope-receptor molecular interaction between peptide-88 and its target by using docking simulations. Three proteins were selected as potential target candidates and tested in enzyme-linked immunosorbent assays with peptide-88: fibronectin, laminin subunit α5 and laminin subunit ß-1. Among them, only laminin subunit ß-1 presented measurable interaction with peptide-88. Peptide-88 showed specific interaction with laminin subunit ß-1, highlighting its importance as a potential biomarker of the laminin changes that may occur at the BBB endothelial cells under pathological inflammation conditions.

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Barrera Hematoencefálica , Células Endoteliales/metabolismo , Inflamación/metabolismo , Laminina/metabolismo , Animales , Bacteriófago M13 , Biomarcadores , Células Cultivadas , Reactivos de Enlaces Cruzados , Fibronectinas/metabolismo , Ontología de Genes , Humanos , Interleucina-1beta/farmacología , Modelos Moleculares , Simulación del Acoplamiento Molecular , Biblioteca de Péptidos , Unión Proteica , Conformación Proteica , Mapeo de Interacción de Proteínas , Ratas

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Aging is a gradual biological process characterized by a decrease in cellular and organism functions. Aging-related processes involve changes in the expression and activity of several proteins. Here, we identified the transmembrane protease serine 11a (TMPRSS11a) as a new age-specific protein that plays an important role in skin wound healing. TMPRSS11a levels increased with age in rodent and human skin and gingival samples. Strikingly, overexpression of TMPRSS11a decreased cell migration and spreading, and inducing cellular senescence. Mass spectrometry, bioinformatics, and functional analyses revealed that TMPRSS11a interacts with integrin ß1 through an RGD sequence contained within the C-terminal domain and that this motif was relevant for cell migration. Moreover, TMPRSS11a was associated with cellular senescence, as shown by overexpression and downregulation experiments. In agreement with tissue-specific expression of TMPRSS11a, shRNA-mediated downregulation of this protein improved wound healing in the skin, but not in the skeletal muscle of old mice, where TMPRSS11a is undetectable. Collectively, these findings indicate that TMPRSS11a is a tissue-specific factor relevant for wound healing, which becomes elevated with aging, promoting cellular senescence and inhibiting cell migration and skin repair.

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Envejecimiento/patología , Movimiento Celular , Fibroblastos/patología , Proteínas de la Membrana/metabolismo , Serina Proteasas/metabolismo , Piel/patología , Cicatrización de Heridas , Adolescente , Adulto , Anciano , Envejecimiento/metabolismo , Animales , Proliferación Celular , Fibroblastos/metabolismo , Encía/metabolismo , Encía/patología , Humanos , Proteínas de la Membrana/genética , Ratones , Persona de Mediana Edad , Serina Proteasas/genética , Transducción de Señal , Piel/metabolismo , Adulto Joven

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Multiple sclerosis (MS) is an autoimmune neurodegenerative disease that affects the central nervous system. It is the second cause of neurological disability in young adults. The exact cause of the disease remains unknown and there is no curative treatment. It is imperative to evaluate the efficacy of newest, biotechnological products modifying the disease. This study was designed to evaluate the use of interferon beta 1a (Rebif®) in patients with relapsing remitting MS treated at International Center for Neurological Restoration. Thirty-one patients with relapsing remitting MS, between 10 and 65 years of age, four males and 27 females, were treated with Rebif® three times per week during 1 year. The safety of the treatment was evaluated based on the adverse events and the efficacy based on the disability scale score, the number of attacks and the number of lesions at magnetic resonance imaging (MRI). The public clinical trial is registered in Cuba (Number B-10-030-L03). Adverse effects occurred in 75% of the cases, but they were mild. A significant reduction in the number of attacks, the disability scale score and the number of lesions at MRI were observed in patients with relapsing remitting MS treated with Rebif®. The use of interferon beta 1a showed safety and efficacy in the treatment of patients with relapsing remitting MS.

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Interferón beta-1a/uso terapéutico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Adolescente , Adulto , Anciano , Niño , Cuba , Evaluación de la Discapacidad , Progresión de la Enfermedad , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad

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ABSTRACT Purpose Herein we evaluated the effects of platelet concentrate (PC) and platelet-poor plasma (PPP) on bone repair using noncritical defects in the calvaria of rabbits and compared them to the presence of TGF-β1 and osteocalcin on reparative sites. Methods Five noncritical defects of 8.7 mm in diameter were created on the calvaria of 15 animals. Each defect was treated differently, using autograft (ABG), ABG associated with PC (ABG + PC), ABG with PPP (ABG + PPP), isolated PPP, and blood clot (control). The animals were submitted to euthanasia on the second, fourth and sixth week post-surgery. Results The defects that received ABG+PC or PPP demonstrated lower bone formation when compared to specimens that received ABG in the same period. These results coincided to significant higher immunopositivity for TGF-β1 for specimens that received PC, and lower presence of cytokine in the group PPP. However, either higher or lower presence of TGF-β1 were also correlated to lower presence of osteocalcin. Likewise, these results were similar to findings in specimens treated only with PPP when compared to control. Conclusions PC and PPP were not effective when applied in association with ABG. Similarly, isolated use of PPP was not beneficial in optimizing the bone repair.

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Animales , Osteogénesis , Factor de Crecimiento Transformador beta1/metabolismo , Conejos , Cráneo/cirugía , Osteocalcina , Autoinjertos

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INTRODUCTION: Multiple sclerosis (MS) is a demyelinating disease of the central nervous system, which occurs in up to 85% of cases as relapsing remitting (RR), with episodes of neurological dysfunction partially forwarded. Its treatment in Chile is financially protected by the Explicit Health Guarantees (GES) and Law 20,850 on high-cost diseases. The Regional Hospital of Talca (HRT) has 25 patients benefiting from Law 20,850 in treatment with second-line biologic therapy. Adverse reactions (RAM) to the use of these drugs have been described and to date there are no case reports or studies of significant adverse events in Chile. Objectives: To present the experience of the use of biologic therapy in EMRR in HRT, in relation to adverse events. METHODS: A review of the current guidelines in Chile for the treatment of relapsing-remitting multiple sclerosis and the protocol of law 20,850 was carried out, the clinical records of 25 patients benefiting from the law in the HRT were reviewed, with emphasis on the adverse events presented before First and second line therapies and the con sequences of these events on the continuity of therapy. RESULTS: Half of the patients who started their treatment with first-line drugs had adverse effects, of which 28% involved a change in therapy, the remaining changed from therapy due to failure to treatment. Of the 26 patients included in the sample, 24 are currently using second-line drugs. The profile of adverse effects should be a variable to consider when indicating a therapy for MS.

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Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Anciano , Esclerosis Múltiple/diagnóstico , Esclerosis Múltiple/tratamiento farmacológico , Chile , Interferón beta/administración & dosificación , Interferón beta/efectos adversos , Guías de Práctica Clínica como Asunto , Acetato de Glatiramer/efectos adversos , Inmunosupresores , Esclerosis Múltiple/complicaciones

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Deleterious effects have been widely associated with chronic pesticide exposure, including cancer development. In spite of several known consequences that pesticides can trigger in the human body, few is known regarding its impact on breast cancer women that are chronically exposed to such substances during agricultural work lifelong. In this context, the present study performed a high-throughput toxicoproteomic study in association with a bioinformatics-based design to explore new putative processes and pathways deregulated by chronic pesticide exposure in breast cancer patients. To reach this goal, we analyzed comparatively non-depleted plasma samples from exposed (n = 130) and non-occupationally exposed (n = 112) women diagnosed with breast cancer by using a label-free proteomic tool. The list of proteins differentially expressed was explored by bioinformatics and the main pathways and processes further investigated. The toxicoproteomic study revealed that women exposed to pesticides exhibited mainly downregulated events, linked to immune response, coagulation and estrogen-mediated events in relation to the unexposed ones. Further investigation shown that the identified deregulated processes and pathways correlated with significant distinct levels tumor necrosis factor alpha and interleukin 1 beta in the blood, and specific clinicopathological characteristics pointed out by bioinformatics analysis as adipose-trophic levels, menopause and intratumoral clots formation. Altogether, these findings reinforce pesticides as downregulators of several biological process and highlight that these compounds can be linked to poor prognosis in breast cancer.

RESUMEN

INTRODUCTION: This study aimed to evaluate (1) the effect of irrigating solutions and intracanal medicaments on the release of transforming growth factor beta 1 (TGF-ß1) and vascular endothelial growth factor (VEGF) from cervical root dentin and (2) the effect of associating triple antibiotic paste (TAP) and calcium hydroxide paste (CH) with 2% chlorhexidine (CHX) on TGF-ß1 release. METHODS: First, 119 specimens from roots (cervical thirds) were obtained and were distributed into 5 groups: 2% CHX, 2.5% sodium hypochlorite, TAP, CH, and 10% EDTA by each growth factor (TGF-ß1 [n = 8] and VEGF [n = 8]). Then, specimens were distributed as follows (n = 13): TAP + 2% CHX, CH + 2% CHX, and 10% EDTA and treated with irrigating solutions and intracanal medicaments. After the treatments, the specimens were immersed in 10% EDTA (20 minutes), and the solution was analyzed using the enzyme-linked immunosorbent assay. The data were submitted to normality, homogeneity of variance, and Mann-Whitney tests (P < .05). RESULTS: Significant differences were found between the irrigating solutions (P < .05) and intracanal medicaments for TGF-ß1 (P < .05). No VEGF release was detected for any group. Our results showed no significant differences among the TAP + 2% CHX and EDTA groups for TGF-ß1 but a significant difference between CH + 2% CHX and the other groups (P < .05). CONCLUSIONS: The use of 2% CHX as the irrigating solution, CH as the intracanal medicament, and 10% EDTA as the final irrigation provides higher TGF-ß1 release from the cervical root dentin, whereas VEGF was not detected. Moreover, TAP and 2% CHX with 10% EDTA as the final irrigation resulted in greater TGF-ß1 release from cervical root dentin than CH + 2% CHX.

Asunto(s)

Irrigantes del Conducto Radicular , Factor A de Crecimiento Endotelial Vascular , Hidróxido de Calcio , Clorhexidina/farmacología , Cavidad Pulpar , Dentina , Irrigantes del Conducto Radicular/farmacología , Factor de Crecimiento Transformador beta1

RESUMEN

BACKGROUND: There is some evidence that components of the renin-angiotensin system and kallikrein-kinin system are not similarly regulated in both sexes. The aim of this work was to analyze the expression of angiotensin-converting enzyme, angiotensin-converting enzyme 2, angiotensin 1 receptor, angiotensin 2 receptor, beta-1 receptor, and beta-2 receptor during the evolution of myocardial infarction. METHODS: Thirty-six male and 36 female Wistar rats were used. Myocardial infarction was induced. Six groups of both sexes were formed, (n=6): (a) sham; (b) 48 h myocardial infarction; (c) one week myocardial infarction; (d) two weeks myocardial infarction; (e) three weeks myocardial infarction and (f) four weeks myocardial infarction. The expression was evaluated by real-time polymerase chain reaction on the penumbra of left ventricle. RESULTS: The mRNA expression of most biomarkers was lower in females than in males. During acute infarction, an increase of all protein expression was found in female and at two weeks while in the male only biomarker changes occurred at three weeks. In addition, in male biomarkers mRNA expression decreased during chronic infarction while in females it did not. CONCLUSIONS: The renin-angiotensin system and kallikrein-kinin system biomarkers expression occurs at earlier times in the female than in the male rat. In addition, during chronic myocardial infarction these biomarkers remained unchanged in females while in males they decreased.

Asunto(s)

Sistema Calicreína-Quinina/genética , Infarto del Miocardio/fisiopatología , Sistema Renina-Angiotensina/genética , Enzima Convertidora de Angiotensina 2/biosíntesis , Enzima Convertidora de Angiotensina 2/genética , Animales , Biomarcadores , Peso Corporal , Enfermedad Crónica , Femenino , Regulación de la Expresión Génica , Ventrículos Cardíacos/metabolismo , Masculino , Peptidil-Dipeptidasa A/biosíntesis , Peptidil-Dipeptidasa A/genética , ARN Mensajero/biosíntesis , Ratas , Ratas Wistar , Receptor de Angiotensina Tipo 1/biosíntesis , Receptor de Angiotensina Tipo 1/genética , Receptor de Angiotensina Tipo 2/biosíntesis , Receptor de Angiotensina Tipo 2/genética , Caracteres Sexuales

Asunto(s)

Humanos , Polimorfismo Genético , Insuficiencia Cardíaca , Brasil , Receptores Adrenérgicos

RESUMEN

UV light catalyzes the ozone formation from air pollutants, like nitrogen oxides. Since ozone reacts with cutaneous sebum lipids to peroxides and, thus, promotes inflammation, tumorigenesis, and aging, even broad-spectrum sunscreens cannot properly protect skin. Meanwhile, xanthophylls, like fucoxanthin, proved their antioxidant and cytoprotective functions, but the safety of their topical application in human cell-based models remains unknown. Aiming for a more detailed insight into the cutaneous fucoxanthin toxicity, we assessed the tissue viability according to OECD test guideline no. 439 as well as changes in inflammation (IL-1α, IL-6, IL-8), homeostasis (EGFR, HSPB1) and metabolism (NAT1). First, we proved the suitability of our 24-well-based reconstructed human skin for irritation testing. Next, we dissolved 0.5% fucoxanthin either in alkyl benzoate or in ethanol and applied both solutions onto the tissue surface. None of the solutions decreased RHS viability below 50%. In contrast, fucoxanthin ameliorated the detrimental effects of ethanol and reduced the gene expression of pro-inflammatory interleukins 6 and 8, while increasing NAT1 gene expression. In conclusion, we developed an organ-on-a-chip compatible RHS, being suitable for skin irritation testing beyond tissue viability assessment. Fucoxanthin proved to be non-irritant in RHS and already showed first skin protective effects following topical application.