ABSTRACT
The syndrome of dampness stagnancy due to spleen deficiency (DSSD) is relatively common globally. Although the pathogenesis of DSSD remains unclear, evidence has suggested that the gut microbiota might play a significant role. Radix Astragali, used as both medicine and food, exerts the effects of tonifying spleen and qi. Astragalus polysaccharide (APS) comprises a macromolecule substance extracted from the dried root of Radix Astragali, which has many pharmacological functions. However, whether APS mitigates the immune disorders underlying the DSSD syndrome via regulating gut microbiota and the relevant mechanism remains unknown. Here, we used DSSD rats induced by high-fat and low-protein (HFLP) diet plus exhaustive swimming, and found that APS of moderate molecular weight increased the body weight gain and immune organ indexes, decreased the levels of interleukin-1β (IL-1β), IL-6, and endotoxin, and suppressed the Toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB) pathway. Moreover, a total of 27 critical genera were significantly enriched according to the linear discriminant analysis effect size (LEfSe). APS increased the diversity of the gut microbiota and changed its composition, such as reducing the relative abundance of Pseudoflavonifractor and Paraprevotella, and increasing that of Parasutterella, Parabacteroides, Clostridium XIVb, Oscillibacter, Butyricicoccus, and Dorea. APS also elevated the contents of short-chain fatty acids (SCFAs). Furthermore, the correlation analysis indicated that 12 critical bacteria were related to the body weight gain and immune organ indexes. In general, our study demonstrated that APS ameliorated the immune disorders in DSSD rats via modulating their gut microbiota, especially for some bacteria involving immune and inflammatory response and SCFA production, as well as the TLR4/NF-κB pathway. This study provides an insight into the function of APS as a unique potential prebiotic through exerting systemic activities in treating DSSD.
Subject(s)
Rats , Animals , NF-kappa B/metabolism , Spleen , Gastrointestinal Microbiome , Toll-Like Receptor 4 , Polysaccharides/pharmacology , Astragalus Plant/metabolism , Immune System Diseases/drug therapy , Body WeightABSTRACT
To date, more than 30 antibodies have been approved worldwide for therapeutic use. While the monoclonal antibody market is rapidly growing, the clinical use of therapeutic antibodies is mostly limited to treatment of cancers and immunological disorders. Moreover, antibodies against only five targets (TNF-alpha, HER2, CD20, EGFR, and VEGF) account for more than 80 percent of the worldwide market of therapeutic antibodies. The shortage of novel, clinically proven targets has resulted in the development of many distinct therapeutic antibodies against a small number of proven targets, based on the premise that different antibody molecules against the same target antigen have distinct biological and clinical effects from one another. For example, four antibodies against TNF-alpha have been approved by the FDA -- infliximab, adalimumab, golimumab, and certolizumab pegol -- with many more in clinical and preclinical development. The situation is similar for HER2, CD20, EGFR, and VEGF, each having one or more approved antibodies and many more under development. This review discusses the different binding characteristics, mechanisms of action, and biological and clinical activities of multiple monoclonal antibodies against TNF-alpha, HER-2, CD20, and EGFR and provides insights into the development of therapeutic antibodies.
Subject(s)
Animals , Humans , Antibodies, Monoclonal/pharmacology , Antigens, CD20/immunology , Drug Discovery , Immune System Diseases/drug therapy , Immunotherapy/trends , Molecular Targeted Therapy , Neoplasms/drug therapy , ErbB Receptors/immunology , Receptor, ErbB-2/immunology , Tumor Necrosis Factor-alpha/immunology , United States , United States Food and Drug Administration , Vascular Endothelial Growth Factor A/immunologyABSTRACT
To date, more than 30 antibodies have been approved worldwide for therapeutic use. While the monoclonal antibody market is rapidly growing, the clinical use of therapeutic antibodies is mostly limited to treatment of cancers and immunological disorders. Moreover, antibodies against only five targets (TNF-alpha, HER2, CD20, EGFR, and VEGF) account for more than 80 percent of the worldwide market of therapeutic antibodies. The shortage of novel, clinically proven targets has resulted in the development of many distinct therapeutic antibodies against a small number of proven targets, based on the premise that different antibody molecules against the same target antigen have distinct biological and clinical effects from one another. For example, four antibodies against TNF-alpha have been approved by the FDA -- infliximab, adalimumab, golimumab, and certolizumab pegol -- with many more in clinical and preclinical development. The situation is similar for HER2, CD20, EGFR, and VEGF, each having one or more approved antibodies and many more under development. This review discusses the different binding characteristics, mechanisms of action, and biological and clinical activities of multiple monoclonal antibodies against TNF-alpha, HER-2, CD20, and EGFR and provides insights into the development of therapeutic antibodies.
Subject(s)
Animals , Humans , Antibodies, Monoclonal/pharmacology , Antigens, CD20/immunology , Drug Discovery , Immune System Diseases/drug therapy , Immunotherapy/trends , Molecular Targeted Therapy , Neoplasms/drug therapy , ErbB Receptors/immunology , Receptor, ErbB-2/immunology , Tumor Necrosis Factor-alpha/immunology , United States , United States Food and Drug Administration , Vascular Endothelial Growth Factor A/immunologyABSTRACT
There are emerging ethical issues with regards to the use of animals in the early stages of drug discovery for anti-inflammatory and degenerative diseases from natural products using the activity-directed isolation pathways when many compounds (eg > 100) are present in the crude extract or fraction and are to be tested. The above-mentioned is the main reason for proposing the use of the in vitro anti-denaturation (stabilization) effects of heat treated (immunogenic) bovine serum albumin (BSA) as an assay. Current methods used for detecting and isolating a wide range of anti-inflammatory compounds in the early stages of the drug discovery process utilize a large number of animals. When BSA is heated and is undergoing denaturation, it expresses antigens associated to Type III hyper-sensitive reaction and which are related to diseases such as serum sickness, glomerulonephritis, rheumatoid arthritis and systemic lupus erythematosus. Thus, the assay that is being proposed should be applicable to the discovery of drugs for treating the above mentioned diseases and others, once the compounds stabilize the denaturation process.
Actualmente surgen problemas éticos en relación con el uso de animales en las etapas tempranas del descubrimiento de medicamentos anti-inflamatorios y contra enfermedades degenerativas, a partir de productos naturales, usando vías de aislamiento dirigido por actividad, cuando muchos compuestos están presentes (p.ej. > 100) en la fracción o extracto crudo, y deben ser probados. Lo anterior representa la razón principal para proponer el uso de los efectos de la anti-desnaturalización (estabilización) in vitro de la albúmina sérica bovina (inmunogénica) tratada con calor (ASB) como ensayo. Los métodos corrientes usados para detectar y aislar una amplia gama de compuestos anti-inflamatorios en las etapas tempranas del proceso de descubrimiento del medicamento, utilizan un gran número de animales. Cuando la ASB es calentada y sometida a un proceso de desnaturalización, expresa antígenos en relación con la reacción hipersensitiva de tipo III, relacionada a su vez con enfermedades tales como la enfermedad del suero, la glomerulonefritis, la artritis reumatoide, y el lupus sistémico y eritematoso. De este modo, el ensayo que aquí proponemos debe ser aplicable al descubrimiento de medicamentos para el tratamiento de las enfermedades anteriormente mencionadas y otras, una vez que los compuestos estabilicen el proceso de desnaturalización.
Subject(s)
Animals , Cattle , Anti-Inflammatory Agents/blood , In Vitro Techniques , Plant Preparations/pharmacology , Protein Denaturation/drug effects , Serum Albumin, Bovine/analysis , Biological Assay , Drug Discovery , Hot Temperature/adverse effects , Immune System Diseases/drug therapy , Mass ScreeningABSTRACT
Introducción: El Síndrome de Activación Macrofágico (SAM) es una entidad poco frecuente en la práctica pediátrica que se caracteriza por una excesiva activación del sistema macrofágico y por una liberación exagerada de citoquinas por parte de los linfocitos T, y que clínicamente se manifiesta como un síndrome semejante a una falla orgánica múltiple. Existe actualmente disparidad en la nomenclatura de este síndrome, y es así como a nivel de la reumatología pediátrica se mantiene el término de SAM, mientras que para los hemato-oncólogos esta enfermedad está incluida dentro de las diferentes variedades de histiocitosis. Objetivo: Actualizar el conocimiento respecto de la etiología, clínica y tratamiento del SAM, enfermedad de baja frecuencia y alta mortalidad, en relación al análisis de 4 casos clínicos. Casos clínicos: 2 pacientes eran portadores de una enfermedad reumatológica, Artritis Idiopática Juvenil, el tercer paciente presentaba elementos de Inmunodeficiencia, y el último niño de linfohistiocitosis familiar congénita. Los factores desencadenantes del SAM fueron fármacos en dos pacientes y una posible causa infecciosa en los dos restantes. Los cuatro pacientes sobrevivieron al proceso inicial después de recibir una terapia agresiva inmunosupresora con esteroides en altas dosis y ciclosporina intravenosa. Conclusión: La importancia de dar a conocer este síndrome, radica en que un diagnóstico precoz y una terapia agresiva, preferentemente con ciclosporina y pulsos de esteroides en altas dosis, puede mejorar significativamente el pronóstico de esta enfermedad.
Subject(s)
Humans , Adolescent , Female , Infant , Child , Arthritis, Juvenile/complications , Arthritis, Juvenile/immunology , Immune System Diseases/diagnosis , Immune System Diseases/etiology , Immune System Diseases/drug therapy , Macrophage Activation , Immunosuppressive Agents/therapeutic use , Histiocytosis , Streptococcal Infections/complications , Methylprednisolone/therapeutic use , Methotrexate/adverse effects , Sulfasalazine , Syndrome , Treatment OutcomeABSTRACT
La ciclosporina (CsA) tiene un papel fundamental en la terapia inmunosupresora de una gran variedad de trasplantes. También se emplea como inmunosupresor de primera o segunda línea en otros padecimientos de origen inmunológico, entre los que destacan: síndrome nefrótico, lupus eritematoso sistémico y dermatitis atópica. En este artículo se hace una revisión de la farmacocinética de CsA en pacientes pediátricos, biodisponibilidad de las diferentes formulaciones con énfasis en el monitoreo terapéutico, así como los padecimientos en donde se ha demostrado su utilidad.
Subject(s)
Cyclosporine , Immunosuppressive Agents , Transplants , Immune System Diseases/drug therapyABSTRACT
Se practicó un estudio prospectivo para determinar la eficacia terapéutica de Ceftazidime en el tratamiento de infecciones en pacientes pediátricos febriles inmunocomprometidos o críticamente enfermos con infecciones severas en comparación con un grupo de pacientes tratados con triple terapia (Amikacina + Meticilina + Piperacilina). 23 pacientes fueron tratados con Ceftazidime y 8 pacientes con triple terapia. De las infecciones tratadas las neumonías y las infecciones de tejidos blandos fueron las más frecuentes. Un 61% de los pacientes tenían infecciones por Gram negativos, un 22% infecciones por Gram positivos y un 17% infecciones polimicrobianas. La eficacia terapéutica de Ceftazidime fue de un 86% frente a un 36.5% de la triple terapia. Se concluye que Ceftazididme puede ser utilizada como terapia primaria inicial en pacientes con fiebre y neutropenia o en infecciones adquiridas en el hospital, sin embargo los pacientes con infecciones bien definidas o neutropenia refractaria podrían requerir modificación de la terapia inicial como ser la asociación con un aminoglucósido o con Vancomicina