Targeting IL-11 to reduce fibrocyte circulation and lung accumulation in animal models of pulmonary hypertension-associated lung fibrosis.

BACKGROUND AND PURPOSE: IL-11 is a member of the IL-6 family of cytokine initially considered as haematopoietic and cytoprotective factor. Recent evidence indicates that IL-11 promotes lung fibrosis and pulmonary hypertension in animal models and is elevated in lung tissue of patients with pulmonary fibrosis and pulmonary hypertension. Fibrocytes are bone marrow-derived circulating cells that participate in lung fibrosis and pulmonary hypertension, but the role of IL-11 on fibrocytes is unknown. We investigated the role of IL-11 system on fibrocyte activation in different in vitro and in vivo models of lung fibrosis associated with pulmonary hypertension. EXPERIMENTAL APPROACH: Human fibrocytes were isolated from peripheral blood of six healthy donors. Recombinant human (rh)-IL-11 and soluble rh-IL-11 receptor, α subunit (IL-11Rα) were used to stimulated fibrocytes in vitro to measure:- cell migration in a chemotactic migration chamber, fibrocyte to endothelial cell adhesion in a microscope-flow chamber and fibrocyte to myofibroblast transition. Mouse lung fibrosis and pulmonary hypertension was induced using either IL-11 (s.c.) or bleomycin (intra-tracheal), while in the rat monocrotaline (intra-tracheal) was used. In vivo siRNA-IL-11 was administered to suppress IL-11 in vivo. KEY RESULTS: RhIL-11 and soluble rhIL-11Rα promote fibrocyte migration, endothelial cell adhesion and myofibroblast transition. Subcutaneous (s.c.) IL-11 infusion elevates blood, bronchoalveolar and lung tissue fibrocytes. SiRNA-IL-11 transfection in bleomycin and monocrotaline animal models reduces blood and lung tissue fibrocytes and reduces serum CXCL12 and CXCL12/CXCR4 lung expression. CONCLUSION AND IMPLICATIONS: Targeting IL-11 reduces fibrocyte circulation and lung accumulation in animal models of pulmonary hypertension-associated lung fibrosis.

Using pharmacokinetics and pharmacogenetics to optimize psychiatric treatments: A systematic review.

OBJECTIVE: Neuropsychiatrists often resort to drugs with broad interindividual pharmacokinetic variability metabolized by highly polymorphic enzymes such as CYP2D6 and CYP2C19. Pharmacokinetics and  pharmacogenetics offer considerable promise as techniques capable to allow individualized adjustments in treatments with psychoactive drugs. The  purpose of this study was to review the existing evidence for the application of  pharmacokinetics and pharmacodynamics to the dosing of drugs used in  neuropsychiatry. METHOD: A literature search was conducted in PubMed and Embase to find  prospective studies published between January 2000 and April 2021 that used  determination of psychotropic drug plasma levels or genotyping to improve  response to treatment or minimize adverse events in adult patients with  psychiatric conditions. MeSH terms and free search terms were used. Each  article was reviewed by two independent reviewers to ensure that they met the  inclusion criteria. A quantitative method was established to assess the  quality of the articles selected. Results: A total of 27 articles met the inclusion  criteria of which 16  used pharmacokinetic and 11 pharmacogenetic techniques.  Fifty percent of pharmacokinetic studies met the five predefined quality criteria. Eight of the 16  papers were on antidepressants; the remainder were on antipsychotics. Two of the latter did not find an association with efficacy or safety. None of the  pharmacogenetic studies met the five quality criteria. Only one of the two  studies on antipsychotics found fewer adverse events with genetics-guided  dosing in patients on CYP2D6 substrate antipsychotics. Six of the nine studies  on antidepressants found that pharmacogeneticsbased dosing improved  efficacy. CONCLUSIONS: The evidence available on pharmacokinetics and  harmacodynamics- based personalization of treatment with psychoactive drugs  is scarce. Many existing studies analyze associations between genotypes and response or toxicity but provide few data on the efficacy of  treatment individualization. The results obtained suggest the existence of  significant differences in pharmacokinetic parameters between responding and  nonresponding patients, particularly in the treatment of depression. Given that  the availability of pharmacogenetic information may be useful at the beginning  of treatment, combining both techniques could help optimize pharmacotherapy.  However, clinical trials are needed to establish  their benefits with greater accuracy.

OBJETIVO: Dentro de la neuropsiquiatría es habitual el empleo de fármacos con  amplia variabilidad farmacocinética interindividual y  etabolizados por enzimas altamente polimórficas como CYP2D6 y CYP2C19. La  farmacocinética y la farmacogenética se vislumbran como herramientas de  ayuda para conseguir un ajuste personalizado en el tratamiento con psicofármacos. El objetivo de este trabajo es revisar la evidencia existente sobre la aplicación de farmacocinética y farmacogenética en la  selección de dosis de los medicamentos empleados en neuropsicofarmacología.Método: Se realizó una búsqueda en PubMed y Embase para localizar estudios  prospectivos, publicados entre enero de 2000 y abril de  021, que utilizasen la determinación de niveles plasmáticos de psicofármacos o  genotipado para mejorar la respuesta o minimizar efectos adversos en  pacientes adultos con trastornos psiquiátricos. Se emplearon términos MeSH y  texto libre. Cada artículo fue revisado por dos revisores independientes para  asegurar que cumplían los criterios de inclusión. Se estableció un método  cuantitativo para valorar la calidad de los artículos incluidos. Resultados: Se incluyeron 27 artículos, 16 utilizaban farmacocinética y 11  farmacogenética. El 50% de los estudios de farmacocinética cumplieron los  cinco criterios de calidad predefinidos. Ocho de los 16 trabajos analizaron  antidepresivos y los estudios restantes antipsicóticos. Dos de estos 8, no  encontraron asociación con eficacia o seguridad. Ninguno de los estudios de  farmacogenética cumplía los cinco criterios de calidad. Sólo 1 de los 2 estudios  de antipsicóticos encuentra reducción de efectos adversos con dosis guiadas  por genética en pacientes con antipsicóticos sustratos del CYP2D6. Seis de los  9 estudios con antidepresivos encuentran mayor eficacia al dosificar utilizando  farmacogenética. CONCLUSIONES: La evidencia disponible sobre farmacocinética y  farmacogénetica en individualización del tratamiento con psicofármacos es escasa. Gran parte de los estudios analizan asociaciones entre genotipos y  respuesta o toxicidad, proporcionando pocos datos sobre la eficacia en la  individualización del tratamiento. Los resultados obtenidos apuntan a la  existencia de diferencias significativas en parámetros farmacocinéticos entre  pacientes respondedores y no respondedores, especialmente en el tratamiento  de la depresión. Disponer de información farmacogenética puede ser de  utilidad al inicio del tratamiento, por lo que combinar ambas técnicas podría  ayudar a optimizar la farmacoterapia, pero hacen falta ensayos clínicos para  establecer claramente su beneficio.

Associated effects of copy number variants on economically important traits in Spanish Holstein dairy cattle.

Copy number variants (CNV) are structural variants consisting of duplications or deletions of genomic fragments longer than 1 kb that present variability in the population and are heritable. The objective of this study was to identify CNV regions (CNVR) associated with 7 economically important traits (production, functional, and type traits) in Holstein cattle: fat yield, protein yield, somatic cell count, days open, stature, foot angle, and udder depth. Copy number variants were detected by using deep-sequencing data from 10 sequenced bulls and the Bovine SNP chip array hybridization signals. To reduce the number of false-positive calls, only CNV identified by both sequencing and Bovine SNP chip assays were kept in the final data set. This resulted in 823 CNVR. After filtering by minor allele frequency >0.01, a total of 90 CNVR appeared segregating in the bulls that had phenotypic data. Linear and quadratic CNVR effects were estimated using Bayesian approaches. A total of 15 CNVR were associated with the traits included in the analysis. One CNVR was associated with fat and protein yield, another 1 with fat yield, 3 with stature, 1 with foot angle, 7 with udder depth, and only 1 with days open. Among the genes located within these regions, highlighted were the MTHFSD gene that belongs to the folate metabolism genes, which play critical roles in regulating milk protein synthesis; the SNRPE gene that is related to several morphological pathologies; and the NF1 gene, which is associated with potential effects on fertility traits. The results obtained in the current study revealed that these CNVR segregate in the Holstein population, and therefore some potential exists to increase the frequencies of the favorable alleles in the population after independent validation of results in this study. However, genetic variance explained by the variants reported in this study was small.