Identifying patterns to uncover the importance of biological pathways on known drug repurposing scenarios.

BACKGROUND: Drug repurposing plays a significant role in providing effective treatments for certain diseases faster and more cost-effectively. Successful repurposing cases are mostly supported by a classical paradigm that stems from de novo drug development. This paradigm is based on the "one-drug-one-target-one-disease" idea. It consists of designing drugs specifically for a single disease and its drug's gene target. In this article, we investigated the use of biological pathways as potential elements to achieve effective drug repurposing. METHODS: Considering a total of 4214 successful cases of drug repurposing, we identified cases in which biological pathways serve as the underlying basis for successful repurposing, referred to as DREBIOP. Once the repurposing cases based on pathways were identified, we studied their inherent patterns by considering the different biological elements associated with this dataset, as well as the pathways involved in these cases. Furthermore, we obtained gene-disease association values to demonstrate the diminished significance of the drug's gene target in these repurposing cases. To achieve this, we compared the values obtained for the DREBIOP set with the overall association values found in DISNET, as well as with the drug's target gene (DREGE) based repurposing cases using the Mann-Whitney U Test. RESULTS: A collection of drug repurposing cases, known as DREBIOP, was identified as a result. DREBIOP cases exhibit distinct characteristics compared with DREGE cases. Notably, DREBIOP cases are associated with a higher number of biological pathways, with Vitamin D Metabolism and ACE inhibitors being the most prominent pathways. Additionally, it was observed that the association values of GDAs in DREBIOP cases were significantly lower than those in DREGE cases (p-value < 0.05). CONCLUSIONS: Biological pathways assume a pivotal role in drug repurposing cases. This investigation successfully revealed patterns that distinguish drug repurposing instances associated with biological pathways. These identified patterns can be applied to any known repurposing case, enabling the detection of pathway-based repurposing scenarios or the classical paradigm.

Unveiling the value of C-reactive protein as a severity biomarker and the IL4/IL13 pathway as a therapeutic target in recessive dystrophic epidermolysis bullosa: A multiparametric cross-sectional study.

Patients with recessive dystrophic epidermolysis bullosa (RDEB) experience numerous complications, which are exacerbated by inflammatory dysregulation and infection. Understanding the immunological mechanisms is crucial for selecting medications that balance inflammation control and immunocompetence. In this cross-sectional study, aiming to identify potential immunotherapeutic targets and inflammatory biomarkers, we delved into the interrelationship between clinical severity and systemic inflammatory parameters in a representative RDEB cohort. Encompassing 84 patients aged 1-67 and spanning all three Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) severity categories, we analysed the interrelationship of infection history, standard inflammatory markers, systemic cytokines and Ig levels to elucidate their roles in RDEB pathophysiology. Our findings identify C-reactive protein as an excellent biomarker for disease severity in RDEB. A type 2 inflammatory profile prevails among moderate and severe RDEB patients, correlating with dysregulated circulating IgA and IgG. These results underscore the IL4/IL13 pathways as potential evidence-based therapeutic targets. Moreover, the complete inflammatory scenario aligns with Staphylococcus aureus virulence mechanisms. Concurrently, abnormalities in IgG, IgE and IgM levels suggest an immunodeficiency state in a substantial number of the cohort's patients. Our results provide new insights into the interplay of infection and immunological factors in the pathogenesis of RDEB.

Protein sequence analysis in the context of drug repurposing.

MOTIVATION: Drug repurposing speeds up the development of new treatments, being less costly, risky, and time consuming than de novo drug discovery. There are numerous biological elements that contribute to the development of diseases and, as a result, to the repurposing of drugs. METHODS: In this article, we analysed the potential role of protein sequences in drug repurposing scenarios. For this purpose, we embedded the protein sequences by performing four state of the art methods and validated their capacity to encapsulate essential biological information through visualization. Then, we compared the differences in sequence distance between protein-drug target pairs of drug repurposing and non - drug repurposing data. Thus, we were able to uncover patterns that define protein sequences in repurposing cases. RESULTS: We found statistically significant sequence distance differences between protein pairs in the repurposing data and the rest of protein pairs in non-repurposing data. In this manner, we verified the potential of using numerical representations of sequences to generate repurposing hypotheses in the future.

BET Protein Inhibitor JQ1 Ameliorates Experimental Peritoneal Damage by Inhibition of Inflammation and Oxidative Stress.

Peritoneal dialysis (PD) is a current replacement therapy for end-stage kidney diseases (ESKDs). However, long-term exposure to PD fluids may lead to damage of the peritoneal membrane (PM) through mechanisms involving the activation of the inflammatory response and mesothelial-to-mesenchymal transition (MMT), leading to filtration failure. Peritoneal damage depends on a complex interaction among external stimuli, intrinsic properties of the PM, and subsequent activities of the local innate-adaptive immune system. Epigenetic drugs targeting bromodomain and extra-terminal domain (BET) proteins have shown beneficial effects on different experimental preclinical diseases, mainly by inhibiting proliferative and inflammatory responses. However the effect of BET inhibition on peritoneal damage has not been studied. To this aim, we have evaluated the effects of treatment with the BET inhibitor JQ1 in a mouse model of peritoneal damage induced by chlorhexidine gluconate (CHX). We found that JQ1 ameliorated the CHX-induced PM thickness and inflammatory cell infiltration. Moreover, JQ1 decreased gene overexpression of proinflammatory and profibrotic markers, together with an inhibition of the nuclear factor-κB (NF-κB) pathway. Additionally, JQ1 blocked the activation of nuclear factor erythroid 2-related factor 2 (NRF2) and restored changes in the mRNA expression levels of NADPH oxidases (NOX1 and NOX4) and NRF2/target antioxidant response genes. To corroborate the in vivo findings, we evaluated the effects of the BET inhibitor JQ1 on PD patients' effluent-derived primary mesothelial cells and on the MeT-5A cell line. JQ1 inhibited tumor necrosis factor-α (TNF-α)-induced proinflammatory gene upregulation and restored MMT phenotype changes, together with the downmodulation of oxidative stress. Taken together, these results suggest that BET inhibitors may be a potential therapeutic option to ameliorate peritoneal damage.

Efecto de Bursera grandiflora sobre el peso corporal y lipemia en ratones obesos / Effect of Bursera grandiflora on body weight and lipemia in obese mice

Obesity and overweight are clearly related to the caloric intake that leads to a chronic systemic inflammation of low degree. Pharmacological therapy is highly recommended for this disease. Within the Burseraceae family there are species used empirically for the treatment of obesity; one of them, Bursera grandiflora, is also reported for exhibiting anti-inflammatory properties. Evaluate the effect produced by B. grandiflora on a mice model of obesity, its toxicity potential, and chemical identification of the major chemical compound. Mice of the C57B1/6 strain were used. All animals were fed for 8 weeks with a hypercaloric diet. Afterwards, during 7 weeks, animals were daily administered with the hidro-alcoholic extract from B. grandiflora or water (control). At the end of the administration period, plasma cholesterol and triglycerides levels were measured. Moreover, toxicity tests were carried out in mice after acute and chronic administering the B. grandiflora extract. Finally, the main compound in the active extract was identified. Animals treated with the B. grandiflora extract showed a greater food consumption and, paradoxically, without increasing the body weight. Moreover, a decrease of the plasma-triglycerides was observed. Toxicological evaluation showed that the extract administration did not produce any death of the experimental animals or modifications on the organs or behavior. The major compound identified in the extract was scopoletin.

El sobrepeso y la obesidad están claramente vinculados con la ingesta calórica que lleva a la instalación crónica de inflamación sistémica de bajo grado. La terapia farmacológica es altamente recomendable para este padecimiento. Dentro de la familia Burseraceae existen especies utilizadas para el tratamiento de la obesidad, de las cuales, Bursera grandiflora es referida también por su efecto anti-inflamatorio. Evaluar el efecto de B. grandiflora en un modelo de obesidad, su potencial toxicológico, e identificación del compuesto mayoritario. Se utilizaron ratones C57Bl/6 alimentados durante 8 semanas con dieta hipercalórica. Posteriormente, durante 7 semanas se administró diariamente un extracto hidroalcohólico de B. grandiflora o agua (control). Al final se cuantificaron colesterol y triglicéridos. Además, se realizaron pruebas de toxicidad en ratones administrando el extracto de B. grandiflora en forma aguda y subcrónica. Finalmente, se identificó el compuesto mayoritario. Los animales tratados con B. grandiflora registraron el mayor consumo de alimento y, paradójicamente, sin mostrar un crecimiento ponderal y con una disminución de los triglicéridos. Las evaluaciones de toxicología revelaron que la administración del extracto no produjo muertes en los animales de experimentación, ni cambios orgánicos o de comportamiento. El compuesto mayoritario identificado en el extracto activo fue escopoletina.

El medio de Kaminski adicionado con nistatina para el aislamiento de dermatofitos y otros hongos patogenos / Modified Kaminski agar for the isolation of dermatophytes and some other pathogenic fungi

Se evaluaron 3 medios du cultivo de composicion diferente (Mycobiotic agar, agfar de Kaminski y agar de Kaminski adicionado con nistatina) para el aislamiento de S. schenckii y hongos negros, agentes de cromomicosis. Con el objeto de puntualizar diferencias entre dichos medios se determinaron, para cada uno, la frecuencia de aislamiento de los hongos, sus cartacteristicas morfologicas y su tiempo de crecimiento, asi como la rapidez e intensidad de la contaminacion bacteriana y/o micotica. Se estudiaron 150 muestras de pacientes con sospecha clinica de dermatofitosis y se hicieron 30 reaislamientos de S. schenckii y 10 de agentes de cronomicosis. Se demostro la utilidad del agar de Kaminski modificado, tanto para el aislamiento como para el reaislamiento de los agentes senalados a pesar de su mayor indice de contaminacion microbiana. Fue, ademas, util para el aislamiento de levaduras del genero Candida

Three culture media with different composition (Mycobiotic agar, Kaminski agarand Kaminski agar modified with nystatin) were evaluated for isolation of dermatophytes and reisolation of S. schenckiiand dematiaceous fungi. One hundred and fifty specimens of cases suspicious of dermatophytosis, as well as 30 strains of S. schenckiiand 10 of chromoblatomycosis agents were studied. The modified Kaminski agar was efficient for the isolation and reisolation of the tested agents, in spite of its greater contamination rate; It was equally adequate for isolation of Candida species

Polimorfismo fenotípico de cepas autóctonas de sporothrix schenkii / Phenotypic polimorphism in indigenous strains of sporothrix schenkii

Se presentan los resultados macroscópicos, de asimilación de azúcares y de virulencia de 55 cepas de Sporothrix schenckii aisladas a partir de lesiones de pacientes con esporotricosis cútanea, que consultaron al laboratorio de micología de la Facultad de Medicina de la Universidad de Antioquia en Medellín, Colombia, y que fueron coleccionadas en el transcurso de 10 años. La morfología macroscópica de las colonias y su pigmentación se evaluaron tanto en agar mycosel como en extracto de malta. La mayoría de las cepas en los dos medios presentaban colonias con 2 ó 3 colores diferentes. En mycosel 5 cepas (9.1 por ciento) fueron monocromáticas y éste fue el medio más estable para definir las características de pigmentación. El 85 por ciento de las cepas en mycosel fueron café claras, café oscuras, plisadas o plisadas y umbilicadas. Todas las cepas asimilaron D-glucosa, glicerol y D-xilosa en el sistema Api 20C y 25 cepas se clasificaron en 9 biotipos de asimilación de la A a la I. La mayoría de las cepas tanto pigmentadas como albinas, resultaron virulentas para ratones. En éstos predominaron los cuerpos en cigarro en forma de naveta y no se visualizaron cuerpos asteroides en los exudados testiculares. Se demuestra así la gran heterogeneidad fenotípica de las cepas autóctonas de S. schenckii, se plantea la importancia de correlacionar estos hallazgos con los patrones de heterogeneidad gen ética informados por investigadores Japoneses y quizás explicar por esta diversidad fenotípica y genotípica, el polimorfismo clínico de la enfermedad y establecer mapas de distribución de los diferentes biotipos o genotipos en Colombia y América Latina. Incluso el cruzar cepas distantes en su biotipo o genotipo podría facilitar la obtención de la forma de reproducción sexual del microorganismo

We studied macroscopic colony findings, sugar assimilation patterns and virulence of 55 Sporothrix schenckij strains obtained from patients with cutaneous sporothrichosis. They were collected during a 10-year period at the Mycology Laboratory, University of Antioquia, School of Medicine, Medellín, Colombia. Pigmentation types and macroscopic morphological characteristics' were studied on mycosel agar and malt extract. In most cases 2 or 3 colony colors were present In both media. In mycosel agar only 5 strains (9.1%) were monochromatic. Pigmentation was very stable in that medium. Eighty five percent of the mycosel agar colonies were beige, brown, pleated or pleated and umbilicated. All strains assimilated D-glucosa, glycerol and D-xylosa. We established 9 patterns of assimilation (blotypes), from A to I In 25 strains. Both pigmented and albino strains were virulent for mice. We emphasize the diversity of our Indigenous strains, and the importance of genotypic characterization and of the correlation studies of phenotypic and genotypic variation with the clinical and geographical patterns of the disease

Dermatomicosis y onicomicosis en estudiantes de una escuela de policia / Dermatomycosis and onycomycosis in trainees of a police academy

Con el fin de conocer la prevalencia de las dermatomicosis y de las micosis ungueales se evaluaron clinica y micologicamente en dos oportunidades 213 hombres jovenes que estaban recibiendo entrenamiento en una escuela de policia. El estudio inicial se hizo al ingreso a la escuela en abril de 1988 y en el se encontro que 126 individuos tenian algun tipo de micosis superficial y que las dermatofitosis constituian el 65.5% de las 200 lesiones diagnosticadas. Los agentes mas frecuentes de dermatofitosis fueron: T. mentagrophytes y E. floccosum. Tambien se encontraron: candidiasis, trichosporiasis, pitiriasis, infecciones mixtas e infecciones por hongos ambientales. Se prescribio tratamiento topico convencional a todos los individuos afectados. Cuatro meses despues de la encuesta inicial, inmediatamente antes del egreso, se llevo a cabo un segundo estudio de caracteristicas similares; en esa oportunidad se incluyeron los 145 individuos que aun permanecian en la escuela; en 105 de ellos se comprobo algun tipo de micosis superficial, con un total de 185 lesiones; se hallaron las mismas entidades que en el primer estudio y nuevamente predominaron las dermatofitosis cuya causa mas frecuente fue el E. floccosum seguido por el T. mentagrophytes. Se obtuvieron muestras de diferentes areas humedas de uso comun, como banos, vestier y piscina; de ellas se aislaron T. rubrum y T. mentagrophytes. Ademas de la alta prevalencia inicial de dermatofitosis y micosis ungueales, reveladora de la importancia de estas enfermedades en las comunidades de origen, los resultados del ...

In order to determine the prevalence of dermatomycosis and ungueal mycosis, we studied 213 young men who were enrolled at a police academy. They received both clinical and mycological evaluation on two separate occasions, the first one at the time of admission In apr1l1988; at this point we found that 126 of them (59.2%) had some type of superficial mycosis and that dermatophytosis represented 65.5% of the 200 lesions observed. The most frequent causative agents were: T. mentagrophytes (30.5%) y E. floccosum (18.3%). Candidiasis, trichosporiasis, pitiriasis, mixed infections and infections caused by environmental fungi were also found. AII received conventionaliocal therapy. Four months later, just before the end of their training, the 145 that were still at the academy were evaluated for the second time. In 105 of them (72.4%), some type of superficial mycosis was diagnosed, for a total of 185 lesions. Findings were similar to those of the first evaluation with dermatophytosis predominating (63.8%). E. floccosum was found in 27.1 % and T. mentagrophytes in 14.4%. Samples were also obtained from public areas specially moist ones like showers, vestiers and swimming pool and from them T. rubrum and T. mentagrophytes were isolated. Besides the high initial prevalence of dermatomycosis and ungueal mycosis which reveal their importance in the environment of people evaluated, our study allows us to postulate that special conditions tied to policemen training (Intense physical exercise, sweating, insufficient drying after shower, boot wear), favor occurrence and persistence of these mycosis

Asma y deficiencia de subclases de IgG / Asthma and IgG subclasses deficiency

Se estudiaron 45 pacientes asmáticos adultos de difícil manejo, de más de 5 años de evolución, 37 de ellos esteroide dependientes y 8 no dependientes, con asma alérgica o intrínseca y algunos con infecciones respiratorias recurrentes de predominio viral. Por nefelometría se midieron los niveles séricos de las Igs G, M y A, y por ELISA se determinó la IgE total. Se encontraron 4 pacientes con deficiencia de IgG total, en el grupo de los esteroide dependientes. Mediante ELISA tlpo sandwich y con anticuerpos monoclonales específicos para las subclases de IgG se investigaron los niveles séricos de IgG1, 2, 3 y 4. En el 55.6 por ceinto de los enfermos se encontraron una O más deficiencias de subclases. No hubo diferencias significativas entre los grupos esteroide y no esteroide dependientes, ni entre los asmáticos alérgicos e intrínsecos, ni entre los con infección recurrente o sin ella. Predominó la deficiencia de IgG1; en total el 46.7 por ciento de los pacientes tenían deficiencia aislada o combinada de IgG1, el 31.1 por ciento de IgG2, el 24.4por ciento de IgG3 y el 17.8 por ciento de Igd4. La alta incidencia de deficiencia de subclases podría deberse a la acción de los esteroides o a una alteración en la regulación de la síntesis de Igs producida por un defecto Inmune primario. Esta deficiencia sería la responsable del comportamiento agresivo de la enfermedad

We studied 45 adult asthmatic patients with difficult to care disease and who had more than five years of evolution; they suffered from elther allergic or intrinsic asthma and some had experienced recurrent respiratory tract infections. predominantly of viral etiology. Serum levels of IgA, IgG and IgM were measured by nephelometry and total lgE was determined by an Enzyme-Linked immunosorbent Assay (ELISA). Total lgG deficiency was found in four steroid. dependent patients. Serum levels of IgG subclasses 1 to 4 were measured by means of a sandwich-like ELISA with specific monoclonal antibodies. One or more subclass deficiencies were present In 55.6% of the patients. Significant differences were not found between the following groups: steroid and nonsteroid dependent patients; allergic or intrinsic, asthma; and individuals with or without history of infection. IgG 1 deficiency was the most commonly found: It was present in 46.7% of the patients, either as an isolated disorder or combined with alteration of other subclasses. Deficiency of other subclasses was present in the following proportions: 31.1% for IgG2; 24.4% for IgG3 and 17.8 for IgG4. The high incidence of subclass deficiency may be due to steroid action or to primary Immune defects leading to disorders of IgG synthesis. Such situation might be responsible for the aggressive behavior of the disease

Dermatomicosis: experiencia en 1984 incluyendo casos de etiología mixta y por mohos ambientales

En 1984 se comprobaron, en dos laboratorios, 724 casos de dermatomicosis; las más frecuentes fueron las dermatofitosis seguidas por las candidosis y la pitiriasis; hubo 23 pacientes con infección mixta y 21 cuyas lesiones eran causadas por mohos ambientales. Se hace notar, en comparación con trabajos previos, la disminución en el porcentaje de casos de Tinea corporis y Tinea capitis y el aumento en el Tinea pedis y Tinea Ungeum. Los pacientes con lesiones de etiología mixta o por mohos ambientales no difirieron cliníca ni micológicamente de los informados previamente en la misma ciudad. Se hace énfasis en la conveniencia de refinar el diagnóstico clínico a fin de disminuir el costo de exámenes innecesarios. Igualmente en la importancia de un diagnóstico micológico cabal que permita detectar los varios agentes de las infecciones mixtas; es concebible que las infecciones debidas a mohos ambientales sean oportunistas que aprovechan circunstancias del huésped aún mal definidas

Esporotricosis. Aspectos clinicos en 78 pacientes. / Sporotrichosis. Clinical aspects in 78 patients

Desde enero de 1981 hasta agosto de 1983 se comprobaron 78 casos de esporotricosis en el laboratorio de micologia de la Facultad de Medicina de la Universidad de Antioquia; ellos representaron el 1,4% del total de pacientes atendidos en ese lapso para propositos de diagnostico micologico; la enfermedad predomino en el sexo masculino con localizacion en los miembros superiores y en las dos primeras decadas de la vida; fue mas frecuente la forma cutanea fija y el cultivo fue positivo en el 88.5% de los casos. Se llama la atencion sobre la necesidad de pensar en esporotricosis a pesar de la ausencia de antecedentes traumaticos de compromiso linfatico

Evaluación de cuatro medios selectivas para el aislamiento de hongos patógenos

Se aislaron cuatro medios de cultivo comerciales para el aislamiento de hongos patógenos que contienen agar, peptona, glucosa, cicloheximida y cloranfenicol. En cada uno se determinó la frecuencia de aislamiento de hongos patógenos así como sus características morfológicas, su tiempo de crecimiento y la rapidez e intensidad de la contaminación bacteriana y/o micótica, con el objeto de puntualizar diferencias entre ellos. Se estudiaron 100 muestras de casos con sospecha clínica de dermatomicosis o micosis subcutáneas y 50 de pacientes con diagnostico presuntivo de micosis profunda. se aislaron 56 patógenos en el primer grupo y P. brasiliensis en tres esputos seriados

Esporotricosis. Estudio comparativo de los antigenos miceliar y levadura de S. schenckii mediante pruebas cutaneas. / Sporotrichosis. Comparative study of micelle antigens and yeast or S. schenckii by means of skin tests

Se estudian 952 individuos mediante pruebas cutaneas de hipersensibilidad retardada para esporotricosis. Se incluyen 78 pacientes con dicha entidad, 82 con micosis distintas de esporotricosis, 100 con dermatosis no micoticas, 23 con sospecha de leishmaniasis, 150 estudiantes sanos de la Facultad de Medicina y 519 individuos asintomaticos de diferentes zonas geograficas de los departamentos de Antioquia y Bolivar; se hace una comparacion entre 2 antigenos metabolicos de S. schenckii, a saber: miceliar y levadura; los resultados demuestran el valor diagnostico de las pruebas cutaneas en esporotricosis, su sensibilidad que supera la del cultivo y su alta especificidad