Your browser doesn't support javascript.
loading
Montrer: 20 | 50 | 100
Résultats 1 - 20 de 150
Filtrer
1.
Planta Med ; 89(3): 286-294, 2023 Mar.
Article de Anglais | MEDLINE | ID: mdl-35896509

RÉSUMÉ

Herein, we describe the antiproliferative effects of two natural dibenzo [b,f]oxepines, pacharin and bauhiniastatin-1, isolated from Bauhinia acuruana on a breast cancer cell line and the mode of action underlying the cytotoxicity. Both compounds were cytotoxic in a panel of six tumor lines analyzed by the MTT assay, and IC50 values ranged from 7.8 to 45.1 µM, including human breast adenocarcinoma (MCF-7) cells. In contrast, none of the compounds were cytotoxic on normal human peripheral blood mononuclear cells (IC50 > 100 µM). Human breast adenocarcinoma (MCF-7) cells treated with pacharin or bauhiniastatin-1 20 µM for 24 h presented a reduction in cell volume and intensification of chromatin condensation, DNA fragmentation, and apoptotic cells. These findings became more evident after 48 h of exposure. Antiapoptotic B-cell lymphoma-2 family members, such as myeloid cell leukemia-1 and B-cell lymphoma-extra large, are important targets in cancer cells since their overexpression confers resistance to cancer treatments. A significant reduction of the myeloid cell leukemia-1 protein levels in human breast adenocarcinoma (MCF-7) cells after 24 h of treatment with pacharin or bauhiniastatin-1 at 20 µM was observed, while the B-cell lymphoma-extra large protein content was reduced in bauhiniastatin-1-treated cells at 40 µM only. The cytotoxic effects of pacharin and bauhiniastatin-1 are likely linked to myeloid cell leukemia-1 inhibition, which leads to the apoptosis of breast adenocarcinoma cells.


Sujet(s)
Adénocarcinome , Antinéoplasiques , Bauhinia , Tumeurs du sein , Leucémies , Humains , Femelle , Tumeurs du sein/métabolisme , Agranulocytes/métabolisme , Agranulocytes/anatomopathologie , Protéine Mcl-1/usage thérapeutique , Antinéoplasiques/pharmacologie , Antinéoplasiques/usage thérapeutique , Apoptose , Cellules MCF-7 , Lignée cellulaire tumorale , Adénocarcinome/traitement médicamenteux
2.
Immunology ; 168(1): 96-109, 2023 01.
Article de Anglais | MEDLINE | ID: mdl-36056642

RÉSUMÉ

Oral leukoplakia (OL) and proliferative verrucous leukoplakia (PVL) are oral potentially malignant disorders (OPMDs) that microscopically show no or varying degrees of dysplasia. Even sharing clinical and microscopic aspects, PVL shows a more aggressive clinical behaviour, with a malignant transformation rate greater than 40%. Inflammatory infiltrate associated with dysplastic lesions may favour malignant transformation of OPMDs. This study aimed to evaluate the density of T cells and cytokines in dysplastic lesions from OL and PVL patients. Additionally, we evaluated whether soluble products produced in vitro by dysplastic keratinocytes are capable of modulating apoptosis rates and Th phenotype (Th1, Th2, Th17 and Treg) of peripheral blood mononuclear cells. The density of CD3, CD4 and CD8 T cells was assessed by immunohistochemistry. Cytokines and chemokines profile from frozen tissue samples were analysed using the LUMINEX system. Apoptosis rates and Th phenotype modulation were evaluated by flow cytometry. Our results showed an increase in the number of CD8 T cell in the subepithelial region from PVL dysplastic lesions in relation to OL samples. PVL showed increased levels of IL-5 and a decrease in IL-1ß and IFN-γ levels compared to OL. Soluble products of PVL and oral carcinoma cell cultures were able to reduce apoptosis rate and promote an imbalance of Th1/Th2 and Th17/Treg. The high-subepithelial density of CD8 T cells and immune imbalance of T lymphocytes subsets probably play an important role in the pathogenesis of PVL and may explain its more aggressive behaviour in relation to OL.


Sujet(s)
Tumeurs de la bouche , États précancéreux , Humains , Agranulocytes/anatomopathologie , Leucoplasie buccale/anatomopathologie , Tumeurs de la bouche/anatomopathologie , États précancéreux/anatomopathologie , Lymphocytes T CD8+/anatomopathologie , Cytokines , Transformation cellulaire néoplasique
3.
Int J Mol Sci ; 23(10)2022 May 13.
Article de Anglais | MEDLINE | ID: mdl-35628256

RÉSUMÉ

The complete regression of clear cell renal cell carcinoma (ccRCC) obtained pre-clinically with anti-carbonic anhydrase IX (CAIX) G36 chimeric antigen receptor (CAR) T cells in doses equivalent to ≅108 CAR T cells/kg renewed the potential of this target to treat ccRCC and other tumors in hypoxia. The immune checkpoint blockade (ICB) brought durable clinical responses in advanced ccRCC and other tumors. Here, we tested CD8α/4-1BB compared to CD28-based anti-CAIX CAR peripheral blood mononuclear cells (PBMCs) releasing anti-programmed cell death ligand-1 (PD-L1) IgG4 for human ccRCC treatment in vitro and in an orthotopic NSG mice model in vivo. Using a ≅107 CAR PBMCs cells/kg dose, anti-CAIX CD28 CAR T cells releasing anti-PD-L1 IgG highly decrease both tumor volume and weight in vivo, avoiding the occurrence of metastasis. This antitumoral superiority of CD28-based CAR PBMCs cells compared to 4-1BB occurred under ICB via PD-L1. Furthermore, the T cell exhaustion status in peripheral CD4 T cells, additionally to CD8, was critical for CAR T cells efficiency. The lack of hepatotoxicity and nephrotoxicity upon the administration of a 107 CAR PMBCs cells/kg dose is the basis for carrying out clinical trials using anti-CAIX CD28 CAR PBMCs cells releasing anti-PD-L1 antibodies or anti-CAIX 4-1BB CAR T cells, offering exciting new prospects for the treatment of refractory ccRCC and hypoxic tumors.


Sujet(s)
Antigène CD274 , Carbonic anhydrase IX , Néphrocarcinome , Tumeurs du rein , Récepteurs chimériques pour l'antigène , Animaux , Anticorps/immunologie , Antigène CD274/antagonistes et inhibiteurs , Antigène CD274/immunologie , Antigène CD28 , Carbonic anhydrase IX/immunologie , Néphrocarcinome/immunologie , Néphrocarcinome/anatomopathologie , Néphrocarcinome/thérapie , Inhibiteurs de points de contrôle immunitaires , Tumeurs du rein/immunologie , Tumeurs du rein/anatomopathologie , Tumeurs du rein/thérapie , Agranulocytes/anatomopathologie , Souris , Récepteurs chimériques pour l'antigène/immunologie , Lymphocytes T/immunologie
4.
Clin Transl Oncol ; 24(6): 1184-1194, 2022 Jun.
Article de Anglais | MEDLINE | ID: mdl-34988921

RÉSUMÉ

PURPOSE: Myeloid-derived suppressors cells (MDSCs) are heterogeneous immunosuppressive cells, closely related to the development, efficacy and prognosis in various tumors. The relationship between clinicopathological characteristics, efficacy of neoadjuvant chemoimmunotherapy (NCIO) and circulating MDSCs in patients with non-small cell lung cancer (NSCLC) was investigated in this study. METHODS: This study analyzed the clinical data of patients diagnosed at Department of Thoracic Surgery, Beijing Chest Hospital from November 2020 to August 2021. MDSCs and T cells subgroups were measured in fresh peripheral blood mononuclear cells(PBMCs) at baseline. Flow cytometry was used to detect MDSCs and T cells subgroups. RESULTS: A total of 78 patients with NSCLC and 20 patients with benign nodule underwent direct surgery. 23 patients with NSCLC scheduled to accept NCIO before surgery. NSCLC had elevated levels of total MDSCs, PMN-MDSCs and M-MDSCs compared to patients with benign nodule. MDSCs subgroups were correlated to the pTNM stage in NSCLC patients. The frequency of total MDSCs were moderately positively correlated with regulatory T cells (Tregs)(r = 0.3597, P < 0.01) and negatively correlated with CD4 + T cells(r = 0.2714, P < 0.05). The baseline levels of total MDSCs, PMN-MDSCs and Tregs in pCR patients were significantly decreased than those of non-pCR patients (P < 0.05). CONCLUSION: Circulating MDSCs were increased in NSCLC patients. MDSC subgroups were related to pTNM stage in NSCLC patients. Total MDSCs were positively correlated with Tregs levels and negatively correlated with CD4 + T cells in peripheral blood. The level of MDSCs and Tregs in peripheral blood may have potential value in predicting pathological response in NSCLC.


Sujet(s)
Carcinome pulmonaire non à petites cellules , Tumeurs du poumon , Cellules myéloïdes suppressives , Carcinome pulmonaire non à petites cellules/traitement médicamenteux , Carcinome pulmonaire non à petites cellules/anatomopathologie , Humains , Agranulocytes/anatomopathologie , Tumeurs du poumon/anatomopathologie , Tumeurs du poumon/thérapie , Cellules myéloïdes suppressives/anatomopathologie , Traitement néoadjuvant
5.
J Endocrinol Invest ; 44(12): 2819-2830, 2021 Dec.
Article de Anglais | MEDLINE | ID: mdl-33991317

RÉSUMÉ

BACKGROUND: Obesity promotes cellular immunometabolism changes that trigger the activation of macrophages and lymphocytes, leading to systemic inflammation. Activated leukocytes undergo metabolic reprogramming, increasing glycolytic activity. OBJECTIVE: To examine whether the reduction in the inflammatory state associated with bariatric surgery is associated with decreased glycolytic activity in leukocytes. Setting Single-center, prospective observational study. METHODS: This study involved 18 patients with obesity undergoing bariatric surgery. All measurements were performed preoperatively and six months postoperatively. Peripheral blood mononuclear cells and plasma were obtained to determine the glycolytic rate and mitochondrial membrane potential as surrogates of the metabolic switching and high-sensitivity C-reactive protein, adipokines, and CD69 expression as inflammatory and activation markers. RESULTS: Glycolytic activity engaged by CD3/CD28 activation was reduced six months after bariatric surgery, associated with decreased levels of T helper (Th) 1 and Th17 signature cytokines. An overall reduction in inflammatory markers was observed, which correlated with a higher adiponectin/leptin ratio. CONCLUSIONS: Metabolic and bariatric surgery-induced weight loss leads to reprogramming in T cells' metabolic machinery, resulting in reduced stimulation of glycolysis after activation, which may explain the decrease in systemic inflammation mediated by cytokines such as interferon-γ and interleukin-17A.


Sujet(s)
Activation métabolique/immunologie , Chirurgie bariatrique/méthodes , Glycolyse/immunologie , Agranulocytes , Obésité morbide , Lymphocytes auxiliaires Th1 , Cellules Th17 , Adulte , Numération cellulaire/méthodes , Reprogrammation cellulaire , Métabolisme énergétique/immunologie , Femelle , Humains , Inflammation/immunologie , Inflammation/métabolisme , Agranulocytes/métabolisme , Agranulocytes/anatomopathologie , Mâle , Obésité morbide/métabolisme , Obésité morbide/chirurgie , Période postopératoire , Lymphocytes auxiliaires Th1/métabolisme , Lymphocytes auxiliaires Th1/anatomopathologie , Cellules Th17/métabolisme , Cellules Th17/anatomopathologie
6.
PLoS One ; 15(10): e0240269, 2020.
Article de Anglais | MEDLINE | ID: mdl-33007040

RÉSUMÉ

OBJECTIVE: It is increasingly common to find patients affected by a combination of type 2 diabetes mellitus (T2DM), dyslipidemia (DLP) and periodontitis (PD), which are chronic inflammatory diseases. More studies able to capture unknown relationships among these diseases will contribute to raise biological and clinical evidence. The aim of this study was to apply association rule mining (ARM) to discover whether there are consistent patterns of clinical features (CFs) and differentially expressed genes (DEGs) relevant to these diseases. We intend to reinforce the evidence of the T2DM-DLP-PD-interplay and demonstrate the ARM ability to provide new insights into multivariate pattern discovery. METHODS: We utilized 29 clinical glycemic, lipid and periodontal parameters from 143 patients divided into five groups based upon diabetic, dyslipidemic and periodontal conditions (including a healthy-control group). At least 5 patients from each group were selected to assess the transcriptome by microarray. ARM was utilized to assess relevant association rules considering: (i) only CFs; and (ii) CFs+DEGs, such that the identified DEGs, specific to each group of patients, were submitted to gene expression validation by quantitative polymerase chain reaction (qPCR). RESULTS: We obtained 78 CF-rules and 161 CF+DEG-rules. Based on their clinical significance, Periodontists and Geneticist experts selected 11 CF-rules, and 5 CF+DEG-rules. From the five DEGs prospected by the rules, four of them were validated by qPCR as significantly different from the control group; and two of them validated the previous microarray findings. CONCLUSIONS: ARM was a powerful data analysis technique to identify multivariate patterns involving clinical and molecular profiles of patients affected by specific pathological panels. ARM proved to be an effective mining approach to analyze gene expression with the advantage of including patient's CFs. A combination of CFs and DEGs might be employed in modeling the patient's chance to develop complex diseases, such as those studied here.


Sujet(s)
Biologie informatique/méthodes , Diabète de type 2/génétique , Diabète de type 2/anatomopathologie , Adulte , Fouille de données , Femelle , Analyse de profil d'expression de gènes/méthodes , Humains , Inflammation/génétique , Inflammation/anatomopathologie , Agranulocytes/métabolisme , Agranulocytes/anatomopathologie , Mâle , Adulte d'âge moyen , Analyse multifactorielle , Réaction de polymérisation en chaine en temps réel
7.
BMC Cancer ; 20(1): 882, 2020 Sep 14.
Article de Anglais | MEDLINE | ID: mdl-32928147

RÉSUMÉ

BACKGROUND: Cytotoxic chemotherapy can cure advanced germ cell tumors. Nevertheless, cancer treatment may induce cellular senescence and accelerate molecular aging. The aging process implies an increase of cells expressing p16INK4a and changes in lymphocyte subpopulations. Our aim was to study the potential induction of premature immunosenescence in testicular cancer survivors (TCS) exposed to chemotherapy. METHODS: Case-control exploratory study of TCS treated with chemotherapy (≥3 BEP cycles, disease-free ≥3 months) compared with age matched healthy controls. Peripheral blood mononuclear cells were isolated, and lymphocyte subpopulations were analyzed by flow cytometry. CDKN2A/p16INK4a expression in T cells was measured using qPCR. The percentage of lymphocyte subpopulations and the CDKN2A/p16INK4a expression in TCS were compared with the control group using the Wilcoxon signed-rank test. RESULTS: We included 16 cases and 16 controls. The median age was 27 years (minimum 24, maximum 54) and the median time on surveillance was 26.5 months (minimum 3, maximum192). TCS had a lower percentage of total T cells and CD4+ T cells in total lymphocytes. Among the CD4+ T lymphocytes, TCS had less naïve CD4+ and increased memory CD4+ cells. Within the CD8+ T lymphocytes, TCS exhibited a decrease in the percentage of naïve cells and an increase in CD8 + CD45RA + CD57+ cells. TCS also exhibited decreased memory CD19+ B cells compared to the controls. The relative expression of CDKN2A/p16INK4a in T cells was increased in TCS (mean 1.54; 95% CI of the mean: 1.074-2.005; p = 0.048). CONCLUSION: In this exploratory study, TCS showed increased expression of CDKN2A/p16INK4a and a lymphocyte phenotype that has been associated with immunosenescence. Further studies are warranted to define the clinical implications of these alterations in TCS.


Sujet(s)
Vieillissement/génétique , Inhibiteur p16 de kinase cycline-dépendante/génétique , Tumeurs embryonnaires et germinales/génétique , Tumeurs du testicule/génétique , Adulte , Lymphocytes T CD4+/métabolisme , Lymphocytes T CD8+/anatomopathologie , Survivants du cancer , Femelle , Humains , Immunosénescence/génétique , Agranulocytes/métabolisme , Agranulocytes/anatomopathologie , Mâle , Adulte d'âge moyen , Tumeurs embryonnaires et germinales/immunologie , Tumeurs embryonnaires et germinales/anatomopathologie , Tumeurs du testicule/immunologie , Tumeurs du testicule/anatomopathologie
8.
Article de Anglais | MEDLINE | ID: mdl-32928373

RÉSUMÉ

Organophosphate (OP) pesticides are biotransformed into metabolites such as dialkylphosphates (DAPs). We have evaluated the genotoxicity of malathion and its metabolite dimethylthiophosphate (DMTP) in the human hepatic cell lines HepG2 and WRL-68 and in peripheral blood mononuclear cells (PBMC). In the Cytokinesis-Block Micronucleus assay (CBMN), malathion and DMTP increased the frequencies of micronuclei (MN) and nucleoplasmic bridges (NPB). Malathion was primarily clastogenic whereas DMTP was aneuploidogenic. When HepG2 or WRL-68 cells were treated with DMTP in the presence of sulconazole, a non-specific cytochrome P450 inhibitor, MN frequency was reduced, indicating that DMTP genotoxicity requires P450-cataliyzed metabolism.


Sujet(s)
Cytocinèse/effets des médicaments et des substances chimiques , Malathion/pharmacologie , Tests de mutagénicité , Mutagènes/pharmacologie , Noyau de la cellule/effets des médicaments et des substances chimiques , Altération de l'ADN/effets des médicaments et des substances chimiques , Humains , Agranulocytes/effets des médicaments et des substances chimiques , Agranulocytes/anatomopathologie , Malathion/toxicité , Mutagènes/toxicité , Pesticides/pharmacologie , Pesticides/toxicité
9.
Indian J Gastroenterol ; 39(2): 186-195, 2020 04.
Article de Anglais | MEDLINE | ID: mdl-32436176

RÉSUMÉ

BACKGROUND: Though a few studies in animal models suggest that intestinal helminths (IH) favorably affect evolution of gastritis associated with Helicobacter pylori (H. pylori) the studies supporting this concept in humans are only a few and are based on serological data. METHODS: To evaluate the possible influence of IH on the human gastric mucosa, three groups of Venezuelan adults with gastropathy (endoscopically diagnosed) were studied: H. pylori-/IH- (n = 17), H. pylori+/IH- (n = 18), and H. pylori+/IH+ (n = 11). Histological analysis (hematoxylin-eosin) and immunohistochemical staining (peroxidase) for cytokines interleukin-1beta (IL-1ß), tumor necrosis factor alpha (TNF-α), gamma interferon (IFN-γ), and interleukin 4 (IL-4) were undertaken in gastric antral biopsies. RESULTS: Expression of the four cytokines was detected in all individuals in varying degrees, but proinflammatory cytokines were expressed in a higher degree in the H. pylori+/IH- group, mainly IL-1ß (Th1-dominant immune response), associated with a higher degree of both histological inflammation and gastric cancer risk index (GCRI), as compared to the H. pylori-/IH- group. In contrast, an increased expression of IL-4 and a reduced expression of proinflammatory cytokines (Th2-dominant response), plus the tendency to a lower degree of mononuclear infiltration, mucosal atrophy in gastric corpus, and GCRI, were evidenced in the coinfected group. CONCLUSIONS: The findings of the present study is perhaps the first histological evidence of a possible modulatory effect of IH on the gastric mucosal inflammatory response due to H. pylori infection in humans.


Sujet(s)
Co-infection/métabolisme , Co-infection/anatomopathologie , Cytokines/métabolisme , Muqueuse gastrique/métabolisme , Muqueuse gastrique/anatomopathologie , Gastrite/microbiologie , Gastrite/anatomopathologie , Infections à Helicobacter , Helicobacter pylori , Médiateurs de l'inflammation/métabolisme , Parasitoses intestinales/métabolisme , Parasitoses intestinales/anatomopathologie , Adolescent , Adulte , Atrophie , Co-infection/immunologie , Femelle , Muqueuse gastrique/immunologie , Gastrite/immunologie , Gastrite/métabolisme , Humains , Immunohistochimie , Parasitoses intestinales/immunologie , Agranulocytes/anatomopathologie , Mâle , Adulte d'âge moyen , Jeune adulte
10.
Mol Med Rep ; 22(1): 507-515, 2020 07.
Article de Anglais | MEDLINE | ID: mdl-32377714

RÉSUMÉ

During the progression of psoriatic lesions, abundant cellular infiltration of myeloid cells, such as macrophages and activated dendritic cells, occurs in the skin and the infiltrating cells interact with naive lymphoid cells to generate a T helper (Th)1 and Th17 environment. Therapies to treat psoriasis include phototherapy, non­steroidal and steroidal drugs, as well as antibodies to block tumor necrosis factor­α, interleukin (IL)­17­A and IL­12/IL­23, which all focus on decreasing the proinflammatory hallmark of psoriasis. The present study obtained the heptapeptide HP3 derived from phage display technology that blocks mononuclear cell adhesion to endothelial cells and inhibits trans­endothelial migration in vitro. The activity of the heptapeptide in a murine model of psoriasis was also assessed, which indicated that early administration inhibited the development of psoriatic lesions. Therefore, the results suggested that HP3 may serve as a potential therapeutic target for psoriasis.


Sujet(s)
Cellules endothéliales/effets des médicaments et des substances chimiques , Agranulocytes/effets des médicaments et des substances chimiques , Oligopeptides/usage thérapeutique , Psoriasis/traitement médicamenteux , Migration transendothéliale et transépithéliale/effets des médicaments et des substances chimiques , Animaux , Lignée cellulaire , Modèles animaux de maladie humaine , Cellules endothéliales/cytologie , Cellules endothéliales/anatomopathologie , Femelle , Humains , Imiquimod , Agranulocytes/cytologie , Agranulocytes/anatomopathologie , Souris , Souris de lignée BALB C , Oligopeptides/composition chimique , Oligopeptides/pharmacologie , Psoriasis/induit chimiquement , Psoriasis/anatomopathologie
11.
Article de Anglais | MEDLINE | ID: mdl-32265833

RÉSUMÉ

Pulmonary tuberculosis (PTB), caused by Mycobacterium tuberculosis (Mtb), is a major health problem worldwide, further aggravated by the convergence of type 2 diabetes mellitus (DM) which constitutes an important risk factor for TB development. The worse scenario of patients with PTB and DM may be partly related to a more unbalanced defensive response. As such, newly diagnosed PTB patients with DM (TB+DM, n = 11) or not (TB, n = 21), as well as DM (n = 18) patients and pair matched controls (Co, n = 22), were investigated for the circulating immuno-endocrine-metabolic profile (ELISA), along with studies in peripheral blood mononuclear cells (PBMC) analyzing transcript expression (RT-qPCR) of mediators involved in glucocorticoid functionality. Given the hyperglycemic/hypercortisolemic scenario of TB+DM patients, PBMC were also exposed to stress-related cortisol concentrations (0.1 and 1 µM) and supraphysiologic glucose doses (10, 20, and 40 mM) and assessed for the specific response against Mtb stimulation (lymphoproliferation, -thymidine incorporation-, and cytokine production -bead-cytometry). All TB patients displayed increased plasma amounts of cortisol, growth hormone -hGH-, and proinflammatory mediators. In turn, TB+DM showed even higher levels of interferon gamma -IFN-γ- and hGH (vs. TB), or IL-6, C reactive protein, cortisol and hGH (vs. DM). Both DM groups had equally augmented values of IL-10. All TB patients showed decreased dehydroepiandrosterone- sulfate concentrations, even more in TB+DM cases. Leptin was also decreased in both TB cases, particularly in the TB group, revealing a lower body mass index, as well. Unlike PBMC from TB cases showing a decreased relationship between the glucocorticoids receptor (GR) isoforms (GRα/GRß; functional isoform/negative isoform), cells from TB+DM patients had no changes in this regard, along with an increased expression of 11-beta hydroxysteroid dehydrogenase type-1, the enzyme facilitating intracellular cortisone to cortisol conversion. TB+DM patients also showed an increased Mtb antigen-driven lymphoproliferation. Compared to TB, DM and HCo counterparts, PBMC from TB+DM patients had a biased Th1 response to Mtb stimulation (increased IL-2 and IFN-γ production), even when exposed to inhibitory cortisol doses. TB+DM patients show a more unbalanced immuno-endocrine relationship, respect the non-diabetic counterparts, with a relative deficiency of cortisol immunomodulatory influences, despite their more favorable microenvironment for cortisol-mediated immune effects.


Sujet(s)
Diabète de type 2 , Système endocrine/physiopathologie , Hydrocortisone/sang , Système immunitaire/physiopathologie , Tuberculose , Adulte , Études cas-témoins , Cellules cultivées , Comorbidité , Cytokines/sang , Diabète de type 2/sang , Diabète de type 2/complications , Diabète de type 2/épidémiologie , Diabète de type 2/immunologie , Femelle , Humains , Hydrocortisone/pharmacologie , Agranulocytes/effets des médicaments et des substances chimiques , Agranulocytes/immunologie , Agranulocytes/anatomopathologie , Mâle , Adulte d'âge moyen , Mycobacterium tuberculosis/effets des médicaments et des substances chimiques , Mycobacterium tuberculosis/immunologie , Tuberculose/sang , Tuberculose/complications , Tuberculose/épidémiologie , Tuberculose/immunologie
12.
PLoS One ; 15(1): e0227314, 2020.
Article de Anglais | MEDLINE | ID: mdl-31951638

RÉSUMÉ

Acute lymphoblastic leukemia (ALL) is the most common cancer in children around the globe. Mexico City has one of the highest incidence rates of childhood leukemia worldwide with 49.5 cases per million children under the age of 15 which is similar to that reported for Hispanic populations living in the United States. In addition, it has been noted a dismal prognosis in Mexican and Hispanic ALL pediatric population. Although ALL, like cancer in general, has its origins in endogenous, exogenous, and genetic factors, several studies have shown that the immune system also plays a deterministic role in cancer development. Among various elements of the immune system, T lymphocytes and NK cells seem to dominate the immune response against leukemia. The aim of the present study was to perform a phenotypic and functional characterization of NK cells in ALL Mexican children at the moment of diagnosis and before treatment initiation. A case-control study was conducted by the Mexican Interinstitutional Group for the Identification of the Causes of Childhood Leukemia (MIGICCL). 41 cases were incident ALL children younger than 17 years old and residents of Mexico City. 14 controls were children without leukemia, matched by age and sex with cases. NK cell function was evaluated by degranulation assays towards K562 cells and SLAM-associated protein (SAP) expression was measured by intracellular staining. All assays were performed using peripheral blood mononuclear cells from controls and patients. The results indicate that NK mediated cytotoxicity, measured by CD107a degranulation assays in response to K562 cells, was reduced in ALL patients compared to controls. Interestingly, an impaired NK cell killing of target cells was not equally distributed among ALL patients. In contrast to patients classified as high-risk, standard-risk patients did not display a significant reduction in NK cell-mediated cytotoxicity. Moreover, patients presenting a leukocyte count ≥ 50,000xmm3 displayed a reduction in NK-cell mediated cytotoxicity and a reduction in SAP expression, indicating a positive correlation between a reduced SAP expression and an impaired NK cell-mediated citotoxicity. In the present study it was observed that unlike patients with standard-risk, NK cells from children presenting high-risk ALL, harbor an impaired cytotoxicity towards K562 at diagnosis. In addition, NK cell function was observed to be compromised in patients with a leukocyte count ≥50,000xmm3, where also it was noticed a decreased expression of SAP compared to patients with a leukocyte count <50,000xmm3. These data indicate NK cell-mediated cytotoxicity is not equally affected in ALL patients, nevertheless a positive correlation between low SAP expression and decreased NK cell-mediated cytotoxicity was observed in ALL patients with a leukocyte count ≥50,000xmm3. Finally, an abnormal NK cell-mediated cytotoxicity may represent a prognostic factor for high-risk acute lymphoblastic leukemia.


Sujet(s)
Cellules tueuses naturelles/immunologie , Leucémie-lymphome lymphoblastique à précurseurs B et T/sang , Protéine associée aux molécules de signalisation de l'activation des lymphocytes/génétique , Lymphocytes T cytotoxiques/métabolisme , Adolescent , Études cas-témoins , Dégranulation cellulaire/génétique , Dégranulation cellulaire/immunologie , Enfant , Enfant d'âge préscolaire , Cytotoxicité immunologique/génétique , Femelle , Régulation de l'expression des gènes tumoraux/génétique , Humains , Cellules K562 , Cellules tueuses naturelles/anatomopathologie , Agranulocytes/métabolisme , Agranulocytes/anatomopathologie , Protéine de membrane-1 associée au lysosome/génétique , Mâle , Mexique , Leucémie-lymphome lymphoblastique à précurseurs B et T/génétique , Leucémie-lymphome lymphoblastique à précurseurs B et T/anatomopathologie , Lymphocytes T cytotoxiques/anatomopathologie
13.
J Cell Mol Med ; 24(2): 1413-1427, 2020 01.
Article de Anglais | MEDLINE | ID: mdl-31778027

RÉSUMÉ

BACKGROUND: Increased Rho-kinase activity in circulating leucocytes is observed in heart failure with reduced ejection fraction (HFrEF). However, there is little information in HFrEF regarding other Rho-kinase pathway components an on the relationship between Rho-kinase and apoptosis. Here, Rho-kinase activation levels and phosphorylation of major downstream molecules and apoptosis levels were measured for the first time both in HFrEF patients and healthy individuals. METHODS: Cross-sectional study comparing HFrEF patients (n = 20) and healthy controls (n = 19). Rho-kinase activity in circulating leucocytes (peripheral blood mononuclear cells, PBMCs) was determined by myosin light chain phosphatase 1 (MYPT1) and ezrin-radixin-moesin (ERM) phosphorylation. Rho-kinase cascade proteins phosphorylation p38-MAPK, myosin light chain-2, JAK and JNK were also analysed along with apoptosis. RESULTS: MYPT1 and ERM phosphorylation were significantly elevated in HFrEF patients, (3.9- and 4.8-fold higher than in controls, respectively). JAK phosphorylation was significantly increased by 300% over controls. Phosphorylation of downstream molecules p38-MAPK and myosin light chain-2 was significantly higher by 360% and 490%, respectively, while JNK phosphorylation was reduced by 60%. Catecholamine and angiotensin II levels were significantly higher in HFrEF patients, while angiotensin-(1-9) levels were lower. Apoptosis in circulating leucocytes was significantly increased in HFrEF patients by 2.8-fold compared with controls and significantly correlated with Rho-kinase activation. CONCLUSION: Rho-kinase pathway is activated in PMBCs from HFrEF patients despite optimal treatment, and it is closely associated with neurohormonal activation and with apoptosis. ROCK cascade inhibition might induce clinical benefits in HFrEF patients, and its assessment in PMBCs could be useful to evaluate reverse remodelling and disease regression.


Sujet(s)
Apoptose , Défaillance cardiaque/sang , Défaillance cardiaque/physiopathologie , Agranulocytes/enzymologie , Agranulocytes/anatomopathologie , Transduction du signal , Débit systolique , rho-Associated Kinases/métabolisme , Angiotensines/sang , Animaux , Antigènes CD/métabolisme , Catécholamines/sang , Cytokines/sang , Protéines du cytosquelette/métabolisme , Modèles animaux de maladie humaine , Activation enzymatique , Femelle , Défaillance cardiaque/imagerie diagnostique , Humains , Kinase Janus-2/métabolisme , Mâle , Protéines membranaires/métabolisme , Protéines des microfilaments/métabolisme , Adulte d'âge moyen , Myocarde/anatomopathologie , Myosin-light-chain phosphatase/métabolisme , Peptide natriurétique cérébral/sang , Phosphorylation , Rats , Systole , Remodelage ventriculaire
14.
Cytokine ; 124: 154456, 2019 12.
Article de Anglais | MEDLINE | ID: mdl-31631862

RÉSUMÉ

Chronic hepatitis C (CHC) is frequently related to liver fibrosis, and several studies have suggested that the immunological activity of HCV antigens contributes to hepatic damage. In the present study, among structural and non-structural HCV antigens, elevatedIL-1ß, IL-6, IL-17 levels were secreted by PBMC cultures obtained from CHC patients following stimulation with core antigen. Moreover, the percentage of core-specific IL-6+IL-17+(CD4+ and CD8+) T cells was significantly higher in patients with worsehepatic lesions, determined on the Metavir scale. When compared with healthy subjects, the percentage of circulating Treg cells was elevated in CHC patients, mainly among those with advanced liver fibrosis. Nevertheless, in this last group of patients, the proportion of CD39+ Treg subsets was very low. Finally, the percentage of senescent (CD57+ CD28-) and exhausted (PD-1+CD28+) core-specific T cells in CHC patients was also found to be a result of fibrotic hepatic status. In summary, imbalances between different core-specific T cell subsets are associated with liver fibrosis severity.


Sujet(s)
Lymphocytes T CD4+/immunologie , Lymphocytes T CD8+/immunologie , Hépatite C chronique/immunologie , Cirrhose du foie/immunologie , Sous-populations de lymphocytes T/immunologie , Adulte , Sujet âgé , Apyrase/métabolisme , Antigène CD28/métabolisme , Lymphocytes T CD4+/métabolisme , Antigènes CD57/métabolisme , Lymphocytes T CD8+/métabolisme , Femelle , Hepacivirus , Humains , Interleukine-17/sang , Interleukine-6/sang , Agranulocytes/métabolisme , Agranulocytes/anatomopathologie , Foie/anatomopathologie , Cirrhose du foie/anatomopathologie , Mâle , Adulte d'âge moyen , Cellules Th17/immunologie , Cellules Th17/métabolisme
15.
J Leukoc Biol ; 106(3): 677-686, 2019 09.
Article de Anglais | MEDLINE | ID: mdl-31256436

RÉSUMÉ

Idiopathic pulmonary fibrosis is characterized by aberrant fibroblast activation and excessive collagen deposition that may eventually lead to organ dysfunction. Lung fibrosis is frequently observed in cancer patients undergoing bleomycin (BLM) treatment. Therefore, BLM instillation in mice is the most frequent model used to investigate pulmonary fibrosis. Angiotensin 1-7 [Ang-(1-7)] is a heptapeptide with anti-inflammatory and proresolving activity. Here, we studied the effects of preventive and therapeutic oral administration of Ang-(1-7) in a model of BLM-induced lung fibrosis in mice. Male C57Bl/6j mice were instilled with BLM and followed for weight loss and survival or euthanized to examine pulmonary inflammation, fibrosis, and lung function. For preventive treatment, mice were treated with Ang-(1-7) 1 h before instillation and then twice daily. We observed that preventive treatment with Ang-(1-7) decreased weight loss, inflammation and collagen deposition, increased survival, and ameliorated lung function. Therapeutic treatment with Ang-(1-7), starting 3 days after BLM instillation resulted in decreased inflammation, decreased collagen deposition, and ameliorated lung function, although the effects were of lower magnitude than the preventive treatment. Therapeutic treatment with Ang-(1-7) starting 7 or 14 days after BLM instillation failed to alter any of the changes observed. Therefore, although oral preventive treatment with Ang-(1-7) is effective to decrease pulmonary inflammation, fibrosis, and functional changes induced by BLM, therapeutic effects are much less significant, arguing against its use in patients with chronic fibrosis. It remains to be determined whether other proresolving molecules will have better therapeutic effects in the context of chronic pulmonary fibrosis.


Sujet(s)
Angiotensine-I/usage thérapeutique , Fragments peptidiques/usage thérapeutique , Fibrose pulmonaire/induit chimiquement , Fibrose pulmonaire/traitement médicamenteux , Angiotensine-I/pharmacologie , Animaux , Bléomycine , Modèles animaux de maladie humaine , Agranulocytes/effets des médicaments et des substances chimiques , Agranulocytes/anatomopathologie , Poumon/effets des médicaments et des substances chimiques , Poumon/physiopathologie , Mâle , Souris de lignée C57BL , Fragments peptidiques/pharmacologie , Fibrose pulmonaire/physiopathologie , Fibrose pulmonaire/prévention et contrôle , Analyse de survie
16.
Stem Cell Res ; 37: 101448, 2019 05.
Article de Anglais | MEDLINE | ID: mdl-31077962

RÉSUMÉ

Induced pluripotent stem cell (iPSC) lines were generated from erythroblasts of two patients with amyotrophic lateral sclerosis (ALS) and two healthy individuals. One familial and one sporadic ALS patients were used, both with genetic alterations in VAPB gene. CytoTune™-iPS 2.0 Sendai Reprogramming Kit (containing the reprogramming factors OCT3/4, KLF4, SOX2 and cMYC) was used to generate the iPSC cell lines. The four iPSCs express pluripotency markers, have normal karyotype and differentiated spontaneously in the three germ layers. The expression of Sendai virus was lost in all iPSC lines after 15 passages.


Sujet(s)
Sclérose latérale amyotrophique/génétique , Différenciation cellulaire , Reprogrammation cellulaire , Cellules souches pluripotentes induites/anatomopathologie , Agranulocytes/anatomopathologie , Mutation , Protéines du transport vésiculaire/génétique , Adulte , Sclérose latérale amyotrophique/anatomopathologie , Cellules cultivées , Volontaires sains , Hétérozygote , Humains , Cellules souches pluripotentes induites/métabolisme , Facteur-4 de type Kruppel , Agranulocytes/métabolisme , Mâle , Phénotype
17.
J Cell Mol Med ; 23(7): 4844-4849, 2019 07.
Article de Anglais | MEDLINE | ID: mdl-31069956

RÉSUMÉ

Currently, there are no confident prognostic markers in patients with coronary artery disease (CAD) undergoing angioplasty. The present study aimed to explore whether basal coronary circulating Mononuclear Progenitor Cells (MPCs) and vascular injury biomarkers were related to development of major adverse cardiovascular events (MACEs) and may impact clinical prognosis. METHODS: The number of MPCs and soluble mediators such as IL-1ß, sICAM-1, MMP-9, malondialdehyde, superoxide dismutase and nitric oxide were determined in coronary and peripheral circulation. Prognostic ability for MACEs occurring at 6 months follow up was assessed by time-to-event and event free survival estimations. RESULTS: Lower coronary circulating MPCs subpopulations CD45+ CD34+ , CD45+ CD34+ CD133+ CD184+ , lower MMP-9 and higher sICAM-1 significantly associated with MACEs presentation and showed prognostic ability; while peripheral blood increase in malondialdehyde and decreased superoxide dismutase were observed in patients with MACEs. CONCLUSION: Coronary concentration of biomarkers related with vascular repair, such as MPCs subpopulations and adhesion molecules, may predict MACEs and impact prognosis in patients with CAD undergoing angioplasty; whereas peripheral pro-oxidative condition may be also associated.


Sujet(s)
Angioplastie , Marqueurs biologiques/sang , Maladies cardiovasculaires/sang , Maladies cardiovasculaires/diagnostic , Circulation coronarienne , Agranulocytes/anatomopathologie , Cellules souches/anatomopathologie , Sujet âgé , Femelle , Humains , Mâle , Pronostic , Solubilité
18.
Immunopharmacol Immunotoxicol ; 41(1): 123-129, 2019 Feb.
Article de Anglais | MEDLINE | ID: mdl-30721634

RÉSUMÉ

Context: Fluconazole (FNZ) is a drug used in antifungal therapy. However, the minimum FNZ dose to interfering with immune responses or inducing DNA damage is still unknown. Objective: This study investigated the toxicological profile of FNZ on cultured human peripheral blood mononuclear cells (PBMCs) treated with different concentrations of this azole. Materials and methods: Cultured PBMCs were exposed to FNZ (6, 12, 30, 60 and 120 µg/mL) and the toxicological profile was assessed by the following parameters: cytotoxic and nuclear division index (necrotic, apoptotic and viable cells), DNA damage (alkaline comet test), mutagenic potential (micronucleus test), cytokine modulation (IL-1, IL-6, IL-10, TNF-α, IFN-γ), and predictive toxicity (Osiris® and LAZAR® programs). Results: Our results demonstrated that FNZ induced cellular DNA damage and mutagenicity at concentrations above the plasma peak (>30 µg/mL) and 6 µg/mL, respectively, which was associated with increased TNF-α, and decrease IL-6 and IL-10 concentrations. These effects may be related to increased apoptosis and cytotoxic nuclear division index in the cultured PBMCs. In silico results indicated potential mutagenic, tumorigenic, irritant, and carcinogenic effects, which were partially confirmed by the above assays. Discussion and conclusions: Together, these findings suggest the need to rationalize the use of FNZ, especially if it is used for long periods or with concomitant pathologies requiring azole therapy that may increase FNZ's plasma concentration.


Sujet(s)
Antifongiques/toxicité , Cytokines/immunologie , Altération de l'ADN , Fluconazole/toxicité , Agranulocytes/effets des médicaments et des substances chimiques , Mutagènes/toxicité , Apoptose/effets des médicaments et des substances chimiques , Apoptose/génétique , Survie cellulaire/effets des médicaments et des substances chimiques , Cellules cultivées , Relation dose-effet des médicaments , Humains , Interleukine-10/immunologie , Interleukine-6/immunologie , Agranulocytes/immunologie , Agranulocytes/anatomopathologie , Facteur de nécrose tumorale alpha/immunologie
19.
Clin Transl Oncol ; 21(9): 1280-1285, 2019 Sep.
Article de Anglais | MEDLINE | ID: mdl-30680609

RÉSUMÉ

PURPOSE: Autophagy has lately emerged as an important biological process with implications in several hematological pathologies. Recently, a growing body of evidence supports a putative role of autophagy in chronic lymphocytic leukemia; however, no definitive clue has been established so far. To elucidate this issue, we have developed a pilot study to measure autophagic flux in peripheral blood mononuclear cells from chronic lymphocytic leukemia patients, and explored its correlation with classical clinical/analytical parameters. METHODS/PATIENTS: Thirty-three chronic lymphocytic leukemia patients participated in the study. Autophagic flux in peripheral blood mononuclear cells was determined by western blot measuring the levels of the proteins p62 and lipidated LC3. Moreover, p62 mRNA levels were analyzed by RT-qPCR. RESULTS: Lymphocytosis and the percentage of tumoral lymphocytes in chronic lymphocytic leukemia patients statistically correlate with a blocked autophagic flux. CONCLUSION: Alterations in autophagic flux could play an important role in the physiopathology of chronic lymphocytic leukemia.


Sujet(s)
Autophagie , Marqueurs biologiques tumoraux/métabolisme , Leucémie chronique lymphocytaire à cellules B/anatomopathologie , Agranulocytes/anatomopathologie , Hyperlymphocytose/anatomopathologie , Sujet âgé , Sujet âgé de 80 ans ou plus , Femelle , Études de suivi , Humains , Leucémie chronique lymphocytaire à cellules B/métabolisme , Agranulocytes/métabolisme , Hyperlymphocytose/métabolisme , Mâle , Adulte d'âge moyen , Projets pilotes , Pronostic
20.
IUBMB Life ; 71(2): 200-212, 2019 02.
Article de Anglais | MEDLINE | ID: mdl-30394663

RÉSUMÉ

Phytol (PHY) (3,7,11,15-tetramethylhexadec-2-en-1-ol) exhibits various pharmacological properties including toxicity and cytotoxicity, and exerts antitumor activity. Owing to the urgent need of new pharmaceutical formulations for breast cancer therapy, this study aimed at the evaluation of antitumor activity of PHY in 7,12-dimethylbenzanthracene-cancer-induced animal model. Comet assay was employed to evaluate the cytogenetics, DNA repair, and antigenotoxic activities of PHY in neoplastic (breast) and non-neoplastic rodent cells (bone marrow, lymphocytes, and liver). Additionally, hematological, biochemical, histopathological, and immunohistochemical analyses were carried out in experimental animals. Thirty nonpregnant female mice (n = 5) underwent 7 weeks treatment with 6 mg/kg pro-carcinogen, PHY (4 mg/kg), and cyclophosphamide (25 mg/kg). Induction of cancer was confirmed by histopathology and immunohistochemistry for Ki-67. Results suggest that PHY exhibits low toxicity in comparison with other groups in hematological, biochemical, histopathological, and organ size parameters. Additionally, PHY showed modulatory effects on the pro-carcinogen, and induced genotoxicity and apoptosis in breast cancer cells. Furthermore, it showed a DNA damage repair capacity in mouse lymphocytes. These data indicate that PHY may have the potential as an anticancer candidate in pharmaceutical consumption. © 2018 IUBMB Life, 71(1):200-212, 2019.


Sujet(s)
Anticarcinogènes/pharmacologie , Antinéoplasiques d'origine végétale/pharmacologie , Réparation de l'ADN/effets des médicaments et des substances chimiques , Tumeurs expérimentales de la mamelle/traitement médicamenteux , Phytol/pharmacologie , 7,12-Diméthyl-benzo[a]anthracène/administration et posologie , 7,12-Diméthyl-benzo[a]anthracène/antagonistes et inhibiteurs , Animaux , Apoptose/effets des médicaments et des substances chimiques , Marqueurs biologiques tumoraux/génétique , Marqueurs biologiques tumoraux/métabolisme , Test des comètes , Cyclophosphamide/pharmacologie , Altération de l'ADN , Calendrier d'administration des médicaments , Femelle , Humains , Antigène KI-67/génétique , Antigène KI-67/métabolisme , Agranulocytes/effets des médicaments et des substances chimiques , Agranulocytes/métabolisme , Agranulocytes/anatomopathologie , Locomotion/effets des médicaments et des substances chimiques , Glandes mammaires animales/effets des médicaments et des substances chimiques , Glandes mammaires animales/métabolisme , Glandes mammaires animales/anatomopathologie , Tumeurs expérimentales de la mamelle/induit chimiquement , Tumeurs expérimentales de la mamelle/métabolisme , Tumeurs expérimentales de la mamelle/anatomopathologie , Souris
SÉLECTION CITATIONS
DÉTAIL DE RECHERCHE