RESUMEN
Introduction: The Cuban population is genetically diverse, and information on the prevalence of genetic variants is still limited. As complex admixture processes have occurred, we hypothesized that the frequency of pharmacogenetic variants and drug responses may vary within the country. The aims of the study were to describe the frequency distribution of 43 single-nucleotide variants (SNVs) from 25 genes of pharmacogenetic interest within the Cuba population and in relation to other populations, while taking into consideration some descriptive variables such as place of birth and skin color. Materials and Methods: SNVs were analyzed in 357 unrelated healthy Cuban volunteers. Genotype, allele frequencies, and ancestry proportions were determined, and the pairwise fixation index (FST ) was evaluated. Results: Hardy-Weinberg equilibrium (HWE) deviations in six loci (rs11572103, rs2740574, rs776746, rs3025039, rs861539, and rs1762429) were identified. Minor allele frequencies (MAFs) ranged from 0.00 to 0.15 for variants in genes encoding xenobiotic metabolizing enzymes. They also ranged from 0.01 to 0.21 for variants in DNA repair, growth factors, methyltransferase, and methyl-binding proteins, while they ranged from 0.04 to 0.27 for variants in the O-6-methylguanine-DNA methyltransferase enzyme. Moderate genetic divergence was observed upon comparison to Africans (FST = 0.071 and SD 0.079), with 19 markers exhibiting moderate-to-large genetic differentiation. The average European, African, and Amerindian ancestry proportions were 67.8%, 27.2%, and 5.3%, respectively. Ancestry proportions differed by skin color and birthplace for both African and European components, with the exception of the European component, which showed no significant difference between individuals from Western and Eastern regions. Meanwhile, the statistical significance varied in comparisons by skin color and birthplace within the Amerindian component. Low genetic divergence was observed across geographical regions. We identified 12 variants showing moderate-to-large differentiation between White/Black individuals. Conclusion: Altogether, our results may support national strategies for the introduction of pharmacogenetic tools in clinical practice, contributing to the development of precision medicine in Cuba.
RESUMEN
Plectranthus neochilus Schltr. (Lamiaceae) is a plant recently introduced in Cuba. Worldwide, it is an ethnomedicinal alternative for its use against microbial infections, but the Cuban population use the extracts to treat sleep disorders. To address this apparent incongruity, four collections (from different seasonal conditions in the year) of Cuban P. neochilus cultivars were analyzed in terms of their pharmacognostic characteristics. Three extracts using fresh and dried leaves were chemically and biologically characterized. UPLC-DAD-MS/MS analysis was performed to determine their chemical composition, while a panel of nine microorganisms was used to evaluate their antimicrobial activity. Finally, cytotoxic effects of different fractions were measured in three cell lines by the resazurin viability assay. In contrast to previously reported micro and macromorphological properties of P. neochilus, the leaves from the Cuban cultivars did not present glandular trichomes, nor did they produce quantifiable levels of essential oils. Moreover, aqueous extracts used by the population revealed no significant antimicrobial activity and were not cytotoxic. The three extracts showed a similar phytochemical composition, i.e., eight flavonoids, seven abietane diterpenes, and rosmarinic acid as the major constituent, most of them reported for the first time in this species. The low yield of essential oil, the absence of glandular trichomes, compounds with a high level of oxidation, and a moderate antimicrobial activity detected were the most distinctive pharmacognostic and biological characteristics of P. neochilus grown in Cuba. These aspects could explain its non-use as an antimicrobial.
RESUMEN
In spite of the current advances and achievements in cancer treatments, colorectal cancer (CRC) persists as one of the most prevalent and deadly tumor types in both men and women worldwide. Drug resistance, adverse side effects and high rate of angiogenesis, metastasis and tumor relapse remain one of the greatest challenges in long-term management of CRC and urges need for new leads of anticancer drugs. We demonstrate that CRC treatment with the phytopharmaceutical mangiferin (MGF), a glucosylxanthone present in Mango tree stem bark and leaves (Mangifera Indica L.), induces dose-dependent tumor regression and decreases lung metastasis in a syngeneic immunocompetent allograft mouse model of murine CT26 colon carcinoma, which increases overall survival of mice. Antimetastatic and antiangiogenic MGF effects could be further validated in a wound healing in vitro model in human HT29 cells and in a matrigel plug implant mouse model. Interestingly, transcriptome pathway enrichment analysis demonstrates that MGF inhibits tumor growth, metastasis and angiogenesis by multi-targeting of mitochondrial oxidoreductase and fatty acid ß-oxidation metabolism, PPAR, SIRT, NFκB, Stat3, HIF, Wnt and GP6 signaling pathways. MGF effects on fatty acid ß-oxidation metabolism and carnitine palmitoyltransferase 1 (CPT1) protein expression could be further confirmed in vitro in human HT29 colon cells. In conclusion, antitumor, antiangiogenic and antimetastatic effects of MGF treatment hold promise to reduce adverse toxicity and to mitigate therapeutic outcome of colorectal cancer treatment by targeting mitochondrial energy metabolism in the tumor microenvironment.
RESUMEN
Introduction Nasal polyposis is a disease characterized by a mechanical dysfunction of the nasal mucosa, closely related to the unique makeup of its extracellular matrix, which develops as the result of an anomalous tissue remodeling process. Transforming growth factor beta 1 (TGF-ß1) is reduced not only in the nasal polypoid tissue, but also in the plasma of aspirin-intolerant patients. These patients exhibit an imbalance in the production of eicosanoids characterized by an increase in leukotrienes. Thus, it is important that the relationship between the production of leukotrienes and TGF-ß1 be assessed. Objective To evaluate the effects of the cysteinyl leukotriene (CysLT) receptor antagonist montelukast on the systemic production of TGF-ß1 in patients with nasal polyposis, with or without concomitant aspirin intolerance. Methods The sample comprised 48 individuals with diagnosis of nasal polyposis and 15 healthy controls for comparison of the baseline TGF-ß1 levels in the peripheral blood and after treatment with CysLT receptor antagonist montelukast in the nasal-polyposis group. Results There was no difference in the change in TGF-ß1 levels after the treatment with montelukast in the subgroup of patients with polyposis and asthma ( p = 0.82) and in the subgroup with polyposis, asthma, and aspirin intolerance ( p = 0.51). Conclusion we found no impact of the therapy with a leukotriene receptor blocker on the production of TGF-ß1, making the antileukotriene therapy a highly questionable choice for the treatment of nasal polyposis, particularly from the standpoint of seeking to modify the remodeling process in this disease.
RESUMEN
Marine plants have become an inexhaustible reservoir of new phytopharmaceuticals for cancer treatment. We demonstrate in vitro/in vivo antitumor efficacy of a standardized polyphenol extract from the marine angiosperm Thalassia testudinum (TTE) in colon tumor cell lines (RKO, SW480, and CT26) and a syngeneic allograft murine colorectal cancer model. MTT assays revealed a dose-dependent decrease of cell viability of RKO, CT26, and SW480 cells upon TTE treatment with IC50 values of, respectively, 175, 115, and 60 µg/mL. Furthermore, TTE significantly prevented basal and bFGF-induced angiogenesis in the chicken chorioallantoic membrane angiogenesis assay. In addition, TTE suppressed bFGF-induced migration of endothelial cells in a wound closure assay. Finally, TTE treatment abrogated CT26 colorectal cancer growth and increased overall organism survival in a syngeneic murine allograft model. Corresponding transcriptome profiling and pathway analysis allowed for the identification of the mechanism of action for the antitumor effects of TTE. In line with our in vitro/in vivo results, TTE treatment triggers ATF4-P53-NFκB specific gene expression and autophagy stress pathways. This results in suppression of colon cancer cell growth, cell motility, and angiogenesis pathways in vitro and in addition promotes antitumor immunogenic cell death in vivo.
Asunto(s)
Antineoplásicos Fitogénicos/uso terapéutico , Movimiento Celular/efectos de los fármacos , Neoplasias Colorrectales/patología , Hydrocharitaceae , Muerte Celular Inmunogénica/efectos de los fármacos , Neovascularización Patológica/patología , Extractos Vegetales/uso terapéutico , Animales , Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Autofagia/efectos de los fármacos , Autofagia/fisiología , Línea Celular Tumoral , Movimiento Celular/fisiología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Humanos , Hydrocharitaceae/química , Muerte Celular Inmunogénica/fisiología , Masculino , Ratones , Ratones Endogámicos BALB C , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismo , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
Abstract Introduction Nasal polyposis is a disease characterized by a mechanical dysfunction of the nasal mucosa, closely related to the unique makeup of its extracellular matrix, which develops as the result of an anomalous tissue remodeling process. Transforming growth factor beta 1 (TGF-β1) is reduced not only in the nasal polypoid tissue, but also in the plasma of aspirin-intolerant patients. These patients exhibit an imbalance in the production of eicosanoids characterized by an increase in leukotrienes. Thus, it is important that the relationship between the production of leukotrienes and TGF-β1 be assessed. Objective To evaluate the effects of the cysteinyl leukotriene (CysLT) receptor antagonist montelukast on the systemic production of TGF-β1 in patients with nasal polyposis, with or without concomitant aspirin intolerance. Methods The sample comprised 48 individuals with diagnosis of nasal polyposis and 15 healthy controls for comparison of the baseline TGF-β1 levels in the peripheral blood and after treatment with CysLT receptor antagonist montelukast in the nasal-polyposis group. Results There was no difference in the change in TGF-β1 levels after the treatment with montelukast in the subgroup of patients with polyposis and asthma (p = 0.82) and in the subgroup with polyposis, asthma, and aspirin intolerance (p = 0.51). Conclusion we found no impact of the therapy with a leukotriene receptor blocker on the production of TGF-β1, making the antileukotriene therapy a highly questionable choice for the treatment of nasal polyposis, particularly from the standpoint of seeking to modify the remodeling process in this disease.
RESUMEN
Introduction The importance of our study lies in the fact that we have demonstrated the occurrence of mechanical dysfunction within polypoid tissues, which promotes the development of polyps in the nasal cavity. Objective To change the paradigm of nasal polyposis (NP). In this new conception, the chronic nasal inflammatory process that occurs in response to allergies, to pollution, to changes in the epithelial barrier, or to other factors is merely the trigger of the development of the disease in individuals with a genetic predisposition to an abnormal tissue remodeling process, which leads to a derangement of the mechanical properties of the nasal mucosa and, consequently, allows it to grow unchecked. Data Synthesis We propose a fundamentally new approach to intervening in the pathological process of NP, addressing biomechanical properties, fluid dynamics, and the concept of surface tension. Conclusion The incorporation of biomechanical knowledge into our understanding of NP provides a new perspective to help elucidate the physiology and the pathology of nasal polyps, and new avenues for the treatment and cure of NP.
RESUMEN
Introduction: The importance of our study lies in the fact that we have demonstrated the occurrence ofmechanical dysfunction within polypoid tissues, which promotes the development of polyps in the nasal cavity. Objective: To change the paradigm of nasal polyposis (NP). In this new conception, the chronic nasal inflammatory process that occurs in response to allergies, to pollution, to changes in the epithelial barrier, or to other factors is merely the trigger of the development of the disease in individuals with a genetic predisposition to an abnormal tissue remodeling process, which leads to a derangement of the mechanical properties of the nasal mucosa and, consequently, allows it to grow unchecked. Data: Synthesis We propose a fundamentally new approach to intervening in the pathological process of NP, addressing biomechanical properties, fluid dynamics, and the concept of surface tension. Conclusion: The incorporation of biomechanical knowledge into our understanding of NP provides a new perspective to help elucidate the physiology and the pathology of nasal polyps, and new avenues for the treatment and cure of NP (AU)
Asunto(s)
Humanos , Pólipos Nasales/fisiopatología , Pólipos Nasales/patología , Inflamación/fisiopatología , Sinusitis/fisiopatología , Fenómenos Biomecánicos , Brasil , Mecánica de Fluidos , Enfermedad Crónica , Edema/fisiopatología , Matriz Extracelular/patología , Presión Hidrostática , Mucosa Nasal/fisiopatología , Mucosa Nasal/patologíaRESUMEN
Mesenchymal stromal cells (MSCs) are considered adult progenitor stem cells and have been studied in a multitude of tissues. In this context, the microenvironment of nasal polyp tissue has several inflammatory cells, but their stroma compartment remains little elucidated. Hence, we isolated MSCs from nasal polyps Polyp-MSCs (PO-MSCs) and compared their molecular features and gene expression pattern with bone marrow-derived MSCs (BM-MSCs). Initially, both PO-MSCs and BM-MSCs were isolated, cultivated, and submitted to morphologic, differentiation, phenotypic, immunosuppressive, and gene expression assays. Compared to BM-MSCs, PO-MSCs showed normal morphology and similar osteogenic/adipogenic differentiation potential, but their immunophenotyping showed lack of immune-associated molecules (e.g., CD117, HLA-DR, PDL-1, and PDL-2), which was linked with less immunoregulatory abilities such as (i) inhibition of lymphocytes proliferation and (ii) regulatory T cell expansion. Furthermore, we detected in the PO-MSCs a distinct gene expression profile in comparison with BM-MSCs. PO-MSC expressed higher levels of progenitor stem cells specific markers (e.g., CD133 and ABCB1), while BM-MSCs showed elevated expression of cytokines and growth factors (e.g., FGF10, KDR, and GDF6). The gene ontology analysis showed that the differentially modulated genes in PO-MSC were related with matrix remodeling process and hexose and glucose transport. For BM-MSCs, the highly expressed genes were associated with behavior, angiogenesis, blood vessel morphogenesis, cell-cell signaling, and regulation of response to external stimulus. Thus, these results suggest that PO-MSCs, while sharing similar aspects with BM-MSCs, express a different profile of molecules, which presumably can be implicated in the development of nasal polyp tissue.
RESUMEN
PURPOSE OF REVIEW: Two main pillars are implicated in nasal polyposis development: a severe imbalance in immunomodulation and a mechanical dysfunction because of an abnormal remodeling process. Dendritic cells play a crucial role in the link between innate and adaptive immune response and orchestrating the T-cell response and are implicated in the severe inflammatory process found in nasal polypoid tissue. This review summarizes the existent knowledge about dendritic cells in nasal polyposis. RECENT FINDINGS: Dendritic cells are found increased in nasal polyposis, regardless of subset. Of interest, plasmacytoid dendritic cells are decreased in patients with a more severe Th2 profile, suggesting an important role of the cytokines milieu in their functional response or that plasmacytoid dendritic cell could act mitigating the inflamed process found in polypoid tissue. SUMMARY: Understanding the dendritic cell subset expression in different environments, as well as the effect of these subsets on T-cell differentiation will greatly improve the development of new therapies in nasal polyposis.
Asunto(s)
Células Dendríticas/inmunología , Pólipos Nasales/inmunología , Rinitis/inmunología , Sinusitis/inmunología , Linfocitos T/inmunología , Animales , Enfermedad Crónica , Progresión de la Enfermedad , Humanos , Activación de LinfocitosRESUMEN
BACKGROUND: Systemic reactions are related to the pathogenesis of Aspirin Exacerbated Respiratory Disease (AERD). With this work we wanted to study the changes in the systemic levels of inflammatory mediators in both baseline and after oral aspirin challenge in patients with and without AERD. METHODS: Patients with nasal polyposis and asthma with AERD (n=20) and without (n=18) were orally challenged with aspirin in a single-blind placebo controlled study. Serum samples and urine were collected before and 6h after placebo and aspirin oral challenges. Serum levels of inflammatory mediators were assayed by using the Luminex technology and ELISA. The concentrations of 9-alpha, 11-beta prostaglandin F2, and leukotriene E4 (uLTE4) were measured in urine samples by ELISA. The expression of T-cell surface markers was analyzed in peripheral blood mononuclear cells isolated before and after the challenges. RESULTS: AERD patients showed significantly higher baseline levels of s-IL-5R-alpha, uLTE4 and percentage of CD4(+)CD25(+)CD127(pos) and CD4(+)CD45RA(-)CD45RO(+) but decreased levels of TGF-ß1 and number of CD4(+)CD25(+)CD127(neg) cells. Aspirin challenge induced the release of uLTE4, IL-6 and increased the number of CD4(+)CD45RA(-)CD45RO(+) memory T-cells only in AERD patients but failed to reduce the levels of sCD40L as observed in non-AERD subjects. Further, IL-8 and sIL-5R-alpha levels directly correlated with the PD20ASA and the effects of aspirin on IL-6 and number of memory T-cells was more pronounced in subjects showing more strong reaction (bronchial and nasal). CONCLUSIONS: AERD patients have a differential baseline inflammatory pattern that supports the role inflammation as underlying mechanism of the disease. Systemic response to oral aspirin challenge was related to an increase in serum IL-6 and the number of circulating memory T-cells in AERD patients.
Asunto(s)
Asma Inducida por Aspirina/metabolismo , Mediadores de Inflamación/análisis , Pólipos Nasales/metabolismo , Rinitis/metabolismo , Sinusitis/metabolismo , Adulto , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/efectos adversos , Aspirina/administración & dosificación , Aspirina/efectos adversos , Asma Inducida por Aspirina/diagnóstico , Asma Inducida por Aspirina/etiología , Enfermedad Crónica , Citocinas/sangre , Femenino , Humanos , Técnicas para Inmunoenzimas , Mediadores de Inflamación/sangre , Mediadores de Inflamación/orina , Leucotrieno E4/orina , Masculino , Persona de Mediana Edad , Prostaglandina D2/orina , Método Simple Ciego , Subgrupos de Linfocitos T/metabolismoRESUMEN
OBJECTIVE: To evaluate TGF-ß1 expression in polypoid mucosa (epithelium and stroma) of patients with chronic rhinosinusitis with nasal polyposis (CRSwNP). METHODS: Cross-sectional study with two groups: 17 patients with nasal polyposis and 11 controls. Polyps and normal nasal mucosa were processed by immunohistochemical methods for TGF-ß1 visualization. Then, the percentage of TGF-ß1 expression in stroma and epithelium was objectively quantified using UT Morph software. RESULTS: A lower percentage of positive expression was found in the epithelium of CRSwNP patients (32.44%) versus normal controls (55.91%) (p < 0.05), and a higher percentage of positive expression in the stroma of CRSwNP patients (23.24%) versus controls (5.88%) (p < 0.05). CONCLUSION: The lower percentage of TGF-ß1 expression in the nasal epithelium of CRSwNP patients may have an impact on epithelium-directed topical treatments employed in this patient population.